EP2866779A2 - Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene - Google Patents

Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene

Info

Publication number
EP2866779A2
EP2866779A2 EP13733189.8A EP13733189A EP2866779A2 EP 2866779 A2 EP2866779 A2 EP 2866779A2 EP 13733189 A EP13733189 A EP 13733189A EP 2866779 A2 EP2866779 A2 EP 2866779A2
Authority
EP
European Patent Office
Prior art keywords
hydroxyl
skin
composition
benzene
bis
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP13733189.8A
Other languages
German (de)
English (en)
French (fr)
Inventor
Simarna Kaur
Michael D. Southall
Robert A. Zivin
Chong Jin Loy
Samantha TUCKER SAMARAS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Johnson and Johnson Consumer Inc
Original Assignee
Johnson and Johnson Consumer Companies LLC
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
Priority claimed from US13/538,054 external-priority patent/US8758731B2/en
Priority claimed from US13/538,017 external-priority patent/US20140005275A1/en
Priority claimed from US13/537,959 external-priority patent/US8846013B2/en
Application filed by Johnson and Johnson Consumer Companies LLC filed Critical Johnson and Johnson Consumer Companies LLC
Publication of EP2866779A2 publication Critical patent/EP2866779A2/en
Withdrawn legal-status Critical Current

Links

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
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • 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
    • 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
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the invention relates to compositions and methods for the topical application of 1- hydroxyl 3,5-bis(4'hydroxyl styryl)benzene.
  • a particular class of anti-inflammatory agents is those that inhibit the cell transcription factor nuclear kappa-B (NFKB).
  • NFKB cell transcription factor nuclear kappa-B
  • substituted resorcinols such as 4-hexyl resorcinol and tetrahydrocurcuminoids are NFKB inhibitors.
  • Such compounds provide anti-aging benefits when applied to the skin.
  • anti-inflammatory compounds used for this purpose is agents that reduce the amount of melanin in melanocytes by means of inhibiting inflammatory mediator molecules.
  • agents that reduce the amount of melanin in melanocytes by means of inhibiting inflammatory mediator molecules are agents that reduce the amount of melanin in melanocytes by means of inhibiting inflammatory mediator molecules.
  • only a relatively small group of compounds have been identified as suitable for topical use to regulate melanin formation in skin.
  • 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene is a potent NFKB inhibitor and is suitable for topical application to skin
  • 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and cosmetically acceptable salts thereof may be used to treat signs of skin aging, are inhibitors of melanin formation in melanocytes, and may be applied to skin in need of skin lightening treatment.
  • the invention provides a composition comprising 1-hydroxyl 3,5- bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof; and a cosmetically acceptable topical carrier comprising an ingredient selected from the group consisting of wetting agents, emulsifiers, emollients, humectants, and fragrances.
  • the invention further provides a method of treating human skin, comprising topically applying to said human skin a composition comprising 1-hydroxyl 3,5- bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof.
  • the invention also provides a method of treating a sign of skin aging, comprising topically applying to skin in need of such treatment a composition comprising 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof.
  • the invention provides a method of lightening skin, comprising the step of topically applying to skin in need of skin lightening treatment a composition comprising 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof.
  • the invention further provides a method of inhibiting the growth of a
  • microorganism comprising applying to said microorganism 1-hydroxyl 3,5- bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof.
  • Products described herein may optionally be in finished packaged form.
  • the package is a container such as a plastic, metal or glass tube or jar containing the composition.
  • the product may further contain additional packaging such as a plastic or cardboard box for storing such container.
  • the product comprises a composition of the invention and contains instructions directing the user to apply the composition to the skin to treat the signs of skin aging as discussed infra. Such instructions may be printed on the container, label insert, or on any additional packaging.
  • topically applying means directly laying on or spreading on outer skin, the scalp, or hair, e.g., by use of the hands or an applicator such as a wipe, roller, or spray.
  • cosmetically acceptable means that the ingredients the term describes are suitable for use in contact with tissues (e.g., the skin or hair) without undue toxicity, incompatibility, instability, irritation, allergic response, or the like.
  • cosmetic refers to a beautifying substance or preparation which preserves, restores, bestows, simulates, or enhances the appearance of bodily beauty or appears to enhance the beauty or youthfulness, specifically as it relates to the appearance of tissue or skin.
  • skin in need of treatment for the signs of aging means a skin that is, but not limited to, sagging, loose, lax, rough, wrinkly, thinned, or uneven. Improving the signs of aging means improving the firmness of the skin, improving the texture of the skin, improving the appearance of wrinkles in skin, improving the skin tone, or the treating external aggressions in skin.
  • "improving the firmness of skin” means the enhancing of the firmness or elasticity of the skin, preventing the loss of firmness or elasticity of skin, or preventing or treating sagging, lax and loose skin.
  • the firmness or elasticity of the skin can be measured by use of a cutometer. See Handbook of Non-Invasive Methods and the Skin, eds. J. Serup, G. Jemec & G. Grove, Chapter 66.1 (2006).
