WO2014015879A2 - Improved sunscreen composition - Google Patents

Improved sunscreen composition Download PDF

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Publication number
WO2014015879A2
WO2014015879A2 PCT/DK2013/050250 DK2013050250W WO2014015879A2 WO 2014015879 A2 WO2014015879 A2 WO 2014015879A2 DK 2013050250 W DK2013050250 W DK 2013050250W WO 2014015879 A2 WO2014015879 A2 WO 2014015879A2
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WO
WIPO (PCT)
Prior art keywords
range
sunscreen
composition
thickening agent
composition according
Prior art date
Application number
PCT/DK2013/050250
Other languages
French (fr)
Other versions
WO2014015879A3 (en
Inventor
Lene BRITZE
Original Assignee
Riemann Trading Aps
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Riemann Trading Aps filed Critical Riemann Trading Aps
Priority to RU2015105502A priority Critical patent/RU2015105502A/en
Priority to BR112015001664A priority patent/BR112015001664A2/en
Priority to KR20157004943A priority patent/KR20150046064A/en
Priority to US14/415,906 priority patent/US20150216782A1/en
Priority to CA2879468A priority patent/CA2879468A1/en
Priority to EP13747961.4A priority patent/EP2877142A2/en
Priority to CN201380050124.4A priority patent/CN104661635A/en
Publication of WO2014015879A2 publication Critical patent/WO2014015879A2/en
Publication of WO2014015879A3 publication Critical patent/WO2014015879A3/en
Priority to IN519DEN2015 priority patent/IN2015DN00519A/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73Polysaccharides
    • A61K8/731Cellulose; Quaternized cellulose derivatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/31Hydrocarbons
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34Alcohols
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35Ketones, e.g. benzophenone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37Esters of carboxylic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41Amines
    • A61K8/411Aromatic amines, i.e. where the amino group is directly linked to the aromatic nucleus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4966Triazines or their condensed derivatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8141Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • A61K8/8158Homopolymers or copolymers of amides or imides, e.g. (meth) acrylamide; Compositions of derivatives of such polymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00Barrier 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
    • A61Q17/04Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/30Characterized by the absence of a particular group of ingredients
    • A61K2800/31Anhydrous
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/30Characterized by the absence of a particular group of ingredients
    • A61K2800/34Free of silicones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/48Thickener, Thickening system

Definitions

  • the present invention relates to sunscreen compositions.
  • the present invention relates to sunscreen compositions comprising a small amount of thickening agent for the purpose of boosting the sun protection factor of the composition.
  • the use of thickening agents to enhance the sun protection factor of a sunscreen composition is also described, as well as a method for manufacturing such sunscreen compositions.
  • UV irradiation causes skin burns, loss of skin elasticity and the appearance of wrinkles, promoting premature skin aging.
  • UV irradiation promotes the triggering of the erythemal reaction or accentuates this reaction in certain individuals and may even be the source of phototoxic or photoallergy reactions.
  • Last, but not least important, UV irradiation has carcinogenic effects.
  • Numerous requirements exist for dermatological compositions for photo- protection of the human skin Compositions are preferred which have a pleasant feel and are formulated as non-greasy sprays, milks and creams that are easily applied. It is further preferred that the compositions exhibit non-adherence to sand, as users of these compositions are often in contact with sand at beaches and play areas.
  • compositions In addition to being convenient for the user the compositions must contain adequate solvent to hold the necessary amount of UV-filter. Need continues to exist for compositions which simultaneously have a low or zero content of preservatives, while exhibiting an optimum stability which is maintained throughout the time of storage and ultimate use of the products. Finally, in instances where a particularly high and lasting protection is desired, as for children's skin or for sensitive skin, it is also preferable to employ compositions which exhibit good water resistance and which thus retain a very good photo protective power even after coming into contact with water.
  • sunscreen formulations comprising dimethicone derivatives, wherein from about 75% to about 100% of an SPF rating of the composition is retained after immersion into water for 80 minutes. Corresponding formulation without dimethicone derivatives perform poorly with respect to water resistance.
  • compositions are oil-in-water emulsions.
  • one of the disadvantages of traditional oil-in-water emulsions is that they very easily lose their effectiveness with respect to UV protection as soon as they come into contact with water; this because the screening agents which they contain in their aqueous phase are removed by the water, during bathing in the sea or in swimming pools, for example, or, alternatively, under the shower or when playing water sports, and the overall photo-protective power of these compositions thus is greatly reduced.
  • sunscreen compositions which are solvent solutions with a low water content rather than oil-in-water emulsions would be advantageous.
  • SPF Sun Protection Factor
  • Sunscreen agents are expensive additives and there are consumer trends towards deselecting certain UV-filters.
  • One way of improving the SPF of a sunscreen composition without adding further sunscreen agents, is to employ SPF booster's, which are normally compounds or additives which do not adsorb UV radiation, but still improves the SPF in various other ways.
  • SPF booster's which are normally compounds or additives which do not adsorb UV radiation, but still improves the SPF in various other ways.
  • WO 2004/110366 discloses photoprotective
  • compositions comprising optimizing agents selected from the group consisting of diols, alcohol, glycol and polyhydric alcohol or derivatives thereof.
  • the optimizing agents boost the SPF of the compositions by several SPF units.
  • 2011/100275 describes a method of boosting the SPF of a sunscreen composition comprising an acidic film former by the addition of amine neutralizing agent.
  • Improved or alternative sunscreen compositions which have improved SPF ratings would be advantageous, and in particular providing sunscreen compositions which have an improved SPF rating and simultaneously maintain a high water resistance, are non-greasy and easily applicable would be advantageous.
  • an object of the present invention relates to the provision of improved or alternative sunscreen compositions.
  • the present inventors surprisingly found that the addition of a small amount of thickening agent, such as for example a polysaccharide thickening agent increases the sun protection factor of the sunscreen composition of the present invention by several units, thereby reducing the needed amount of sunscreen agents to achieve a given sun protection factor.
  • one aspect of the invention relates to a sunscreen composition
  • a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, at least one solvent, and at least one thickening agent, wherein said thickening agent is present in an amount in the range of 0.01-0.2%(w/w).
  • Another aspect of the present invention relates to the use of a thickening agent for increasing the sun protection factor of a sunscreen composition
  • a thickening agent for increasing the sun protection factor of a sunscreen composition
  • a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, and at least one solvent.
  • Yet another aspect of the present invention relates to a process for the
  • step ii) admixing the components of step i) to provide a sunscreen
  • sunscreen composition or photoprotective composition is to be understood as a liquid composition comprising agents that reduces the amount of UV radiation being absorbed by the skin, when said sunscreen composition is applied to the skin.
  • a sunscreen composition may either absorb or block the UV rays.
  • UV radiation may include UVA and UVB radiation.
  • Sunscreen compositions may be formulated as solutions, emulsions, milks or oils, and may be applied to the skin by the means of sprays, creams, or lotions.
  • sunscreen agent is any cosmetologically approved agent capable of adsorbing or blocking UV radiation, such as UVA and/or UVB radiation.
  • Sunscreen agents that absorb UV radiation are also referred to as UV filters, UVA, UVB or broad spectrum filters.
  • sunscreen agents are often organic compounds or molecules, which absorb light in the UV region, the UV region being at wavelengths from 290 to 400 nanometers.
  • Sunscreen agents that block the UV rays may include substances that leave a white coating on the skin, such as certain metal oxides including for example titanium oxide or other white substances.
  • film forming polymer also sometimes referred to as a "waterproofing agent” is a polymer capable of forming a film on e.g. skin as the carrier or solvent that it is dissolved in evaporates.
  • a film forming polymer may be a uniform homo-polymer or a co-polymer, such as for example a block-copolymer.
  • the polymer may preferably be cosmetologically approved.
  • co-polymer relates to a polymer formed when two (or more) different types of monomer are linked in the same polymer chain, as opposed to a homo- polymer where only one monomer is used.
  • solvent also sometimes referred to as a carrier, is any liquid capable of dissolving the components of the sunscreen composition.
  • a solvent may be a mixture of different solvents or it may be a single solvent.
  • the solvent should be suitable for use in cosmetics and may preferably be cosmetologically approved.
  • alcohol refers to an organic compound in which a hydroxyl group (-OH) is attached to a saturated carbon atom.
  • Alcohols have the general formula ROH, where R may be a lower-aliphatic or cyclic carbon chain and may include aromatic rings. Alcohols are further classified as primary, secondary or tertiary, according to the position of the hydroxyl group on the lower-aliphatic carbon chain. Alcohols may also be classified by the number of hydroxyl groups present in the molecule; for example, a compound with two hydroxyl groups (a diol), and with three hydroxyl groups (a triol).
  • the alcohol may comprise a denaturant.
  • Alcohol Denaturant relates to ethyl alcohol that is denatured with one or more denaturing agents. One such denaturing agents may be Denatonium Benzoate.
  • thickening agent is any agent which is capable of increasing the viscosity of a cosmetic composition such as for example a sunscreen composition.
  • the thickening agent may preferably be cosmetologically approved.
  • polysaccharide is any saccharide or derivative thereof that comprises several monosaccharide units, such as more than 2 monosaccharide units, more than 5 monosaccharide units, preferably more than 10 monosaccharide units.
  • a “polysaccharide thickening agent” is any thickening agent based on a polysaccharide or derivative thereof.
  • a “solution” according to the present invention consists of a solvent and a range of ingredients which are all entirely dissolved in said solvent.
  • a solution does not comprise any solid dispersed material, i.e. it is not a dispersion.
  • a solution does not comprise other liquid immiscible components which may or may not form vesicles that are dispersed in said solution, i.e. the solution is not an emulsion.
  • an “anhydrous” composition means a composition which is essentially free of water. Essentially free of water entails that no water is added to a composition, however minor amounts of water may be present since other components added to the composition may comprise small amount of water.
  • anhydrous composition means a composition entirely free of water.
  • MED minimal erythema dose
  • Sun protection factor refers to the UV energy required to produce an MED on protected skin divided by the UV energy required to produce an MED on unprotected skin.
  • the "sun protection factor” term may also be defined as the ratio of the minimum erythemal dose on protected skin (MEDp) to the minimum erythemal dose on unprotected skin (MED U ) :
  • the Sun Protection Factor value on an individual subject (SPFi), for any product or composition, either before or after water immersion, may be determined as the ratio of the minimum erythemal dose on protected skin (MED P ) to the minimum erythemal dose on unprotected skin (MED U ) of the same subject.
  • SPF S static sun protection factor
  • SPFw wet sun protection factor
  • the static and wet SPF values are determined according to the current published International Sun Protection Factor (SPF) Test Method (I-SPF-TM) as defined in 2006 by COLIPA (CTFA SA - JCIA - CFTA US) as well as international standard ISO 24444: 2010(E).
  • SPF International Sun Protection Factor
  • I-SPF-TM International Sun Protection Factor Test Method
  • a first aspect of the present invention is a sunscreen composition
  • a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, at least one solvent, and at least one thickening agent, wherein said thickening agent is present in an amount in the range of 0.01-0.2%(w/w).
  • the sunscreen composition may preferably be a sprayable sunscreen composition.
  • sprayable or “sprayable sunscreen composition” relates to a composition which is capable of being formulated and dispensed as a spray.
