WO2016068975A1 - Compositions topiques et procédés d'utilisation de ces compositions - Google Patents

Compositions topiques et procédés d'utilisation de ces compositions Download PDF

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Publication number
WO2016068975A1
WO2016068975A1 PCT/US2014/063317 US2014063317W WO2016068975A1 WO 2016068975 A1 WO2016068975 A1 WO 2016068975A1 US 2014063317 W US2014063317 W US 2014063317W WO 2016068975 A1 WO2016068975 A1 WO 2016068975A1
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WIPO (PCT)
Prior art keywords
skin
improvement
compound
topical composition
appearance
Prior art date
Application number
PCT/US2014/063317
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English (en)
Inventor
Kai Xi
Jolanta Idkowiak Baldys
Uma Santhanam
John W. Lyga
Original Assignee
Avon Products, Inc.
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.)
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Publication date
Application filed by Avon Products, Inc. filed Critical Avon Products, Inc.
Priority to PCT/US2014/063317 priority Critical patent/WO2016068975A1/fr
Priority to EP14905127.8A priority patent/EP3212186A1/fr
Publication of WO2016068975A1 publication Critical patent/WO2016068975A1/fr

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • 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
    • A61Q19/06—Preparations for care of the skin for countering cellulitis
    • 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
    • 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
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists

Definitions

  • the invention relates generally to topical compositions for applications to human integuments. More particularly, the invention provides topical compositions and associated methods for improving the appearance of skin, including improving skin tone, reducing dark circles around the eye area, and reducing inflammation, which can further lead to anti-aging effects, such as reduction and/or prevention of fine lines or wrinkles.
  • rosacea a common and chronic disorder, is characterized by flushing and persistent redness (erythema) in the central facial area.
  • erythema redness
  • Such skin conditions may have considerable psychosocial impact and may cause embarrassment, anxiety and low self- esteem.
  • adrenergic receptors In the neurovascular regulation pathway. Adrenergic agonists stimulate a response from the adrenergic receptors.
  • the five main types of adrenergic receptors are: al, a2, ⁇ , ⁇ 2, and ⁇ 3, and agonists vary in specificity between these receptors, and may be classified accordingly.
  • the ⁇ receptors are divided into ⁇ , ⁇ 2 and ⁇ 3.
  • adrenergic receptor agonists possess vasoconstrictive activity and are effective to reduce erythema of rosacea.
  • These include Brimonidine tartrate, an al adrenergic receptor agonist, as described in "Once-daily topical brimonidine tartrate gel 0.5% is a novel treatment of moderate to severe facial erythema of rosacea: results of two multicenter, randomized and vehicle-controlled studies," British Journal of Dermatology, Mar 2012; 166(3): 633-641 ; Oxymetazoline, an al and a2 adrenergic receptor agonist, as described in "Successful Treatment of the Erythema and Flushing of Rosacea Using a Topically Applied Selective 1 -Adrenergic Receptor Agonist, Oxymetazoline,” Arch
  • the invention provides compounds, topical compositions and methods for improving the appearance of skin, including, without limitation, improvement of skin tone, reduction of dark circles around the eye area, and reduction of inflammation of human skin.
  • the compounds of the invention are adrenergic receptor (e.g., al and a2 adrenergic receptor) agonists, with little or no activity as ⁇ 2 receptor agonists.
  • the compounds of the invention are believed to possess vasoconstrictive activity that can lead to skin benefits, including improved skin tone, reduction of dark circle around eye area, and reduced inflammation of the skin that can lead to further anti-aging effects such as anti- wrinkle benefit for cosmetic skin care use.
  • One aspect of the invention provides compounds that are human adrenergic receptor agonists (in particular, at the al and a2 receptor, e.g., at the alA and a2A receptor).
  • the compounds are alA and/or a2A adrenergic receptor agonists, although it is contemplated that the compounds may act on any of al, a2, ⁇ , ⁇ 2, and ⁇ 3 adrenergic receptors or have non-specific activity (e.g., agonist activity) across two or more of these receptors.
  • non-specific activity e.g., agonist activity
  • These compounds may effect vasoconstriction in human tissues, such as skin.
  • the compounds of the invention are contemplated to be beneficial in improving skin appearance and reducing signs of aging (e.g., wrinkles and fine lines).
  • the compounds are contemplated to be useful in reducing inflammation, including by topical application to the skin.
