JP2017088558A - Ceramide synthesis enhancer - Google Patents
Ceramide synthesis enhancer Download PDFInfo
- Publication number
- JP2017088558A JP2017088558A JP2015222294A JP2015222294A JP2017088558A JP 2017088558 A JP2017088558 A JP 2017088558A JP 2015222294 A JP2015222294 A JP 2015222294A JP 2015222294 A JP2015222294 A JP 2015222294A JP 2017088558 A JP2017088558 A JP 2017088558A
- Authority
- JP
- Japan
- Prior art keywords
- ceramide synthesis
- ceramide
- skin
- expression
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 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 53
- 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 53
- 229940106189 ceramide Drugs 0.000 title claims abstract description 53
- 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 53
- 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 53
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 46
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 45
- 239000003623 enhancer Substances 0.000 title abstract 2
- 108010024814 Serine C-palmitoyltransferase Proteins 0.000 claims abstract description 29
- 102000015785 Serine C-Palmitoyltransferase Human genes 0.000 claims abstract description 28
- 239000002628 heparin derivative Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 230000002265 prevention Effects 0.000 claims description 5
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 4
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 4
- 206010000496 acne Diseases 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- 206010021198 ichthyosis Diseases 0.000 claims description 4
- 230000009390 immune abnormality Effects 0.000 claims description 4
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- 210000001339 epidermal cell Anatomy 0.000 abstract description 9
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- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
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- 150000001298 alcohols Chemical class 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KVYGGMBOZFWZBQ-UHFFFAOYSA-N benzyl nicotinate Chemical compound C=1C=CN=CC=1C(=O)OCC1=CC=CC=C1 KVYGGMBOZFWZBQ-UHFFFAOYSA-N 0.000 description 2
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Landscapes
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Abstract
Description
本発明は、セリンパルミトイルトランスフェラーゼの発現を促進し、セラミド合成を促進できるセラミド合成促進剤に関する。 The present invention relates to a ceramide synthesis promoter that can promote the expression of serine palmitoyltransferase and promote ceramide synthesis.
皮膚は、生体の最外層を覆い、外界との境界を形成して外界物質の浸入防止、水分を包含する体内成分の損失防止等の生命維持に必須なバリア機能を有している。角質細胞間には、セラミドを主成分とする脂質がラメラ構造を形成し、バリア機能を発揮する上で重要な役割を果たしている。 The skin covers the outermost layer of the living body, forms a boundary with the outside world, and has a barrier function essential for life support such as prevention of entry of outside substances and prevention of loss of internal components including moisture. Between keratinocytes, lipids mainly composed of ceramide form a lamellar structure and play an important role in exerting a barrier function.
セラミドが、加齢、紫外線暴露等の内的又は外的な要因によって減少すると、バリア機能が低下し、アトピー性皮膚炎、魚鱗癬、ニキビ、皮膚免疫異常、皮膚感染症等の様々な皮膚障害を誘発することが知られている。従来、セラミドの減少によって誘発される皮膚障害を抑制するために、減少したセラミドを外部から補給する手法が試みられている。しかしながら、減少したセラミドを外部から補給する手法では、効果の持続性が不十分であったりするため、その効果は満足できるものではない。 When ceramide is decreased due to internal or external factors such as aging, UV exposure, etc., the barrier function decreases, and various skin disorders such as atopic dermatitis, ichthyosis, acne, skin immune abnormalities, skin infections, etc. It is known to induce. Conventionally, in order to suppress the skin damage induced by the decrease in ceramide, a method of replenishing the decreased ceramide from the outside has been attempted. However, the method of replenishing the reduced ceramide from the outside is not satisfactory because the sustainability of the effect is insufficient.
一方、表皮細胞が角化する過程において、セラミドは、セリンパルミトイルトランスフェラーゼが触媒するセリンとパルミトイル−ＣｏＡの縮合反応からはじまり、いくつかの反応を経て合成されることが知られている。また、セラミドの生合成において、セリンパルミトイルトランスフェラーゼによる縮合反応が律速になっていることも知られている。 On the other hand, in the process of keratinization of epidermal cells, it is known that ceramide is synthesized through several reactions starting from the condensation reaction of serine and palmitoyl-CoA catalyzed by serine palmitoyltransferase. It is also known that the condensation reaction by serine palmitoyltransferase is rate-limiting in ceramide biosynthesis.
そこで、近年、セラミドの減少によって誘発される皮膚障害を抑制する手法として、セリンパルミトイルトランスフェラーゼの発現を促進させることにより、細胞自身によるセラミドの合成を促進させる方法が検討されており、セリンパルミトイルトランスフェラーゼの発現を促進させる成分も見出されている。例えば、特許文献１には、アシタバの抽出物、イラクサの抽出物、インチンコウの抽出物、クマザサの抽出物、ゲンチアナの抽出物、及びトウニンの抽出物には、セリンパルミトイルトランスフェラーゼの発現を促進する作用があることが報告されている。また、特許文献２には、イロハモミジの抽出物には、セリンパルミトイルトランスフェラーゼの発現を促進する作用があることが報告されている。しかしながら、製剤処方の多様化、セラミド合成促進作用の更なる向上等の要望に追従するために、セリンパルミトイルトランスフェラーゼの発現を促進させる新たな成分の開発が望まれている。 Therefore, in recent years, as a technique for suppressing skin damage induced by the decrease in ceramide, a method for promoting the synthesis of ceramide by the cell itself by promoting the expression of serine palmitoyltransferase has been studied. Components that promote expression have also been found. For example, Patent Document 1 discloses that an extract of Ashitaba, an extract of nettle, an extract of Inchinkou, an extract of Kumazasa, an extract of gentiana, and an extract of tonin have an effect of promoting the expression of serine palmitoyltransferase. It has been reported that there is. Patent Document 2 reports that the extract of Japanese maple has an action of promoting the expression of serine palmitoyltransferase. However, development of a new component that promotes the expression of serine palmitoyltransferase is desired in order to follow the demands for diversification of pharmaceutical formulations and further improvement of ceramide synthesis promoting action.