  • a further preferred quality to a sprayable composition is that said composition when dispensed using a spray dispenser, preferably a spray dispenser not comprising a propellant, is dispensed in a way which allows sufficient and even distribution of the composition onto the skin.
  • a sprayable sunscreen composition should preferably have a viscosity which allows it to form an aerosol upon dispensing it as a spray, and it should preferably be dispensable in a volume which allows for sufficient coverage of the skin.
  • the present sunscreen composition is formulated as a spray.
  • the viscosity of said sunscreen composition may be below 120 cP at 25 °C, such as below 110 cP at 25 °C, 100 cP at 25 °C, 80 cP at 25 °C, 60 cP at 25 °C, 40 cP at 25 °C, 20 cP at 25 °C, 15 cP at 25 °C, such as below 10 cP at 25 °C.
  • the sunscreen composition may thus have a viscosity in the range of 1-120 cP at 25 °C, such as in the range of 1-110 cP at 25 °C, 1-100 cP at 25 °C, 1-80 cP at 25 °C, 1-60 cP at 25 °C, 1-40 cP at 25 °C, 1-30 cP at 25 °C, 1-20 cP at 25 °C, 1-15 cP at 25 °C, 1-14 cP at 25 °C, 2-13 cP at 25 °C, 3-12 cP at 25 °C, preferably in the range of 4-10 cP at 25 °C.
  • the viscosity may preferable be the viscosity as measured at 25 °C and 60 rpm on a Brookfield LVDV II+P viscometer.
  • the thickening agent which provides the surprising effect in terms of increased SPF values in comparison to similar or equal composition with no thickening agent or less thickening agent may preferably be a polysaccharide thickening agent.
  • the polysaccharide thickening agent may preferably be a cellulosic material or cellulose derivative.
  • the polysaccharide thickening agent is selected from the group consisting of cellulose, carboxymethyl hydroxyethylcellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulphate, hydroxyethylcellulose,
  • hydroxypropylcellulose and any mixtures thereof. Even more preferred thickening agents are hydroxyethylcellulose or hydroxypropylcellulose, and the most preferred thickening agent is
  • the thickening agent may surprisingly boost the SPF of the composition of the present invention even when present in relatively small amounts. Also, the inventors must consider that the viscosity of the composition must not become too high, particularly for preferred embodiments wherein the composition is formulated as a spray.
  • the thickening agent is preferably present in an amount in the range of 0.01-0.15%(w/w), such as 0.01- 0.10%(w/w), 0.01-0.09%(w/w), 0.01-0.08%(w/w), 0.01-0.07%(w/w), 0.01- 0.06%(w/w), 0.01-0.05%(w/w), 0.01-0.04%(w/w), 0.01-0.03%(w/w), 0.02- 0.15%(w/w), 0.02-0.10%(w/w), 0.02-0.09%(w/w), 0.02-0.08%(w/w), 0.02- 0.07%(w/w), 0.02-0.06%(w/w), 0.02-0.05%(w/w), 0.02-0.04%(w/w), 0.02- 0.03%(w/w), such as in the range of 0.025-0.035%(w/w).
  • water does not need to be added to the present sunscreen composition, since solvation of the added components and the desired properties of the composition, such as stability, viscosity and clarity is achieved without adding water.
  • said sunscreen composition comprises water in an amount of 0-2%(w/w), such as 0-l%(w/w), such as 0- 0.8%(w/w), 0-0.6%(w/w), 0-0.4%(w/w), 0-0.2%(w/w), 0-0.1%(w/w), 0- 0.05%(w/w), such as 0-0.01%(w/w).
  • the composition is essentially anhydrous and most preferably the composition is anhydrous.
  • the solvent of the present invention may preferably be an alcohol.
  • Said alcohol may be a mono alcohol having 2-8 carbon atoms, such as 2-4 carbon atoms.
  • the alcohol is selected from the group consisting of ethanol, 1- propanol, 2-propanol, ethyleneglycol, 1-butanol, 2-butanol or any combination thereof. Ethanol is particularly preferred.
  • the alcohol may comprise a denaturant, particularly when the alcohol is ethanol.
  • the solvent content may preferably be in the range of 10-90%(w/w), such as in the range of 15-85%(w/w), 20-80%(w/w), 30-70%(w/w), 35-65%(w/w), 40-60%(w/w), such as in the range of 40- 55%(w/w).
  • the sunscreen composition according to the present invention is a solution.
  • the components of the present compositions are preferably dissolved entirely in the solvent without forming for example emulsions or milks, and even more preferably the sunscreen composition does not comprise emulsifiers.
  • the sunscreen composition comprises one or more sunscreen agents, which provide the adsorption or blocking of the UV radiation, before it reaches the skin.
  • the sunscreen agent may be selected from the group consisting of Avobenzone, Cinoxate, Dioxybenzone, Homosalate, Menthyl anthranilate, Octocrylene, Octyl methoxycinnamate, Octyl salicylate, Oxybenzone, Padimate O,
  • Phenylbenzimidazole sulfonic acid Sulisobenzone, Titanium dioxide, Trolamine salicylate, Zinc oxide, Benzophenone-3 , Ethylhexyl Methoxycinnamate,
  • dibenzimidazole tetrasulfonate bis-ethylhexyloxyphenol methoxyphenol triazine
  • methylene bisbenzotriazolyl tetramethylbutylphenol bisethylhexyloxyphenol methoxyphenyl triazine and any combination thereof.
  • the sunscreen agent is selected from the group consisting of Homosalate, Octocrylene, Ethylhexyl Methoxycinnamate, Butyl Methoxydibenzoylmethane (BMBM), Diethylamino Hydroxybenzoyl Hexyl
  • Benzoate diethylhexyl butamido triazone or any combination thereof. Even more preferred is a composition comprising Homosalate, Octocrylene, Ethylhexyl Methoxycinnamate, Butyl Methoxydibenzoylmethane (BMBM), Diethylamino Hydroxybenzoyl Hexyl Benzoate and diethylhexyl butamido triazone.
  • BMBM Butyl Methoxydibenzoylmethane
  • the amount of each individual sunscreen agent used in a given sunscreen composition is determined by the desired SPF value and regulatory limitations for the percentage (w/w) of sunscreen agent allowed in sunscreen compositions for a given jurisdiction. To achieve broad range UV protection it may advantageous to add both UVA, UVB and broad range UV filters. Finally, if the desired SPF is not achieved with a given set of sunscreen agents, further amounts of a different sunscreen agent may be added or preferably the SPF may be boosted by other means, such as described herein. Therefore, in preferred embodiments
  • Diethylamino Hydroxybenzoyl Hexyl Benzoate is used in concentrations of at the most 10 %(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 2- 10%(w/w), e.g. in the range 3-10%(w/w), such as in the range of 4-10%(w/w), and/or Ethylhexyl Methoxycinnamate is used in concentrations of at the most 2%(w/w), e.g. in the range of 0.01-2%(w/w), such as in the range of 0.01- l%(w/w), e.g.
  • Octocrylene is used in concentrations of at the most 10%(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 0.5-8%(w/w), e.g. in the range l-6%(w/w), such as in the range of 3-5%(w/w), e.g. in the range 6-10%(w/w), such as in the range of 8- 10%(w/w) and/or Butyl Methoxydibenzoylmethane (BMBM) is used in concentrations of at the most 10%(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 0.5-8%(w/w), e.g. in the range l-6%(w/w), such as in the range of 3-5%(w/w), e.g. in the range 6-10%(w/w), such as in the range of 8- 10%(w/w) and/or Butyl Methoxydi
  • concentrations of at the most 5%(w/w), such as in the range of 0.5-5%(w/w), e.g. in the range 3-5%(w/w), such as in the range of 4-5%(w/w) and/or homosalate is used in concentrations of at the most 10%(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 0.5-8%(w/w), e.g.
  • the sunscreen composition may comprise several sunscreen agents to achieve the desired SPF value.
  • the composition comprises at least 2 sunscreen agents, such as 3 sunscreen agents, e.g.4 sunscreen agents, such as 5 sunscreen agents, e.g. 6 sunscreen agents, such as 7 sunscreen agents.
  • the composition may comprise 2-7 sunscreen agents, such as 3-7, 4-7, 5-7, such as preferably 6-7 sunscreen agents.
  • the present composition does not comprise ethylhexyl salicylate and/or butyloctyl salicylate.
  • the present sunscreen composition comprises a film forming polymer, which provides for better water resistance of the composition.
  • the film forming polymer is selected from the group consisting of polyvinylpyrrolidone (PVP), acrylates, acrylamides, and any copolymers thereof or any combination thereof.
  • the film forming polymer may preferably be selected from the group consisting of acrylate/octylacrylamide copolymer, acrylates copolymer, acrylates/Ci 2 - 2 2 alkyl methacrylate copolymer, butylated PVP),
  • the film forming polymer is acrylate/octylacrylamide copolymer.
  • the film forming polymer may preferably be added in an amount in the range of 0.1-10%(w/w), such as in the range of 0.2-8%(w/w), e.g. in the range of 0.3-6%(w/w), such as in the range of 0.3-5%(w/w), e.g. in the range of 0.4-3%(w/w), such as in the range of 0.4-2%, e.g.
  • Silicone derivatives are used as emollients in for example sunscreen compositions and they also provide for improved skin feel. Since silicone derivatives may become subject of regulatory limitations "silicone alternatives" are also available, which provide similar effects to silicone derivatives but are mostly non-silicone compounds or compound mixtures derived from natural sources.
  • the composition further comprises a siloxane or a silane or silicone alternative, such as a siloxane or a silane or silicone alternative selected from the group consisting of Ci 3 -i 6 isoparaffin, Ci 2 -i 4 isoparaffin, Ci 3 _i 5 Alkane, Isodecane and Hydrogenated Polydecene and Bis-Behenyl/Isostearyl/Phytostearyl Dimer Dilinoleyl/Dimer Dilinoleate, Silyburn Marianum Ethyl Ester, Cs is lkyl Ester, cyclic dimethyl polysiloxane or cyclopentasiloxane.
  • a siloxane or a silane or silicone alternative selected from the group consisting of Ci 3 -i 6 isoparaffin, Ci 2 -i 4 isoparaffin, Ci 3 _i 5 Alkane, Isodecane and Hydrogenated Polydecene and Bis-Behenyl/Iso
  • the siloxane or a silane or silicone alternative may be present in an amount in the range of 0.1- 20%(w/w), such as in the range of 0.5-15%(w/w), e.g. in the range of 1- 10%(w/w), such as in the range of 2-7%(w/w), e.g. in the range of 2-5%(w/w), such as in the range of 2-4%(w/w), e.g. in the range of 2-3%(w/w).
  • the present sunscreen composition may advantageously comprise an alkoxylated alcohol, which may serve as an emollient and/or co-solvent.
  • the alkoxylated alcohol may preferably a long chain C 11 -C15 aliphatic alkoxylated alcohol and may be selected from the group consisting of PPG-11 stearyl ether, PPG-15 Stearyl ether, or any combination thereof.
  • the alkoxylated alcohol may be added in an amount in the range of 0.1-20%(w/w), such as in the range of 0.5-15%(w/w), e.g. in the range of l-10%(w/w), such as in the range of 2-7%(w/w), e.g. in the range of 5-7%(w/w).