  • topical compositions for improving the appearance of the human integumentary system, including improving skin tone and reducing inflammation discoloration, erythema or pigmentation of human integuments (e.g., skin) comprising, in a topically acceptable vehicle (e.g., a water- in-oil or oil-in- water emulsion, gel or an aqueous serum), an effective amount (e.g., from about 0.0001% to about 0.01%, or to about 0.1%, or to about 1%, or to about 10% by weight) of a compound (e.g., an adrenergic receptor agonist compound) according to formula (I):
  • a topically acceptable vehicle e.g., a water- in-oil or oil-in- water emulsion, gel or an aqueous serum
  • an effective amount e.g., from about 0.0001% to about 0.01%, or to about 0.1%, or to about 1%, or to about 10% by weight
  • a compound e.g
  • X may be selected from oxygen, sulfur, NR*, or CR*R* (but is typically oxygen);
  • Ri and R2 are independently selected from hydrogen or R* (typically at least one of Ri and R2 is R*), wherein Ri and R2 may together form a 3-6-membered ring; and wherein Ri is typically lower alkyl (e.g., methyl, ethyl, propyl, butyl, etc.) and more typically methyl; and R2 is typically hydrogen;
  • p is an integer from 1-5, indicating the number of available positions on the phenyl ring having a group Y attached thereto; for example, p may be one, two, three or four with Y being the same or different at each position; and in some embodiments, p is one; the groups Y may be attached ortho, meta and/or para to the group X; and in one embodiment, there is a group Y ortho to X; in one embodiment p is one and Y is ortho to X;
  • R* is independently at each occurrence hydrogen or a straight chained, branched, or cyclic Ci-C 2 o (or C1-16 or Ci-i 2 or Ci-8 or Ci-6 or C1-4) hydrocarbon radical, such as alkyl, alkenyl, alkynyl, aryl, aryl-alkyl, alkyl-aryl, heteroaryl, etc., optionally substituted with one or more groups Y or with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur, or halogen and combinations thereof; and ins some embodiments, R* is methyl; and wherein any two adjacent R* moieties may together form a 3-6 membered ring;
  • Topically acceptable salts e.g., acid addition salts of the compounds according to formula (I) are also suitable.
  • topical compositions comprising, in a topically acceptable vehicle (e.g., an emulsion, gel or serum), an effective amount (e.g. , from about 0.0001% to about 0.01%, or to about 0.1%, or to about 1%, or to about 10% by weight) of a compound (e.g., an adrenergic receptor agonist compound) having the structure of formula (II), or a topically acceptable salt thereof:
  • a topically acceptable vehicle e.g., an emulsion, gel or serum
  • an effective amount e.g., from about 0.0001% to about 0.01%, or to about 0.1%, or to about 1%, or to about 10% by weight
  • a compound e.g., an adrenergic receptor agonist compound having the structure of formula (II), or a topically acceptable salt thereof:
  • topical compositions comprising, in a topically acceptable vehicle (e.g., an emulsion, gel, or serum), an effective amount (e.g., from about 0.0001% to about 0.01%, or to about 0.1%, or to about 1%, or to about 10% by weight) of a compound (e.g., an adrenergic receptor agonist compound) selected from
  • Compounds III, IV, and V may be provided as racemic mixtures, or as pure R or S enantiomers, or as mixtures of R and S enantiomers having an enantiomeric excess of one or the other of R or S of more than 60% or more than 70% or more than 80% or more than 90%.
  • compositions of the invention typically comprise (e.g., from about 50% to about 99% by weight) a vehicle, for example a water-in-oil or oil-in-water emulsion, and may further include various adjuvants such as thickeners, rheology modifiers, emulsifiers, gellants, emollients, humectants, UV absorbers, antioxidants, pH adjusters, chelators, film formers, waxes, preservatives, colorants, fragrances, and the like.
  • a vehicle for example a water-in-oil or oil-in-water emulsion
  • adjuvants such as thickeners, rheology modifiers, emulsifiers, gellants, emollients, humectants, UV absorbers, antioxidants, pH adjusters, chelators, film formers, waxes, preservatives, colorants, fragrances, and the like.
  • the adjuvants may comprise, individually or collectively, from about 0.00001% to about 98% by weight of the composition (more typically from about 0.001-50% or 0.001-20%).
  • the topical preparations of the invention may further include one or more additional active agents, such as a retinoid (e.g., retinol, retinyl palmitate, retinyl acetate, retinaldehyde, retinoic acid, etc.), an antioxidant (e.g., ascorbic acid, BHT, thiodipropionic acid or esters thereof, including dilauryl thiodipropionate), a-hydroxy acids (e.g., glycolic acid, lactic acid, etc.), collagenase inhibitors, anti-inflammatories, anti-acne agents, salicylic acid and derivatives (e.g., Ci_i6 esters), depigmenting agents (e.g., hydroquinone, kojic acid, etc.), N-ace
  • the compositions include one or more of hydroquinone, kojic acid, salicylic acid or its derivatives, thiodipropionic acid (or C 1-20 mono- or diesters thereof), and retinoids (e.g., retinol). Additional actives may individually or collectively comprise from about 0.0001% to about 20% by weight of the composition.
  • Topical compositions comprising any of the compounds of formulas (I-V) may be applied topically to skin for a time sufficient to achieve an improvement in skin appearance, including, without limitation, improved skin tone and/or reduction of the appearance of dark circles under the eyes and/or reduction in inflammation or erythema in the area of application. This may entail application at least once, twice or more daily for at least one week, at least two weeks, at least four weeks, or at least eight weeks or longer. In some embodiments, the compositions are topically applied daily (at least once) to achieve and/or maintain improved skin tone and/or reduction of dark circles and/or inflammation or erythema in the skin.
  • a method for modulation of adrenergic receptors comprising administering (e.g., topical application) the compounds of formulas (I-V) to a human (e.g., to human skin).
  • the compounds of formulas (I-V) act as adrenergic receptor (e.g., al and 2 receptor, or the alA and a2A receptor) agonists i.e., adrenergic receptor activators, which may result in vasoconstriction, which may lead to improvements in the aesthetic appearance of skin, including improved skin tone, reduction of dark circles around the eye area, and reduced inflammation, which may further lead to anti- aging effects, such as reduction, and/or prevention of fine lines or wrinkles and other aesthetic effects.
  • adrenergic receptor e.g., al and 2 receptor, or the alA and a2A receptor
  • adrenergic receptor activators i.e., adrenergic receptor activators
  • hydrocarbon moieties described herein e.g., alkyl, alkenyl, alkynyl, aryl, alkyl-aryl, aryl-alkyl, heteroalkyl, etc.