  • the loss of skin elasticity or firmness may be a result of a number of factors, including but not limited to aging, environmental damage, or the result of an application of a cosmetic to the skin.
  • improving the texture of skin means the smoothing of the surface of the skin to remove either bumps or crevasses on the skin surface.
  • wrinkles means preventing, retarding, arresting, or reversing the process of wrinkle formation in skin.
  • wrinkle includes fine lines, fine wrinkles, or coarse wrinkles. Examples of wrinkles include, but are not limited to, fine lines around the eyes (e.g., "crow's feet"), forehead and cheek wrinkles, frown-lines, and laugh-lines around the mouth.
  • uneven skin means a condition of the skin associated with diffuse or mottled pigmentation, which may be classified as hyperpigmentation, such as post-inflammatory hyperpigmentation.
  • blotchiness means a condition of the skin associated with redness or erythema.
  • treatment of external aggressions in skin means the reduction or prevention of the damage from external aggressions in skin.
  • external aggressions include, but are not limited to, damage to the skin from the use of cleansers (e.g., topical cleansers containing surfactants), make-up, shaving as well as environmental damage such as from UV light (e.g., sundamage from sunlight or damage from non- natural sources such as UV lamps and solar simulators), ozone, exhaust, pollution, chlorine and chlorine containing compounds, and cigarette smoke.
  • Effects of external aggressions on the skin include, but are not limited to, oxidative and/or nitrosative damage to and modifications on lipids, carbohydrates, peptides, proteins, nucleic acids, and vitamins. Effects of external aggressions on the skin also include, but are not limited to, loss of cell viability, loss or alteration of cell functions, and changes in gene and/or protein expression.
  • improving the skin tone means the lightening of the appearance of the skin (e.g., lightening pigmented marks or lesions, reducing skin sallowness, and/or evening the color of the skin).
  • skin in need of reducing skin inflammation means a skin exhibiting redness or erythema, edema, or being reactive or sensitive to external elements.
  • External elements include, but are not limited to, sun rays (UV, visible, IR),
  • Inflammatory disorders and related conditions which may be treated or prevented by use of the compositions of this invention include, but are not limited to the following: arthritis, bronchitis, contact dermatitis, atophic dermatitis, psoriasis, seborrheic dermatitis, eczema, allergic dermatitis, polymorphous light eruptions, inflammatory dermatoses, folliculitis, alopecia, poison ivy, insect bites, acne inflammation, irritation induced by extrinsic factors including, but not limited to, chemicals, trauma, pollutants (such as cigarette smoke) and sun exposure, secondary conditions resulting from inflammation including but not limited to xerosis, hyperkeratosis, pruritus, postinflammatory hyperpigmentation, scarring and the like.
  • the inflammatory disorders and related conditions which may be treated or prevented using the methods of the invention are arthritis, inflammatory dermatoses, contact dermatitis, allergic dermatitis, atopic dermatitis, polymorphous light eruptions, irritation, including erythema induced by extrinsic factors, acne inflammation, psoriasis, seborrheic dermatitis, eczema, poison ivy, insect bites, folliculitus, alopecia, and secondary conditions and the like.
  • the term "lightening the skin” refers generally to lightening, brightening, whitening, and/or evening of the skin tone, skin color, and/or shade of skin, and/or to the reduction in sallowness, and/or to the lightening and/or fading of hyperpigmented marks and/or lesions including, but not limited to, pigmented spots, melanin spots, age spots, sun spots, senile lentigos, freckles, lentigos simplex, pigmented solar keratosis, seborrhoeic keratosis, melasma, acne marks, post-inflammatory hyperpigmentation, lentigines, ephelides, combinations of two or more thereof and the like.
  • lightening the skin also refers to increased skin radiance, glow, translucency and/or luminescence and/or obtaining a more radiant, glowing, translucent or luminous skin tone appearance or a less yellow or sallow skin tone.
  • lightening the skin refers to lightening and evening the skin tone, increasing skin radiance and/or lightening age spots.
  • skin in need of skin lightening treatment refers generally to skin that exhibits one or more property selected from the group consisting of: skin having a measured Individual Typology Angle (IT A) value below 41 as determined per the COLIPA GUIDELINE: GUIDELINE FOR THE COLORIMETRIC
  • skin color is defined function of the ITA value as: very light skin >55; Light skin 41-55, Intermediate 28-41, and Tan skin ⁇ 28.
  • skin in need of skin lightening refers to individuals with a skin having an ITA value of less than 41, such as about 40 or less, about 35 or less, about 30 or less, or more preferably about 28 or less.
  • the present invention is directed to compositions and methods for use on skin in need of skin lightening treatment selected from sallow and/or darkened skin.
  • the present invention is directed to compositions and methods for use on skin in need of skin lightening treatment selected from the group consisting of age spots, freckles, marks left after acne, and combinations of two or more thereof.
  • compositions are weight percent of active/solids ingredient based on the total weight of composition.
  • substantially free of an ingredient means containing less than about 1% by weight, such as less than about 0.5% by weight, such as less than about 0.25% by weight, such as less than about 0.1% by weight of such ingredient. In one embodiment, “substantially free” means completely free of such ingredient.
  • compositions of the present invention are suitable for treating human skin, e.g., skin on the face or body, for signs of skin aging, or for inflammation.
