JP2022133743A - Ceramide production promoter - Google Patents
Ceramide production promoter Download PDFInfo
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- 229940106189 ceramide Drugs 0.000 title claims abstract description 73
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 title claims abstract description 68
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 title claims abstract description 68
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 title claims abstract description 68
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 34
- 229920000642 polymer Polymers 0.000 claims abstract description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 210000002615 epidermis Anatomy 0.000 abstract description 10
- 239000000178 monomer Substances 0.000 description 20
- 238000006116 polymerization reaction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 10
- 210000003491 skin Anatomy 0.000 description 10
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- -1 2-ethylhexyl Chemical group 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000005227 gel permeation chromatography Methods 0.000 description 6
- 239000003505 polymerization initiator Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 150000001783 ceramides Chemical class 0.000 description 5
- 229920001577 copolymer Polymers 0.000 description 5
- 229920001519 homopolymer Polymers 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010012438 Dermatitis atopic Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 201000008937 atopic dermatitis Diseases 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 210000000434 stratum corneum Anatomy 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 206010048222 Xerosis Diseases 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 150000002305 glucosylceramides Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 208000017520 skin disease Diseases 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- NMOALOSNPWTWRH-UHFFFAOYSA-N tert-butyl 7,7-dimethyloctaneperoxoate Chemical compound CC(C)(C)CCCCCC(=O)OOC(C)(C)C NMOALOSNPWTWRH-UHFFFAOYSA-N 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- NJNWCIAPVGRBHO-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium Chemical group OCC[N+](C)(C)C#P=O NJNWCIAPVGRBHO-UHFFFAOYSA-N 0.000 description 2
- MKTOIPPVFPJEQO-UHFFFAOYSA-N 4-(3-carboxypropanoylperoxy)-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)OOC(=O)CCC(O)=O MKTOIPPVFPJEQO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BBAFBDLICMHBNU-MFZOPHKMSA-N N-(2-hydroxyoctadecanoyl)-4-hydroxysphinganine Chemical compound CCCCCCCCCCCCCCCCC(O)C(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC BBAFBDLICMHBNU-MFZOPHKMSA-N 0.000 description 2
- ATGQXSBKTQANOH-UWVGARPKSA-N N-oleoylphytosphingosine Chemical compound CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@H](CO)NC(=O)CCCCCCC\C=C/CCCCCCCC ATGQXSBKTQANOH-UWVGARPKSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
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- 229940079593 drug Drugs 0.000 description 2
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- ZSZRUEAFVQITHH-UHFFFAOYSA-N 2-(2-methylprop-2-enoyloxy)ethyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CC(=C)C(=O)OCCOP([O-])(=O)OCC[N+](C)(C)C ZSZRUEAFVQITHH-UHFFFAOYSA-N 0.000 description 1
- IXHVFQAWXRNZCZ-UHFFFAOYSA-N 2-methyl-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]peroxypropanoic acid Chemical compound CC(C)(C)OC(=O)C(C)(C)OOC(C)(C)C(O)=O IXHVFQAWXRNZCZ-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 231100000960 LabCyte EPI-MODEL 24 Toxicity 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- KZTJQXAANJHSCE-OIDHKYIRSA-N N-octodecanoylsphinganine Chemical compound CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)CCCCCCCCCCCCCCC KZTJQXAANJHSCE-OIDHKYIRSA-N 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 206010059516 Skin toxicity Diseases 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 210000005175 epidermal keratinocyte Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000036074 healthy skin Effects 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940056211 paraffin Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- BWJUFXUULUEGMA-UHFFFAOYSA-N propan-2-yl propan-2-yloxycarbonyloxy carbonate Chemical compound CC(C)OC(=O)OOC(=O)OC(C)C BWJUFXUULUEGMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000007870 radical polymerization initiator Substances 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 230000005808 skin problem Effects 0.000 description 1
- 231100000438 skin toxicity Toxicity 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
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- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- OPQYOFWUFGEMRZ-UHFFFAOYSA-N tert-butyl 2,2-dimethylpropaneperoxoate Chemical compound CC(C)(C)OOC(=O)C(C)(C)C OPQYOFWUFGEMRZ-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
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- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
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- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
Description
本発明は、皮膚表皮中のセラミドの組成バランスを整え、セラミド量を増加させるセラミド産生促進剤に関する。 TECHNICAL FIELD The present invention relates to a ceramide production promoter that adjusts the compositional balance of ceramide in the skin epidermis and increases the amount of ceramide.