  • alkyl alkenyl, alkynyl, aryl, alkyl-aryl, aryl-alkyl, heteroalkyl, etc.
  • examples include C 1 -2 6, C 1-2 o, C 1-18 , C ie, C 1-12 , C 1-8 , C e, and C 1-4 hydrocarbons.
  • Compounds of the invention may be provided as racemic mixtures, or as pure R or S enantiomers, or as mixtures of R and S enantiomers having an enantiomeric excess of one or the other, for example and enantiomeric excess (of R or S) of more than 60% or more than 70% or more than 80% or more than 90%.
  • the phrase "individual in need thereof” refers to a human that could benefit from improved dermal appearance or health, including males or females.
  • an individual in need thereof has a clinical diagnosis of a particular skin indication.
  • the individual in need thereof is a female (e.g., a pre- or post- menopausal female).
  • skin includes, without limitation, the lips, skin of the face, hands, arms, neck, scalp, and chest.
  • the term "consisting essentially of is intended to limit the invention to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention, as understood from a reading of this specification. This may include, without limitation, specificity to adrenergic receptor subtype(s).
  • the term “modulator” may refer to an agonist or an antagonist.
  • the compounds are adrenergic receptor agonists.
  • a compound is said to have activity against a receptor subtype if it has an EC50 value of less than about 1,000 nm, preferably less than about 500 nm, more preferably less than about 400 nm, even more preferably less than about 300 nm, or about 250 nm, or about 200 nm.
  • an agonist will have an EC50 of less than 100 nm, less than 50 nm, less than 10 nm, or less than 1 nm.
  • a compound is said to have little or no activity against a receptor subtype if it has an EC50 value of greater than about 1,000 nm, or greater than about 1,500 nm, or greater than a about 2,000 nm, or greater than about 2,500 nm.
  • compositions may be used for, among other things, improving the appearance of human skin, including, without limitation, improving skin tone, reducing dark circles under the eye area, and/or reducing inflammation of the human integumentary system, including but not limited to, keratinous surfaces such as skin, hair, lips, and nails.
  • the compositions are typically topical compositions that once applied to the integumentary system result in the narrowing of the blood vessels (vasoconstriction) of the integument to which it is applied.
  • the compounds of the invention may have the structure of formula (I):
  • Ri and R2 are independently selected from hydrogen or R*, and wherein Ri and R2 may together form a 3-6-membered ring; and in some embodiments, Ri and/or R2 are methyl, ethyl, propyl, or butyl, and in other embodiments Ri is methyl; and in other embodiments R2 is hydrogen;
  • p is an integer from 1-5, indicating the number of available positions on the phenyl ring having a group Y attached thereto; for example, p may be one, two, three or four with Y being the same or different at each position; and in some embodiments, p is one; the groups Y may be attached ortho, meta and/or para to the group X; and in one embodiment, there is a group Y ortho to X; in one embodiment p is one and Y is ortho to X;
  • R* is independently at each occurrence hydrogen or a straight chained, branched, or cyclic C1-C2 0 (or or C 1-12 or C 1-8 or Ci_6 or C 1-4 ) hydrocarbon radical, such as alkyl, alkenyl, alkynyl, aryl, aryl-alkyl, alkyl-aryl, heteroaryl, etc., optionally substituted with one or more groups Y or with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur, or halogen and combinations thereof; and ins some embodiments, R* is methyl; and wherein any two adjacent R* moieties may together form a 3-6 membered ring;
  • X is oxygen
  • Ri and R2 may independently be selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, and hexyl. In certain implementations, Ri is methyl. In some embodiments, R2 is hydrogen. In some embodiments, Y is present at one, two, three, four or five positions on the ring to which it is attached. In some embodiments, Y is present at one position on the ring to which it is attached. In some embodiments, Y is an aliphatic Ci-C hydrocarbon radical; a Cs-Cs aromatic hydrocarbon radical; or a Cs-Cs heteroaryl radical; or a group
  • Compounds III, IV, and V may be provided as racemic mixtures, or as pure R or S enantiomers, or as mixtures of R and S enantiomers having an enantiomeric excess of one or the other of more than 60% or more than 70% or more than 80% or more than 90%.
  • compositions according to the invention can be formulated in a variety of forms for topical application and will typically comprise from about 0.00001% by weight to about 20% by weight of one or more compounds according to Formula (I)-(V), and preferably will comprise from about 0.0001% by weight to about 10% by weight, and more preferably from about 0.001% by weight to about 5% by weight of the composition.
  • the active will comprise from about 0.01% by weight to about 0.1% by weight or to about 0.5% by weight or to about 1% by weight of the composition.
  • the compositions will comprise and effective amount of the compound according to Formula (I)-(V), by which is meant an amount sufficient to have a vasoconstrictive effect in a given area of skin when topically applied thereto.
  • the cosmetically acceptable vehicle may be in the form of an emulsion.
  • suitable emulsions include water-in-oil emulsions, oil-in-water emulsions, silicone-in-water emulsions, water-in-silicone emulsions, wax-in-water emulsions, water-oil- water triple emulsions or the like having the appearance of a cream, gel or microemulsions.
  • oil includes silicone oils unless otherwise indicated.
  • the emulsion may include an emulsifier, such as a nonionic, anionic or amphoteric surfactant, or a gellant, typically in an amount from about 0.001% to about 10% by weight.