  • a composition according to the invention is used to treat the presence of lines and wrinkles and/or loss of elasticity.
  • Compositions of the present invention are suitable for treating human skin, e.g., skin on the face or body, to lighten the skin.
  • compositions of the present invention comprise 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof.
  • 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene can be made by reacting 1 -(bromomethyl)-4-methoxybenzene with triethyl phosphate using an Arbuzov reaction to produce diethyl [(4- methoxyphenyl)methyl]phosphonate.
  • This is coupled with 5-methoxybenzene-l,3- dicarbaldehy de-using sodium hydride as base in THF, followed by reaction with boron trichloride and dichloromethane to replace methoxy groups with hydroxy Is.
  • Salts of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene can be made by, for example, reacting the 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene with a base such as piperazine, or another base, to produce at least some phenoxide salt of 1-hydroxyl 3,5- bis(4'hydroxyl styryl)benzene.
  • a base such as piperazine, or another base
  • the 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or salt thereof is present in the composition in a cosmetically effective amount, such as from about 0.01% to about 10%, preferably from about 0.1% to about 5%, more preferably from about 0.2% to about 2%, even more preferably from about 0.5% to about 1.5%, by weight of the composition.
  • compositions of the present invention are applied topically to human skin and/or hair.
  • compositions may be spreadable. They may be topically applied by spreading, for example spreading over the skin or hair, in particular over skin of the face or hands.
  • composition of the invention is topically applied without a voltage.
  • the composition may further include a cosmetically acceptable topical carrier that may be from about 50% to about 99.99%, by weight, of the composition (e.g., from about 80% to about 99%, by weight, of the composition).
  • a cosmetically acceptable topical carrier includes water.
  • the cosmetically acceptable topical carrier may be unsuitable for ingestion.
  • the cosmetically acceptable topical carrier may include an ingredient selected from one or more of the following five classes: wetting agents, emulsifiers, emollients, humectants, and fragrances.
  • the cosmetically acceptable topical carrier includes ingredients from two or more of the above-mentioned classes, such as ingredients from at least three or more of such classes.
  • the cosmetically acceptable topical carrier includes water, an emulsifier, and an emollient.
  • compositions may be made into a wide variety of product types that include but are not limited to lotions, creams, gels, sticks, sprays, ointments, cleansing liquid washes and solid bars, shampoos and hair conditioners, hair fixers, pastes, foams, powders, mousses, shaving creams, wipes, patches, hydrogels, film- forming products, facial masks and skin masks, films and make-up such as foundations, and mascaras.
  • product types may contain several types of cosmetically acceptable topical carriers including, but not limited to solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels, solids and liposomes.
  • cosmetically acceptable topical carriers including, but not limited to solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels, solids and liposomes.
  • compositions useful in the present invention can be formulated as solutions.
  • Solutions typically include an aqueous or organic solvent (e.g., from about 50% to about 99.99% or from about 90% to about 99% of a cosmetically acceptable aqueous or organic solvent).
  • suitable organic solvents include humectants (e.g., water-retaining or hygroscopic materials) such as propylene glycol, pentylene glycol, polyethylene glycol, polypropylene glycol, glycerol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol; as well as ethanol, and mixtures thereof.
  • Solutions can optionally include a wetting agent, such as to provide foam, e.g, an anionic, non-ionic, or cationic wetting agent.
  • compositions useful in the subject invention may be formulated as a solution comprising an emollient.
  • Such compositions preferably contain from about 2% to about 50% of an emollient(s).
  • emollients refer to materials used for the prevention or relief of dryness, such as by preventing the transepidermal loss of water from the skin.
  • emollients include hydrophobic compounds such as vegetable oils, mineral oils (e.g., petrolatum), fatty esters (e.g., isopropyl palmitate, cl2-cl5 alkyl benzoate) including those fatty esters of glycerol, silicone oils (e.g., dimethicone) and the like.
  • a lotion can be made from such a solution.
  • Lotions typically contain from about 1% to about 20% (e.g., from about 5% to about 10%) of an emollient(s) and from about 50% to about 90% (e.g., from about 60% to about 80%) of water.
  • a cream typically contains from about 5% to about 50% (e.g., from about 10% to about 20%) of an emollient(s) and from about 45% to about 85% (e.g., from about 50% to about 75%) of water.
  • composition of the present invention includes water
  • the composition may alternatively be anhydrous or an ointment that includes no water but organic and/or silicone solvents, oils, lipids and waxes.
  • An ointment may contain a simple base of animal or vegetable oils or semi-solid hydrocarbons.
  • An ointment may contain from about 2% to about 10% of an emollient(s) plus from about 0.1 % to about 2% of a thickening (gelling) agent(s).
  • composition may be formulated as an emulsion. If the topical carrier is an emulsion, from about 1% to about 10% (e.g., from about 2% to about 5%) of the topical carrier contains an emulsifier(s). Emulsifiers may be nonionic, anionic or cationic.
  • Suitable emulsifiers include those typically identified as such in the art of personal care and cosmetic formulations, e.g., cationic emulsifiers such as
  • non-ionic emulsifiers such as stereth-2, stereth-21 ; anionic emulsifiers such as potassium cetyl phosphate; polymeric emulsifiers such as
  • Lotions and creams can be formulated as emulsions.