皮膚の最外層に存在する角層は、表皮角化細胞由来の角層細胞で構成され、角層細胞の間をセラミド、コレステロール、脂肪酸からなる細胞間脂質がラメラ構造を形成して細胞間隔を埋めることにより、体内からの水分蒸散を抑制している。細胞間脂質の主成分であるセラミドは、加齢によって減少し、皮膚からの水分蒸散量が増大することで、かさつき、キメの乱れ、柔軟性低下、皮膚炎等、様々な皮膚トラブルが生じることが知られている。さらに、アトピー性皮膚炎、乾皮症、乾癬等の皮膚疾患では、セラミドの代謝が妨げられることで、角層中のセラミドが減少することも報告されている。
このようなセラミド減少による皮膚トラブルを抑制するために、セラミドを外部から補給する方法が試みられているが、この方法では、効果の持続性が不十分である。
The stratum corneum, which is the outermost layer of the skin, is composed of stratum corneum cells derived from epidermal keratinocytes. By burying it, the evaporation of water from the body is suppressed. Ceramide, which is the main component of intercellular lipids, decreases with age, and the amount of water that evaporates from the skin increases, causing various skin problems such as dryness, uneven texture, decreased flexibility, and dermatitis. It is known. Furthermore, it has also been reported that in skin diseases such as atopic dermatitis, xerosis and psoriasis, ceramide in the stratum corneum is reduced due to inhibition of ceramide metabolism.
In order to suppress such skin troubles due to reduction of ceramide, a method of supplying ceramide from the outside has been attempted, but this method has insufficient sustainability of effect.
そこで、表皮細胞のセラミド産生を促進する種々のセラミド産生促進剤が提案されている。例えば、セラミド前駆体であるグルコシルセラミド（特許文献１）や特定の植物抽出物（特許文献２）からなるセラミド産生促進剤が特定の皮膚中セラミド含量を増大させることが開示されている。
近年、セラミドの総量だけでなく、ヒト表皮内に１２種存在するセラミドの組成バランスも皮膚トラブルを抑制するために重要であることが示唆されている。例えば、アトピー性皮膚炎患者のセラミド組成バランスは健常皮膚のものとは大きく異なることが報告されている。しかしながら従来のセラミド産生促進剤は、特定のセラミド含量を増大させるものが多く、セラミドの組成バランスが崩れるといった課題があり、セラミドの組成比バランスを維持しつつ、セラミド含量を増大できるセラミド産生促進剤が求められていた。
Therefore, various ceramide production promoters have been proposed to promote ceramide production in epidermal cells. For example, it is disclosed that a ceramide production promoter consisting of a ceramide precursor glucosylceramide (Patent Document 1) or a specific plant extract (Patent Document 2) increases the specific ceramide content in the skin.
In recent years, it has been suggested that not only the total amount of ceramides but also the compositional balance of 12 types of ceramides present in the human epidermis are important for suppressing skin troubles. For example, it has been reported that the ceramide composition balance of patients with atopic dermatitis is significantly different from that of healthy skin. However, many of the conventional ceramide production promoters increase the specific ceramide content, and there is a problem that the compositional balance of ceramide is lost. was sought.
本発明の目的は、表皮中のセラミドの組成バランスを維持、調整しつつ、表皮中のセラミド含量を増大させることができるセラミド産生促進剤を提供することである。 An object of the present invention is to provide a ceramide production promoter capable of increasing the ceramide content in the epidermis while maintaining and adjusting the compositional balance of ceramide in the epidermis.
本発明者らは、皮膚刺激性、毒性のない安全な重合体である、ホスホリルコリン基を有する単量体の単独重合体又はホスホリルコリン基を有する単量体と他の単量体との共重合体について鋭意検討した結果、これらが皮膚になんら悪影響を及ぼすことなくセラミド産生促進剤として優れた特性を有することを見いだし、本発明を完成するに至った。
すなわち、本発明によれば、下記式（１）で表される構成単位を５０モル％以上有する、重量平均分子量２，０００～１，０００，０００の重合体Ａを含むことを特徴とするセラミド産生促進剤が提供される。
（式中、Ｒ１は水素原子又はメチル基を示す。）
The present inventors have developed a homopolymer of a monomer having a phosphorylcholine group or a copolymer of a monomer having a phosphorylcholine group and other monomers, which is a safe polymer without skin irritation and toxicity. As a result of intensive studies, the present inventors have found that these have excellent properties as ceramide production promoters without having any adverse effect on the skin, and have completed the present invention.