  • the gellant may be an oil phase or aqueous phase.
  • the cosmetically acceptable vehicle may include water; vegetable oils; mineral oils; ester oils such as octal palmitate, isopropyl myristate and isopropyl palmitate; ethers such as dicapryl ether and dimethyl isosorbide; alcohols such as ethanol and isopropanol; fatty alcohols such as cetyl alcohol, cetearyl alcohol, stearyl alcohol and behenyl alcohol; isoparaffins such as isooctane, isododecane (IDD) and isohexadecane; silicone oils such as cyclomethicone, dimethicone, dimethicone cross-polymer, polysiloxanes and their derivatives, preferably organomodified derivatives including PDMS, dimethicone copolyol, dimethiconols, and amodimethiconols; hydrocarbon oils such as mineral oil, petrolatum, isoeicosane and polyolefins,
  • the compositions may include additional skin actives, including but not limited to, retinoids, botanicals, keratolytic agents, desquamating agents, keratinocyte proliferation enhancers, collagenase inhibitors, elastase inhibitors, depigmenting agents, anti-inflammatory agents, steroids, anti-acne agents, antioxidants, a-hydroxy acids, and advanced glycation end-product (AGE) inhibitors, to name but a few.
  • skin actives including but not limited to, retinoids, botanicals, keratolytic agents, desquamating agents, keratinocyte proliferation enhancers, collagenase inhibitors, elastase inhibitors, depigmenting agents, anti-inflammatory agents, steroids, anti-acne agents, antioxidants, a-hydroxy acids, and advanced glycation end-product (AGE) inhibitors, to name but a few.
  • the amounts of these various ingredients are those conventionally used in the cosmetic field to achieve their intended purpose, and range individually or
  • Exemplary anti-aging components include, without limitation, botanicals (e.g.,
  • Butea frondosa extract phytol; phytonic acid; retinoids; hydroxy acids (including alpha- hydroxy acids and beta-hydroxy acids), salicylic acid and alkyl salicylates; exfoliating agents (e.g., glycolic acid, 3,6,9-trioxaundecanedioic acid, etc.), estrogen synthetase stimulating compounds (e.g., caffeine and derivatives); compounds capable of inhibiting 5 alpha- reductase activity (e.g., linolenic acid, linoleic acid, finasteride, and mixtures thereof); and barrier function enhancing agents (e.g., ceramides, glycerides, cholesterol and its esters, alpha-hydroxy and omega-hydroxy fatty acids and esters thereof, etc.), to name a few.
  • exfoliating agents e.g., glycolic acid, 3,6,9-trioxaundecanedioic acid, etc.
  • estrogen synthetase stimulating compounds
  • retinoids include, without limitation, retinoic acid (e.g., all-trans, or 9-cis, or 13-cis), and derivatives thereof, retinaldehyde, retinol (Vitamin A) and esters thereof, such as retinyl palmitate, retinyl acetate and retinyl propionate, and salts thereof. Particular mention may be made of retinol.
  • the retinoids will typically be included in amounts from about 0.0001% to about 5% by weight, more typically from about 0.01% to about 2.5% by weight, or from about 0.1% to about 1.0% by weight.
  • Compositions according to this embodiment will typically include an antioxidant such as ascorbic acid and/or BHT and/or a chelating agent such as EDTA or a salt thereof (e.g., disodium EDTA).
  • compositions of the invention may further comprise one or more of Amorphophallus Campanulatus Rhizome/Root Extract, Glycine Max (Soybean) Symbiosome Extract, Vitis Vinifera (Grape) Fruit Cell Extract, Malus Domestica Fruit Cell Culture Extract, Eclipta Prostrata Extract, Palmitoyl Lysyl Aminovaleroyl Lysine, Palmitoyl Oligopeptide, Palmitoyl Tetrapeptide-10, Palmitoyl Tetrapeptide-7, Melicope Leaf Extract, Saccharomyces Ferment Lysate Filtrate, Thiazolylalanine, Mesyloxybenzyl Isobutylbenzenesulfonamide, Phytol, Thiodipropionic Acid, Dilauryl Thiodipropionate, Coffea Arabica (Coffee) Seed Oil, Foeniculum Vulgare (Fennel) Fruit Extract, Ceramide 2, Crataegus Monogyn
  • Saccharomyces/Manganese Ferment Saccharomyces/Iron Ferment, Saccharomyces/Silicon Ferment, and Saccharomyces Ferment Lysate Filtrate.
  • additional active(s) may be present individually or collectively in an amount from about 0.0001% to about 20% by weight of the composition.
  • the topical compositions of the present invention may also include one or more of the following: a skin penetration enhancer; an emollient, such as isopropyl myristate, petrolatum, volatile or non-volatile silicones oils (e.g., methicone, dimethicone), ester oils, mineral oils, and fatty acid esters; a humectant, such as glycerin, hexylene glycol or caprylyl glycol; a skin plumper, such as palmitoyl oligopeptide, collagen, collagen and/or glycosaminoglycan (GAG) enhancing agents; a sunscreen, such as avobenzone or octyl methoxycinnamate; an exfoliating agent; and an antioxidant.
  • a skin penetration enhancer such as isopropyl myristate, petrolatum, volatile or non-volatile silicones oils (e.g., methicone, dimethicone), ester oils,
  • Suitable exfoliating agents include, for example, alpha-hydroxy acids, beta- hydroxy acids, oxa-acids, oxadiacids, and their derivatives such as esters, anhydrides and salts thereof.