  • lotions contain from 0.5% to about 5% of an emulsifier(s).
  • Such creams typically contain from about 1% to about 20% (e.g., from about 5% to about 10%) of an emollient(s); from about 20% to about 80% (e.g., from 30% to about 70%) of water; and from about 1% to about 10% (e.g., from about 2% to about 5%) of an emulsifier(s).
  • Single emulsion skin care preparations such as lotions and creams, of the oil-in- water type and water-in-oil type are well-known in the cosmetic art and are useful in the subject invention.
  • Multiphase emulsion compositions such as the water-in-oil-in-water type or the oil-in-water-in-oil type, are also useful in the subject invention.
  • such single or multiphase emulsions contain water, emollients, and emulsifiers as essential ingredients.
  • compositions of this invention can also be formulated as a gel (e.g., an aqueous, alcohol, alcohol/water, or oil gel using a suitable gelling agent(s)).
  • suitable gelling agents for aqueous and/or alcoholic gels include, but are not limited to, natural gums, (cross-linked) acrylic acid and acrylate polymers and copolymers, and cellulose derivatives (e.g., hydroxymethyl cellulose and hydroxypropyl cellulose).
  • Suitable gelling agents for oils include, but are not limited to, hydrogenated butylene/ethylene/styrene copolymer and hydrogenated ethylene/propylene/styrene copolymer.
  • Such gels typically contains between about 0.1% and 5%, by weight, of such gelling agents.
  • compositions of the present invention can also be formulated into a solid formulation (e.g., a wax-based stick, soap bar composition, powder, or a wipe containing powder).
  • a solid formulation e.g., a wax-based stick, soap bar composition, powder, or a wipe containing powder.
  • compositions useful in the subject invention may contain, in addition to the aforementioned components, a wide variety of additional oil-soluble materials and/or water-soluble materials conventionally used in compositions for use on skin and hair, at their art-established levels.
  • Additional Cosmetically Active Agents may contain, in addition to the aforementioned components, a wide variety of additional oil-soluble materials and/or water-soluble materials conventionally used in compositions for use on skin and hair, at their art-established levels.
  • the composition includes an additional NFicB-inhibitor such as a substituted resorcinol, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile (such as "Bay 11-7082,” commercially available from Sigma- Aldrich of St.
  • an additional NFicB-inhibitor such as a substituted resorcinol, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile (such as "Bay 11-7082,” commercially available from Sigma- Aldrich of St.
  • a tetrahydrocurcuminoid such as Tetrahydrocurcuminoid CG, available from Sabinsa Corporation of Piscataway, NJ
  • paulownin extracts of Paulownia wood (for example the wood of Paulownia tomentosa, Paulownia fortunei, Paulownia elongate, Paulownia taiwaniana, d/orPaulownia kawakamii,), and combinations thereof.
  • the composition further contains another cosmetically active agent.
  • a "cosmetically active agent” is a compound (e.g., a synthetic compound or a compound isolated from a natural source or a natural extract) that has a cosmetic or therapeutic effect on the skin including, but not limiting to anti-aging actives, anti-inflammatory agents, tropoelastin promoters, anti-acne agents, anti-microbial agents, anti-inflammatory agents, anti-mycotic agents, external analgesics, sunscreens, antioxidants, keratolytic agents, vitamins, skin lightening agents and skin firming agents.
  • the composition includes a skin-lightening agent such as a tyrosinase inhibitor, melanin-degradation agent, melanosome transfer inhibiting agent including PAR-2 antagonists, retinoids, antioxidants, tranexamic acid, tranexamic acid cetyl ester hydrochloride, skin bleaching agent, linoleic acid, adenosine monophosphate disodium salt, Chamomilla extract, allantoin, opacifier, talc or silica, zinc salt, or the like, or other agent as described in Solano et al. Pigment Cell Res. 19 (550-571) and Ando et al. Int J Mol Sci 11 (2566-2575).
  • a skin-lightening agent such as a tyrosinase inhibitor, melanin-degradation agent, melanosome transfer inhibiting agent including PAR-2 antagonists, retinoids, antioxidants, tranexamic acid, tranexamic acid cetyl este
  • Suitable tyrosinase inhibitors include but, are not limited to, vitamin
  • vitamin E and its derivatives vitamin E and its derivatives, kojic acid, arbutin, resorcinols, hydroquinone, flavones e.g., licorice flavanoids, licorice root extract, mulberry root extract, dioscorea coposita root extract, saxifraga extract and the like, ellagic acid, salicylates and derivatives, glucosamine and derivatives, fullerene, hinokitiol, dioic acid, acetyl glucosamine, 5,5'-dipropyl-biphenyl-2,2'-diol (magnolignan), 4-(4- hydroxyphenyl)-2-butanol (4-HPB), combinations of two or more thereof, and the like.
  • flavones e.g., licorice flavanoids, licorice root extract, mulberry root extract, dioscorea coposita root extract, saxifraga extract
  • vitamin C derivatives include, but are not limited to, ascorbic acid and salts, ascorbic acid-2-glucoside, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, and natural extract enriched in vitamin C.
  • vitamin E derivatives include, but are not limited to, alpha- tocopherol, beta, tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta- tocotrienol, gamma-tocotrienol, delta-tocotrienol and mixtures thereof, tocopherol acetate, tocopherol phosphate and natural extracts enriched in vitamin E derivatives.
  • resorcinol derivatives include, but are not limited to, resorcinol, 4- substituted resorcinols like 4-alkylresorcinols such as 4-butyresorcinol (rucinol), 4- hexylresorcinol (SY OVEA HR, SY THEON), phenylethyl resorcinol (SYMWHITE, SYMRISE), 1 -(2,4-dihydroxyphenyl)-3 -(2,4-dimethoxy-3 -methylphenyl)-propane (nivitol, U IGEN) and the like and natural extracts enriched in resorcinols.
  • 4-butyresorcinol rucinol
  • 4- hexylresorcinol SY OVEA HR, SY THEON
  • phenylethyl resorcinol SYMWHITE, SYMRISE
