WO2019151285A1 - Skin composition for external use - Google Patents

Skin composition for external use Download PDF

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Publication number
WO2019151285A1
WO2019151285A1 PCT/JP2019/003074 JP2019003074W WO2019151285A1 WO 2019151285 A1 WO2019151285 A1 WO 2019151285A1 JP 2019003074 W JP2019003074 W JP 2019003074W WO 2019151285 A1 WO2019151285 A1 WO 2019151285A1
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skin
pps
examples
composition
barrier function
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PCT/JP2019/003074
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French (fr)
Japanese (ja)
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勇輝 上田
幸司 生川
石井　宏
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マルホ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention relates to an external composition for skin having a skin barrier function improving action.
  • the skin is composed of the epidermis, the dermis, and the underlying subcutaneous tissue from the outside, and the epidermis, the outermost layer of the skin, plays the most important role in maintaining the skin barrier function.
  • the skin barrier function plays a role in preventing moisture from evaporating inside the stratum corneum and preventing foreign substances (allergens, bacteria, etc.) from entering the outside world. Therefore, when the skin barrier function is reduced, the skin is stimulated from the outside. This causes problems such as weakening the skin and facilitating loss of moisture in the skin, leading to various skin problems.
  • Patent Document 1 substances that can enhance the skin barrier function have been studied conventionally (see, for example, Patent Document 1 and Patent Document 2), but the development of an external composition for skin having an excellent skin barrier function improvement effect is still available. Is desired.
  • an object of the present invention is to provide a composition capable of recovering a lowered skin barrier function when applied to the skin.
  • the present inventors have studied a substance having an effect of improving skin barrier function, and as a result, found that pentosan polysulfate and / or a salt thereof has an excellent effect of improving barrier function. Thus, the present invention has been completed.
  • the present invention is an external composition for skin having an action of improving the skin barrier function, characterized by containing pentosan polysulfate and / or a salt thereof as an active ingredient.
  • the external composition for skin contains sodium pentosan polysulfate (hereinafter referred to as “PPS”) as an active ingredient.
  • PPS sodium pentosan polysulfate
  • the skin external composition is useful for preventing and / or treating a disease caused by a decrease in protein forming a tight junction.
  • the external composition for skin is useful for preventing and / or treating a disease selected from the group consisting of sebum deficiency, atopic dermatitis, psoriasis, sebum-deficient eczema, hand eczema, ichthyosis, and rosacea.
  • a disease selected from the group consisting of sebum deficiency, atopic dermatitis, psoriasis, sebum-deficient eczema, hand eczema, ichthyosis, and rosacea.
  • hand eczema include keratinized hand eczema, progressive palmokeratosis, money-type hand eczema, recurrent blister-type (sweat-type) hand eczema, and dry / cracked hand eczema.
  • the skin external composition is particularly useful for preventing and / or treating a disease selected from atopic dermatitis, ichthyosis (especially ichthyosis vulgaris) and hand eczema.
  • composition for external use of the present invention has an excellent skin barrier function improving action, it is useful for the prevention and / or treatment of various diseases caused by a decrease in skin barrier function.
  • pentosan polysulfate which is an active ingredient is a plant-derived compound and has high safety, it is possible to provide a composition for external use with few side effects.
  • Relative expression level of caspase 14 by PPS and control substances xylohexaose (O-XHE), hyaluronic acid (HA), and chondroitin sulfate (ChS) (the expression level in the evaluation substance-free group is 1)
  • O-XHE xylohexaose
  • HA hyaluronic acid
  • ChS chondroitin sulfate
  • 5 is a graph showing the relative expression level of claudin 1 by PPS and control substances O-XHE, HA and ChS (the expression level of the evaluation substance-free group is 1).
  • 5 is a graph showing the relative expression level of occludin by PPS and control substances O-XHE, HA and ChS (the expression level in the evaluation substance-free group is 1).
  • 3 is a graph showing the relative expression level of ZO-1 by PPS and control substances O-XHE, HA and ChS (the expression level of the evaluation substance non-added group is
  • the pentosan polysulfate and / or salt thereof contained as an active ingredient in the composition of the present invention is a semi-synthetic polysulfated polysaccharide containing a mixture of polyanionic polysaccharides.
  • Pentosan polysulfate is produced by chemical sulfation of polysaccharides (eg, xylan) obtained from woody, eg, beech. In general, it is considered to be a polysulfated product in which O-methylglucuronic acid is bonded as a side chain to a xylan chain. At this time, the pentosan polysulfate may be present in the form of a salt.
  • Preferred salts include alkali metal salts such as sodium pentosan polysulfate and potassium potassium pentosan polysulfate, and alkaline earth metals such as pentosan polycalcium sulfate. Examples thereof include salts and pentosan polymagnesium sulfate. A particularly preferred salt is sodium pentosan polysulfate.
  • the PPS is not particularly limited, but those having a weight average molecular weight of 1000 to 30000 are preferable, and those having 4000 to 6500 are more preferable.
  • pentosan polysulfate and / or a salt thereof enhances the expression of filaggrin, tight junction forming protein (claudin-1, occludin, ZO-1) and caspase-14.
  • These proteins are substances that play an important role in the skin barrier function, and it is known that their expression is decreased in diseases accompanied by a decrease in the skin barrier function (for example, “The American American Journal of Pathology, Vol. 178, No. 5, May 2011 ",” Journal of Controlled Release 242 (2016) 105-118 “,” Jinshukai: 124 ⁇ (3), 305-314, 2014 ",” Jpn. J. Clin. Immunol., 40 (6) 416-427 (2017) "," British Journal of Dermatology (2016) 175, 1243-1250 “and” PLoS One. 2016 Sep 2; 11 (9): e0161759 ”) .
  • the mammalian skin barrier is composed of two elements, a horny barrier and a tight junction (TJ) barrier existing in the epidermis.
  • the epidermis the outermost layer of the skin, is composed of the stratum corneum (corneal layer), granule layer, spiny layer, and basal layer.
  • Filaggrin is the stratum corneum (the outermost layer of the epidermis). It exists as a major protein that fills the cytoplasm of the cell. Since filaggrin is degraded by proteolytic enzymes such as caspase-14 in the stratum corneum and becomes a natural moisturizing factor (NMF), it plays an important role in the formation of keratin barrier function and water retention. Yes.
  • Tight junction is an intercellular adhesion structure existing in the granule layer, and is considered to play a role of preventing leakage of moisture and ions of the body and invasion of foreign substances such as pathogens.
  • the tight junction is composed of the claudin family and occludin, which are cell membrane proteins, and ZO-1, which is an intracellular lining protein. That is, these proteins form a tight junction barrier. .
  • composition of the present invention containing pentosan polysulfate and / or a salt thereof has an action of enhancing the expression of these proteins and recovering the reduced barrier function of the skin, sebum deficiency, atopic dermatitis, Psoriasis, sebum-deficient eczema, hand eczema (including keratinized hand eczema, progressive palmokeratosis, monetary hand eczema, recurrent blister-type (sweat-type) hand eczema and dry / cracked hand eczema) It is particularly useful for the prevention / treatment of ichthyosis and / or rosacea.
  • the present invention therefore also relates to methods for preventing and / or
  • the composition of the present invention capable of increasing the expression of these proteins is atopy.
  • composition of the present invention is not particularly limited as long as it is a preparation form applicable to the skin.
  • the ointment, plaster, patch, cream, liniment or lotion described in the Japanese Pharmacopoeia And the like can be used as a pharmaceutical composition together with pharmaceutically acceptable additives.
  • the content of pentosan polysulfuric acid and / or a salt thereof as an active ingredient in the composition of the present invention is preferably 0.0001 to 30% by weight, more preferably 0.001 to 10% by weight, and 0.01 to 1% by weight is particularly preferred.
  • the amount and frequency of application of the composition according to the present invention to the skin are appropriately determined according to the target disease and the degree of its symptoms, the concentration of pentosan polysulfate and / or its salt in the composition, age, weight, etc.
  • pentosan polysulfate and / or a salt thereof 0.015 ⁇ g to 5 mg, preferably 0.15 ⁇ g to 2 mg per 10 cm 2 may be applied once or several times a day.
  • examples of the additive blended in the ointment include a base, a humectant, a thickener, and an emulsifier.
  • a base higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used.
  • higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc.
  • waxes include beeswax, white beeswax, lanolin, ceresin wax and the like
  • fatty acids include stearin.
  • examples include acids and oleic acid
  • higher alcohols include lanolin alcohol and cetostearyl alcohol
  • esters include isopropyl myristate and stearyl myristate.