That is, according to the present invention, a ceramide characterized by comprising a polymer A having a weight average molecular weight of 2,000 to 1,000,000 and having 50 mol% or more of structural units represented by the following formula (1): A production promoter is provided.
(In the formula, R 1 represents a hydrogen atom or a methyl group.)
本発明のセラミド産生促進剤によれば、表皮におけるセラミドの組成バランスを維持、調整しつつ、表皮中のセラミド含量を増大させることができる。そのため、皮膚のバリア機能や保湿機能等の改善だけでなく、アトピー性皮膚炎や乾皮症、乾癬等の皮膚疾患患者の皮膚状態を改善することができる。 The ceramide production promoter of the present invention can increase the ceramide content in the epidermis while maintaining and adjusting the compositional balance of ceramide in the epidermis. Therefore, it is possible not only to improve the skin barrier function, moisturizing function, etc., but also to improve the skin condition of patients with skin diseases such as atopic dermatitis, xerosis, and psoriasis.
以下、さらに詳細に本発明の説明をする。
本発明のセラミド産生促進剤は、前記式（１）で示される構成単位を有する重合体Ａを含む。該重合体Ａはセラミド産生促進能を有する基剤成分である。
式（１）において、Ｒ１は水素原子又はメチル基を示す。
式（１）で表される構成単位は、下記式（１’）で表される単量体である２－（（メタ）アクリロイルオキシ）エチル‐２’－（トリメチルアンモニオ）エチルホスフェートの重合から誘導される構成単位である。該単量体としては、２－（メタクリロイルオキシ）エチル‐２’－（トリメチルアンモニオ）エチルホスフェート（以下、ＭＰＣと略す）が好ましい。
The present invention will now be described in more detail.
The ceramide production promoter of the present invention contains a polymer A having a structural unit represented by the formula (1). The polymer A is a base component capable of promoting ceramide production.
In formula (1), R 1 represents a hydrogen atom or a methyl group.
Polymerization of 2-((meth)acryloyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate, which is a monomer represented by the following formula (1'), is a structural unit represented by formula (1): is a structural unit derived from As the monomer, 2-(methacryloyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate (hereinafter abbreviated as MPC) is preferred.
（式中Ｒ１は水素原子又はメチル基を示す。）
(In the formula, R1 represents a hydrogen atom or a methyl group.)
本発明のセラミド産生促進剤に含まれる重合体Ａは、式（１）で表される構成単位を５０モル％以上含有する。式（１）で表される構成単位が５０モル％未満であると、セラミド産生促進効果が低下する。重合体Ａにおける式（１）で表される構成単位は、好ましくは６０モル％以上であり、より好ましくは７０モル％以上である。
重合体Ａは１種の重合体のみからなるものであってもよいし、２種以上の重合体を併用するものであってもよい。
Polymer A contained in the ceramide production promoter of the present invention contains 50 mol % or more of the structural unit represented by formula (1). If the structural unit represented by formula (1) is less than 50 mol%, the effect of promoting ceramide production is reduced. The structural unit represented by formula (1) in the polymer A is preferably 60 mol% or more, more preferably 70 mol% or more.
The polymer A may consist of only one kind of polymer, or may use two or more kinds of polymers in combination.
重合体Ａは、式（１）で表される構成単位以外の構成単位を含んでもよい。式（１）で表される構成単位以外の構成単位としては、以下の式（２）で表される構成単位が好ましい。
（式中Ｒ２は水素原子又はメチル基を示す。Ｒ３は炭素数１～２２の直鎖または分岐を有していてもよいアルキル基を示す。）
Polymer A may contain a structural unit other than the structural unit represented by formula (1). As a structural unit other than the structural unit represented by formula (1), a structural unit represented by the following formula (2) is preferable.
(In the formula, R 2 represents a hydrogen atom or a methyl group. R 3 represents an optionally linear or branched alkyl group having 1 to 22 carbon atoms.)
重合体Ａが式（２）で表される構成単位を含む場合は、重合体Ａにおける式（２）で表される構成単位は、好ましくは５モル％以上であり、より好ましくは１０モル％以上であり、そして、５０モル％未満であり、好ましくは４０モル％以下であり、さらに好ましくは３０モル％以下である。 When polymer A contains a structural unit represented by formula (2), the structural unit represented by formula (2) in polymer A is preferably 5 mol% or more, more preferably 10 mol%. and is less than 50 mol %, preferably 40 mol % or less, more preferably 30 mol % or less.