  • salicylates include, but are not limited to, 4-methoxy potassium salicylate, salicylic acid, acetylsalicylic acid, 4-methoxysalicylic acid and their salts.
  • the tyrosinase inhibitors include a 4-substituted resorcinol, a vitamin C derivative, or a vitamin E derivative.
  • the tyrosinase inhibitor comprises phenylethyl resorcinol, 4-hexyl resorcinol, or ascorbyl-2-glucoside.
  • melanin-degradation agents include, but are not limited to, peroxides and enzymes such as peroxidases and ligninases.
  • the melanin-inhibiting agents include a peroxide or a ligninase.
  • suitable melanosome transfer inhibiting agents include PAR-2 antagonists such as soy trypsin inhibitor or Bowman-Birk Inhibitor, vitamin B3 and derivatives such as niacinamide, essential soy, whole soy, soy extract.
  • the melanosome transfer inhibiting agents includes a soy extract or niacinamide.
  • retinoids include, but are not limited to, retinol (vitamin A alcohol), retinal (vitamin A aldehyde), retinyl acetate, retinyl propionate, retinyl linoleate, retinoic acid, retinyl palmitate, isotretinoin, tazarotene, bexarotene, adapalene, combinations of two or more thereof and the like.
  • the retinoid is selected from the group consisting of retinol, retinal, retinyl acetate, retinyl propionate, retinyl linoleate, and combinations of two or more thereof.
  • the retinoid is retinol.
  • Other skin lightening agents include vitamin B5, vitamin B12, glycolic acid and extracts of Paulownia wood (for example the wood of Paulownia tomentosa, Paulownia fortunei, Paulownia elongate, Paulownia taiwaniana, and/ 'or Paulownia kawakamii).
  • antioxidants include, but are not limited to, water-soluble antioxidants such as sulfhydryl compounds and their derivatives (e.g., sodium
  • stilbenoids such as resveratrol and derivatives, lactoferrin, iron and copper chelators and ascorbic acid and ascorbic acid derivatives (e.g., ascobyl-2-glucoside, ascorbyl palmitate and ascorbyl polypeptide).
  • Oil-soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to, butylated hydroxytoluene, retinoids (e.g., retinol and retinyl palmitate), tocopherols (e.g., tocopherol acetate), tocotrienols, and ubiquinones.
  • Natural extracts containing antioxidants suitable for use in the compositions of this invention include, but not limited to, extracts containing flavonoids and isoflavonoids and their derivatives (e.g., genistein and diadzein), extracts containing resveratrol and the like.
  • Such natural extracts include grape seed, green tea, black tea, white tea, pine bark, feverfew, parthenolide-free feverfew, oat extracts, blackberry extract, cotinus extract, soy extract, pomelo extract, wheat germ extract, hesperedin, grape extract, portulaca extract, licochalcone, chalcone, 2,2'-dihydroxy chalcone, primula extract, propolis, and the like.
  • Other Materials include grape seed, green tea, black tea, white tea, pine bark, feverfew, parthenolide-free feverfew, oat extracts, blackberry extract, cotinus extract, soy extract, pomelo extract, wheat germ extract, hesperedin, grape extract, portulaca extract, licochalcone, chalcone, 2,2'-dihydroxy chalcone, primula extract, propolis, and the like.
  • compositions may also be present in the composition, as known in the art. These include humectants, pH adjusters, chelating agents (e.g., EDTA), fragrances, dyes and preservatives (e.g., BHT, benzyl alcohol).
  • the composition is substantially free, preferably completely free, of preservatives. This is because, advantageously, 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and salts thereof are active for inhibiting and/or killing microorganisms. Accordingly, compositions according to the invention can be formulated with little or no conventional preservatives.
  • preservatives for example are selected from the group consisting of parabens, benzoic acid and salts thereof, phenoxyethanol, isothaizolones, imidazolidinyl urea, iodo propynyl butyl carbamate, DMDM hydantoin, caprylyl glycol, dehydroacetic acid, sorbic acids and salts thereof, chlorophensin, glyceryl caprylate, phenylpropanol, sodium levulinate, anisic acid, ethylhexylglycerin, benzyl alcohol and combinations thereof.
  • compositions and formulations and products containing such compositions of the present invention may be prepared using methodology that is well known by an artisan of ordinary skill.
  • compositions of the present invention may be topically applied to human skin, e.g., skin that is in need of treatment for one or more signs of skin aging as described above.
  • the compositions are applied to skin in need of treatment for lines and wrinkles and/or loss of elasticity.
  • the compositions may be applied to the skin in need of such treatment according to a suitable treatment regimen, e.g., every month, every week, every other day, every day, twice a day, or the like.
  • 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene, cosmetically acceptable salts thereof and compositions containing the same may be used to provide antimicrobial effects (e.g., antibacterial, antifungal, antiviral, or anti-parasitic effects).
  • the invention provides a method of inhibiting the growth of a microorganism, comprising applying to said microorganism 1-hydroxyl 3,5- bis(4'hydroxyl styryl)benzene, a cosmetically acceptable salt thereof, or a composition containing the same.
  • Microorganisms that may be inhibited or killed by such application include gram positive bacteria, gram negative bacteria and fungi including Staphylococcus aureus, Staphylococcus epidermidis, Propionibacterium acnes, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger.
  • Example 1 NFicB-Inhibition
  • NFKB- ⁇ TESTS were performed on various concentrations of 1- hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and a vehicle control (DMSO).
  • DMSO vehicle control
  • the 1- hydroxyl 3,5-bis(4'hydroxyl styryl)benzene was prepared as described in US Patent No. 7,745,670.
  • H9c2 cells were purchased from ATCC (Manassas, VA.). Cultures were maintained in Dulbecco's modified Eagle's medium (DMEM, Invitrogen Life Technologies, Carlsbad, CA.) supplemented with 10% fetal bovine serum, 100 units/ml penicillin, and 50 ug/ml streptomycin (Invitrogen life technologies, Carlsbad, CA.). 1x104 cells grown in 96-well plates were transiently transfected with 0.45ug total DNA per well using Lipofectamine 2000 (Invitrogen life technologies, Carlsbad, Calif).