  • humectant examples include glycerin and 1,3-butylene glycol.
  • thickener examples include carboxyvinyl polymer and carboxymethyl cellulose.
  • emulsifier examples include a cationic surfactant and an anionic interface. An activator, an amphoteric surfactant, a nonionic surfactant, etc. are mentioned.
  • Additives blended in plasters or patches include thickeners, moisturizers, fillers, crosslinking agents, solubilizers, emulsifiers and the like.
  • the thickener include sodium alginate, gelatin, methylcellulose, carboxyvinyl polymer, sodium polyacrylate and the like
  • examples of the humectant include glycerin and the like
  • examples of the filler include kaolin, titanium dioxide
  • examples of the cross-linking agent include acetaldehyde, dimethyl ketone, and aluminum sulfate.
  • the solubilizer include alcohols such as ethanol and isopropanol.
  • the emulsifier include an anionic surfactant. Examples thereof include agents and nonionic surfactants.
  • an oil-soluble substance a water-soluble substance, an emulsifier, etc.
  • blended with a cream an oil-soluble substance, a water-soluble substance, an emulsifier, etc.
  • oil-soluble substance higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used.
  • higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc.
  • waxes include beeswax, white beeswax, lanolin, ceresin wax and the like
  • fatty acids include stearin.
  • Acid, oleic acid, etc., higher alcohols include lanolin alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol, etc., and esters include isopropyl myristate, stearyl myristate, etc. Can be mentioned.
  • water purified water
  • thickeners examples include carboxyvinyl polymer and carboxymethyl cellulose
  • humectant examples include glycerin, propylene glycol, and 1,3-butylene glycol.
  • emulsifier examples include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.
  • examples of the additive added to the external liquid or spray include oil-soluble substances, water-soluble substances, and emulsifiers.
  • oil-soluble substance hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used.
  • hydrocarbons include squalane, ⁇ -olefin oligomers, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, and waxes include beeswax, white beeswax, lanolin, ceresin wax, and the like.
  • examples of fatty acids include stearic acid and oleic acid
  • examples of higher alcohols include lanolin alcohol, cetyl alcohol, and cetostearyl alcohol.
  • esters include isopropyl myristate, stearyl myristate, and octyldodecyl myristate. Etc.
  • water purified water
  • thickeners examples include carboxyvinyl polymer and carboxymethylcellulose
  • humectant examples include glycerin and 1,3-butylene glycol.
  • emulsifier examples include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.
  • Examples of the additive blended in the gel include bases, and isopropanol, propylene glycol and the like are used as the base.
  • cationic surfactant examples include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, dioctadecyldimethylammonium chloride, and the like.
  • anionic surfactant examples include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, coconut alcohol sodium ethoxy sulfate, sodium ⁇ -olefin sulfonate, emulsified cetostearyl alcohol and the like.
  • Nonionic surfactants include polyoxyethylene alkyl ethers such as polyoxyethylene oleyl ether and polyoxyethylene octyldodecyl ether, polyoxyethylene alkylphenol ether, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and glyceryl monostearate.
  • Glycerin fatty acid esters such as glyceryl monostearate, glyceryl monostearate, glyceryl palmitate, glyceryl myristate, glyceryl oleate, glyceryl triisooctanoate, diglycerin laurate, diglyceryl stearate, diglycerin oleate Diglycerin fatty acid esters such as sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, Oil fatty acid sorbitan, sorbitan tristearate, sorbitan fatty acid esters such as sorbitan trioleate, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyethylene glycol fatty acid esters such as polyethylene glycol monooleate and the like.
  • amphoteric surfactant include N-alkyl-N, N-dimethylammonium betaine and imidazoline type amphoteric surfact
  • plasters, patches, creams, liquids for external use, sprays, gels, etc., pH adjusters, preservatives, macrogols, etc. are used as necessary.
  • Examples of the pH regulator include diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, sodium citrate, phosphoric acid, tartaric acid, dl-malic acid, glacial acetic acid and the like.
  • Examples of the agent include thymol, dibutylhydroxytoluene, sodium edetate hydrate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.
  • Example 1 Action of PPS in a guinea pig dry skin model
  • a cartropen bet injection solution containing PPS (100 mg / mL, DS Pharma Animal Health Co., Ltd.) was diluted with a 0.01% Tween 80 aqueous solution to prepare a test solution.
  • Produced As test animals, 6 guinea pigs (Slc: Hartley, female, 3 weeks old) were used in each group.
  • the guinea pig is treated with an acetone / ether (1: 1) mixture and water (A / E / W treatment), and this treatment is repeated until the transepidermal water transpiration (TEWL) value is 30 to 50 g / hm 2.
  • a dry skin model was prepared.
  • Control 0.01% Tween 80
  • 0.03% PPS solution and 0.3% PPS solution both in% w / v
  • the TEWL value and stratum corneum moisture content were measured before A / E / W treatment, immediately after treatment (Day 0) and 1 to 5 days after treatment.
  • the TEWL value was measured using a portable moisture transpiration meter Vapometer (Delphine Technologies) and evaluated as an index of the skin barrier function recovery action.
  • the stratum corneum moisture content was measured as high-frequency conductivity using an epidermis stratum corneum moisture measuring device SKICON-200EX (Yayoi Co., Ltd.) and evaluated as an index of a stratum corneum moisture retention enhancing action.
  • the TEWL recovery rate was calculated by the following formula.
  • Example 2 Amount of bound water in the presence of PPS stratum corneum homogenate As PPS, sodium pentosan polysulfate (weight average molecular weight 4000-6500, sulfur content 13.0-20.0% w / w, glucuron, manufactured by Mollone Labs) An acid content of 2.5-4.0% w / w) was used.
  • PPS sodium pentosan polysulfate
  • a human skin sample (back) (purchased from the non-profit organization HB Research Organization), a PPS-containing stratum corneum homogenate aqueous solution (PPS final concentration: 0, 0.3, 1, 3, 10, and 20) % W / v) and using a high-sensitivity differential scanning calorimeter DSC7000X (Hitachi High-Tech Science Co., Ltd.), the temperature was increased from ⁇ 30 ° C. to 25 ° C. at a temperature increase rate of 5 ° C./min. The heat of fusion ( ⁇ H (J / g)) was measured. The measurement was performed 3 times. From the obtained ⁇ H, the amount of free water and bound water per gram of sample and the apparent amount of bound water per gram of stratum corneum were calculated according to the following formula.
  • RNA was extracted using RNeasy Plus Mini Kit (QIAGEN). Thereafter, cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). Synthesized cDNA, TaqMan Gene Expression Master Mix (Applied Biosystems) and TaqMan Gene Expression Assays (Applied Biosystems) were mixed, and the amount of filaggrin and caspase 14 mRNA was measured using a real-time PCR system (Applied Biosystems). . In addition, GAPDH was used as a control gene, and the variation between samples was corrected. The relative expression level indicates the expression level ratio of each evaluation substance addition group when the expression level of the evaluation substance non-addition group is 1. Each evaluation substance addition group and non-addition group were made into 4 cases (n 4).
  • Example 4 Action of expression of tight junction protein in human epidermal keratinocytes of PPS
  • PPS sodium pentosan polysulfate (weight average molecular weight: 4000-6500, sulfur content: 13.0-20.0% w / m) manufactured by Mollone Labs. w, glucuronic acid content 2.5-4.0% w / w).
  • O-XHE, HA and ChS were used as in Example 3.
  • Cell suspension of adult human epidermal keratinocytes (purchased from Thermo Fisher Scientific) is seeded on a 24-well microplate at 1.25 ⁇ 10 5 cells / well and cultured at 37 ° C., 5% CO 2 , 95% air. did.
  • a medium 0.1, 1, 10 ⁇ g / mL
  • one of the evaluation substances PPS and control substance
  • a non-containing medium is added to the wells seeded with the cells so as to be 500 ⁇ L / well.
  • the cells were cultured at 37 ° C., 5% CO 2 and 95% air for 24 hours.
  • total RNA was extracted using RNeasy Plus Mini Kit (QIAGEN).
  • cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems).
  • the synthesized cDNA, TaqMan Gene Expression Master Mix (Applied Biosystems) and TaqMan Gene Expression Assays (Applied Biosystems) are mixed, and the mRNA levels of claudin-1, occludin, and ZO-1 are mixed with a real-time PCR system (Applied Biosystems). ).
  • GAPDH was used as a control gene, and the variation between samples was corrected.