  • the present composition may further comprise an ester, which may serve as an emollient and/or co-solvent.
  • the ester may preferably be selected from the group consisting of Ethylhexyl Benzoate, Dibutyl Adipate, Neopentyl Glycol
  • the ester may be present in an amount in the range of l-30%(w/w), such as in the range of 5-25%(w/w), 7-22%(w/w), 8-20%(w/w), preferably in the range of 9- 17%(w/w).
  • the ability of a sunscreen composition to be water resistant is highly desirable as explained above.
  • the sunscreen composition having a static sun protection factor after the composition has been applied to the skin of a human is at least 60% of the static sun protection factor, such as at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, such as at least 115% after the composition has been contacted with water, particularly after the composition has been immersed in water in vivo for 80 minutes.
  • the composition having a static sun protection factor after the composition has been applied to the skin of a human the sun protection factor of the composition is capable of being increased to a higher wet sun protection factor when the composition is contacted with water.
  • a preferred sunscreen composition is a composition wherein the wet sun protection factor is increased by at least 5% relative to the static sun protection factor, such as increased by at least 10% relative to the static sun protection factor, e.g.
  • the water resistance of a sunscreen composition may be measured according to internationally or regionally approved standards such as for example the
  • a sunscreen having a particularly high water resistance according to the regional or international standard may be designated by a "very water resistance” (VWR) value.
  • Very Water Resistance is measured in vivo after a test subject has been immersed in water for a total of 80 minutes i.e. 4 times 20 minutes with 15 min drying time in between.
  • the present invention is a composition wherein the Very Water Resistance value of said composition is above 50, such as above 60, above 70, above 80, such as above 85, above 90, above 95, above 100, above 105, above 110, such as above 115.
  • One purpose of the present invention is to provide a sunscreen composition with a boosted SPF value in the sense that the SPF value achieved is not achieved by the addition of further sunscreen agents alone, but also by the addition of a
  • the present invention relates to a composition wherein said composition comprises no more than 5 sunscreen agents and wherein the sun protection factor is at least 15, such as at least 16, at least 17, at least 18 , at least 19, such at least 20.
  • a composition is preferred wherein said composition comprises no more than 6 sunscreen agents and wherein the sun protection factor is at least 30, such as at least 32, at least 34, at least 36, at least 38, at least 40, at least 42, at least 44, at least 46, at least 48, such as at least 50.
  • composition that comprises no more than 5 sunscreen agents and wherein the sun protection factor is at least 30, such as at least 32, at least 34, at least 36, at least 38, at least 40, at least 42, at least 44, at least 46, at least 48, such as at least 50.
  • a preferred embodiment is a sunscreen composition wherein the sun protection factor is increased by at least 5 SPF units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to a composition comprising the same overall weight percentage in %(w/w) of sunscreen agents and no thickening agent.
  • An even more preferred embodiment is a composition wherein the sun protection factor is increased by at least 5 SPF units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to an essentially identical composition not comprising a thickening agent.
  • the essentially identical composition not comprising thickening agent is the identical composition, wherein the thickening agent has been replaced by solvent.
  • UVA protection may either be expressed via the so-called COLIPA ratio or via the Boots star rating system, the guidelines for both of these rating systems being described in the below examples.
  • the present sunscreen compositions may preferably have a COLIPA ratio below 3, such as below 2, below 1.5, such as below 1.2, preferably below 1.1.
  • the present sunscreen composition has a boots star rating of at least 4 stars, such as preferably at least 5 stars.
  • a preferred embodiment of the present invention is a sunscreen composition wherein the SPF value of said composition 10 hours after application in vivo is at least 60%, such as at least 65%, at least 70%, at least 75%, such as at least 78% of the SPF value of said sunscreen composition 15 minutes after application in vivo.
  • SPF value is the static SPF value.
  • a second aspect of the present invention is the use of a thickening agent for increasing the sun protection factor of a sunscreen composition
  • a thickening agent for increasing the sun protection factor of a sunscreen composition
  • said thickening agent is present in an amount in the range of 0.01-0.2%(w/w).
  • the thickening agent is a polysaccharide thickening agent, such as a cellulosic material or cellulose derivative. Even more preferably said
  • polysaccharide thickening agent is selected from the group consisting of cellulose, carboxymethyl hydroxyethylcellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulphate, hydroxyethylcellulose, hydroxypropylcellulose, and mixtures thereof.
  • the thickening agent may preferably be hydroxyethylcellulose or
  • hydroxypropylcellulose such as preferably hydroxypropylcellulose.
  • a preferred embodiment is the use of a thickening agent for increasing the sun protection factor of a sunscreen composition wherein the sun protection factor is increased by at least 5 SPF units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to a composition comprising the same overall weight percentage %(w/w) of sunscreen agents and no thickening agent.
  • Another preferred use is a use wherein the sun protection factor is increased by at least 5 SPF units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to an essentially identical composition not comprising a thickening agent.
  • the essentially identical composition not comprising thickening agent may be the identical composition, wherein the thickening agent has been replaced by solvent.
  • a thickening agent described for the present invention is applied to a sunscreen composition which is sprayable.
  • the sunscreen composition is sprayable and anhydrous. It may preferably be formulated as a spray, and also it may preferable have a viscosity as described in the previous section.
  • a third aspect of the present invention is a process for the manufacture of a sunscreen composition comprising the steps of
  • step ii) admixing the components of step i) to provide a sunscreen
  • the mixture or composition is not heated during the process and the temperature is in the range of 0-60 °C, such as in the range of 5-55 °C, 15-50 °C, 20-50 °C, 30-45 °C, such as about 40 °C.
  • no water is added to the composition during said process, and even more preferably the components provided in step i) are admixed in the order provided in step i). Further additives as described herein may be added in step i). Each component added is dissolved under stirring before the next component is added. Stirring time may vary from 1- 25 minutes.
  • Example 1 Sunscreen compositions and manufacture thereof
  • Sunscreen compositions were prepared according to the tables shown below for compositions A1/A2 and B1/B2.
  • the B1/B2 compositions are comparable but comprise higher amounts of sunscreen agents than the A1/A2 compositions (also comparable) to achieve higher SPF values.
  • the amount of thickening agent is varied in Al vs A2 and Bl vs B2 to elucidate the effect of said thickening agent.
  • Table 1 Sunscreen composition Al (0.01 %(w/w) thickening agent)
  • Steps Ingredients Amount w/w %
  • Composition A2 has several alterations as compared to Al, but comprises the same overall amount %(w/w) of sunscreen agents as Al.
  • Mainly A2 comprises more thickening agent than Al.
  • Steps Ingredients Amount w/w %
  • Composition B2 is equal to Bl except for the replacement of 0.03 %(w/w) solvent with the thickening agent in B2.
  • compositions were manufactured by addition of the listed components in the order they are listed under stirring using a Silverson L4RT high shear mixer.
  • the present example demonstrates that the addition of a thickening agent enhances the SPF value of the present sunscreen compositions.
  • the test is based on the International-Sun Protection Factor-Test Method (SPF) as defined in 2006 by COLIPA - CTFA SA - JCIA- CTFA US, as well as on the international standard ISO 24444, Cosmetics - Sun protection test methods - in vivo determination of the sun protection factor (SPF), ISO 24444: 2010 (E); First edition 2010-11-15.
  • SPF International-Sun Protection Factor-Test Method
  • the minimum degree of protection provided by a sunscreen product is an SPF of 6.
  • SPF values and SPF label values in the present examples are to be understood within the framework of the European recommendations and the SPF values are determined and/or calculated as described in the detailed description.
  • 2 mg/cm 2 sunscreen composition is applied to test subjects a provided by the guidelines.
  • Sunscreen compositions A1/A2 and B1/B2 were prepared according to exam 1 and subjected to in vivo SPF determination as prescribed by the above mentioned guidelines. The tests were performed by Institute Dr. Schrader
  • the wet SPF as measured in vivo is the SPF value measured after application of sunscreen and subsequent immersion of the test 20 individual in water for 80 minutes.
  • the immersion in water for 80 minutes is
  • compositions A 2 and B2 are compositions A 2 and B2
  • Example 5 UVA protection and Boots star rating of Sunscreen compositions
  • the protection against UVA radiation may be determined by the COLIPA ratio as defined in the COLIPA guideline (in vitro method for the determination of the UVA protection factor and "critical wavelength" values of sunscreen products".
  • COLIPA Ratio SPFiabei/UVA-PF where UVA-PF is the actual "SPF" obtained for UVA irradiation measured in vitro according to the guidelines.
  • the present compositions A2 and B2 were tested and displayed a COLIPA ratio of 0.9 and 1.0 respectively, which fulfils the recommendation from COLIPA which is a ratio below 3.
  • UVA protection was also determined by the Boots star rating system
  • the viscosity of the present sunscreen compositions must be within certain limits for the compositions to remain sprayable.
  • the viscosity of composition B2 was investigated along with compositions having less and more thickening agent (solvent amounts being adjusted accordingly). The viscosities were measured at 25 °C at 60 rpm using a Brookfield LVDV-II + P viscometer with a small sample adapter and Spindle S18.
  • HPC hydroxypropylcellulose
  • sunscreen products and the claims made relating thereto (notified under document number C(2006) 4089) (Text with EEA relevance) (2006/647/EC); Official Journal of the European Union, L 265/3

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Abstract

One aspect of the invention relates to a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, at least one solvent, and at least one thickening agent, wherein said thickening agent is present in an amount in the range of 0.01-0.2%(w/w). Another aspect of the present invention relates to the use of a thickening agent for increasing the sun protection factor of a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, and at least one solvent. Yet another aspect of the present invention relates to a process for the manufacture of a sunscreen composition comprising the steps of i) providing at least one solvent, at least one thickening agent, at least one film forming polymer and at least one sunscreen agent, ii) admixing the components of step i) to provide a sunscreen composition.

Description

Improved sunscreen composition
Technical field of the invention
The present invention relates to sunscreen compositions. In particular the present invention relates to sunscreen compositions comprising a small amount of thickening agent for the purpose of boosting the sun protection factor of the composition. The use of thickening agents to enhance the sun protection factor of a sunscreen composition is also described, as well as a method for manufacturing such sunscreen compositions.
Background of the invention
It is a well-established fact that UV irradiation causes skin burns, loss of skin elasticity and the appearance of wrinkles, promoting premature skin aging. In addition, UV irradiation promotes the triggering of the erythemal reaction or accentuates this reaction in certain individuals and may even be the source of phototoxic or photoallergy reactions. Last, but not least important, UV irradiation has carcinogenic effects. For these reasons, continuous need exists for means for protecting the skin against the harmful effects of UV irradiation. Numerous requirements exist for dermatological compositions for photo- protection of the human skin : Compositions are preferred which have a pleasant feel and are formulated as non-greasy sprays, milks and creams that are easily applied. It is further preferred that the compositions exhibit non-adherence to sand, as users of these compositions are often in contact with sand at beaches and play areas.