  • DMEM Dulbecco's modified Eagle's medium
  • 1x104 cells grown in 96-well plates were transiently transfected with 0.45ug total DNA per well using Lipofectamine 2000 (Invitrogen life technologies, Carlsbad, Calif).
  • a construct with the thymidine kinase promoter and the Renilla luciferase reporter gene (pRL-TK, Promega, Madison Wis.) was included as an internal control in addition to the NF-kB luciferase promoter.
  • pRL-TK Renilla luciferase reporter gene
  • the firefly luciferase activity was measured first (representing NF-kB promoter activity), followed by the renilla luciferase (internal control), using luminometer LMAX, from Molecular Devices (Sunnyvale, Calif). The ratio of these two luciferase activities (RLU) was used to evaluate the activity of each promoter:
  • NF- ⁇ Inhibition [1— ( RLUsample /RLUcontrol)] * 100 where RLUsample and RLUcontrol are the normalized luciferase activity ratios of the sample and control, respectively.
  • Elastin (Qiagen) and Collagenlal primers custom sequence -sense: 5'-TCC-CCA-GCT-GTC-TTA-TGG- CT-3' and anti-sense: 5'-CAG-GCA-CGG-AAA-TTC-CTC-C-3') were used.
  • the housekeeping gene GAPDH was used for normalization (custom primer sequence: F 5'- ATC-TCT-GCC-CCC-TCT-GCT-G-3' and R 5'-ATG-GTT-CAC-ACC-CAT-GAC-GA- 3'; Invitrogen/Life Technologies, Carlsbad, CA). Fold-changes in PCR (normalized to GAPDH) were calculated from untreated.
  • 1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene increased the expression of genes associated with collagen and elastin production.
  • Example 4 Inhibition of TNF-a - Induced MMP-9 levels
  • TNF-a induced MMP-9 The ability of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene to inhibit TNF-a induced MMP-9 levels was tested at different concentrations as follows. The formation of TNF-a induced MMP-9 is involved in the undesirable breakdown of extracellular matrix in human skin.
  • Epidermal equivalents (EPI 200 HCF) were purchased from MatTek (Ashland, MA). Upon receipt, the epidermal equivalents were incubated for 24 hours at 37°C in maintenance medium without hydrocortisone. The equivalents were topically treated (2mg/cm 2 ) with 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene extracts in a 70% ethanol/30% propylene glycol vehicle 2 hours before treatment with TNF-a (lOOng/mL). the equivalents were incubated for 48 hours at 37°C with maintenance medium then supernatants were analyzed for MMP -9 using commercially available kits (R&D
  • UV radiation from the sun is the most important external stimulus for melanin formation leading to skin darkening. Reducing melanin formation in the skin may be achieved by inhibiting multiple steps of the melanin biogenesis process.
  • Tyrosinase is the key regulatory enzyme of melanogenesis. Agents that inhibit tyrosinase will reduce melanin synthesis.
  • Mushroom tyrosinase samples (Sigma, T7755, 10 U/reaction) were treated with the samples of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and control samples.
  • Tyrosinase activity was measured by recording light absorption (optical density) at
  • T contro i the tyrosinase activity of the control
  • T samp i e the tyrosinase activity in the presence of test compound.
  • Samples were tested in duplicate and Percent Inhibition of Tyrosinase was averaged and standard deviation was reported.
  • the control had an average optical density of 0.622.
  • One or more samples of B16(F10) cells were prepared and each pre-treated with a test sample followed by UVB exposure as described below. Upon treatment, UVB stimulated melanogenesis in the cells and test compounds were evaluated based on their ability to inhibit or slow down the rate of melanogenesis. The cells were lysed for protein measurement at 595nm and melanin content at 470nm. The potency of the test compounds were determined by comparing the % inhibition achieved by the test compounds against the treated control.
  • murine melanoma B16(F 10) cells were seeded in 60mm plates with a density of ⁇ 1 million cells per plate and incubated for 48hrs at 37 °C, 5% CO 2 .
  • the cells with a confluency rate of 90-100% were treated with test compound at a predetermined concentration (e.g. 25 ⁇ g/mL) for two hours (for test compound samples only) followed by exposure to UVB 200mJ/cm 2 (for test samples and treated control).
  • the cells were harvested on day 3 (24 h post UVB irradiation for test samples and treated control) and lysed in protein lysis buffer (50mM Tris, pH 8, 2mM EDTA, 150mM NaCl, and 1%TRIT0N X 100 - a nonionic surfactant purchased from BioRad Cat.#: 161-0407), and centrifuged.
  • protein lysis buffer 50mM Tris, pH 8, 2mM EDTA, 150mM NaCl, and 1%TRIT0N X 100 - a nonionic surfactant purchased from BioRad Cat.#: 161-0407
  • the resulting supernatant was mixed well with a protein dye assay (Bio-rad protein assay reagent) and a spectrophotometer (Molecular Devices VERSAmax) was used to determine the optical density (OD) of the sample at 595nm, which was recorded as the "protein assay OD.”
  • a protein dye assay Bio-rad protein assay reagent
  • a spectrophotometer Molecular Devices VERSAmax
  • the cell pellet remaining after removal of the supernatant was dissolved in alkaline DMSO buffer, and the resulting solution was similarly tested using a spectrophotometer for melanin absorbance assay at 470 nm. The absorbance was recorded as the "melanin assay OD.”
  • Control samples of B16(F10) murine melanoma cells were prepared and harvested as indicated above, but without addition of any test sample and without exposure to UVB (untreated control). Other samples were prepared and harvested as indicated above, but without addition of test sample and exposed to UVB as described below (treated control).
  • Normalized Melanin melanin assay OD/protein assay OD.
  • the average Percent Inhibition was calculated as the sum of the three resulting Inhibition % values for each test sample divided by three.