  • the relative expression level indicates the expression level ratio of each evaluation substance addition group when the expression level of the evaluation substance non-addition group is 1.

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Abstract

Provided is a skin composition for external use that has skin barrier function-enhancing effects. This skin composition for external use comprises pentosan polysulphate and/or a salt thereof as an active ingredient. The skin composition for external use is useful for preventing and/or treating diseases selected from the group consisting of atopic dermatitis, psoriasis, asteatotic eczema, hand eczema, ichthyosis, and rosacea.

Description

皮膚外用組成物Skin external composition
　本発明は、皮膚バリア機能改善作用を有する皮膚外用組成物に関する。 The present invention relates to an external composition for skin having a skin barrier function improving action.
　皮膚は外側から表皮、真皮、その下の皮下組織で構成されており、皮膚の最外層である表皮は、皮膚バリア機能の維持に最も重要な役割を果たしている。皮膚バリア機能は、角層の内側の水分の蒸散を防ぎ、外界からの異物（アレルゲン・細菌など）の侵入を防ぐ役割を担っているため、皮膚バリア機能が低下すると、皮膚が外部からの刺激に弱くなる／皮膚の水分が失われやすくなるといった問題が生じ、様々な皮膚トラブルへとつながる。 The skin is composed of the epidermis, the dermis, and the underlying subcutaneous tissue from the outside, and the epidermis, the outermost layer of the skin, plays the most important role in maintaining the skin barrier function. The skin barrier function plays a role in preventing moisture from evaporating inside the stratum corneum and preventing foreign substances (allergens, bacteria, etc.) from entering the outside world. Therefore, when the skin barrier function is reduced, the skin is stimulated from the outside. This causes problems such as weakening the skin and facilitating loss of moisture in the skin, leading to various skin problems.
　このため、従来から、皮膚バリア機能を増強できる物質が研究されているが（例えば、特許文献１及び特許文献２参照）、今なお、優れた皮膚バリア機能改善効果を有する皮膚外用組成物の開発が望まれている。 For this reason, substances that can enhance the skin barrier function have been studied conventionally (see, for example, Patent Document 1 and Patent Document 2), but the development of an external composition for skin having an excellent skin barrier function improvement effect is still available. Is desired.
特開２０１７－２０１３号公報Japanese Unexamined Patent Publication No. 2017-2013 特開２０１６－１３２６６６号公報JP 2016-132666 A
　したがって、本発明は、皮膚に適用することにより、低下した皮膚バリア機能を回復させることができる組成物を提供することを課題とする。 Therefore, an object of the present invention is to provide a composition capable of recovering a lowered skin barrier function when applied to the skin.
　本発明者らは、上記課題を解決するために、皮膚バリア機能改善効果を有する物質について検討を行った結果、ペントサンポリ硫酸及び／又はその塩が、優れたバリア機能改善効果を有することを見出して、本発明を完成した。 In order to solve the above-mentioned problems, the present inventors have studied a substance having an effect of improving skin barrier function, and as a result, found that pentosan polysulfate and / or a salt thereof has an excellent effect of improving barrier function. Thus, the present invention has been completed.
　すなわち、本発明は、皮膚バリア機能の改善作用を有する皮膚外用組成物であって、有効成分としてペントサンポリ硫酸及び／又はその塩を含有することを特徴とする。 That is, the present invention is an external composition for skin having an action of improving the skin barrier function, characterized by containing pentosan polysulfate and / or a salt thereof as an active ingredient.
　より好ましくは、前記皮膚外用組成物は、ペントサンポリ硫酸ナトリウム（以下、「ＰＰＳ」という）を有効成分として含有する。 More preferably, the external composition for skin contains sodium pentosan polysulfate (hereinafter referred to as “PPS”) as an active ingredient.
　前記皮膚外用組成物は、タイトジャンクションを形成するタンパク質の減少によって引き起こされる疾患を予防及び／又は治療するのに有用である。 The skin external composition is useful for preventing and / or treating a disease caused by a decrease in protein forming a tight junction.
　前記皮膚外用組成物は、皮脂欠乏症、アトピー性皮膚炎、乾癬、皮脂欠乏性湿疹、手湿疹、魚鱗癬、及び酒さから成る群より選ばれた疾患を予防及び／又は治療するのに有用である。手湿疹としては、角化型手湿疹、進行性指掌角皮症、貨幣型手湿疹、再発性水疱型（汗疱型）手湿疹及び乾燥・亀裂型手湿疹が挙げられる。 The external composition for skin is useful for preventing and / or treating a disease selected from the group consisting of sebum deficiency, atopic dermatitis, psoriasis, sebum-deficient eczema, hand eczema, ichthyosis, and rosacea. is there. Examples of hand eczema include keratinized hand eczema, progressive palmokeratosis, money-type hand eczema, recurrent blister-type (sweat-type) hand eczema, and dry / cracked hand eczema.
　前記皮膚外用組成物は、特に、アトピー性皮膚炎、魚鱗癬（特に、尋常性魚鱗癬）及び手湿疹から選ばれた疾患を予防及び／又は治療するのに有用である。 The skin external composition is particularly useful for preventing and / or treating a disease selected from atopic dermatitis, ichthyosis (especially ichthyosis vulgaris) and hand eczema.
　本発明の皮膚外用組成物は、優れた皮膚バリア機能改善作用を有するため、皮膚バリア機能の低下に起因する様々な疾患の予防及び／又は治療に有用である。
　又、有効成分であるペントサンポリ硫酸が植物由来の化合物であり、安全性が高いために、副作用の少ない皮膚外用組成物を提供することができる。 Since the composition for external use of the present invention has an excellent skin barrier function improving action, it is useful for the prevention and / or treatment of various diseases caused by a decrease in skin barrier function.
Moreover, since pentosan polysulfate which is an active ingredient is a plant-derived compound and has high safety, it is possible to provide a composition for external use with few side effects.
ＰＰＳ溶液及びコントロールによる、ＴＥＷＬ（transepidermal water loss：経表皮水分蒸散量）の回復率を示すグラフである。It is a graph which shows the recovery rate of TEWL (transepidermal water loss) by a PPS solution and control. ＰＰＳ溶液及びコントロールによる、角層水分含量（高周波伝導度として表す）を示すグラフである。It is a graph which shows a stratum corneum moisture content (expressed as a high frequency conductivity) by a PPS solution and control. ＰＰＳ処理角層における結合水量を示すグラフである。It is a graph which shows the amount of bound water in a PPS processing stratum corneum. ＰＰＳによるフィラグリンの相対発現量（評価物質非添加群の発現量を１とする）を示すグラフである。It is a graph which shows the relative expression level of filaggrin by PPS (the expression level of an evaluation substance non-addition group is set to 1). ＰＰＳ、及び、対照物質であるキシロヘキサオース（Ｏ－ＸＨＥ）、ヒアルロン酸（ＨＡ）及びコンドロイチン硫酸（ＣｈＳ）によるカスパーゼ１４の相対発現量（評価物質非添加群の発現量を１とする）を示すグラフである。Relative expression level of caspase 14 by PPS and control substances xylohexaose (O-XHE), hyaluronic acid (HA), and chondroitin sulfate (ChS) (the expression level in the evaluation substance-free group is 1) It is a graph to show. ＰＰＳ、及び、対照物質であるＯ－ＸＨＥ、ＨＡ及びＣｈＳによるクローディン１の相対発現量（評価物質非添加群の発現量を１とする）を示すグラフである。5 is a graph showing the relative expression level of claudin 1 by PPS and control substances O-XHE, HA and ChS (the expression level of the evaluation substance-free group is 1). ＰＰＳ、及び、対照物質であるＯ－ＸＨＥ、ＨＡ及びＣｈＳによるオクルディンの相対発現量（評価物質非添加群の発現量を１とする）を示すグラフである。5 is a graph showing the relative expression level of occludin by PPS and control substances O-XHE, HA and ChS (the expression level in the evaluation substance-free group is 1). ＰＰＳ、及び、対照物質であるＯ－ＸＨＥ、ＨＡ及びＣｈＳによるＺＯ－１の相対発現量（評価物質非添加群の発現量を１とする）を示すグラフである。3 is a graph showing the relative expression level of ZO-1 by PPS and control substances O-XHE, HA and ChS (the expression level of the evaluation substance non-added group is 1).