In addition to being convenient for the user the compositions must contain adequate solvent to hold the necessary amount of UV-filter. Need continues to exist for compositions which simultaneously have a low or zero content of preservatives, while exhibiting an optimum stability which is maintained throughout the time of storage and ultimate use of the products. Finally, in instances where a particularly high and lasting protection is desired, as for children's skin or for sensitive skin, it is also preferable to employ compositions which exhibit good water resistance and which thus retain a very good photo protective power even after coming into contact with water. For example WO 2009/016537 describes sunscreen formulations comprising dimethicone derivatives, wherein from about 75% to about 100% of an SPF rating of the composition is retained after immersion into water for 80 minutes. Corresponding formulation without dimethicone derivatives perform poorly with respect to water resistance.
Many photoprotective, dermatological compositions are oil-in-water emulsions. However, one of the disadvantages of traditional oil-in-water emulsions is that they very easily lose their effectiveness with respect to UV protection as soon as they come into contact with water; this because the screening agents which they contain in their aqueous phase are removed by the water, during bathing in the sea or in swimming pools, for example, or, alternatively, under the shower or when playing water sports, and the overall photo-protective power of these compositions thus is greatly reduced. Thus, sunscreen compositions which are solvent solutions with a low water content rather than oil-in-water emulsions would be advantageous. Finally, it is also desirable to achieve a high Sun Protection Factor (SPF) while using relatively small amounts of sunscreen agents in the composition. Sunscreen agents are expensive additives and there are consumer trends towards deselecting certain UV-filters. One way of improving the SPF of a sunscreen composition without adding further sunscreen agents, is to employ SPF booster's, which are normally compounds or additives which do not adsorb UV radiation, but still improves the SPF in various other ways. For example, WO 2004/110366 discloses photoprotective
compositions comprising optimizing agents selected from the group consisting of diols, alcohol, glycol and polyhydric alcohol or derivatives thereof. The optimizing agents boost the SPF of the compositions by several SPF units. Also, WO
2011/100275 describes a method of boosting the SPF of a sunscreen composition comprising an acidic film former by the addition of amine neutralizing agent. Improved or alternative sunscreen compositions which have improved SPF ratings would be advantageous, and in particular providing sunscreen compositions which have an improved SPF rating and simultaneously maintain a high water resistance, are non-greasy and easily applicable would be advantageous.
Summary of the invention
Thus, an object of the present invention relates to the provision of improved or alternative sunscreen compositions. In particular, it is an object of the present invention to provide a sunscreen composition that solves the above mentioned problems of providing sunscreen compositions which are safe, have an improved SPF rating and simultaneously maintain a high water resistance. Thus, the present inventors surprisingly found that the addition of a small amount of thickening agent, such as for example a polysaccharide thickening agent increases the sun protection factor of the sunscreen composition of the present invention by several units, thereby reducing the needed amount of sunscreen agents to achieve a given sun protection factor.
Thus, one aspect of the invention relates to a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, at least one solvent, and at least one thickening agent, wherein said thickening agent is present in an amount in the range of 0.01-0.2%(w/w).
Another aspect of the present invention relates to the use of a thickening agent for increasing the sun protection factor of a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, and at least one solvent.
Yet another aspect of the present invention relates to a process for the
manufacture of a sunscreen composition comprising the steps of
i) providing at least one solvent, at least one thickening agent, at least one film forming polymer and at least one sunscreen agent,
ii) admixing the components of step i) to provide a sunscreen
composition. The present invention will now be described in more detail in the following.
Detailed description of the invention
Definitions
Prior to discussing the present invention in further details, the following terms and conventions will first be defined :
In the present context "sunscreen composition" or photoprotective composition is to be understood as a liquid composition comprising agents that reduces the amount of UV radiation being absorbed by the skin, when said sunscreen composition is applied to the skin. A sunscreen composition may either absorb or block the UV rays. UV radiation may include UVA and UVB radiation. Sunscreen compositions may be formulated as solutions, emulsions, milks or oils, and may be applied to the skin by the means of sprays, creams, or lotions.
In the context of the present invention "sunscreen agent" is any cosmetologically approved agent capable of adsorbing or blocking UV radiation, such as UVA and/or UVB radiation. Sunscreen agents that absorb UV radiation are also referred to as UV filters, UVA, UVB or broad spectrum filters. Such sunscreen agents are often organic compounds or molecules, which absorb light in the UV region, the UV region being at wavelengths from 290 to 400 nanometers. Sunscreen agents that block the UV rays may include substances that leave a white coating on the skin, such as certain metal oxides including for example titanium oxide or other white substances.
In the present context "film forming polymer", also sometimes referred to as a "waterproofing agent", is a polymer capable of forming a film on e.g. skin as the carrier or solvent that it is dissolved in evaporates. A film forming polymer may be a uniform homo-polymer or a co-polymer, such as for example a block-copolymer. The polymer may preferably be cosmetologically approved. In the present context the term "co-polymer" relates to a polymer formed when two (or more) different types of monomer are linked in the same polymer chain, as opposed to a homo- polymer where only one monomer is used. Herein "solvent", also sometimes referred to as a carrier, is any liquid capable of dissolving the components of the sunscreen composition. A solvent may be a mixture of different solvents or it may be a single solvent. The solvent should be suitable for use in cosmetics and may preferably be cosmetologically approved.
In relation to the present invention the term "alcohol" refers to an organic compound in which a hydroxyl group (-OH) is attached to a saturated carbon atom. Alcohols have the general formula ROH, where R may be a lower-aliphatic or cyclic carbon chain and may include aromatic rings. Alcohols are further classified as primary, secondary or tertiary, according to the position of the hydroxyl group on the lower-aliphatic carbon chain. Alcohols may also be classified by the number of hydroxyl groups present in the molecule; for example, a compound with two hydroxyl groups (a diol), and with three hydroxyl groups (a triol). The alcohol may comprise a denaturant. In the present context the term "Alcohol Denaturant" relates to ethyl alcohol that is denatured with one or more denaturing agents. One such denaturing agents may be Denatonium Benzoate.
Herein "thickening agent" is any agent which is capable of increasing the viscosity of a cosmetic composition such as for example a sunscreen composition. The thickening agent may preferably be cosmetologically approved.
Herein "polysaccharide" is any saccharide or derivative thereof that comprises several monosaccharide units, such as more than 2 monosaccharide units, more than 5 monosaccharide units, preferably more than 10 monosaccharide units. Hence, a "polysaccharide thickening agent" is any thickening agent based on a polysaccharide or derivative thereof.
A "solution" according to the present invention consists of a solvent and a range of ingredients which are all entirely dissolved in said solvent. Thus, a solution does not comprise any solid dispersed material, i.e. it is not a dispersion. Also a solution does not comprise other liquid immiscible components which may or may not form vesicles that are dispersed in said solution, i.e. the solution is not an emulsion. In the present context an "anhydrous" composition means a composition which is essentially free of water. Essentially free of water entails that no water is added to a composition, however minor amounts of water may be present since other components added to the composition may comprise small amount of water. Preferably, anhydrous composition means a composition entirely free of water.
In the present context the term "minimal erythema dose (MED)" refers to the quantity of erythema-effective energy (expressed as Joules per square meter or milli joules per square centimeter) required to produce the first perceptible, redness reaction in the skin with clearly defined borders.
Guidelines for labelling of Sun Protection Factor (SPF) and product categories are suggested by COLIPA (The European Cosmetic Toiletry and perfumery
Association) in Europe. These are as listed in the table below:
Figure imgf000007_0002
In the present context the term "Sun protection factor" (SPF) refers to the UV energy required to produce an MED on protected skin divided by the UV energy required to produce an MED on unprotected skin. The "sun protection factor" term may also be defined as the ratio of the minimum erythemal dose on protected skin (MEDp) to the minimum erythemal dose on unprotected skin (MEDU) :
Figure imgf000007_0001
The Sun Protection Factor value on an individual subject (SPFi), for any product or composition, either before or after water immersion, may be determined as the ratio of the minimum erythemal dose on protected skin (MEDP) to the minimum erythemal dose on unprotected skin (MEDU) of the same subject.
Further, the term "static sun protection factor", (SPFS), relates to the sun protection factor before water immersion, while the term "wet sun protection factor" (SPFw) refers to the sun protection factor after water immersion.
The static and wet SPF values are determined according to the current published International Sun Protection Factor (SPF) Test Method (I-SPF-TM) as defined in 2006 by COLIPA (CTFA SA - JCIA - CFTA US) as well as international standard ISO 24444: 2010(E).
Sunscreen composition
A first aspect of the present invention is a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, at least one solvent, and at least one thickening agent, wherein said thickening agent is present in an amount in the range of 0.01-0.2%(w/w).
The sunscreen composition may preferably be a sprayable sunscreen composition. Herein "sprayable" or "sprayable sunscreen composition" relates to a composition which is capable of being formulated and dispensed as a spray. In the context of sunscreen compositions a further preferred quality to a sprayable composition is that said composition when dispensed using a spray dispenser, preferably a spray dispenser not comprising a propellant, is dispensed in a way which allows sufficient and even distribution of the composition onto the skin. In this respect a sprayable sunscreen composition should preferably have a viscosity which allows it to form an aerosol upon dispensing it as a spray, and it should preferably be dispensable in a volume which allows for sufficient coverage of the skin.
Preferably the present sunscreen composition is formulated as a spray.
In order to enhance the sunscreen compositions performance as a sprayable sunscreen composition the viscosity of said sunscreen composition may be below 120 cP at 25 °C, such as below 110 cP at 25 °C, 100 cP at 25 °C, 80 cP at 25 °C, 60 cP at 25 °C, 40 cP at 25 °C, 20 cP at 25 °C, 15 cP at 25 °C, such as below 10 cP at 25 °C. The sunscreen composition may thus have a viscosity in the range of 1-120 cP at 25 °C, such as in the range of 1-110 cP at 25 °C, 1-100 cP at 25 °C, 1-80 cP at 25 °C, 1-60 cP at 25 °C, 1-40 cP at 25 °C, 1-30 cP at 25 °C, 1-20 cP at 25 °C, 1-15 cP at 25 °C, 1-14 cP at 25 °C, 2-13 cP at 25 °C, 3-12 cP at 25 °C, preferably in the range of 4-10 cP at 25 °C. The viscosity may preferable be the viscosity as measured at 25 °C and 60 rpm on a Brookfield LVDV II+P viscometer.