  • Suitable hydroxy acids include, for example, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, 2-hydroxyalkanoic acid, mandelic acid, salicylic acid and derivatives thereof.
  • One exemplary exfoliating agent is glycolic acid.
  • the exfoliating agent may comprise from about 0.001% to about 20% by weight of the composition.
  • antioxidants examples include compounds having phenolic hydroxy functions, such as ascorbic acid and its derivatives/esters; beta-carotene; catechins; curcumin; ferulic acid derivatives (e.g., ethyl ferulate, sodium ferulate); gallic acid derivatives (e.g., propyl gallate); lycopene; reductic acid; rosmarinic acid; tannic acid; tetrahydrocurcumin; tocopherol and its derivatives, including tocopheryl acetate; uric acid; or any mixtures thereof.
  • ferulic acid derivatives e.g., ethyl ferulate, sodium ferulate
  • gallic acid derivatives e.g., propyl gallate
  • lycopene reductic acid
  • rosmarinic acid tannic acid
  • tetrahydrocurcumin tocopherol and its derivatives, including tocopheryl acetate; uric acid; or any mixtures thereof
  • antioxidants are those that have one or more thiol functions (-SH), in either reduced or non-reduced form, such as glutathione, lipoic acid, thioglycolic acid, and other sulfhydryl compounds.
  • the antioxidant may be inorganic, such as bisulfites, metabisulfites, sulfites, or other inorganic salts and acids containing sulfur.
  • Antioxidants may comprise, individually or collectively, from about 0.001% to about 10 % (w/w), or from about 0.01% to about 5% (w/w) of the total weight of the composition.
  • vitamins such as tocopherol and ascorbic acid
  • vitamin derivatives such as ascorbyl monopalmitate, tocopheryl acetate, and Vitamin E palmitate
  • thickeners such as hydroxyalkyl cellulose, carboxymethylcellulose, carbombers, and vegetable gums such as xanthan gum
  • gelling agents such as ester-terminated polyester amides
  • structuring agents such as metal chelating agents such as EDTA or salts thereof
  • pigments such as ethanolamine, sodium hydroxide, etc.
  • pH adjusters citric acid, ethanolamine, sodium hydroxide, etc.
  • compositions may optionally comprise other components known to those skilled in the art including, but not limited to, film formers, moisturizers, minerals, viscosity and/or rheology modifiers, anti-acne agents, insect repellents, skin cooling compounds, skin protectants, lubricants, fragrances, preservatives, stabilizers, and mixtures thereof.
  • cosmetic compositions of the invention may contain any other compound for the treatment of skin disorders.
  • compositions contemplated by this disclosure can include one or more compatible cosmetically acceptable adjuvants commonly used and known by the skilled practitioner, such as colorants, pearls, chromalites, micas, pigments, dyes, fragrances, emollients, humectants, preservatives, vitamins, chelators, thickeners, anesthetics, anti- allergenics, antifungals, antimicrobials, other anti-inflammatory agents, antioxidants, antiseptics, depigmenting agents, film formers, insect repellents, pharmaceutical agents, photostabilizing agents, sunscreens, stabilizers, surfactants, thickeners, viscosity modifiers, and botanicals.
  • compatible cosmetically acceptable adjuvants commonly used and known by the skilled practitioner, such as colorants, pearls, chromalites, micas, pigments, dyes, fragrances, emollients, humectants, preservatives, vitamins, chelators, thickeners, anesthetics, anti- allergenics, anti
  • the topical compositions of the present disclosure may also include a skin penetration enhancer, a surface smoother, a skin plumper, an optical diffuser, an exfoliation promoter, and an antioxidant. Details with respect to these and other suitable cosmetic ingredients can be found in the "International Cosmetic Ingredient Dictionary and Handbook," 10th Edition (2004), published by the Cosmetic, Toiletry, and Fragrance Association (CTFA), at pp. 2177-2299, which is herein incorporated by reference in its entirety.
  • CTFA Cosmetic, Toiletry, and Fragrance Association
  • the amounts of these various substances are those that are conventionally used in the cosmetic or pharmaceutical fields, for example, they can constitute from about 0.01% to about 20% of the total weight of the composition.
  • a sunscreen may be included to protect the skin from damaging ultraviolet rays.
  • the sunscreen provides both UVA and UVB protection, by using either a single sunscreen or a combination of sunscreens.
  • the sunscreens that can be employed in the present compositions are avobenzone, cinnamic acid derivatives (such as octylmethoxy cinnamate), octyl salicylate, oxybenzone, octocrylene, titanium dioxide, zinc oxide, or any mixtures thereof.
  • the sunscreen may be present from about 1 wt % to about 30 wt % of the total weight of the composition.
  • the topical composition will have a pH range from 1 to
  • the composition will have a pH in the range of from 3.5 to 7 or from 7-10.5. In some embodiments, the pH will be in the range of 3-4, or 4-5, or 5-6, or 6-7, or 7-8, or 8-9, or 9-10, or 10-1 1, or 1 1-12. Suitable pH adjusters such as sodium hydroxide, citric acid and triethanolamine may be added to bring the pH within the desired range.
  • Another embodiment of the present disclosure is directed to the delivery of the described compositions by the use of targeted delivery systems, for example, liposomes, microspheres (see, e.g., U.S. Pat. No. 5,770,222 to Unger et al), and the like, so that the components and/or active constituents can more readily reach and affect the subcutaneous layer of the area of application, e.g., face or neck, or the other area of the skin.