上記式（２）で表される構成単位は、下記式（２’）で表される単量体の重合から誘導される構成単位である。
（式中Ｒ２は水素原子又はメチル基を示す。Ｒ３は炭素数１～２２の直鎖または分岐を有していてもよいアルキル基を示す。）
The structural unit represented by the above formula (2) is a structural unit derived from polymerization of a monomer represented by the following formula (2').
(In the formula, R 2 represents a hydrogen atom or a methyl group. R 3 represents an optionally linear or branched alkyl group having 1 to 22 carbon atoms.)
式（２’）で表される単量体としては、例えば、メチル（メタ）アクリレート、エチル（メタ）アクリレート、ブチル（メタ）アクリレート、２－エチルヘキシル（メタ）アクリレート、デシル（メタ）アクリレート、ドデシル（メタ）アクリレート、テトラデシル（メタ）アクリレート、ヘキサデシル（メタ）アクリレート、オクタデシル（メタ）アクリレート、ドコサニル（メタ）アクリレート等の直鎖または分岐アルキル（メタ）アクリレート等が挙られるが、ブチルメタクリレートが好ましい。また、式（２’）で表される単量体として、これらの１種または２種以上を混合して用いても良い。 Examples of monomers represented by formula (2′) include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, decyl (meth) acrylate, dodecyl Linear or branched alkyl (meth)acrylates such as (meth)acrylate, tetradecyl (meth)acrylate, hexadecyl (meth)acrylate, octadecyl (meth)acrylate, docosanyl (meth)acrylate and the like can be mentioned, but butyl methacrylate is preferred. Also, as the monomer represented by the formula (2'), one or a mixture of two or more of these may be used.
本発明のセラミド産生促進剤に含まれる重合体Ａは、上記した式（１’）で表される単量体、及び必要に応じて配合される式（２’）で表される単量体を含む単量体組成物をラジカル重合することによって得ることができる。該単量体組成物は、上記単量体の他に、共重合可能な他の重合性単量体を含んでいてもよい。 The polymer A contained in the ceramide production accelerator of the present invention is the monomer represented by the above formula (1′), and the monomer represented by the formula (2′) blended as necessary. It can be obtained by radically polymerizing a monomer composition containing. The monomer composition may contain other copolymerizable polymerizable monomers in addition to the above monomers.
本発明のセラミド産生促進剤に含まれる重合体Ａの重量平均分子量は、製造する際の重合温度、重合開始剤使用量、重合度調整剤の使用等によって様々なものとなるが、２，０００～１，０００，０００であり、好ましくは５，０００～１，０００，０００の範囲内である。さらに好ましくは、１０，０００～６００，０００の範囲内である。重量平均分子量が２０００未満となるよう重合体の分子量制御をすることは難しく、重量平均分子量が１，０００，０００超であると粘度が高くなり取り扱いにくくなる。重合体Ａの重量平均分子量は、ゲルパーミエーションクロマトグラフィー（ＧＰＣ）を用いてポリエチレングリコール換算で求めることができ、詳細は実施例に記載のとおりである。 The weight-average molecular weight of the polymer A contained in the ceramide production accelerator of the present invention varies depending on the polymerization temperature during production, the amount of polymerization initiator used, the use of the degree-of-polymerization modifier, etc., but is 2,000. ~1,000,000, preferably within the range of 5,000 to 1,000,000. More preferably, it is within the range of 10,000 to 600,000. It is difficult to control the molecular weight of the polymer so that the weight average molecular weight is less than 2,000. The weight-average molecular weight of polymer A can be determined in terms of polyethylene glycol using gel permeation chromatography (GPC), and the details are as described in Examples.