　本発明の組成物において有効成分として含有されるペントサンポリ硫酸及び／又はその塩は、多価陰イオン性多糖の混合物を含む、半合成ポリ硫酸化多糖である。ペントサンポリ硫酸は、木本、例えばブナから得られる多糖（例えばキシラン）の化学的硫酸化により生成される。一般に、キシラン鎖に側鎖としてＯ-メチルグルクロン酸が結合したものの多硫酸化体と考えられている。この際、ペントサンポリ硫酸は、塩の形態で存在していてもよく、好ましい塩としては、ペントサンポリ硫酸ナトリウム、ペントサンポリ硫酸カリウム塩等のアルカリ金属塩、ペントサンポリ硫酸カルシウム等のアルカリ土類金属塩、ペントサンポリ硫酸マグネシウム等が挙げられる。特に好ましい塩は、ペントサンポリ硫酸ナトリウムである。
　ＰＰＳとしては、特に限定されないが、重量平均分子量が、１０００～３００００のものを用いることが好ましく、４０００～６５００のものを用いることがより好ましい。 The pentosan polysulfate and / or salt thereof contained as an active ingredient in the composition of the present invention is a semi-synthetic polysulfated polysaccharide containing a mixture of polyanionic polysaccharides. Pentosan polysulfate is produced by chemical sulfation of polysaccharides (eg, xylan) obtained from woody, eg, beech. In general, it is considered to be a polysulfated product in which O-methylglucuronic acid is bonded as a side chain to a xylan chain. At this time, the pentosan polysulfate may be present in the form of a salt. Preferred salts include alkali metal salts such as sodium pentosan polysulfate and potassium potassium pentosan polysulfate, and alkaline earth metals such as pentosan polycalcium sulfate. Examples thereof include salts and pentosan polymagnesium sulfate. A particularly preferred salt is sodium pentosan polysulfate.
The PPS is not particularly limited, but those having a weight average molecular weight of 1000 to 30000 are preferable, and those having 4000 to 6500 are more preferable.
　本発明者らは、ペントサンポリ硫酸及び／又はその塩が、フィラグリン、タイトジャンクション形成タンパク質（クローディン-１、オクルディン、ＺＯ－１）及びカスパーゼ１４の発現を亢進させることを見い出した。これらのタンパク質は、皮膚バリア機能において重要な役割を果たす物質であり、皮膚バリア機能の低下を伴う疾患では、これらの発現が低下していることが知られている（例えば、"The American Journal of Pathology, Vol. 178, No. 5, May 2011", "Journal of Controlled Release 242 (2016) 105-118", "日皮会誌：124 (3), 305-314, 2014", "Jpn. J. Clin. Immunol., 40(6) 416-427 (2017)"，"British Journal of Dermatology (2016) 175, 1243-1250"、及び"PLoS One. 2016 Sep 2;11(9):e0161759"参照）。 The present inventors have found that pentosan polysulfate and / or a salt thereof enhances the expression of filaggrin, tight junction forming protein (claudin-1, occludin, ZO-1) and caspase-14. These proteins are substances that play an important role in the skin barrier function, and it is known that their expression is decreased in diseases accompanied by a decrease in the skin barrier function (for example, “The American American Journal of Pathology, Vol. 178, No. 5, May 2011 "," Journal of Controlled Release 242 (2016) 105-118 "," Jinshukai: 124 会 (3), 305-314, 2014 "," Jpn. J. Clin. Immunol., 40 (6) 416-427 (2017) "," British Journal of Dermatology (2016) 175, 1243-1250 "and" PLoS One. 2016 Sep 2; 11 (9): e0161759 ") .
　より具体的に説明すると、哺乳類の皮膚バリアは、表皮に存在する角質バリアとタイトジャンクション（ＴＪ）バリアの２つの要素から構成されている。皮膚の最外層である表皮は、角質層（角層）・顆粒層・有棘層・基底層から構成されており、フィラグリン（Filaggrin）は、角質層（表皮の最も外側の層）において、角質細胞の細胞質内を満たす主要なタンパク質として存在する。フィラグリンは、角質層においてカスパーゼ１４（caspase-14）などのタンパク質分解酵素により分解され、天然保湿因子（NMF：Natural moisturizing factor）となるため、角質バリア機能の形成や水分保持に重要な役割を果たしている。
　タイトジャンクションは、顆粒層に存在する細胞間接着構造であり、身体の水分やイオンなどの漏出を防ぐとともに、病原体などの異物の侵入を防ぐ役割を担っていると考えられている。タイトジャンクションは、細胞膜タンパク質であるクローディン(claudin)ファミリー及びオクルディン(occludin)、細胞内裏打ちタンパク質であるＺＯ－１などで構成されており、すなわち、これらのタンパク質がタイトジャンクションバリアを形成している。 More specifically, the mammalian skin barrier is composed of two elements, a horny barrier and a tight junction (TJ) barrier existing in the epidermis. The epidermis, the outermost layer of the skin, is composed of the stratum corneum (corneal layer), granule layer, spiny layer, and basal layer. Filaggrin is the stratum corneum (the outermost layer of the epidermis). It exists as a major protein that fills the cytoplasm of the cell. Since filaggrin is degraded by proteolytic enzymes such as caspase-14 in the stratum corneum and becomes a natural moisturizing factor (NMF), it plays an important role in the formation of keratin barrier function and water retention. Yes.
Tight junction is an intercellular adhesion structure existing in the granule layer, and is considered to play a role of preventing leakage of moisture and ions of the body and invasion of foreign substances such as pathogens. The tight junction is composed of the claudin family and occludin, which are cell membrane proteins, and ZO-1, which is an intracellular lining protein. That is, these proteins form a tight junction barrier. .
　皮膚のバリア機能異常をともなう皮膚疾患では、フィラグリンやその分解酵素であるカスパーゼ１４の発現低下だけでなく、タイトジャンクションの構成タンパク質であるクローディン、オクルディン、及び／又はＺＯ－１の発現低下が報告されている。ペントサンポリ硫酸及び／又はその塩を含有する本発明の組成物は、これらのタンパク質の発現を亢進させて、皮膚の低下したバリア機能を回復させる作用を有するため、皮脂欠乏症、アトピー性皮膚炎、乾癬、皮脂欠乏性湿疹、手湿疹（角化型手湿疹、進行性指掌角皮症、貨幣型手湿疹、再発性水疱型(汗疱型)手湿疹及び乾燥・亀裂型手湿疹を含む）、魚鱗癬、及び／又は酒さの予防／治療に特に有用である。それゆえ、本発明は、これらの疾患を予防及び／又は治療する方法にも関する。 In skin diseases with abnormal skin barrier function, not only decreased expression of filaggrin and its degradation enzyme caspase 14, but also decreased expression of tight junction constituent proteins claudin, occludin, and / or ZO-1. Has been. Since the composition of the present invention containing pentosan polysulfate and / or a salt thereof has an action of enhancing the expression of these proteins and recovering the reduced barrier function of the skin, sebum deficiency, atopic dermatitis, Psoriasis, sebum-deficient eczema, hand eczema (including keratinized hand eczema, progressive palmokeratosis, monetary hand eczema, recurrent blister-type (sweat-type) hand eczema and dry / cracked hand eczema) It is particularly useful for the prevention / treatment of ichthyosis and / or rosacea. The present invention therefore also relates to methods for preventing and / or treating these diseases.
　また、フィラグリン及びタイトジャンクション形成タンパク質の低下は、特にアトピー性皮膚炎及び魚鱗癬に関連することが知られているため、これらのタンパク質の発現を増加させることができる本発明の組成物は、アトピー性皮膚炎、魚鱗癬及び手湿疹から選ばれた疾患を、予防及び／又は治療するのに非常に適しており、特に魚鱗癬（典型的には、尋常性魚鱗癬）を治療するのに適している。 In addition, since the decrease in filaggrin and tight junction-forming protein is known to be particularly associated with atopic dermatitis and ichthyosis, the composition of the present invention capable of increasing the expression of these proteins is atopy. Very suitable for the prevention and / or treatment of diseases selected from dermatitis, ichthyosis and hand eczema, especially for the treatment of ichthyosis (typically vulgaris ichthyosis) ing.
　本発明の組成物は、皮膚に適用可能な製剤形態であれば特に限定されるものではなく、例えば、日本薬局方に記載の軟膏剤、硬膏剤、貼付剤、クリーム剤、リニメント剤又はローション剤等の外用液剤、スプレー剤、ゲル剤等が挙げられ、薬学的に許容される添加剤と共に医薬組成物として使用することができる。 The composition of the present invention is not particularly limited as long as it is a preparation form applicable to the skin. For example, the ointment, plaster, patch, cream, liniment or lotion described in the Japanese Pharmacopoeia And the like, and can be used as a pharmaceutical composition together with pharmaceutically acceptable additives.