The thickening agent which provides the surprising effect in terms of increased SPF values in comparison to similar or equal composition with no thickening agent or less thickening agent may preferably be a polysaccharide thickening agent. The polysaccharide thickening agent may preferably be a cellulosic material or cellulose derivative. Preferably the polysaccharide thickening agent is selected from the group consisting of cellulose, carboxymethyl hydroxyethylcellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulphate, hydroxyethylcellulose,
hydroxypropylcellulose, and any mixtures thereof. Even more preferred thickening agents are hydroxyethylcellulose or hydroxypropylcellulose, and the most preferred thickening agent is
hydroxypropylcellulose. The thickening agent may surprisingly boost the SPF of the composition of the present invention even when present in relatively small amounts. Also, the inventors must consider that the viscosity of the composition must not become too high, particularly for preferred embodiments wherein the composition is formulated as a spray. Achieving the correct balance between viscosity and SPF boosting effect may therefore be important and thus the thickening agent is preferably present in an amount in the range of 0.01-0.15%(w/w), such as 0.01- 0.10%(w/w), 0.01-0.09%(w/w), 0.01-0.08%(w/w), 0.01-0.07%(w/w), 0.01- 0.06%(w/w), 0.01-0.05%(w/w), 0.01-0.04%(w/w), 0.01-0.03%(w/w), 0.02- 0.15%(w/w), 0.02-0.10%(w/w), 0.02-0.09%(w/w), 0.02-0.08%(w/w), 0.02- 0.07%(w/w), 0.02-0.06%(w/w), 0.02-0.05%(w/w), 0.02-0.04%(w/w), 0.02- 0.03%(w/w), such as in the range of 0.025-0.035%(w/w). Even more preferred is a composition where the thickening agent is present in an amount of about 0.03%(w/w). Unexpectedly, water does not need to be added to the present sunscreen composition, since solvation of the added components and the desired properties of the composition, such as stability, viscosity and clarity is achieved without adding water. Thus in as preferred embodiment said sunscreen composition comprises water in an amount of 0-2%(w/w), such as 0-l%(w/w), such as 0- 0.8%(w/w), 0-0.6%(w/w), 0-0.4%(w/w), 0-0.2%(w/w), 0-0.1%(w/w), 0- 0.05%(w/w), such as 0-0.01%(w/w). In an even more preferred embodiment the composition is essentially anhydrous and most preferably the composition is anhydrous.
The solvent of the present invention may preferably be an alcohol. Said alcohol may be a mono alcohol having 2-8 carbon atoms, such as 2-4 carbon atoms. Preferably the alcohol is selected from the group consisting of ethanol, 1- propanol, 2-propanol, ethyleneglycol, 1-butanol, 2-butanol or any combination thereof. Ethanol is particularly preferred. The alcohol may comprise a denaturant, particularly when the alcohol is ethanol. The solvent content may preferably be in the range of 10-90%(w/w), such as in the range of 15-85%(w/w), 20-80%(w/w), 30-70%(w/w), 35-65%(w/w), 40-60%(w/w), such as in the range of 40- 55%(w/w).
Preferably the sunscreen composition according to the present invention is a solution. Thus the components of the present compositions are preferably dissolved entirely in the solvent without forming for example emulsions or milks, and even more preferably the sunscreen composition does not comprise emulsifiers.
The sunscreen composition comprises one or more sunscreen agents, which provide the adsorption or blocking of the UV radiation, before it reaches the skin. The sunscreen agent may be selected from the group consisting of Avobenzone, Cinoxate, Dioxybenzone, Homosalate, Menthyl anthranilate, Octocrylene, Octyl methoxycinnamate, Octyl salicylate, Oxybenzone, Padimate O,
Phenylbenzimidazole sulfonic acid, Sulisobenzone, Titanium dioxide, Trolamine salicylate, Zinc oxide, Benzophenone-3 , Ethylhexyl Methoxycinnamate,
Octocrylene, Butyl Methoxydibenzoylmethane (BMBM), Diethylamino
hydroxybenzoyl Hexyl Benzoate, Diethylhexyl Butamido Triazone, PABA, camphor benzalkonium methosulfate, phenylbenzimidazole sulfonic acid, terephthalidene dicamphor sulfonic acid, benzylidene camphor sulfonic acid, polyacrylamidomethyl benzylidene camphor, PEG-25 PABA, isoamyl p-methoxycinnamate, ethylhexyl triazone, drometrizole trielloxane, 4-methylbenzylidene camphor, 3-benzylidene camphor, ethylhexyl salicylate, ethylhexyl dimethyl PABA, benzophenone-4, methylene bis-benztriazolyl tetramethylbutylphenol, disodium phenyl
dibenzimidazole tetrasulfonate, bis-ethylhexyloxyphenol methoxyphenol triazine, methylene bisbenzotriazolyl tetramethylbutylphenol, bisethylhexyloxyphenol methoxyphenyl triazine and any combination thereof.
In an even more preferred embodiment the sunscreen agent is selected from the group consisting of Homosalate, Octocrylene, Ethylhexyl Methoxycinnamate, Butyl Methoxydibenzoylmethane (BMBM), Diethylamino Hydroxybenzoyl Hexyl
Benzoate, diethylhexyl butamido triazone or any combination thereof. Even more preferred is a composition comprising Homosalate, Octocrylene, Ethylhexyl Methoxycinnamate, Butyl Methoxydibenzoylmethane (BMBM), Diethylamino Hydroxybenzoyl Hexyl Benzoate and diethylhexyl butamido triazone.
The amount of each individual sunscreen agent used in a given sunscreen composition is determined by the desired SPF value and regulatory limitations for the percentage (w/w) of sunscreen agent allowed in sunscreen compositions for a given jurisdiction. To achieve broad range UV protection it may advantageous to add both UVA, UVB and broad range UV filters. Finally, if the desired SPF is not achieved with a given set of sunscreen agents, further amounts of a different sunscreen agent may be added or preferably the SPF may be boosted by other means, such as described herein. Therefore, in preferred embodiments
Diethylamino Hydroxybenzoyl Hexyl Benzoate is used in concentrations of at the most 10 %(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 2- 10%(w/w), e.g. in the range 3-10%(w/w), such as in the range of 4-10%(w/w), and/or Ethylhexyl Methoxycinnamate is used in concentrations of at the most 2%(w/w), e.g. in the range of 0.01-2%(w/w), such as in the range of 0.01- l%(w/w), e.g. in the range 0.01-0.05%(w/w) and/or Octocrylene is used in concentrations of at the most 10%(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 0.5-8%(w/w), e.g. in the range l-6%(w/w), such as in the range of 3-5%(w/w), e.g. in the range 6-10%(w/w), such as in the range of 8- 10%(w/w) and/or Butyl Methoxydibenzoylmethane (BMBM) is used in
concentrations of at the most 5%(w/w), such as in the range of 0.5-5%(w/w), e.g. in the range 3-5%(w/w), such as in the range of 4-5%(w/w) and/or homosalate is used in concentrations of at the most 10%(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 0.5-8%(w/w), e.g. in the range 6- 10%(w/w), such as in the range of 8-10%(w/w) and/or diethylhexyl butamido triazone is used in concentrations of at the most 5%(w/w), such as in the range of 0.1-5%(w/w), e.g. 0.1-3%(w/w), such as 0.1-l%(w/w). The sunscreen composition may comprise several sunscreen agents to achieve the desired SPF value. Thus in a preferred embodiment the composition comprises at least 2 sunscreen agents, such as 3 sunscreen agents, e.g.4 sunscreen agents, such as 5 sunscreen agents, e.g. 6 sunscreen agents, such as 7 sunscreen agents. The composition may comprise 2-7 sunscreen agents, such as 3-7, 4-7, 5-7, such as preferably 6-7 sunscreen agents.
In a preferred embodiment the present composition does not comprise ethylhexyl salicylate and/or butyloctyl salicylate. The present sunscreen composition comprises a film forming polymer, which provides for better water resistance of the composition. In a preferred
embodiment the film forming polymer is selected from the group consisting of polyvinylpyrrolidone (PVP), acrylates, acrylamides, and any copolymers thereof or any combination thereof. The film forming polymer may preferably be selected from the group consisting of acrylate/octylacrylamide copolymer, acrylates copolymer, acrylates/Ci2-22 alkyl methacrylate copolymer, butylated PVP),
VA/butyl maleate/isobornyl acrylate copolymer vinyl
caprolactam/VP/dimethylaminoethyl methacrylate copolymer, most preferably the film forming polymer is acrylate/octylacrylamide copolymer. The film forming polymer may preferably be added in an amount in the range of 0.1-10%(w/w), such as in the range of 0.2-8%(w/w), e.g. in the range of 0.3-6%(w/w), such as in the range of 0.3-5%(w/w), e.g. in the range of 0.4-3%(w/w), such as in the range of 0.4-2%, e.g. in the range of 0.5-1.5%(w/w), such as in the range of 0.5- 1.2%(w/w), e.g. in the range of 0.6-1.0%(w/w), such as in the range of 0.6- 0.9%(w/w), e.g. in the range of 0.7-0.8%(w/w), such as about 0.75%(w/w). Silicone derivatives are used as emollients in for example sunscreen compositions and they also provide for improved skin feel. Since silicone derivatives may become subject of regulatory limitations "silicone alternatives" are also available, which provide similar effects to silicone derivatives but are mostly non-silicone compounds or compound mixtures derived from natural sources. Thus, in a preferred embodiment the composition further comprises a siloxane or a silane or silicone alternative, such as a siloxane or a silane or silicone alternative selected from the group consisting of Ci3-i6 isoparaffin, Ci2-i4 isoparaffin, Ci3_i5 Alkane, Isodecane and Hydrogenated Polydecene and Bis-Behenyl/Isostearyl/Phytostearyl Dimer Dilinoleyl/Dimer Dilinoleate, Silyburn Marianum Ethyl Ester, Cs is lkyl Ester, cyclic dimethyl polysiloxane or cyclopentasiloxane. The siloxane or a silane or silicone alternative may be present in an amount in the range of 0.1- 20%(w/w), such as in the range of 0.5-15%(w/w), e.g. in the range of 1- 10%(w/w), such as in the range of 2-7%(w/w), e.g. in the range of 2-5%(w/w), such as in the range of 2-4%(w/w), e.g. in the range of 2-3%(w/w).
The present sunscreen composition may advantageously comprise an alkoxylated alcohol, which may serve as an emollient and/or co-solvent. The alkoxylated alcohol may preferably a long chain C11-C15 aliphatic alkoxylated alcohol and may be selected from the group consisting of PPG-11 stearyl ether, PPG-15 Stearyl ether, or any combination thereof. The alkoxylated alcohol may be added in an amount in the range of 0.1-20%(w/w), such as in the range of 0.5-15%(w/w), e.g. in the range of l-10%(w/w), such as in the range of 2-7%(w/w), e.g. in the range of 5-7%(w/w).
The present composition may further comprise an ester, which may serve as an emollient and/or co-solvent. The ester may preferably be selected from the group consisting of Ethylhexyl Benzoate, Dibutyl Adipate, Neopentyl Glycol
Dicaprylate/Dica prate, and Ci2_i5 Alkyl benzoate or any combination thereof. The ester may be present in an amount in the range of l-30%(w/w), such as in the range of 5-25%(w/w), 7-22%(w/w), 8-20%(w/w), preferably in the range of 9- 17%(w/w). The ability of a sunscreen composition to be water resistant is highly desirable as explained above. Thus in a preferred embodiment the sunscreen composition having a static sun protection factor after the composition has been applied to the skin of a human, the wet sun protection factor of the composition is at least 60% of the static sun protection factor, such as at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, such as at least 115% after the composition has been contacted with water, particularly after the composition has been immersed in water in vivo for 80 minutes. In a highly preferred embodiment the composition having a static sun protection factor after the composition has been applied to the skin of a human, the sun protection factor of the composition is capable of being increased to a higher wet sun protection factor when the composition is contacted with water. A preferred sunscreen composition is a composition wherein the wet sun protection factor is increased by at least 5% relative to the static sun protection factor, such as increased by at least 10% relative to the static sun protection factor, e.g.
increased by at least 15% relative to the static sun protection factor, such as increased by at least 20% relative to the static sun protection factor, e.g.
increased by at least 25% relative to the static sun protection factor. Particularly, after the composition has been immersed in water in vivo for 80 minutes.