  • MatTek's MelanoDermTM System Skin epidermal equivalent tissues obtained from MatTek's MelanoDermTM System were used as follows.
  • MatTek's MelanoDermTM System consists of normal, human- derived epidermal keratinocytes (HEK) and melanocytes (HM) which have been cultured to form a multilayered, highly differentiated model of the human epidermis.
  • HEK human- derived epidermal keratinocytes
  • HM melanocytes
  • MEL-300-B tissues, each 9mm in diameter were used in the following tests.
  • the Degree of Lightness for each skin model tissue was measured using a spectrophotometer (Konica Minolta CM-2600d).
  • the AL degree of lightness as compared to vehicle-treated control
  • a 4% (40mg/mL) stock solution was prepared by weighing 200mg of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene powder (test article) in an amber-vial and dissolving it in 5mL DMSO by vortexing at room temperature.
  • MIC Concentration of the test article was performed by broth assay based on the standard National Committee for Clinical Laboratory Standards (NCCLS) protocol (NCCLS, 2000). The MIC in this assay was defined as the lowest concentration of the test article that inhibited the visible growth of the microorganism under study.
  • Staphylococcus aureus (MO-012-015), Staphylococcus epidermidis (MO-012-045), and Propionibacterium acnes (ATCC# 6919)
  • two (2) gram negative bacteria Escherichia coli (ATCC# 8739) and Pseudomonas aeruginosa (ATCC# 9027)
  • two (2) fungal species Candida albicans (ATCC# 10231) and Aspergillus niger (ATCC# 16404)
  • All species, minus the Staphylococcus spp. were obtained from the American Type Culture Collection (ATCC).
  • the two (2) Staphylococcus spp. were obtained as clinical isolates.
  • the MIC for each of the seven strains was determined for the test article using dilutions made from the original 4% w/v stock of the test article to yield preparations of a 1.00% w/v starting concentration and a 0.25% w/v starting concentration for the assay.
  • the antimicrobial susceptibility test was performed in a 96-well microtitre plate. In this assay, two-fold dilutions of the test article starting concentrations were performed sequentially along the first 10 rows of the microtiter plate (rows 11 and 12 served as positive and negative controls for test organism).
  • a suspension of inoculum was created for each test organism and adjusted to the turbidity of an optical density at 600 nm (OD600). This inoculum was diluted 1: 100 and lOOul was added to each well of the microtiter plate, to yield a final inoculum of ⁇ 1 x 10 6 CFU/well.
  • Plates were covered and incubated at 35° C for bacteria (Propionibacterium acnes incubated under anaerobic conditions), and 25° C for fungi. Microplates were examined 48 hours later and determined for MIC (Propionibacterium acnes plates were incubated for -72 hours, and fungal spp. plates were incubated for -120 hours). The MIC was the lowest concentration of antimicrobial agent that yielded no growth by visual reading after incubation.
  • the Minimal Biocide Concentration (MBC) assay is designed to determine the lowest concentration at which the test article will demonstrate bactericidal or fungicidal properties against a particular microorganism.
  • MBC Minimal Biocide Concentration
  • MBC biocide concentration
  • a composition according to the invention is prepared by blending the ingredients in Table 9.
  • a composition according to the invention is prepared by blending the ingredients in Table 10.
  • Water is added to a process vessel and the temperature is set to 85° C. Mixing is begun and glycerin is added and mixed until dissolved. VARISOFT TA-100 is added, along with petrolatum and ISOFOL 28, DOW CORNING Q7-9120 20 CS, and isopropyl palmitate. The composition is mixed at 85 °C for another 10-15 minutes. The composition is then removed from heat, mixed and cooled.
  • composition according to the invention is prepared by blending the ingredients in Table 11. TABLE 11
  • Phase B is added to Phase A very slowly under continuous mixing. Mixing is continued for 15 minutes until a uniform emulsion is formed.
  • ARISTOFLEX AVC is added to the emulsion under continuous mixing at high speed to obtain a thick, smooth and homogenous formulation.
  • a composition according to the invention is prepared by blending the ingredients in Table 12.
  • An oil phase is prepared by adding FINSOLV TN to a clean glass beaker.
  • a water phase is prepared by adding water to a clean glass beaker. Agitation is begun and the vessel is heated to 55-60 °C. Disodium EDTA is added. At 55-60 °C, the ingredients are mixed for 15 min or until homogeneous. The temperature is then held at 55-60 °C with mixing for phasing.
  • the oil phase is added to the water phase with increased agitation and then mixed at high speed for 10-20 min. At 50 °C or lower, dimethicone is added. At 40 °C or lower, PHENONIP XB is added. The phases are then mixed for 10 min or until uniform.
  • Sodium hydroxide is added (target pH is 5.4). The composition is then mixed for 10 min or until uniform. LYS'LASTI E and SYMMATRIX are then added. 1-hydroxyl 3,5- bis(4'-hydroxyl styryl)benzene is weighed and dissolved in glycerin and added to the mixture, which is mixed until uniform. Water is then added to QS and the composition is mixed for 10 additional minutes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Emergency Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Birds (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP13733189.8A 2012-06-29 2013-06-18 Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene Withdrawn EP2866779A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US13/538,054 US8758731B2 (en) 2012-06-29 2012-06-29 Skin lightening by topical application of 1-hydroxyl 3,5-bis(4′hydroxyl styryl)benzene
US13/538,017 US20140005275A1 (en) 2012-06-29 2012-06-29 Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene
US13/537,959 US8846013B2 (en) 2012-06-29 2012-06-29 Topical application of 1-hydroxyl-3,5-BIS(4′hydroxy styryl)benzene
PCT/US2013/046354 WO2014004177A2 (en) 2012-06-29 2013-06-18 Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene

Publications (1)

Publication Number Publication Date
EP2866779A2 true EP2866779A2 (en) 2015-05-06

Family

ID=48741561

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13733189.8A Withdrawn EP2866779A2 (en) 2012-06-29 2013-06-18 Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene

Country Status (8)

Country Link
EP (1) EP2866779A2 (zh)
KR (1) KR20150023891A (zh)
CN (1) CN104411288B (zh)
AU (1) AU2013280916B2 (zh)
BR (1) BR112014032739A2 (zh)
CA (1) CA2877471A1 (zh)
RU (1) RU2648763C2 (zh)
WO (1) WO2014004177A2 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104840399B (zh) * 2015-05-18 2018-10-23 中山安理汇日用品有限公司 具备自防腐特性的紧肤霜配方

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030113388A1 (en) * 2001-12-13 2003-06-19 Dung Phan Methods of treatment for skin disorders using turmeric extract and a hydroxy acid
AU2003270283A1 (en) * 2002-10-01 2004-04-23 Dr. Andre Rieks - Labor Fur Enzymtechnologie Gmbh Novel curcumin/tetrahydrocurcumin derivatives for using in cosmetics, pharmaceuticals and for nutrition
RU2383341C2 (ru) * 2007-11-29 2010-03-10 Ольга Викторовна Кухарева Способ омоложения кожи
US7745670B2 (en) * 2008-06-27 2010-06-29 Codman & Shurtleff, Inc. Curcumin-Resveratrol hybrid molecule
KR101095026B1 (ko) * 2009-01-23 2011-12-20 한국과학기술연구원 비스(스티릴)피리미딘 및 비스(스티릴)벤젠 유도체, 이의 약학적으로 허용 가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 베타아밀로이드 집적 관련 질환의 예방 또는 치료용 약학적 조성물
EP2482809B1 (en) * 2009-10-02 2018-06-13 Johnson & Johnson Consumer Inc. Compositions comprising an anti-inflammatory blend

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014004177A2 *

Also Published As

Publication number Publication date
RU2648763C2 (ru) 2018-03-28
AU2013280916B2 (en) 2018-03-15
RU2015102833A (ru) 2016-08-20
CN104411288A (zh) 2015-03-11
BR112014032739A2 (pt) 2017-06-27
WO2014004177A3 (en) 2014-08-07
AU2013280916A1 (en) 2015-01-22
CN104411288B (zh) 2017-10-17
CA2877471A1 (en) 2014-01-03
KR20150023891A (ko) 2015-03-05
WO2014004177A2 (en) 2014-01-03

Similar Documents

Publication Publication Date Title
KR102084385B1 (ko) 피부 라이트닝 방법
EP2572701B1 (en) Compositions comprising a retinoid and an nfkb-inhibitor and their methods of use
EP2316413B1 (en) Compositions comprising an nfkb-inhibitor and a non-retinoid collagen promoter
US9629794B2 (en) Compositions comprising an NFκB-inhibitor and a tropoelastin promoter
JP6833858B2 (ja) シマレンガタケの細胞培養抽出物を使用した、皮膚を美白するための方法及び組成物
KR20120068708A (ko) 마르타곤 나리 추출물을 포함하는 조성물 및 이의 용도
KR20120068707A (ko) 마르타곤 나리 추출물을 포함하는 조성물 및 이의 용도
MX2014005713A (es) Composiciones que comprenden extractos de bursera simaruba.
AU2013280916B2 (en) Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene
US8846013B2 (en) Topical application of 1-hydroxyl-3,5-BIS(4′hydroxy styryl)benzene
WO2014004178A2 (en) Compositions comprising substituted phenols and topical application thereof
US8758731B2 (en) Skin lightening by topical application of 1-hydroxyl 3,5-bis(4′hydroxyl styryl)benzene
US20150257992A1 (en) Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene
US20140005275A1 (en) Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20150129

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20170123

RIC1 Information provided on ipc code assigned before grant

Ipc: A61Q 19/08 20060101ALI20180515BHEP

Ipc: A61Q 17/00 20060101ALI20180515BHEP

Ipc: A61Q 19/02 20060101ALI20180515BHEP

Ipc: A61K 8/34 20060101AFI20180515BHEP

Ipc: A61K 31/05 20060101ALI20180515BHEP

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20190705

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20191116