　本発明の組成物中の、有効成分であるペントサンポリ硫酸及び／又はその塩の含有率は、０．０００１～３０重量％が好ましく、０．００１～１０重量％がより好ましく、０．０１～１重量％が特に好ましい。 The content of pentosan polysulfuric acid and / or a salt thereof as an active ingredient in the composition of the present invention is preferably 0.0001 to 30% by weight, more preferably 0.001 to 10% by weight, and 0.01 to 1% by weight is particularly preferred.
　また、本発明に係る組成物の皮膚への適用量・適用頻度は、対象疾患及びその症状の程度、組成物中のペントサンポリ硫酸及び／又はその塩の濃度、年齢・体重等に応じて適宜調節すればよいが、例えばペントサンポリ硫酸及び／又はその塩として１０ｃｍ２あたり０．０１５μｇ～５ｍｇ、好ましくは０．１５μｇ～２ｍｇを、１日１回または数回適用すればよい。 In addition, the amount and frequency of application of the composition according to the present invention to the skin are appropriately determined according to the target disease and the degree of its symptoms, the concentration of pentosan polysulfate and / or its salt in the composition, age, weight, etc. For example, as pentosan polysulfate and / or a salt thereof, 0.015 μg to 5 mg, preferably 0.15 μg to 2 mg per 10 cm 2 may be applied once or several times a day.
　本発明の皮膚外用組成物が軟膏剤の製剤形態である場合に、当該軟膏剤中に配合される添加剤としては、基剤、保湿剤、増粘剤、乳化剤等が挙げられる。基剤には高級炭化水素、油脂類、ロウ類、脂肪酸、高級アルコール、エステル類等を用いることができる。高級炭化水素としては、例えば、スクワラン、合成パラフィン、流動パラフィン、白色ワセリン、マイクロクリスタリンワックス等が挙げられ、ロウ類としては、ミツロウ、サラシミツロウ、ラノリン、セレシンロウ等が挙げられ、脂肪酸としては、ステアリン酸、オレイン酸等が挙げられ、高級アルコールとしては、ラノリンアルコール、セトステアリルアルコール等が挙げられ、エステル類としては、ミリスチン酸イソプロピル、ミリスチン酸ステアリル等が挙げられる。 When the external composition for skin of the present invention is in the form of an ointment, examples of the additive blended in the ointment include a base, a humectant, a thickener, and an emulsifier. As the base, higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc., waxes include beeswax, white beeswax, lanolin, ceresin wax and the like, and fatty acids include stearin. Examples include acids and oleic acid, higher alcohols include lanolin alcohol and cetostearyl alcohol, and esters include isopropyl myristate and stearyl myristate.
　保湿剤としては、グリセリン、１，３－ブチレングリコール等が挙げられ、増粘剤としては、カルボキシビニルポリマー、カルボキシメチルセルロース等が挙げられ、乳化剤としては、陽イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤等が挙げられる。 Examples of the humectant include glycerin and 1,3-butylene glycol. Examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose. Examples of the emulsifier include a cationic surfactant and an anionic interface. An activator, an amphoteric surfactant, a nonionic surfactant, etc. are mentioned.
　硬膏剤ないし貼付剤に配合される添加剤としては、増粘剤、保湿剤、充填剤、架橋剤、溶解剤、乳化剤等が挙げられる。具体的には、増粘剤としては、アルギン酸ナトリウム、ゼラチン、メチルセルロース、カルボキシビニルポリマー、ポリアクリル酸ナトリウム等が挙げられ、保湿剤としてはグリセリン等が挙げられ、充填剤としてはカオリン、二酸化チタン、亜鉛華等が挙げられ、架橋剤としては、アセトアルデヒド、ジメチルケトン、硫酸アルミニウム等が挙げられ、溶解剤としては、エタノール、イソプロパノール等のアルコール類等が挙げられ、乳化剤としては、陰イオン性界面活性剤、非イオン性界面活性剤等が各々例示される。 Additives blended in plasters or patches include thickeners, moisturizers, fillers, crosslinking agents, solubilizers, emulsifiers and the like. Specifically, examples of the thickener include sodium alginate, gelatin, methylcellulose, carboxyvinyl polymer, sodium polyacrylate and the like, examples of the humectant include glycerin and the like, examples of the filler include kaolin, titanium dioxide, Examples of the cross-linking agent include acetaldehyde, dimethyl ketone, and aluminum sulfate. Examples of the solubilizer include alcohols such as ethanol and isopropanol. Examples of the emulsifier include an anionic surfactant. Examples thereof include agents and nonionic surfactants.
　又、クリーム剤に配合される添加剤としては、油溶性物質、水溶性物質、乳化剤等が挙げられる。油溶性物質には高級炭化水素、油脂類、ロウ類、脂肪酸、高級アルコール、エステル類等を用いることができる。高級炭化水素としては、例えば、スクワラン、合成パラフィン、流動パラフィン、白色ワセリン、マイクロクリスタリンワックス等が挙げられ、ロウ類としては、ミツロウ、サラシミツロウ、ラノリン、セレシンロウ等が挙げられ、脂肪酸としては、ステアリン酸、オレイン酸等が挙げられ、高級アルコールとしては、ラノリンアルコール、ミリスチルアルコール、セチルアルコール、ステアリルアルコール、セトステアリルアルコール、コレステロール等が挙げられ、エステル類としては、ミリスチン酸イソプロピル、ミリスチン酸ステアリル等が挙げられる。 Moreover, as an additive mix | blended with a cream, an oil-soluble substance, a water-soluble substance, an emulsifier, etc. are mentioned. As the oil-soluble substance, higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc., waxes include beeswax, white beeswax, lanolin, ceresin wax and the like, and fatty acids include stearin. Acid, oleic acid, etc., higher alcohols include lanolin alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol, etc., and esters include isopropyl myristate, stearyl myristate, etc. Can be mentioned.
　水溶性物質としては、水（精製水）、増粘剤、保湿剤等を用いることができる。増粘剤としては、カルボキシビニルポリマー、カルボキシメチルセルロース等が挙げられ、保湿剤としては、グリセリン、プロピレングリコール、１，３－ブチレングリコール等が挙げられる。 As water-soluble substances, water (purified water), thickeners, humectants, and the like can be used. Examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose, and examples of the humectant include glycerin, propylene glycol, and 1,3-butylene glycol.
　乳化剤としては、陽イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤等が挙げられる。 Examples of the emulsifier include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.
　更に、外用液剤ないしスプレー剤に配合される添加剤としては、油溶性物質、水溶性物質、乳化剤等が挙げられる。油溶性物質には炭化水素類、油脂類、ロウ類、脂肪酸、高級アルコール、エステル類等を用いることができる。炭化水素類としては、例えば、スクワラン、α－オレフィンオリゴマー、合成パラフィン、流動パラフィン、白色ワセリン、マイクロクリスタリンワックス等が挙げられ、ロウ類としては、ミツロウ、サラシミツロウ、ラノリン、セレシンロウ等が挙げられ、脂肪酸としては、ステアリン酸、オレイン酸等が挙げられ、高級アルコールとしては、ラノリンアルコール、セチルアルコール、セトステアリルアルコール等が挙げられ、エステル類としては、ミリスチン酸イソプロピル、ミリスチン酸ステアリル、ミリスチン酸オクチルドデシル等が挙げられる。 Furthermore, examples of the additive added to the external liquid or spray include oil-soluble substances, water-soluble substances, and emulsifiers. As the oil-soluble substance, hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of hydrocarbons include squalane, α-olefin oligomers, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, and waxes include beeswax, white beeswax, lanolin, ceresin wax, and the like. Examples of fatty acids include stearic acid and oleic acid, examples of higher alcohols include lanolin alcohol, cetyl alcohol, and cetostearyl alcohol. Examples of esters include isopropyl myristate, stearyl myristate, and octyldodecyl myristate. Etc.
　水溶性物質としては、水（精製水）、増粘剤、保湿剤等を用いることができる。増粘剤としては、カルボキシビニルポリマー、カルボキシメチルセルロース等が挙げられ、保湿剤としては、グリセリン、１，３－ブチレングリコール等が挙げられる。 As water-soluble substances, water (purified water), thickeners, humectants, and the like can be used. Examples of the thickener include carboxyvinyl polymer and carboxymethylcellulose, and examples of the humectant include glycerin and 1,3-butylene glycol.
　乳化剤としては、陽イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤等が挙げられる。 Examples of the emulsifier include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.