The water resistance of a sunscreen composition may be measured according to internationally or regionally approved standards such as for example the
Guidelines for Evaluating Sun Product Water Resistance (COLIPA 2005). A sunscreen having a particularly high water resistance according to the regional or international standard may be designated by a "very water resistance" (VWR) value. Very Water Resistance is measured in vivo after a test subject has been immersed in water for a total of 80 minutes i.e. 4 times 20 minutes with 15 min drying time in between. Thus, in a preferred embodiment the present invention is a composition wherein the Very Water Resistance value of said composition is above 50, such as above 60, above 70, above 80, such as above 85, above 90, above 95, above 100, above 105, above 110, such as above 115.
One purpose of the present invention is to provide a sunscreen composition with a boosted SPF value in the sense that the SPF value achieved is not achieved by the addition of further sunscreen agents alone, but also by the addition of a
thickening agent. Therefore in a preferred embodiment the present invention relates to a composition wherein said composition comprises no more than 5 sunscreen agents and wherein the sun protection factor is at least 15, such as at least 16, at least 17, at least 18 , at least 19, such at least 20. Preferably a composition wherein said composition comprises no more than 4 sunscreen agents and wherein the sun protection factor is at least 15, such as at least 16, at least 17, at least 18 , at least 19, such at least 20. Alternatively a composition is preferred wherein said composition comprises no more than 6 sunscreen agents and wherein the sun protection factor is at least 30, such as at least 32, at least 34, at least 36, at least 38, at least 40, at least 42, at least 44, at least 46, at least 48, such as at least 50. Preferably a composition that comprises no more than 5 sunscreen agents and wherein the sun protection factor is at least 30, such as at least 32, at least 34, at least 36, at least 38, at least 40, at least 42, at least 44, at least 46, at least 48, such as at least 50.
The present sunscreen composition has the ability to achieve higher SPF values by the addition of a thickening agent. Therefore, a preferred embodiment is a sunscreen composition wherein the sun protection factor is increased by at least 5 SPF units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to a composition comprising the same overall weight percentage in %(w/w) of sunscreen agents and no thickening agent. An even more preferred embodiment is a composition wherein the sun protection factor is increased by at least 5 SPF units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to an essentially identical composition not comprising a thickening agent. Preferably the essentially identical composition not comprising thickening agent is the identical composition, wherein the thickening agent has been replaced by solvent.
It is desirable to provide a composition which delivers a high protection against the particularly harmful UVA radiation. UVA protection may either be expressed via the so-called COLIPA ratio or via the Boots star rating system, the guidelines for both of these rating systems being described in the below examples. Thus, the present sunscreen compositions may preferably have a COLIPA ratio below 3, such as below 2, below 1.5, such as below 1.2, preferably below 1.1. Preferably the present sunscreen composition has a boots star rating of at least 4 stars, such as preferably at least 5 stars.
The overall stability and particularly the photo-stability of sunscreen compositions must preferably be high in order to provide prolonged protection against UV radiation without the need for excessive and repeated topical administration during exposure to the sun. Therefore, a preferred embodiment of the present invention is a sunscreen composition wherein the SPF value of said composition 10 hours after application in vivo is at least 60%, such as at least 65%, at least 70%, at least 75%, such as at least 78% of the SPF value of said sunscreen composition 15 minutes after application in vivo. Preferably said SPF value is the static SPF value.
Use of thickening agent for increasing SPF
A second aspect of the present invention is the use of a thickening agent for increasing the sun protection factor of a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, and at least one solvent. Preferably said thickening agent is present in an amount in the range of 0.01-0.2%(w/w).
Preferably the thickening agent is a polysaccharide thickening agent, such as a cellulosic material or cellulose derivative. Even more preferably said
polysaccharide thickening agent is selected from the group consisting of cellulose, carboxymethyl hydroxyethylcellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulphate, hydroxyethylcellulose, hydroxypropylcellulose, and mixtures thereof. The thickening agent may preferably be hydroxyethylcellulose or
hydroxypropylcellulose, such as preferably hydroxypropylcellulose.
A preferred embodiment is the use of a thickening agent for increasing the sun protection factor of a sunscreen composition wherein the sun protection factor is increased by at least 5 SPF units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to a composition comprising the same overall weight percentage %(w/w) of sunscreen agents and no thickening agent. Another preferred use is a use wherein the sun protection factor is increased by at least 5 SPF units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to an essentially identical composition not comprising a thickening agent. The essentially identical composition not comprising thickening agent may be the identical composition, wherein the thickening agent has been replaced by solvent.
In a preferred embodiment the use of a thickening agent described for the present invention is applied to a sunscreen composition which is sprayable. Preferably the sunscreen composition is sprayable and anhydrous. It may preferably be formulated as a spray, and also it may preferable have a viscosity as described in the previous section.
All the embodiments described for the aspect relating to a sunscreen composition may naturally also apply to the sunscreen composition described for the present use of a thickening agent.
Method of manufacturing a sunscreen composition
A third aspect of the present invention is a process for the manufacture of a sunscreen composition comprising the steps of
i) providing at least one solvent, at least one thickening agent, at least one film forming polymer and at least one sunscreen agent,
ii) admixing the components of step i) to provide a sunscreen
composition
Generally heating is used when manufacturing sunscreen compositions, however for the present invention the inventors surprisingly found that heating was unnecessary, and all the components dissolves to a satisfactory level without applying heat, beyond the heat generated during solvation and stirring. Therefore, preferably the mixture or composition is not heated during the process and the temperature is in the range of 0-60 °C, such as in the range of 5-55 °C, 15-50 °C, 20-50 °C, 30-45 °C, such as about 40 °C. Preferably, no water is added to the composition during said process, and even more preferably the components provided in step i) are admixed in the order provided in step i). Further additives as described herein may be added in step i). Each component added is dissolved under stirring before the next component is added. Stirring time may vary from 1- 25 minutes.
All the embodiments described for the aspect relating to a sunscreen composition may naturally also apply to the sunscreen composition described for the present method of manufacturing.
Generally, it should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention. All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.
The invention will now be described in further details in the following non-limiting examples.
Examples
Example 1 - Sunscreen compositions and manufacture thereof
Sunscreen compositions were prepared according to the tables shown below for compositions A1/A2 and B1/B2. The B1/B2 compositions are comparable but comprise higher amounts of sunscreen agents than the A1/A2 compositions (also comparable) to achieve higher SPF values. The amount of thickening agent is varied in Al vs A2 and Bl vs B2 to elucidate the effect of said thickening agent. Table 1 : Sunscreen composition Al (0.01 %(w/w) thickening agent)
Steps Ingredients Amount w/w %
1.1 Alcohol denat. (solvent) 50.73
1.2 Hydroxypropylcellulose (thickening agent) 0.01
1.3 Aqua 5.0
1.4 Acrylates/Octylacrylamide Copolymer (Film former, 0.75 a synthetic polymer)
1.5 PPG-15 Stearyl Ether (Emolient/weak emulisifier, 6.0 an alkoxylated alcohol)
1.6 Hexyldecanol 6.0
1.7 Cyclopentasiloxane (Emolient, a Siloxane/silane) 3.0
1.8 Ethylhexyl Methoxycinnamate (Sunscreen agent, an 0.01 ester)
1.9 Octocrylene (Sun screen agent, an ester) 10.0
1.10 Homosalate (Sun Screen Agent) 10.0
1.11 Butyl methoxydibenzoylmethane (Sun Screen 3.0
Agent)
1.12 Diethylamino Hydroxybenzoyl Hexyl Benzoate (Sun 3.0 screen agent)
1.13 Diethylhexyl butamido triazone (sunscreen agent) 2.5
Total 100
Table 2: Sunscreen composition A2 (0.03%(w/w) thickening agent)
Figure imgf000020_0001
Composition A2 has several alterations as compared to Al, but comprises the same overall amount %(w/w) of sunscreen agents as Al. Mainly A2 comprises more thickening agent than Al.
Table 3: Sunscreen composition Bl (without thickening agent)
Steps Ingredients Amount w/w %
1.1 Alcohol denat. (solvent) 43.24
1.2 Acrylates/Octylacrylamide Copolymer (Film former, 0.75 a synthetic polymer)
1.3 PPG-15 Stearyl Ether (Emolient/weak emulisifier, 6.0 an alkoxylated alcohol)
1.4 C12-15 Alkyl Benzoate (Emolient) 10.0
1.5 Cyclopentasiloxane (Emolient, a Siloxane/silane) 3.0
1.6 Ethylhexyl Methoxycinnamate (Sunscreen agent, an 0.01 ester)
1.7 Octocrylene (Sun screen agent, an ester) 10.0
1.8 Homosalate (Sun Screen Agent) 10.0
1.9 Diethylhexyl Butamido Triazone (Sun Screen 1.0
Agent)
1.10 Butyl methoxydibenzoylmethane (Sun Screen 5.0
Agent)
1.11 Diethylamino Hydroxybenzoyl Hexyl Benzoate (Sun 10.0 screen agent)
Total 100
Table 4: Sunscreen composition B2 (comprising thickening agent)
Figure imgf000022_0001
Composition B2 is equal to Bl except for the replacement of 0.03 %(w/w) solvent with the thickening agent in B2.
The compositions were manufactured by addition of the listed components in the order they are listed under stirring using a Silverson L4RT high shear mixer.
Stirring time in between additions of components is variable between 1-25 minutes. No heating is of the solution was performed. The temperature of the mixture was between 20 °C and 40 °C at all times. Example 2 - Effect of thickening agent on Sun Protection Factor
The present example demonstrates that the addition of a thickening agent enhances the SPF value of the present sunscreen compositions. The test is based on the International-Sun Protection Factor-Test Method (SPF) as defined in 2006 by COLIPA - CTFA SA - JCIA- CTFA US, as well as on the international standard ISO 24444, Cosmetics - Sun protection test methods - in vivo determination of the sun protection factor (SPF), ISO 24444: 2010 (E); First edition 2010-11-15.
Based on the European Commission Recommendation from September 2006 as well as COLIPA statement (26.09.2006), basis of labeling should be the mean SPF obtained in application of the I-SPF-TM 2006 / ISO 24444: 2010(E). The efficacy of sunscreen products should be indicated on the label by reference to categories. The category of sunscreen products should be indicated on the label at least as prominently as the SPF. The variety of numbers used on labels for indicating the SPF is restricted to those and only those shown in the following Table. The range of SPF's for each category and the respective labeling is defined as follows: Table 5: Protection categories according to EC recommendations
Figure imgf000023_0001
The minimum degree of protection provided by a sunscreen product is an SPF of 6. SPF values and SPF label values in the present examples are to be understood within the framework of the European recommendations and the SPF values are determined and/or calculated as described in the detailed description. In the present example 2 mg/cm2 sunscreen composition is applied to test subjects a provided by the guidelines.
Sunscreen compositions A1/A2 and B1/B2 were prepared according to exam 1 and subjected to in vivo SPF determination as prescribed by the above mentioned guidelines. The tests were performed by Institute Dr. Schrader
Hautphysiologie, Holzminden, Germany.