前記ラジカル重合を行なう際には、単量体組成物に重合開始剤を添加して重合することができる。重合開始剤としては、通常のラジカル重合開始剤であれば特に限定されないが、例えば２，２’－アゾビスイソブチロニトリル、過酸化ベンゾイル、ジイソプロピルペルオキシジカーボネート、ｔ－ブチルペルオキシ－２－エチルヘキサノエート、ｔ－ブチルペルオキシピバレ－ト、ｔ－ブチルペルオキシジイソブチレ－ト、ｔ－ブチルペルオキシネオデカノエート、サクシニルペルオキシド、過硫酸カリウム、過硫酸アンモニウム等の過硫酸塩等が挙げられる。これらの重合開始剤は単独又は混合物として用いることができる。また、重合開始剤と共に、レドックス系のラジカル促進剤を併用してもよい。
重合開始剤の使用量としては全単量体１００重量部に対して０．０１～１０重量部が好ましく、特に好ましくは０．１～５重量部である。
When carrying out the radical polymerization, a polymerization initiator can be added to the monomer composition for polymerization. The polymerization initiator is not particularly limited as long as it is an ordinary radical polymerization initiator, and examples include 2,2'-azobisisobutyronitrile, benzoyl peroxide, diisopropylperoxydicarbonate, t-butylperoxy-2-ethyl. persulfates such as hexanoate, t-butylperoxypivalate, t-butylperoxydiisobutyrate, t-butylperoxyneodecanoate, succinylperoxide, potassium persulfate, ammonium persulfate, and the like; These polymerization initiators can be used alone or as a mixture. A redox radical accelerator may be used together with the polymerization initiator.
The amount of the polymerization initiator to be used is preferably 0.01 to 10 parts by weight, particularly preferably 0.1 to 5 parts by weight, per 100 parts by weight of all the monomers.
前記重合を行なう際の重合条件は、好ましくは３０～８０℃、特に好ましくは４０～７０℃において１０分～７２時間重合させるのが望ましい。この際、重合反応をより円滑に行なうために溶媒を用いてもよく、該溶媒としては、水、メタノ－ル、エタノ－ル、プロパノ－ル、ジメチルホルムアミド及びこれらの混合物等を挙げることができる。 The polymerization conditions for the above polymerization are preferably 30 to 80° C., more preferably 40 to 70° C., for 10 minutes to 72 hours. In this case, a solvent may be used in order to facilitate the polymerization reaction, and examples of the solvent include water, methanol, ethanol, propanol, dimethylformamide and mixtures thereof. .
本発明のセラミド産生促進剤は、医薬品、医薬部外品、化粧品等に配合する場合、好ましくは、０．０２～１０質量％、さらに好ましくは、０．０５～２質量％、より好ましくは、０．１～１質量％配合される。 When the ceramide production promoter of the present invention is incorporated in pharmaceuticals, quasi-drugs, cosmetics, etc., it is preferably 0.02 to 10% by mass, more preferably 0.05 to 2% by mass, more preferably 0.1 to 1% by mass is blended.
本発明のセラミド産生促進剤における式（１）で示される構成単位を有する重合体Ａの含有量は、好ましくは５０～１００質量％であり、より好ましくは８０～１００質量％である。 The content of the polymer A having the structural unit represented by formula (1) in the ceramide production promoter of the present invention is preferably 50 to 100% by mass, more preferably 80 to 100% by mass.
本発明のセラミド産生促進剤は、式（１）で示される構成単位を有する重合体Ａ以外に、他の成分を配合することができる。他の成分としては、特に限定されないが、一般的に医薬品、医薬部外品、化粧品等に配合される任意の成分を配合することができる。かかる成分としては多価アルコール、油分、ワックス、酸、アルカリ、界面活性剤、粉末、顔料、染料、防腐剤、酸化防止剤、紫外線吸収剤、キレート剤、水溶性高分子、アルコール、溶媒ならびに香料等を挙げることができる。
特に、美容液、軟膏剤、クリーム剤の基剤として本発明のセラミド産生促進剤を調製する際には、例えば脂肪油、ラノリン、ワセリン、パラフィン、グリコール類、高級脂肪酸、アルカリ、界面活性剤、高級アルコール等を配合することができ、さらに必要に応じて、安定化剤、防腐剤、乳化剤、懸濁化剤等を添加することができる。
The ceramide production promoter of the present invention can contain other components in addition to the polymer A having the structural unit represented by formula (1). Other ingredients are not particularly limited, but any ingredients that are generally added to pharmaceuticals, quasi-drugs, cosmetics, etc. can be blended. Such components include polyhydric alcohols, oils, waxes, acids, alkalis, surfactants, powders, pigments, dyes, preservatives, antioxidants, ultraviolet absorbers, chelating agents, water-soluble polymers, alcohols, solvents and fragrances. etc. can be mentioned.
In particular, when preparing the ceramide production-enhancing agent of the present invention as a base for serums, ointments, and creams, for example, fatty oils, lanolin, petrolatum, paraffin, glycols, higher fatty acids, alkalis, surfactants, Higher alcohols and the like can be blended, and if necessary, stabilizers, preservatives, emulsifiers, suspending agents and the like can be added.