　ゲル剤に配合される添加剤としては、基剤等が挙げられ、基剤にはイソプロパノール、プロピレングリコール等が使用される。 Examples of the additive blended in the gel include bases, and isopropanol, propylene glycol and the like are used as the base.
　本発明において上記の各製剤で使用できる陽イオン性界面活性剤の具体例としては、例えば、セチルトリメチルアンモニウムクロリド、ラウリルジメチルベンジルアンモニウムクロリド、テトラブチルアンモニウムクロリド、ジオクタデシルジメチルアンモニウムクロリド等が挙げられる。
　陰イオン性界面活性剤としては、例えばアルキルベンゼンスルホン酸ナトリウム、ドデシル硫酸ナトリウム、ヤシアルコールエトキシ硫酸ナトリウム、α－オレフィンスルホン酸ナトリウム、乳化セトステアリルアルコール等が挙げられる。
　非イオン性界面活性剤としては、ポリオキシエチレンオレイルエーテル、ポリオキシエチレンオクチルドデシルエーテル等のポリオキシエチレンアルキルエーテル、ポリオキシエチレンアルキルフェノールエーテル、ポリオキシエチレン硬化ヒマシ油、ステアリン酸ポリオキシル、モノステアリン酸グリセリン、自己乳化型モノステアリン酸グリセリン、モノイソステアリン酸グリセリン、パルミチン酸グリセリン、ミリスチン酸グリセリン、オレイン酸グリセリン、トリイソオクタン酸グリセリン等のグリセリン脂肪酸エステル、ラウリン酸ジグリセリン、ステアリン酸ジグリセリン、オレイン酸ジグリセリン等のジグリセリン脂肪酸エステル、モノパルミチン酸ソルビタン、モノステアリン酸ソルビタン、モノオレイン酸ソルビタン、ヤシ油脂肪酸ソルビタン、トリステアリン酸ソルビタン、トリオレイン酸ソルビタン等のソルビタン脂肪酸エステル、モノラウリン酸ポリエチレングリコール、モノステアリン酸ポリエチレングリコール、モノオレイン酸ポリエチレングリコール等のポリエチレングリコール脂肪酸エステル等が例示できる。
　両性界面活性剤としては、例えば、Ｎ－アルキル－Ｎ，Ｎ－ジメチルアンモニウムベタイン、イミダゾリン型両性界面活性剤等が挙げられる。
　上記界面活性剤はいずれも、単独又は組み合わせて使用することができる。 Specific examples of the cationic surfactant that can be used in each of the above preparations in the present invention include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, dioctadecyldimethylammonium chloride, and the like.
Examples of the anionic surfactant include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, coconut alcohol sodium ethoxy sulfate, sodium α-olefin sulfonate, emulsified cetostearyl alcohol and the like.
Nonionic surfactants include polyoxyethylene alkyl ethers such as polyoxyethylene oleyl ether and polyoxyethylene octyldodecyl ether, polyoxyethylene alkylphenol ether, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and glyceryl monostearate. Glycerin fatty acid esters such as glyceryl monostearate, glyceryl monostearate, glyceryl palmitate, glyceryl myristate, glyceryl oleate, glyceryl triisooctanoate, diglycerin laurate, diglyceryl stearate, diglycerin oleate Diglycerin fatty acid esters such as sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, Oil fatty acid sorbitan, sorbitan tristearate, sorbitan fatty acid esters such as sorbitan trioleate, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyethylene glycol fatty acid esters such as polyethylene glycol monooleate and the like.
Examples of the amphoteric surfactant include N-alkyl-N, N-dimethylammonium betaine and imidazoline type amphoteric surfactant.
Any of the above surfactants can be used alone or in combination.
　上記の軟膏剤、硬膏剤、貼付剤、クリーム剤、外用液剤、スプレー剤、ゲル剤等の剤型において、必要によりｐＨ調節剤、保存剤、マクロゴール類等が使用される。 In the above-mentioned ointments, plasters, patches, creams, liquids for external use, sprays, gels, etc., pH adjusters, preservatives, macrogols, etc. are used as necessary.
　ｐＨ調節剤としては、例えば、ジイソプロパノールアミン、トリイソプロパノールアミン、トリエタノールアミン、水酸化カリウム、水酸化ナトリウム、クエン酸ナトリウム、リン酸、酒石酸、ｄｌ－リンゴ酸、氷酢酸等が挙げられ、保存剤としては、チモール、ジブチルヒドロキシトルエン、エデト酸ナトリウム水和物、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル等が挙げられる。
　以下、本発明の実施例を示して本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。 Examples of the pH regulator include diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, sodium citrate, phosphoric acid, tartaric acid, dl-malic acid, glacial acetic acid and the like. Examples of the agent include thymol, dibutylhydroxytoluene, sodium edetate hydrate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.
EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples of the present invention, but the present invention is not limited to the following examples.
［実施例１］モルモット乾燥皮膚モデルにおけるＰＰＳの作用
　ＰＰＳを含むカルトロフェン・べット注射液（１００ｍｇ／ｍＬ、ＤＳファーマアニマルヘルス株式会社）を０．０１％Ｔｗｅｅｎ８０水溶液で希釈して、試験溶液を作製した。
　試験動物として、モルモット（Ｓｌｃ：Ｈａｒｔｌｅｙ、雌性、３週齢）各群６匹を用いた。上記モルモットをアセトン／エーテル（１：１）混液及び水で処置（Ａ／Ｅ／Ｗ処置）し、この処置を経表皮水分蒸散量（ＴＥＷＬ）値が３０～５０ｇ／ｈｍ２となるまで繰り返して、乾燥皮膚モデルを作製した。
　コントロール（０．０１％Ｔｗｅｅｎ８０）、０．０３％ＰＰＳ溶液及び０．３％ＰＰＳ溶液（いずれも、％ｗ／ｖ）を、Ａ／Ｅ／Ｗ処置初日から１日１回５日間、０．０１ｍＬ（１ｃｍ２）で塗布した。
　Ａ／Ｅ／Ｗ処置前、処置直後（Ｄａｙ０）及び処置後１～５日後のＴＥＷＬ値及び角層水分含量を測定した。ＴＥＷＬ値はポータブル水分蒸散計Ｖａｐｏｍｅｔｅｒ（デルフィンテクノロジーズ社）を用いて測定し、皮膚バリア機能回復作用の指標として評価した。角層水分含量は表皮角層水分量測定装置ＳＫＩＣＯＮ－２００ＥＸ（株式会社ヤヨイ）を用いて高周波伝導度として測定し、角質水分保持増強作用の指標として評価した。
　ＴＥＷＬ回復率は以下の式により算出した。
Figure JPOXMLDOC01-appb-M000001
 [Example 1] Action of PPS in a guinea pig dry skin model A cartropen bet injection solution containing PPS (100 mg / mL, DS Pharma Animal Health Co., Ltd.) was diluted with a 0.01% Tween 80 aqueous solution to prepare a test solution. Produced.
As test animals, 6 guinea pigs (Slc: Hartley, female, 3 weeks old) were used in each group. The guinea pig is treated with an acetone / ether (1: 1) mixture and water (A / E / W treatment), and this treatment is repeated until the transepidermal water transpiration (TEWL) value is 30 to 50 g / hm 2. A dry skin model was prepared.
Control (0.01% Tween 80), 0.03% PPS solution and 0.3% PPS solution (both in% w / v) were administered once daily from the first day of A / E / W treatment for 5 days. It was applied at 01 mL (1 cm 2 ).
The TEWL value and stratum corneum moisture content were measured before A / E / W treatment, immediately after treatment (Day 0) and 1 to 5 days after treatment. The TEWL value was measured using a portable moisture transpiration meter Vapometer (Delphine Technologies) and evaluated as an index of the skin barrier function recovery action. The stratum corneum moisture content was measured as high-frequency conductivity using an epidermis stratum corneum moisture measuring device SKICON-200EX (Yayoi Co., Ltd.) and evaluated as an index of a stratum corneum moisture retention enhancing action.
The TEWL recovery rate was calculated by the following formula.