  • compositions may be formulated in a variety of product forms, such as, for example, a lotion, cream, serum, spray, aerosol, cake, ointment, essence, gel, paste, patch, pencil, towelette, mask, stick, foam, elixir, concentrate, and the like, particularly for topical administration.
  • a lotion, cream, serum, spray, aerosol, cake, ointment, essence, gel, paste, patch, pencil, towelette, mask, stick, foam, elixir, concentrate, and the like particularly for topical administration.
  • the composition is formulated as a lotion, cream, ointment, or gel.
  • the compositions and methods are for improving skin tone (in particular for skin of the face), which includes evening, lightening, or optimizing the tone of the skin.
  • the compositions and methods are for treating dark circles under the subject's eye area.
  • the compositions and methods are for reducing redness and inflammation in the skin, including without limitation treating, ameliorating, diminishing the appearance of, or preventing inflammation in the skin.
  • the compositions may be applied directly to a localized site of affected skin.
  • compositions and methods of the invention are also contemplated to be useful for treating, reducing, ameliorating, improving, alleviating, and/or eliminating the dermatological effects of aging and/or environmental stress.
  • the compositions and methods are suitable for use in treating dermatological conditions of the skin, including treatment of fine lines and wrinkles, reducing hyperpigmentation or unwanted pigmentation, or treatment of erythema in numerous areas of the body, including, without limitation, the face, forehead, lips, neck, arms, hands, legs, knees, feet, chest, back, groin, buttocks, thighs, and the like.
  • the compositions are applied topically to the skin of the face.
  • the compositions are applied topically to improve the aesthetic appearance of human skin.
  • the method comprises topically applying to an area of the skin in need thereof a composition comprising an effective amount of a compound of Formula (I) or (II) for a time sufficient to improve the aesthetic appearance of said human skin.
  • the compositions are topically applied to the skin in effective amounts, by which is meant an amount sufficient to achieve a measurable improvement in skin health or reduction in one or more dermatological signs of aging with daily (once, twice, etc.) administration, typically for a period of at least one week or more.
  • the aesthetic improvement of human skin may be an improvement of any attribute or characteristic of skin, including without limitation:
  • a method for the treatment of wrinkles and/or fine lines on the skin human skin comprising topically applying to an area of the skin in need thereof (e.g., applying to a wrinkle or fine line) a composition of Formula (I)-(V), for a time sufficient to improve the aesthetic appearance of said human skin.
  • the treatment may be a least once or twice daily and may last for a period of at least four weeks, typically at least eight weeks or longer.
  • composition may optionally further comprise a retinoid (e.g., retinol or retinyl palmitate) and/or an alpha-hydroxy acid (e.g., glycolic acid) and/or a beta-hydroxy acid (e.g., salicylic acid or derivative) in amounts effective to improve the appearance of skin.
  • a retinoid e.g., retinol or retinyl palmitate
  • an alpha-hydroxy acid e.g., glycolic acid
  • beta-hydroxy acid e.g., salicylic acid or derivative
  • methods for enhancing the production of collagen or pro-collagen in human skin comprising topically applying to an area of the skin in need thereof (e.g., sagging skin, thinning skin, skin suffering from wrinkles and fine lines, etc.) a topical composition comprising a cosmetically acceptable vehicle, and an effective amount of a compound of Formula (I)-(V), for a time sufficient to improve the appearance thereof.
  • the treatment may be a least once or twice daily and may last for a period of at least four weeks, typically at least eight weeks or longer.
  • composition may optionally further comprise a retinoid and/or an alpha-hydroxy acid (e.g., glycolic acid) and/or a beta-hydroxy acid (e.g., salicylic acid or a derivative) in amounts effective to improve the appearance of skin.
  • a retinoid and/or an alpha-hydroxy acid e.g., glycolic acid
  • a beta-hydroxy acid e.g., salicylic acid or a derivative
  • methods for reducing the severity of, reducing the number of, or preventing or forestalling the onset of, wrinkles or fine lines on human skin comprising topically applying to an area of the skin in need thereof (e.g., wrinkled skin), an effective amount (e.g., 0.0001% - 1% by weight, w/w) of a compound of Formula (I)-(V), in combination with an effective amount (e.g., 0.01% - 5% by weight, w/w) of retinol and/or an effective amount (e.g., 0.001% - 5% by weight, w/w) of an alpha- hydroxy acid (e.g., glycolic acid) and/or a beta-hydroxy acid (e.g., salicylic acid).
  • an effective amount e.g., 0.0001% - 1% by weight, w/w
  • an effective amount e.g., 0.01% - 5% by weight, w/w
  • an effective amount e.g.,
  • the invention provides a method for treating aging skin by topically applying a composition comprising a collagen-stimulating compound of Formula (I)-(V), typically in a cosmetically acceptable vehicle, over the affected area for a period of time sufficient to remediate, reverse, reduce, ameliorate, or prevent dermatological signs of aging.