Table 6 - Comparative in vivo measurements of SPF dependence on thickening agent for compositions A1/A2 and B1/B2
Figure imgf000024_0001
The above experiment demonstrates that the sun protection factor of the composition with thickening agent (in this case hydroxypropylcellulose) is significantly larger than that of the product with reduced amounts or no thickening agent. This leads to a higher attainable label SPF and label category without the addition of further sunscreen agents.
Example 3 - Effect of thickening agent on SPF kinetics
The effect of thickening agent on the kinetics, i.e. SPF performance over time was measured in vivo in separate experiments. Sunscreen compositions A1/A2 and B1/B2 were prepared according to example 1 and subjected to in vivo SPF determination as prescribed by the above mentioned guidelines. The tests were performed by Institute Dr. Schrader Hautphysiologie, Holzminden, Germany. Table 7 - Comparative in vivo measurements of SPF kinetics and dependence on thickening agent for compositions A1/A2 and B1/B2
Figure imgf000025_0001
5 The measurements show that the improvements achieved when adding thickening agent are maintained over time, so that after 10 hours, the compositions with increased amounts of thickening agent (A2, B2) are still superior to those with less or no thickening agent (Al, Bl).
10 Example 4 - Water resistance of sunscreen compositions
The effect of thickening agent on the water resistance of the compositions of the present invention was measured in vivo. Sunscreen compositions A2 and B2 were prepared according to example 1 and subjected to in vivo SPF determination as prescribed by the Guidelines for Evaluating Sun Product Water Resistance (COLIPA
15 2005). The tests were performed by Institute Dr. Schrader Hautphysiologie,
Holzminden, Germany.
For very water resistance the wet SPF as measured in vivo is the SPF value measured after application of sunscreen and subsequent immersion of the test 20 individual in water for 80 minutes. The immersion in water for 80 minutes is
divided into 4 immersions of 20 minutes with 15 minutes of drying time in air before first immersion, in between immersions, and after the fourth immersion.
The very water resistance value (in percentage) is calculated as: VWR = 100 x SPFW/SPFS where the lower limits of the confidence intervals (95% CI) is used for SPFW and SPFS based on statistics performed on the data from 12 test subjects.
Table 8 -in vivo measurements of very water resistance for sunscreen
compositions A 2 and B2
Figure imgf000026_0001
Based on SPF (static and wet) measurements in vivo on 12 individuals The tests show that the compositions of the present invention retain a very high water resistance, which justifies the label "very water resistant" according to the recommendations in the abovementioned guidelines. The requirement for this label is a very water resistance of 50% or more. Example 5 - UVA protection and Boots star rating of Sunscreen compositions The protection against UVA radiation may be determined by the COLIPA ratio as defined in the COLIPA guideline (in vitro method for the determination of the UVA protection factor and "critical wavelength" values of sunscreen products".
Guideline, COLIPA, March 2011). The COLIPA ratio is calculated as
COLIPA Ratio = SPFiabei/UVA-PF where UVA-PF is the actual "SPF" obtained for UVA irradiation measured in vitro according to the guidelines. The present compositions A2 and B2 were tested and displayed a COLIPA ratio of 0.9 and 1.0 respectively, which fulfils the recommendation from COLIPA which is a ratio below 3.
The UVA protection was also determined by the Boots star rating system
(Measurement of UVA: UVB ratios according to the boots star rating system [2001 revision]; the Boots company PLC, Nottingham NG2 3AA, UK, September 2011), which is based on the ratio between UVA and UVB protection before and after exposing the sample to UV irradiation. The best Boots star rating of five stars (*****) requires a UVA: UVB ratio above 0.9 before UV exposure and above 0.86 after UV exposure. Compositions A2 and B2 fulfils these criteria. Table 9: Boots star rating of composition A2
Figure imgf000027_0001
mean product quantity = 0.55 mg/cm2, mean plate temp. = 22.0 °C.
Table 10: Boots star rating of composition B2
Figure imgf000028_0001
mean product quantity = 0.68 mg/cm2, mean plate temp. = 25.9 °C
Example 6 - Viscosity of sunscreen compositions
The viscosity of the present sunscreen compositions must be within certain limits for the compositions to remain sprayable. Thus, the viscosity of composition B2 was investigated along with compositions having less and more thickening agent (solvent amounts being adjusted accordingly). The viscosities were measured at 25 °C at 60 rpm using a Brookfield LVDV-II + P viscometer with a small sample adapter and Spindle S18.
Table 11 - Viscosity of composition B2 and variants
Figure imgf000028_0002
HPC = hydroxypropylcellulose The tests show that at 0.03%(w/w) HPC (composition B2) the viscosity remains comparable to the viscosity without thickening agent (composition Bl), whereas at higher levels of thickening agent the viscosity reaches levels which may start to affect the sprayability, particularly when applying standard retail type topical administration pumps.
References
• WO 2009/016537
• WO 2004/110366
· WO 2011/100275
• Commission Recommendation of 22 September 2006 on the efficacy of
sunscreen products and the claims made relating thereto (notified under document number C(2006) 4089) (Text with EEA relevance) (2006/647/EC); Official Journal of the European Union, L 265/3

Claims

Claims
1. A sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, at least one solvent, and at least one thickening agent, wherein said thickening agent is present in an amount in the range of 0.01- 0.2%(w/w).
2. A sunscreen composition according to claim 1, wherein said composition is a sprayable sunscreen composition.
3. A sunscreen composition according to any of claims 1-2, wherein said thickening agent is a polysaccharide thickening agent.
4. A sunscreen composition according to claim 3, wherein said polysaccharide thickening agent is selected from the group consisting of cellulose, carboxymethyl hydroxyethylcellulose, hydroxypropyl methylcellulose, methyl
hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulphate, hydroxyethylcellulose, hydroxypropylcellulose, and any mixtures thereof.
5. A sunscreen composition according to any of claims 3-4, wherein said polysaccharide thickening agent is hydroxyethylcellulose or
hydroxypropylcellulose.
6. A sunscreen composition according to any of claims 3-5, wherein said polysaccharide thickening agent is hydroxypropylcellulose.
7. A sunscreen composition according to any of claims 1-6, wherein said thickening agent is present in an amount in the range of 0.01-0.15%(w/w), such as 0.01-0.10%(w/w), 0.01-0.09%(w/w), 0.01-0.08%(w/w), 0.01-0.07%(w/w), 0.01-0.06%(w/w), 0.01-0.05%(w/w), 0.01-0.04%(w/w), 0.01-0.03%(w/w), 0.02-0.15%(w/w), 0.02-0.10%(w/w), 0.02-0.09%(w/w), 0.02-0.08%(w/w), 0.02-0.07%(w/w), 0.02-0.06%(w/w), 0.02-0.05%(w/w), 0.02-0.04%(w/w), 0.02-0.03%(w/w), such as in the range of 0.025-0.035%(w/w).
8. A sunscreen composition according to any of claims 1-7, wherein said sunscreen composition comprises water in an amount of 0-2%(w/w), such as 0- l%(w/w), such as 0-0.8%(w/w), 0-0.6%(w/w), 0-0.4%(w/w), 0-0.2%(w/w), 0- 0.1%(w/w), 0-0.05%(w/w), such as 0-0.01%(w/w).
9. A sunscreen composition according to any of claims 1-8, wherein said composition is anhydrous.
10. A sunscreen composition according to any of claims 1-9, wherein said solvent is an alcohol.
11. A sunscreen composition according to claim 10, wherein said alcohol is a mono alcohol having 2-8 carbon atoms, such as 2-4 carbon atoms.
12. A sunscreen composition according to any of claims 10-11, wherein said alcohol is selected from the group consisting of ethanol, 1-propanol, 2-propanol, ethyleneglycol, 1-butanol, 2-butanol or any combination thereof.
13. A sunscreen composition according to any of claims 1-12, wherein the solvent content is in the range of 10-90%(w/w), such as in the range of 15-85%(w/w),
20-80%(w/w), 30-70%(w/w), 35-65%(w/w), 40-60%(w/w), such as in the range of 40-55%(w/w).
14. A sunscreen composition according to any of claims 1-13, wherein said sunscreen agent is selected from the group consisting of Avobenzone, Cinoxate, Dioxybenzone, Homosalate, Menthyl anthranilate, Octocrylene, Octyl
methoxycinnamate, Octyl salicylate, Oxybenzone, Padimate O,
Phenylbenzimidazole sulfonic acid, Sulisobenzone, Titanium dioxide, Trolamine salicylate, Zinc oxide, Benzophenone-3 , Ethylhexyl Methoxycinnamate,
Octocrylene, Butyl Methoxydibenzoylmethane (BMBM), Diethylamino
hydroxybenzoyl Hexyl Benzoate, Diethylhexyl Butamido Triazone, PABA, camphor benzalkonium methosulfate, phenylbenzimidazole sulfonic acid, terephthalidene dicamphor sulfonic acid, benzylidene camphor sulfonic acid, polyacrylamidomethyl benzylidene camphor, PEG-25 PABA, isoamyl p-methoxycinnamate, ethylhexyl triazone, drometrizole trielloxane, 4-methylbenzylidene camphor, 3-benzylidene camphor, ethylhexyl salicylate, ethylhexyl dimethyl PABA, benzophenone-4, methylene bis-benztriazolyl tetramethylbutylphenol, disodium phenyl
dibenzimidazole tetrasulfonate, bis-ethylhexyloxyphenol methoxyphenol triazine, methylene bisbenzotriazolyl tetramethylbutylphenol, bisethylhexyloxyphenol methoxyphenyl triazine and any combination thereof.
15. A sunscreen composition according to any of claims 1-4, wherein said sunscreen agent is selected from the group consisting of Homosalate,
Octocrylene, Ethylhexyl Methoxycinnamate, Butyl Methoxydibenzoylmethane (BMBM), Diethylamino HydroxybenzoyI Hexyl Benzoate, diethylhexyl butamido triazone or any combination thereof.
16. A sunscreen composition according to any of claims 1-15, wherein
Diethylamino HydroxybenzoyI Hexyl Benzoate is used in concentrations of at the most 10 %(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 2- 10%(w/w), e.g. in the range 3-10%(w/w), such as in the range of 4-10%(w/w), and/or Ethylhexyl Methoxycinnamate is used in concentrations of at the most 2%(w/w), e.g. in the range of 0.01-2%(w/w), such as in the range of 0.01- l%(w/w), e.g. in the range 0.01-0.05%(w/w) and/or Octocrylene is used in concentrations of at the most 10%(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 0.5-8%(w/w), e.g. in the range l-6%(w/w), such as in the range of 3-5%(w/w), e.g. in the range 6-10%(w/w), such as in the range of 8- 10%(w/w) and/or Butyl Methoxydibenzoylmethane (BMBM) is used in
concentrations of at the most 5%(w/w), such as in the range of 0.5-5%(w/w), e.g. in the range 3-5%(w/w), such as in the range of 4-5%(w/w) and/or homosalate is used in concentrations of at the most 10%(w/w), e.g. in the range of 0.1-10%(w/w), such as in the range of 0.5-8%(w/w), e.g. in the range 6- 10%(w/w), such as in the range of 8-10%(w/w) and/or diethylhexyl butamido triazone is used in concentrations of at the most 5%(w/w), such as in the range of 0.1-5%(w/w), e.g. 0.1-3%(w/w), such as 0.1-l%(w/w).