Figure JPOXMLDOC01-appb-M000001
　結果を図１及び図２に示す。図中の＃Ｐ＜０．０５、＃＃Ｐ＜０．０１はコントロール群に対する有意差を示す。図１の結果から、ＴＥＷＬ回復率を指標として、ＰＰＳが皮膚バリア機能回復作用を有することが確認され、図２の結果から、角層水分含量を指標として、ＰＰＳが角質水分保持増強作用を有することが確認された。なお、別途の試験によりＰＰＳには膜形成作用が確認されなかったので、上記モルモット乾燥モデルで認められたＰＰＳによるＴＥＷＬ回復率の上昇は、単純な膜形成作用によるものではないと考えられる。 The results are shown in FIG. 1 and FIG. In the figure, #P <0.05 and ## P <0.01 indicate significant differences from the control group. From the results of FIG. 1, it was confirmed that PPS has a skin barrier function recovery action using TEWL recovery rate as an index. From the results of FIG. 2, PPS has a stratum corneum water retention enhancing function using stratum corneum water content as an index. It was confirmed. In addition, since a film forming action was not confirmed in PPS by a separate test, it is considered that the increase in TEWL recovery rate due to PPS recognized in the guinea pig drying model is not due to a simple film forming action.
［実施例２］ＰＰＳの角層ホモジネート存在下における結合水量
　ＰＰＳとして、Ｍｏｌｃｌｏｎｅ　Ｌａｂｓ社製のペントサンポリ硫酸ナトリウム（重量平均分子量４０００～６５００、硫黄含量１３．０～２０．０％ｗ／ｗ、グルクロン酸含量２．５～４．０％ｗ／ｗ）を使用した。
　ヒト皮膚試料（背部）（特定非営利活動法人エイチ・エー・ビー研究機構より購入）を用いて、ＰＰＳ含有角層ホモジネート水溶液（ＰＰＳ終濃度：０、０．３、１、３、１０及び２０％ｗ／ｖ）を調製し、高感度型示差走査熱量計ＤＳＣ７０００Ｘ（株式会社日立ハイテクサイエンス）を用いて、５℃／分の昇温速度で－３０℃から２５℃まで昇温させたときの融解熱（ΔＨ（Ｊ／ｇ））を測定した。測定は３回行った。
　得られたΔＨから以下の式に従い、試料１ｇ当たりの自由水量及び結合水量並びに角層１ｇ当たりの見かけの結合水量を算出した。
Figure JPOXMLDOC01-appb-M000002
 [Example 2] Amount of bound water in the presence of PPS stratum corneum homogenate As PPS, sodium pentosan polysulfate (weight average molecular weight 4000-6500, sulfur content 13.0-20.0% w / w, glucuron, manufactured by Mollone Labs) An acid content of 2.5-4.0% w / w) was used.
Using a human skin sample (back) (purchased from the non-profit organization HB Research Organization), a PPS-containing stratum corneum homogenate aqueous solution (PPS final concentration: 0, 0.3, 1, 3, 10, and 20) % W / v) and using a high-sensitivity differential scanning calorimeter DSC7000X (Hitachi High-Tech Science Co., Ltd.), the temperature was increased from −30 ° C. to 25 ° C. at a temperature increase rate of 5 ° C./min. The heat of fusion (ΔH (J / g)) was measured. The measurement was performed 3 times.
From the obtained ΔH, the amount of free water and bound water per gram of sample and the apparent amount of bound water per gram of stratum corneum were calculated according to the following formula.
Figure JPOXMLDOC01-appb-M000002
　角層における結合水量の結果を図３に示す。図３の結果から、単位重量当たりのヒト角層（ｇ）に対する見かけの結合水量はＰＰＳの濃度に応じて増加し、角層存在下において、ＰＰＳが水分保持作用を有することが確認された。 The result of the amount of bound water in the stratum corneum is shown in FIG. From the results shown in FIG. 3, it was confirmed that the apparent amount of water bound to the human stratum corneum (g) per unit weight increased according to the concentration of PPS, and that PPS has a water retaining action in the presence of the stratum corneum.
［実施例３］ＰＰＳのヒト表皮角化細胞におけるフィラグリン及びカスパーゼ１４発現作用
　ＰＰＳとして、Ｍｏｌｃｌｏｎｅ　Ｌａｂｓ社製のペントサンポリ硫酸ナトリウム（重量平均分子量４０００～６５００、硫黄含量１３．０～２０．０％ｗ／ｗ、グルクロン酸含量２．５～４．０％ｗ／ｗ）を使用した。比較用の対照物質としては、キシロヘキサオース（略称：Ｏ－ＸＨＥ、Ｍｅｇａｚｙｍｅ社）、ヒアルロン酸（略称：ＨＡ、東京化成工業株式会社）及びコンドロイチン硫酸（略称：ＣｈＳ、マルホ株式会社）を用いた。 [Example 3] Expression of filaggrin and caspase 14 in human epidermal keratinocytes by PPS As PPS, sodium pentosan polysulfate (weight average molecular weight 4000-6500, sulfur content 13.0-20.0% w) manufactured by Molcone Labs. / W, glucuronic acid content 2.5-4.0% w / w). As control substances for comparison, xylohexaose (abbreviation: O-XHE, Megazyme), hyaluronic acid (abbreviation: HA, Tokyo Chemical Industry Co., Ltd.) and chondroitin sulfate (abbreviation: ChS, Maruho Co., Ltd.) were used. .
　成人ヒト表皮角化細胞（Thermo Fisher Scientific社より購入）の細胞浮遊液を１．２５×１０5細胞／ウェルで２４ウェルマイクロプレートに播種し、３７℃、５％ＣＯ２、９５％ａｉｒで培養した。その翌日に評価物質（ＰＰＳ及び対照物質）の１つを含有する培地（０．１、１、１０μｇ／ｍＬ）又は非含有培地を、５００μＬ／ウェルとなるように前記の細胞を播種したウェルに添加し、３７℃、５％ＣＯ２、９５％ａｉｒで２４時間培養した。培養上清を除去し、ＰＢＳで細胞を洗浄した後、RNeasy Plus Mini Kit（QIAGEN社）を用いてtotal ＲＮＡを抽出した。その後、High-Capacity cDNA Reverse Transcription Kit（Applied Biosystems社）を用いてｃＤＮＡを合成した。合成したｃＤＮＡ、TaqMan Gene Expression Master Mix（Applied Biosystems社）、TaqMan Gene Expression Assays（Applied Biosystems社）を混合し、フィラグリン及びカスパーゼ１４のｍＲＮＡ量を、リアルタイムＰＣＲシステム（Applied Biosystems社）を用いて測定した。なお、コントロール遺伝子として、ＧＡＰＤＨを使用し、サンプル間の変動を補正した。相対発現量は、評価物質非添加群の発現量を１とした場合の各評価物質添加群の発現量比を示す。各評価物質添加群及び非添加群は４例（ｎ＝４）とした。 Cell suspension of adult human epidermal keratinocytes (purchased from Thermo Fisher Scientific) is seeded on a 24-well microplate at 1.25 × 10 5 cells / well and cultured at 37 ° C., 5% CO 2 , 95% air. did. On the next day, a medium (0.1, 1, 10 μg / mL) containing one of the evaluation substances (PPS and control substance) or a non-containing medium is added to the wells seeded with the cells so as to be 500 μL / well. Then, the cells were cultured at 37 ° C., 5% CO 2 and 95% air for 24 hours. After removing the culture supernatant and washing the cells with PBS, total RNA was extracted using RNeasy Plus Mini Kit (QIAGEN). Thereafter, cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). Synthesized cDNA, TaqMan Gene Expression Master Mix (Applied Biosystems) and TaqMan Gene Expression Assays (Applied Biosystems) were mixed, and the amount of filaggrin and caspase 14 mRNA was measured using a real-time PCR system (Applied Biosystems). . In addition, GAPDH was used as a control gene, and the variation between samples was corrected. The relative expression level indicates the expression level ratio of each evaluation substance addition group when the expression level of the evaluation substance non-addition group is 1. Each evaluation substance addition group and non-addition group were made into 4 cases (n = 4).
　結果を図４及び５に示す。図中の＊Ｐ＜０．０５、＊＊Ｐ＜０．０１はコントロール群に対する有意差を示す。
　ＰＰＳ添加群では、フィラグリンの発現量の増加、及びカスパーゼ１４の濃度依存的な発現量の増加が確認された。また、対照物質Ｏ－ＸＨＥ、ＨＡ及びＣｈＳと比較して、ＰＰＳ添加群でのカスパーゼ１４の発現増加は顕著であった。これらの結果から、ＰＰＳは表皮角化細胞におけるフィラグリン及びカスパーゼ１４の発現増加作用を有し、角質バリア機能の形成や水分保持を改善することが示唆された。 The results are shown in FIGS. * P <0.05 and ** P <0.01 in the figure indicate significant differences from the control group.