  • the improvement in the condition and/or aesthetic appearance is selected from the group consisting of: reducing dermatological signs of chronological aging, photo-aging, hormonal aging, and/or actinic aging; preventing and/or reducing the appearance of lines and/or wrinkles; reducing the noticeability of facial lines and wrinkles, facial wrinkles on the cheeks, forehead, perpendicular wrinkles between the eyes, horizontal wrinkles above the eyes, and around the mouth, marionette lines, and particularly deep wrinkles or creases; improving the appearance of suborbital lines and/or periorbital lines; reducing the appearance of crow's feet; rejuvenating and/or revitalizing skin, particularly aging skin; reducing skin fragility; preventing and/or reversing of loss of glycosaminoglycans and/or collagen; ameliorating the effects of estrogen imbalance; preventing skin atrophy; preventing, reducing, and/or treating hyperpigmentation or hypopigmentation; minimizing skin discoloration; improving skin tone, radiance, clarity and/or
  • the compounds of Formulas (I)-(V) will be used to reduce the severity of fine lines or wrinkles, often in combination with retinol.
  • the composition will typically be applied to the skin one, two, or three times daily for as long as is necessary to achieve desired results.
  • the treatment regimen may comprise daily application for at least one week, at least two weeks, at least four weeks, at least eight weeks, or at least twelve weeks or more. Chronic treatment regimens are also contemplated.
  • the effect of a composition on the formation or appearance of fine lines and wrinkles can be evaluated qualitatively, e.g., by visual inspection, or quantitatively, e.g., by microscopic or computer assisted measurements of wrinkle morphology (e.g., the number, depth, length, area, volume and/or width of wrinkles per unit area of skin).
  • the cosmetic compositions of the invention will be applied to the skin in an amount from about 0.001 to about 100 mg/cm 2 , more typically from about 0.01 to about 20 mg/cm 2 , or from about 0.1 to about 10 mg/cm 2 .
  • compositions of the invention will be useful for treating thin skin by topically applying the composition to thin skin of an individual in need thereof.
  • Thiin skin is intended to include skin that is thinned due to chronological aging, menopause, or photo-damage and skin that is thinning prematurely.
  • the treatment is for thin skin in men, whereas other embodiments treat thin skin in women, pre-menopausal or post-menopausal, as it is believed that skin thins differently with age in men and women, and in particular in women at different stages of life.
  • the method of the invention may be employed prophylactically to forestall aging including in individuals that have not manifested signs of skin aging, most commonly in individuals under 25 years of age.
  • the method may also reverse or treat signs of aging once manifested as is common in individuals over 25 years of age, or to slow the progression of dermatological aging in such individuals.
  • the compositions of the invention are applied to human skin to reduce sebum production or improve the appearance of skin affected by cellulite, and/or reduce unwanted lipogenesis or increase lipolysis.
  • the compounds of Formulas (I)-(V) can be formulated in cosmetically acceptable vehicles (as described herein) and may include one or more additional agents such as anti-acne ingredients (e.g., salicylic acid, benzoyl peroxide and other peroxides, sulfur, retinoids, etc.) in the case of a facial composition, or, in the case of a cellulite treatment, the formulation may comprise any ingredients suitable for treatment of cellulite, including without limitation, perilla oil and other unsaturated fatty oils and omega-3 fatty acids such as alpha-linolenic acid; caffeine; theophylline; xanthines; retinoids (e.g., retinol); and the like.
  • anti-acne ingredients e.g., salicylic acid, benzoyl peroxid
  • a cellulite treatment according to the invention will typically be applied topically to skin suffering from cellulite, including skin of the buttocks and thighs for a period of time sufficient to improve the appearance thereof, including for example, daily treatment for at least four weeks, at least eight weeks, at least twelve weeks, or longer.
  • the compositions are topically applied to treat acne.
  • the compounds of Formulas (I)-(V) are intended for oral use, including for pharmaceutical use.
  • Pharmaceutical formulations will include pharmaceutically acceptable carriers (i.e., diluents and excipients).
  • the pharmaceutical compositions may be included in solid dosage forms, including compressed tablets and capsules, or in liquid or powder forms.
  • Pharmaceutical dosage forms will typically include from about 0.5 mg to about 200 mg, or from about 1 mg to about 100 mg of the compound of Formulas (I)-(V).
  • the dosage forms may be immediate release, in which case they will typically comprise a water-soluble or dispersible carrier such as microcrystalline cellulose, mannitol, hydroxypropyl methyl cellulose, PVP or the like, or may be delayed, sustained, or modified release, in which case they may comprise water-insoluble polymers such as cellulose ethers (e.g., ethylcellulose), alone or in combination with water soluble or dispersible polymers, to regulate the rate of dissolution of the dosage form in the stomach.
  • a water-soluble or dispersible carrier such as microcrystalline cellulose, mannitol, hydroxypropyl methyl cellulose, PVP or the like
  • water-insoluble polymers such as cellulose ethers (e.g., ethylcellulose)
  • the composition is intended for use as a non-therapeutic treatment.
  • the composition is an article intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance, in accordance with the US FD&C Act, ⁇ 201(i).
  • the compounds of Formulas (III)-(V) stimulate alA adrenergic receptor activity and/or a2A receptor activity, but are not specifically active at the ⁇ 2 receptor.
  • a compound has insignificant activity against the ⁇ 2 receptor if the EC5 0 is greater than about 500 nM.
  • the adrenergic receptor agonists will have an EC5 0 at the ⁇ 2 receptor of greater than 1,000 nM or greater than 1,500 nM, or greater than 2,000 nM.
  • a compound is a "selective" agonist if it has activity at alA and/or a2A receptors with an EC5 0 of less than 1,000 nM (preferably less than 500 nM) and insignificant activity at the ⁇ 2 receptor.