以下、実施例により本発明を説明するが、本発明はこれらに限定されるものではない。 EXAMPLES The present invention will be described below with reference to Examples, but the present invention is not limited to these.
（合成例１；ＭＰＣ単独重合体１の合成）
ＭＰＣ（２－メタクリロイルオキシエチルホスホリルコリン）単量体２０ｇ（６８ｍｍｏｌ）とサクシニルペルオキシド０．６ｇ（２．６ｍｍｏｌ）をイオン交換水８０ｇに溶解し、１時間窒素を吹き込みバブリングした。次いで、６０℃まで昇温し５時間重合させて、ＭＰＣ単独重合体１からなるセラミド産生促進剤を１９．５重量％含有する重合体粗水性溶液を得た。反応終了後、得られた重合体粗水性溶液を分画分子量６０００～８０００の透析膜（スペクトラポア社製）に接触させ、透析液としてイオン交換水１５リットルを使用し、２４時間毎に２度透析液を交換し合計７２時間透析を行った。
得られた重合体水溶液を下記に示す条件でゲルパーミエーションクロマトグラフィー（ＧＰＣ）に供したところ、ＭＰＣ単独重合体１の重量平均分子量は１８０，０００であった。また、得られた重合体水溶液中のＭＰＣ単独重合体１の含有割合は１５．２重量％であった。この重合体水溶液をイオン交換水で所定の濃度に調製し、後述する実施例に示す試験を行った。
＜分子量測定＞
得られた重合体３０ｍｇを０．０５Ｍの硝酸ナトリウム水溶液３０ｇに溶解し、試料液として、ゲルパーミエーションクロマトグラフィー（ＧＰＣ）により重量平均分子量を測定した。その他の条件は以下の通りである。
カラム：Ｓｈｏｄｅｘ ＯＨｐａｋ ＳＢ－８０２ ＨＱ、ＳＢ－８０６Ｍ ＨＱ（昭和電工（株）製）、標準物質：ポリエチレングリコール、検出：示差屈折率計ＲＩ－７１Ｓ、解析ソフト：ＪＡＳＣＯ－ＢＯＲＷＩＮ Ｖｅｒ． １．５０（日本分光（株）製）、流速１ｍＬ／分、カラム温度：４０℃
(Synthesis Example 1; Synthesis of MPC Homopolymer 1)
20 g (68 mmol) of MPC (2-methacryloyloxyethylphosphorylcholine) monomer and 0.6 g (2.6 mmol) of succinyl peroxide were dissolved in 80 g of deionized water, and nitrogen was bubbled for 1 hour. Then, the temperature was raised to 60° C. and polymerization was carried out for 5 hours to obtain a crude polymer aqueous solution containing 19.5% by weight of a ceramide production accelerator composed of MPC homopolymer 1. After completion of the reaction, the resulting crude aqueous polymer solution was brought into contact with a dialysis membrane (manufactured by Spectrapore) having a molecular weight cutoff of 6000 to 8000, and 15 liters of ion-exchanged water was used as a dialysate, twice every 24 hours. The dialysate was exchanged and dialysis was performed for a total of 72 hours.
When the resulting polymer aqueous solution was subjected to gel permeation chromatography (GPC) under the conditions shown below, the weight average molecular weight of MPC homopolymer 1 was 180,000. The content of MPC homopolymer 1 in the obtained polymer aqueous solution was 15.2% by weight. This polymer aqueous solution was adjusted to a predetermined concentration with ion-exchanged water, and the test described later in Examples was conducted.
<Molecular weight measurement>
30 mg of the obtained polymer was dissolved in 30 g of a 0.05 M sodium nitrate aqueous solution, and the weight average molecular weight was measured by gel permeation chromatography (GPC) as a sample liquid. Other conditions are as follows.