17. A sunscreen composition according to any of claims 1-16, wherein said composition does not comprise ethylhexyl salicylate and/or butyloctyl salicylate.
18. A sunscreen composition according to any of claims 1-17, wherein said film forming polymer is selected from the group consisting of polyvinylpyrrolidone (PVP), acrylates, acrylamides, and any copolymers thereof or any combination thereof.
19. A sunscreen composition according to any of claims 1-18, wherein said film forming polymer is selected from the group consisting of acrylate/octylacrylamide copolymer, acrylates copolymer, acrylates/Ci2-22 alkyl methacrylate copolymer, butylated PVP), VA/butyl maleate/isobornyl acrylate copolymer vinyl
caprolactam/VP/dimethylaminoethyl methacrylate copolymer, most preferably acrylate/octylacrylamide copolymer.
20. A sunscreen composition according to any of claims 1-19, wherein the film forming polymer is added in an amount in the range of 0.1-10%(w/w), such as in the range of 0.2-8%(w/w), e.g. in the range of 0.3-6%(w/w), such as in the range of 0.3-5%(w/w), e.g. in the range of 0.4-3%(w/w), such as in the range of 0.4-2%, e.g. in the range of 0.5-1.5%(w/w), such as in the range of 0.5- 1.2%(w/w), e.g. in the range of 0.6-1.0%(w/w), such as in the range of 0.6- 0.9%(w/w), e.g. in the range of 0.7-0.8%(w/w), such as about 0.75%(w/w).
21. A sunscreen composition according to any of claims 1-20, wherein the composition further comprises a siloxane or a silane or silicone alternative, such as a siloxane or a silane or silicone alternative selected from the group consisting of Ci3-i6 isoparaffin, C12-14 isoparaffin, C13-15 Alkane, Isodecane and Hydrogenated Polydecene and Bis-Behenyl/Isostearyl/Phytostearyl Dimer Dilinoleyl/Dimer Dilinoleate, Silyburn Marianum Ethyl Ester, Cs-is Alkyl Ester, cyclic dimethyl polysiloxane or cyclopentasiloxane.
22. A sunscreen composition according to claim 20, wherein the siloxane, silane or silicone alternative is present in an amount in the range of 0.1-20%(w/w), such as in the range of 0.5-15%(w/w), e.g. in the range of l-10%(w/w), such as in the range of 2-7%(w/w), e.g. in the range of 2-5%(w/w), such as in the range of 2- 4%(w/w), e.g. in the range of 2-3%(w/w).
23. A sunscreen composition according to any of claims 1-22, wherein the composition further comprises an alkoxylated alcohol, such as PPG-11 stearyl ether, PPG-15 Stearyl ether, or any combination thereof.
5 24. A sunscreen composition according to claim 23, wherein the alkoxylated
alcohol is added in an amount in the range of 0.1-20%(w/w), such as in the range of 0.5-15%(w/w), e.g. in the range of l-10%(w/w), such as in the range of 2- 7%(w/w), e.g. in the range of 5-7%(w/w).
10 25. A sunscreen composition according to any of claims 1-24, wherein said
composition further comprises an ester, such as an ester selected from the group consisting of Ethylhexyl Benzoate, Dibutyl Adipate, Neopentyl Glycol
Dicaprylate/Dicaprate and C12-15 Alkyl benzoate or any combination thereof.
15 26. A sunscreen composition according to claim 25, wherein said ester is present in an amount in the range of l-30%(w/w), such as in the range of 5-25%(w/w), 7-22%(w/w), 8-20%(w/w), preferably in the range of 9-17%(w/w).
27. A sunscreen composition according to any of claims 1-26, wherein said 20 composition is formulated as a spray.
28. A sunscreen composition according to any of claims 1-27, wherein the viscosity of said sunscreen composition is below 120 cP at 25 °C, such as below 110 cP at 25 °C, 100 cP at 25 °C, 80 cP at 25 °C, 60 cP at 25 °C, 40 cP at 25 °C,
25 20 cP at 25 °C, 15 cP at 25 °C, such as below 10 cP at 25 °C.
29. A sunscreen composition according to any of claims 1-27, wherein the viscosity of said sunscreen composition is in the range of 1-120 cP at 25 °C, such as in the range of 1-110 cP at 25 °C, 1-100 cP at 25 °C, 1-80 cP at 25 °C, 1-60 cP
30 at 25 °C, 1-40 cP at 25 °C, 1-30 cP at 25 °C, 1-20 cP at 25 °C, 1-15 cP at 25 °C, 1-14 cP at 25 °C, 2-13 cP at 25 °C, 3-12 cP at 25 °C, preferably in the range of 4- 10 cP at 25 °C.
30. A sunscreen composition according to any of claims 1-29, wherein the
35 composition comprises at least 2 sunscreen agents, such as 3 sunscreen agents, e.g. 4 sunscreen agents, such as 5 sunscreen agents, e.g. 6 sunscreen agents, such as 7 sunscreen agents.
31. A sunscreen composition according to any of claims 1-30, wherein the composition having a static sun protection factor after the composition has been applied to the skin of a human, the sun protection factor of the composition is at least 60% of the static sun protection factor, such as at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, such as at least 115% when the composition is contacted with water.
32. A sunscreen composition according to any of claims 1-30, wherein the composition having a static sun protection factor after the composition has been applied to the skin of a human, the sun protection factor of the composition is capable of being increased to a higher wet sun protection factor when the composition is contacted with water.
33. A sunscreen composition according to any of claims 1-30, wherein the wet sun protection factor is increased by at least 5% relative to the static sun protection factor, such as increased by at least 10% relative to the static sun protection factor, e.g. increased by at least 15% relative to the static sun protection factor, such as increased by at least 20% relative to the static sun protection factor, e.g. increased by at least 25% relative to the static sun protection factor.
34. A sunscreen composition according to any of claims 1-30, wherein the Very Water Resistance value of said composition is above 50, such as above 60, above
70, above 80, such as above 85, above 90, above 95, above 100, above 105, above 110, such as above 115.
35. A sunscreen composition according to any of claims 1-34, wherein said composition comprises no more than 5 sunscreen agents and wherein the sun protection factor is at least 15, such as at least 16, at least 17, at least 18 , at least 19, such at least 20.
36. A sunscreen composition according to any of claims 1-34, wherein said composition comprises no more than 4 sunscreen agents and wherein the sun protection factor is at least 15, such as at least 16, at least 17, at least 18 , at least 19, such at least 20.
37. A sunscreen composition according to any of claims 1-34, wherein said composition comprises no more than 6 sunscreen agents and wherein the sun protection factor is at least 30, such as at least 32, at least 34, at least 36, at least 38, at least 40, at least 42, at least 44, at least 46, at least 48, such as at least 50.
38. A sunscreen composition according to any of claims 1-34, wherein said composition comprises no more than 5 sunscreen agents and wherein the sun protection factor is at least 30, such as at least 32, at least 34, at least 36, at least 38, at least 40, at least 42, at least 44, at least 46, at least 48, such as at least 50.
39. A sunscreen composition according to any of claims 1-38, wherein the sun protection factor is increased by at least 5 units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to a composition comprising the same overall weight percentage in %(w/w) of sunscreen agents and no thickening agent.
40. A sunscreen composition according to any of claims 1-38, wherein the sun protection factor is increased by at least 5 units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to an essentially identical composition not comprising a thickening agent.
41. A sunscreen composition according to claim 40, wherein the essentially identical composition not comprising thickening agent is the identical composition, wherein the thickening agent has been replaced by solvent.
42. A sunscreen composition according to any of claims 1-41, wherein said composition is a solution.
43. Use of a thickening agent for increasing the sun protection factor of a sunscreen composition comprising at least one sunscreen agent, at least one film forming polymer, and at least one solvent.
5 44. The use according to claim 43, wherein said thickening agent is present in an amount in the range of 0.01-0.2%(w/w).
45. The use according to any of claims 43-44, wherein said thickening agent is a polysaccharide thickening agent.
10
46. The use according to claim 45, wherein said polysaccharide thickening agent is selected from the group consisting of cellulose, carboxymethyl
hydroxyethylcellulose, hydroxypropyl methylcellulose, methyl
hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulphate,
15 hydroxyethylcellulose, hydroxypropylcellulose, and mixtures thereof.
47. The use according to any of claims 45-46, wherein said polysaccharide thickening agent is hydroxyethylcellulose or hydroxypropylcellulose.
20 48. The use according to any of claims 43-47, wherein the sun protection factor is increased by at least 5 units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to a composition comprising the same overall weight percentage %(w/w) of sunscreen agents and no thickening agent.
25
49. The use according to any of claims 43-47, wherein the sun protection factor is increased by at least 5 units, such as at least 6 units, 8 units, 10 units, 11 units, 12 units, 13 units when a thickening agent is comprised as compared to an essentially identical composition not comprising a thickening agent.
30
50. The use according to claim 49, wherein the essentially identical composition not comprising thickening agent is the identical composition, wherein the thickening agent has been replaced by solvent.
51. A process for the manufacture of a sunscreen composition comprising the steps of
i) providing at least one solvent, at least one thickening agent, at least one film forming polymer and at least one sunscreen agent,
ii) admixing the components of step i) to provide a sunscreen
composition
52. A process according to claim 51, wherein the mixture is not heated during the process and the temperature is in the range of 0-60 °C.
53. A process according to claim 52, wherein the process temperature is in the range of 5-55 °C, 15-50 °C, 20-50 °C, 30-45 °C, such as about 40 °C.
54. A process according to any of claims 51-53, wherein no water is added to the composition.
55. A process according to any of claims 51-54, wherein the components provided in step i) are admixed in the order provided in step i).
PCT/DK2013/050250 2012-07-26 2013-07-25 Improved sunscreen composition WO2014015879A2 (en)

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Application Number Priority Date Filing Date Title
RU2015105502A RU2015105502A (en) 2012-07-26 2013-07-25 IMPROVED SUN PROTECTIVE COMPOSITION
BR112015001664A BR112015001664A2 (en) 2012-07-26 2013-07-25 improved sunscreen composition
KR20157004943A KR20150046064A (en) 2012-07-26 2013-07-25 Improved sunscreen composition
US14/415,906 US20150216782A1 (en) 2012-07-26 2013-07-25 Sunscreen composition comprising a thickening system, having improved water-resistance
CA2879468A CA2879468A1 (en) 2012-07-26 2013-07-25 Improved sunscreen composition
EP13747961.4A EP2877142A2 (en) 2012-07-26 2013-07-25 Sunscreen composition comprising a thickening system, having improved water-resistance
CN201380050124.4A CN104661635A (en) 2012-07-26 2013-07-25 Improved sunscreen composition comprising a thickening system, having improved water-resistance
IN519DEN2015 IN2015DN00519A (en) 2012-07-26 2015-01-21

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DKPA201200478 2012-07-26

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BR (1) BR112015001664A2 (en)
CA (1) CA2879468A1 (en)
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WO2014015879A3 (en) 2014-07-17
RU2015105502A (en) 2016-09-20
US20150216782A1 (en) 2015-08-06
KR20150046064A (en) 2015-04-29
CA2879468A1 (en) 2014-01-30
EP2877142A2 (en) 2015-06-03
CN104661635A (en) 2015-05-27
BR112015001664A2 (en) 2017-07-04

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