  • Compound (III) is a selective alA and a2A receptor agonist (e.g., insignificant activity against ⁇ 2)
  • Compound (IV) is a selective alA receptor agonist
  • Compound (V) is a selective alA and a2A receptor agonist.
  • EMBODIMENTS 1.
  • a topical composition comprising, in a topically acceptable vehicle, an effective amount of a compound capable of modulation of adrenergic receptors having the structure of formula (I):
  • X is selected from oxygen, sulfur, NR*, or CR*R*;
  • Ri and R2 are independently selected from hydrogen or R*, wherein Ri and R2 may together form a 3-6-membered ring;
  • p is an integer from 1-5;
  • R* is independently at each occurrence hydrogen or a straight chained, branched, or cyclic C1-C2 0 hydrocarbon radical, optionally substituted with one or more groups Y or with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur, or halogen and combinations thereof; and topically acceptable salts thereof.
  • composition of claim 1 wherein the compound of formula (I) is capable of modulating adrenergic receptors of subtype alA, a2A, and/or ⁇ 2.
  • composition of claim 9 wherein said compound is an adrenergic receptor agonist.
  • composition of claim 9 wherein said compound is an agonist of alA and/or a2A adrenergic receptors.
  • composition according to claim 13 wherein said cosmetically acceptable vehicle comprises a water-in-oil, oil-in-water, silicone-in-water, or water-in-silicone emulsion and further comprises an emulsifier.
  • a method for modulating adrenergic receptors in human skin comprising topically applying to an area of the skin in need thereof a composition comprising, in a cosmetically acceptable vehicle, an effective amount of a compound having the structure of formula (I):
  • Ri and R2 are independently selected from hydrogen or R*, wherein Ri and R2 may together form a 3-6-membered ring;
  • p is an integer from 1-5;
  • R* is independently at each occurrence hydrogen or a straight chained, branched, or cyclic C1-C2 0 hydrocarbon radical, optionally substituted with one or more groups Y or with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur, or halogen and combinations thereof; and topically acceptable salts thereof.
  • a method for improving the appearance of human skin comprising topically applying to an area of the skin in need thereof a composition comprising, in a cosmetically acceptable vehicle, an effective amount of a compound having the structure of formula (I):
  • X is selected from oxygen, sulfur, NR*, or CR*R*;
  • p is an integer from 1-5;
  • R* is independently at each occurrence hydrogen or a straight chained, branched, or cyclic C1-C20 hydrocarbon radical, optionally substituted with one or more groups Y or with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur, or halogen and combinations thereof; and topically acceptable salts thereof.
  • improving the appearance of human skin comprises improving skin tone and/or reducing dark circles under the eye area.
  • improvement in the appearance of skin is selected from a group consisting of:

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  • Gerontology & Geriatric Medicine (AREA)
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Abstract

L'invention concerne d'une manière générale des compositions utiles pour améliorer l'aspect esthétique de la peau humaine et l'utilisation de ces composés pour améliorer l'aspect de la peau humaine, notamment l'amélioration du teint de la peau, la réduction de l'apparition de cercles sombres sous les yeux et la réduction de l'inflammation de la peau. Les compositions comprennent classiquement des agonistes du récepteur adrénergique.
PCT/US2014/063317 2014-10-31 2014-10-31 Compositions topiques et procédés d'utilisation de ces compositions WO2016068975A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018014098A1 (fr) * 2016-07-19 2018-01-25 Doris Maria Hexsel Utilisation d'une composition pharmaceutique destinée au traitement de l'érythème cutané des cernes
CN109234447A (zh) * 2018-11-26 2019-01-18 山西省农业科学院农作物品种资源研究所 一种鉴定抗大豆胞囊线虫4号小种大豆资源的方法及专用ssr引物

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US20020037297A1 (en) * 1997-09-22 2002-03-28 Crespo Maria Del Carmen Diez Process for the topical treatment of rhinitis, conjunctivitis cold, and cold-like and flu symptoms
US7652055B2 (en) * 2007-07-02 2010-01-26 Hoffman-La Roche Inc. 2-imidazolines
US20130190317A1 (en) * 2010-08-06 2013-07-25 Galderma Research & Development Snc Combination of compounds for treating or preventing skin diseases

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
US4343808A (en) * 1979-10-25 1982-08-10 The Dow Chemical Company Method of inhibiting sickling of sickle erythrocytes
US20020037297A1 (en) * 1997-09-22 2002-03-28 Crespo Maria Del Carmen Diez Process for the topical treatment of rhinitis, conjunctivitis cold, and cold-like and flu symptoms
US7652055B2 (en) * 2007-07-02 2010-01-26 Hoffman-La Roche Inc. 2-imidazolines
US20130190317A1 (en) * 2010-08-06 2013-07-25 Galderma Research & Development Snc Combination of compounds for treating or preventing skin diseases

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018014098A1 (fr) * 2016-07-19 2018-01-25 Doris Maria Hexsel Utilisation d'une composition pharmaceutique destinée au traitement de l'érythème cutané des cernes
CN109234447A (zh) * 2018-11-26 2019-01-18 山西省农业科学院农作物品种资源研究所 一种鉴定抗大豆胞囊线虫4号小种大豆资源的方法及专用ssr引物
CN109234447B (zh) * 2018-11-26 2021-06-11 山西省农业科学院农作物品种资源研究所 一种鉴定抗大豆胞囊线虫4号小种大豆资源的方法及专用ssr引物

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