In the PPS addition group, an increase in the expression level of filaggrin and an increase in the expression level dependent on the concentration of caspase 14 were confirmed. In addition, compared with the control substances O-XHE, HA and ChS, the increase in the expression of caspase 14 in the PPS addition group was remarkable. From these results, it was suggested that PPS has an action of increasing the expression of filaggrin and caspase 14 in epidermal keratinocytes, and improves the formation of keratin barrier function and water retention.
［実施例４］ＰＰＳのヒト表皮角化細胞におけるタイトジャンクションタンパク発現作用
　ＰＰＳとして、Ｍｏｌｃｌｏｎｅ　Ｌａｂｓ社製のペントサンポリ硫酸ナトリウム（重量平均分子量４０００～６５００、硫黄含量１３．０～２０．０％ｗ／ｗ、グルクロン酸含量２．５～４．０％ｗ／ｗ）を使用した。比較用の対照物質としては、実施例３と同様、Ｏ－ＸＨＥ、ＨＡ及びＣｈＳを用いた。
　成人ヒト表皮角化細胞（Thermo Fisher Scientific社より購入）の細胞浮遊液を１．２５×１０5細胞／ウェルで２４ウェルマイクロプレートに播種し、３７℃、５％ＣＯ２、９５％ａｉｒで培養した。その翌日に評価物質（ＰＰＳ及び対照物質）の１つを含有する培地（０．１、１、１０μｇ／ｍＬ）又は非含有培地を、５００μＬ／ウェルとなるように前記の細胞を播種したウェルに添加し、３７℃、５％ＣＯ２、９５％ａｉｒで２４時間培養した。培養上清を除去し、ＰＢＳで細胞を洗浄した後、RNeasy Plus Mini Kit（QIAGEN社）を用いてtotal ＲＮＡを抽出した。その後、High-Capacity cDNA Reverse Transcription Kit（Applied Biosystems社）を用いてｃＤＮＡを合成した。合成したｃＤＮＡ、TaqMan Gene Expression Master Mix（Applied Biosystems社）、TaqMan Gene Expression Assays（Applied Biosystems社）を混合し、クローディン-１、オクルディン、及びＺＯ－１のｍＲＮＡ量をリアルタイムＰＣＲシステム（Applied Biosystems社）を用いて測定した。なお、コントロール遺伝子として、ＧＡＰＤＨを使用し、サンプル間の変動を補正した。相対発現量は、評価物質非添加群の発現量を１とした場合の各評価物質添加群の発現量比を示す。各評価物質添加群及び非添加群は４例（ｎ＝４）とした。 [Example 4] Action of expression of tight junction protein in human epidermal keratinocytes of PPS As PPS, sodium pentosan polysulfate (weight average molecular weight: 4000-6500, sulfur content: 13.0-20.0% w / m) manufactured by Mollone Labs. w, glucuronic acid content 2.5-4.0% w / w). As comparative materials for comparison, O-XHE, HA and ChS were used as in Example 3.
Cell suspension of adult human epidermal keratinocytes (purchased from Thermo Fisher Scientific) is seeded on a 24-well microplate at 1.25 × 10 5 cells / well and cultured at 37 ° C., 5% CO 2 , 95% air. did. On the next day, a medium (0.1, 1, 10 μg / mL) containing one of the evaluation substances (PPS and control substance) or a non-containing medium is added to the wells seeded with the cells so as to be 500 μL / well. Then, the cells were cultured at 37 ° C., 5% CO 2 and 95% air for 24 hours. After removing the culture supernatant and washing the cells with PBS, total RNA was extracted using RNeasy Plus Mini Kit (QIAGEN). Thereafter, cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). The synthesized cDNA, TaqMan Gene Expression Master Mix (Applied Biosystems) and TaqMan Gene Expression Assays (Applied Biosystems) are mixed, and the mRNA levels of claudin-1, occludin, and ZO-1 are mixed with a real-time PCR system (Applied Biosystems). ). In addition, GAPDH was used as a control gene, and the variation between samples was corrected. The relative expression level indicates the expression level ratio of each evaluation substance addition group when the expression level of the evaluation substance non-addition group is 1. Each evaluation substance addition group and non-addition group were made into 4 cases (n = 4).
　結果を図６～８に示す。図中の＊Ｐ＜０．０５、＊＊Ｐ＜０．０１はコントロール群に対する有意差を示す。ＰＰＳ添加群では、各種タイトジャンクションタンパクの濃度依存的な発現量の増加が確認された。また、対照物質Ｏ－ＸＨＥ、ＨＡ及びＣｈＳと比較して、ＰＰＳ添加群での各種タイトジャンクションタンパクの発現増加は顕著であった。これらの結果から、ＰＰＳは表皮角化細胞におけるバリア機能関連因子の発現増加作用を有し、皮膚バリア機能を改善することが示唆された。 The results are shown in Figs. * P <0.05 and ** P <0.01 in the figure indicate significant differences from the control group. In the PPS addition group, the concentration-dependent increase in the expression level of various tight junction proteins was confirmed. In addition, as compared with the control substances O-XHE, HA and ChS, the increase in expression of various tight junction proteins in the PPS addition group was remarkable. From these results, it was suggested that PPS has an action of increasing the expression of a barrier function-related factor in epidermal keratinocytes and improves the skin barrier function.

Claims (5)

  1. 　皮膚バリア機能の改善作用を有する皮膚外用組成物であって、有効成分としてペントサンポリ硫酸及び／又はその塩を含有することを特徴とする、皮膚外用組成物。 An external composition for skin having an action of improving the skin barrier function, comprising pentosan polysulfate and / or a salt thereof as an active ingredient.
  2. 　前記有効成分がペントサンポリ硫酸ナトリウムである、請求項１に記載の組成物。 The composition according to claim 1, wherein the active ingredient is sodium pentosan polysulfate.
  3. 　タイトジャンクションを形成するタンパク質の減少によって引き起こされる疾患を予防及び／又は治療するために用いられる、請求項１又は２に記載の組成物。 The composition according to claim 1 or 2, which is used for preventing and / or treating a disease caused by a decrease in a protein forming a tight junction.
  4. 　皮脂欠乏症、アトピー性皮膚炎、乾癬、皮脂欠乏性湿疹、手湿疹、魚鱗癬、及び酒さから成る群より選ばれた疾患を予防及び／又は治療するために用いられる、請求項１又は２に記載の組成物。 Use according to claim 1 or 2 for preventing and / or treating a disease selected from the group consisting of sebum deficiency, atopic dermatitis, psoriasis, sebum deficiency eczema, hand eczema, ichthyosis, and rosacea. The composition as described.
  5. 　アトピー性皮膚炎、魚鱗癬及び手湿疹より選ばれた疾患を予防及び／又は治療するために用いられる、請求項１又は２に記載の組成物。 The composition according to claim 1 or 2, which is used for preventing and / or treating a disease selected from atopic dermatitis, ichthyosis and hand eczema.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022114111A1 (en) * 2020-11-27 2022-06-02 マルホ株式会社 Pharmaceutical or cosmetic composition
WO2024050599A1 (en) * 2022-09-06 2024-03-14 Paradigm Biopharmaceuticals Ltd Treatment of psoriasis, psoriatic arthritis and dermatitis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5514667A (en) * 1990-11-05 1996-05-07 Arthropharm Pty. Limited Method for topical treatment of herpes infections
JP2009013134A (en) * 2007-07-06 2009-01-22 Maruho Co Ltd Barrier function recovery-accelerating agent
JP2017088559A (en) * 2015-11-12 2017-05-25 小林製薬株式会社 Filaggrin production enhancer
WO2018221547A1 (en) * 2017-05-31 2018-12-06 王子ホールディングス株式会社 Moisturizing topical preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5514667A (en) * 1990-11-05 1996-05-07 Arthropharm Pty. Limited Method for topical treatment of herpes infections
JP2009013134A (en) * 2007-07-06 2009-01-22 Maruho Co Ltd Barrier function recovery-accelerating agent
JP2017088559A (en) * 2015-11-12 2017-05-25 小林製薬株式会社 Filaggrin production enhancer
WO2018221547A1 (en) * 2017-05-31 2018-12-06 王子ホールディングス株式会社 Moisturizing topical preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HORIKAWA, TATSUYA: "Moisturizing provides benefits", FRAGRANCE JOURNAL, vol. 33, no. 9, September 2005 (2005-09-01), pages 107 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022114111A1 (en) * 2020-11-27 2022-06-02 マルホ株式会社 Pharmaceutical or cosmetic composition
WO2024050599A1 (en) * 2022-09-06 2024-03-14 Paradigm Biopharmaceuticals Ltd Treatment of psoriasis, psoriatic arthritis and dermatitis

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