Column: Shodex OHpak SB-802 HQ, SB-806M HQ (manufactured by Showa Denko KK), standard substance: polyethylene glycol, detection: differential refractometer RI-71S, analysis software: JASCO-BORWIN Ver. 1.50 (manufactured by JASCO Corporation), flow rate 1 mL/min, column temperature: 40°C
（合成例２、３；ＭＰＣ－ＢＭＡ共重合体２、３の合成）
ＭＰＣ単量体３０ｇ（１０２ｍｍｏｌ）とブチルメタクリレート（以下ＢＭＡと略す）３．６ｇ（２６ｍｍｏｌ）と、ｔ－ブチルペルオキシネオデカノエート０．０６ｇ（０．３５ｍｍｏｌ）とをエタノール８０ｇに溶解し、４つ口フラスコに入れて３０分間窒素を吹き込んだ。その後、５０℃でｔ－ブチルペルオキシネオデカノエート（商品名：パーブチル－ＮＤ、日油（株）製）（以下、ＰＢ－ＮＤと略す）０．０６ｇ（０．３５ｍｍｏｌ）を加えて６時間重合反応させた後、ＮａＯＨ６ｇを添加して中和を行った。重合液を３Ｌのヘキサン中にかきまぜながら滴下し、析出した沈殿を濾過し、４８時間室温で真空乾燥を行って、白色粉末としてＭＰＣ－ＢＭＡ共重合体２からなるセラミド産生促進剤を得た。このＭＰＣ－ＢＭＡ共重合体２をイオン交換水で所定濃度に調製し、後述する実施例にて試験を行った。
モノマー組成比を表１のとおりとした以外は合成例２と同様な方法にて重合および精製を行い、ＭＰＣ－ＢＭＡ重合体３からなるセラミド産生促進剤を得た。このＭＰＣ－ＢＭＡ共重合体３をイオン交換水で所定濃度に調製し、後述する実施例にて試験を行った。
得られた重合体について、上記の分子量測定に従い分子量を測定した結果を表１に示す。
(Synthesis Examples 2 and 3; Synthesis of MPC-BMA Copolymers 2 and 3)
30 g (102 mmol) of MPC monomer, 3.6 g (26 mmol) of butyl methacrylate (hereinafter abbreviated as BMA), and 0.06 g (0.35 mmol) of t-butyl peroxyneodecanoate were dissolved in 80 g of ethanol. It was placed in a one-necked flask and nitrogen was blown in for 30 minutes. Then, 0.06 g (0.35 mmol) of t-butyl peroxyneodecanoate (trade name: Perbutyl-ND, manufactured by NOF Corporation) (hereinafter abbreviated as PB-ND) was added at 50°C for 6 hours. After the polymerization reaction, 6 g of NaOH was added for neutralization. The polymerization solution was added dropwise to 3 L of hexane with stirring, and the deposited precipitate was filtered and vacuum-dried at room temperature for 48 hours to obtain a ceramide production accelerator composed of MPC-BMA copolymer 2 as a white powder. This MPC-BMA copolymer 2 was adjusted to a predetermined concentration with deionized water, and tested in Examples described later.
Polymerization and purification were carried out in the same manner as in Synthesis Example 2, except that the monomer composition ratio was as shown in Table 1, to obtain a ceramide production accelerator comprising MPC-BMA polymer 3. This MPC-BMA copolymer 3 was adjusted to a predetermined concentration with deionized water, and tested in Examples described later.
Table 1 shows the results of measuring the molecular weight of the obtained polymer according to the molecular weight measurement described above.
表１中に用いた略号についての詳細は以下の通りである。
ＢＭＡ：ブチルメタクリレート（日油（株）製）式（２’）において、Ｒ２＝メチル基、Ｒ３＝ブチル基
Details of the abbreviations used in Table 1 are as follows.
BMA: butyl methacrylate (manufactured by NOF Corporation) In formula (2′), R 2 = methyl group, R 3 = butyl group
＜実施例１～３および比較例１～２＞
本発明のセラミド産生促進剤を添加する細胞として、ヒト３次元培養表皮モデル（ＬａｂＣｙｔｅ ＥＰＩ－ＭＯＤＥＬ ２４）を用い、上記合成例で得られた重合体水溶液及びグルコシルセラミド（株式会社岡安製）の水溶液を角層側から適用して７日間培養した。
培養後、皮膚を回収し、クロロホルム：メタノール（２：１）液中で超音波処理し、脂質を抽出した。濃縮後、高性能薄層クロマトグラフィーで（Ｈｉｇｈ Ｐｅｒｆｏｒｍａｎｃｅ Ｔｈｉｎ Ｌａｙｅｒ Ｃｈｒｏｍａｔｏｇｒａｐｈｙ）にて、セラミドを種類別に分離し、画像自動検出システムＣｅｍｉＤｏｃ ＸＲＳ Ｉｍａｇｉｎｇ Ｓｙｓｔｅｍｓ（Ｂｉｏ－Ｒａｄ社製）により、バンド密度からセラミドＮＳ（ＣｅｒＮＳ）、セラミドＮＰ（ＣｅｒＮＰ）、セラミドＡＳ（ＣｅｒＡＳ）、セラミドＡＰ（ＣｅｒＡＰ）及び総セラミド量を定量した。セラミドを添加していない参考例をコントロールとし、セラミド産生促進剤を添加した実施例の各種セラミド含有量及び、総セラミド量に対する各種セラミドの比率を表２に示した。
＜セラミド組成バランス評価＞
定量した各種セラミドの総セラミド量に対する比率を算出し、下記の評価基準にて評価した。
◎：４種全てのセラミドの比率の変動がコントロールと比較して２％未満である
〇：４種全てのセラミドの比率の変動がコントロールと比較して２％以上５％未満である
×：４種全てのセラミドの比率の変動がコントロールと比較して５％以上である
<Examples 1-3 and Comparative Examples 1-2>
A human three-dimensional cultured epidermis model (LabCyte EPI-MODEL 24) was used as the cells to which the ceramide production promoter of the present invention was added, and the aqueous polymer solution and the aqueous solution of glucosylceramide (manufactured by Okayasu Co., Ltd.) obtained in the above synthesis example were used. was applied from the stratum corneum side and cultured for 7 days.
After incubation, the skin was harvested and sonicated in chloroform:methanol (2:1) to extract lipids. After concentration, ceramide was separated by type by High Performance Thin Layer Chromatography, and ceramide NS ( CerNS), ceramide NP (CerNP), ceramide AS (CerAS), ceramide AP (CerAP) and total ceramide content were quantified. Table 2 shows the contents of various ceramides and the ratios of the various ceramides to the total amount of ceramides in Examples to which the ceramide production promoter was added, while the Reference Example to which no ceramide was added was used as a control.
<Evaluation of ceramide composition balance>
The ratio of each quantified ceramide to the total amount of ceramide was calculated and evaluated according to the following evaluation criteria.
◎: Variation in the ratio of all four types of ceramide is less than 2% compared to the control ○: Variation in the ratio of all four types of ceramide is 2% or more and less than 5% compared to the control ×: 4 Variation in the proportion of ceramide in all species is greater than or equal to 5% compared to controls
実施例１～３より、本発明のセラミド産生促進剤は、いずれもセラミド組成バランスを維持したまま、表皮中のセラミド含有量を増大させることができた。
一方、比較例では十分な効果が得られていない。比較例１では、本願のセラミド産生促進剤に相当する重合体の式（１）で表される単量体のモル比率が５０％未満である為、セラミド産生促進効果が不十分である。比較例２では、本願のセラミド産生促進剤とは異なるグルコシルセラミドを使用している為、特定のセラミドに対する産生促進効果を有するものの、セラミド組成バランスが悪化している。
このように、従来のセラミド産生促進剤は皮膚本来のセラミド組成バランスを崩す可能性があるが、本願のセラミド産生促進剤を使用することで、健常な皮膚本来のセラミド組成バランスを維持したまま、セラミド含有量を増大させることができ、アトピー性皮膚炎や乾皮症、乾癬等の皮膚疾患患者の皮膚状態の改善効果も期待できる。
From Examples 1 to 3, all of the ceramide production promoters of the present invention were able to increase the ceramide content in the epidermis while maintaining the ceramide compositional balance.
On the other hand, sufficient effects are not obtained in the comparative examples. In Comparative Example 1, the molar ratio of the monomer represented by formula (1) in the polymer corresponding to the ceramide production-enhancing agent of the present application is less than 50%, so the effect of promoting ceramide production is insufficient. In Comparative Example 2, since glucosylceramide different from the ceramide production promoter of the present application is used, the ceramide composition balance is deteriorated although it has the production promotion effect for a specific ceramide.
As described above, conventional ceramide production promoters may disrupt the original ceramide composition balance of the skin, but by using the ceramide production promoter of the present application, it is possible to It is possible to increase the ceramide content, and it is expected to improve the skin conditions of patients with skin diseases such as atopic dermatitis, xerosis, and psoriasis.
Claims (1)
（式中、Ｒ１は水素原子又はメチル基を示す。）
A ceramide production promoter characterized by containing a polymer A having a weight average molecular weight of 2,000 to 1,000,000 and having 50 mol% or more of structural units represented by the following formula (1).
(In the formula, R 1 represents a hydrogen atom or a methyl group.)
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