本発明は、セリンパルミトイルトランスフェラーゼの発現を促進し、セラミド合成を促進できるセラミド合成促進剤を提供することを目的とする。 An object of the present invention is to provide a ceramide synthesis promoter that can promote the expression of serine palmitoyltransferase and promote the synthesis of ceramide.
本発明者は、前記課題を解決すべく鋭意検討を行ったところ、硫酸化グルコサミノグリカンには、セリンパルミトイルトランスフェラーゼの発現を促進する作用があり、表皮細胞によるセラミド合成を促進できることを見出した。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。 The present inventor conducted intensive studies to solve the above problems, and found that sulfated glucosaminoglycan has an action of promoting the expression of serine palmitoyltransferase and can promote ceramide synthesis by epidermal cells. . The present invention has been completed by further studies based on this finding.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１． 硫酸化グルコサミノグリカンを含有することを特徴とする、セラミド合成促進剤。
項２． 前記硫酸化グルコサミノグリカンがヘパリン類似物質である、項１に記載のセラミド合成促進剤。
項３． 皮膚外用剤である、項１又は２に記載のセラミド合成促進剤。
項４． アトピー性皮膚炎、魚鱗癬、ニキビ、皮膚免疫異常、又は皮膚感染症の予防又は治療に使用される、項１〜３のいずれかに記載のセラミド合成促進剤。
項５． 硫酸化グルコサミノグリカンを含有することを特徴とする、セリンパルミトイルトランスフェラーゼ発現促進剤。
That is, this invention provides the invention of the aspect hung up below.
Item 1. A ceramide synthesis promoter comprising sulfated glucosaminoglycan.
Item 2. Item 2. The ceramide synthesis promoter according to Item 1, wherein the sulfated glucosaminoglycan is a heparin-like substance.
Item 3. Item 3. The ceramide synthesis promoter according to item 1 or 2, which is an external preparation for skin.
Item 4. Item 4. The ceramide synthesis promoter according to any one of Items 1 to 3, which is used for prevention or treatment of atopic dermatitis, ichthyosis, acne, skin immune abnormality, or skin infection.
Item 5. A serine palmitoyltransferase expression promoter characterized by containing sulfated glucosaminoglycan.
本発明のセラミド合成促進剤によれば、表皮細胞のセリンパルミトイルトランスフェラーゼの発現を促進することにより、セラミドの合成を促進できるので、セラミドの減少によって誘発される皮膚障害の予防又は治療に有効である。 According to the ceramide synthesis promoter of the present invention, ceramide synthesis can be promoted by promoting the expression of serine palmitoyltransferase in epidermal cells, which is effective in preventing or treating skin disorders induced by ceramide reduction. .
１．セラミド合成促進剤
本発明のセラミド合成促進剤は、硫酸化グルコサミノグリカンを含有することを特徴とする。以下、本発明のセラミド合成促進剤について詳述する。
1. Ceramide synthesis promoter The ceramide synthesis promoter of the present invention is characterized by containing a sulfated glucosaminoglycan. Hereinafter, the ceramide synthesis promoter of the present invention will be described in detail.
硫酸化グルコサミノグリカン
硫酸化グルコサミノグリカンとは、アミノ糖を構成単位の１つとして含み、硫酸基を有しているムコ多糖である。
Sulfated glucosaminoglycan Sulfated glucosaminoglycan is a mucopolysaccharide containing an amino sugar as one of the structural units and having a sulfate group.
本発明で使用される硫酸化グルコサミノグリカンの種類については、薬学的に許容されることを限度として、特に制限されないが、例えば、ヘパリン類似物質、ヘパラン硫酸、コンドロイチン硫酸、ケラタン硫酸、ヘパリン等が挙げられる。なお、硫酸化グルコサミノグリカンは、ナトリウム、カリウム、カルシウム、マグネシウム、鉄、マンガン等の金属塩；アンモニウム塩等の塩の形態であってもよい。 The type of sulfated glucosaminoglycan used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, heparin-like substance, heparan sulfate, chondroitin sulfate, keratan sulfate, heparin, etc. Is mentioned. The sulfated glucosaminoglycan may be in the form of a metal salt such as sodium, potassium, calcium, magnesium, iron, or manganese; or a salt such as an ammonium salt.
これらの硫酸化グルコサミノグリカンは、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。これらの中でも、より一層効果的にセラミド合成を促進させるという観点から、好ましくはヘパリン類似物質が挙げられる。 These sulfated glucosaminoglycans may be used alone or in combination of two or more. Among these, heparin-like substances are preferable from the viewpoint of more effectively promoting ceramide synthesis.
また、硫酸化グルコサミノグリカンの由来については、特に制限されず、例えば、ムコ多糖類を多硫酸化することにより得られたもの、食用獣の組織（例えば、ヘパリン類似物質の場合であれば、ウシやブタ等の気管軟骨を含む肺臓）等から抽出したもの等が挙げられる。 In addition, the origin of sulfated glucosaminoglycan is not particularly limited, for example, obtained by polysulfating mucopolysaccharide, edible beast tissue (for example, in the case of heparin-like substance) , Lungs containing tracheal cartilage such as cows and pigs) and the like.
また、例えば、硫酸化グルコサミノグリカンとしてヘパリン類似物質を使用する場合であれば、日本薬局方外医薬品規格に収戴されているヘパリン類似物質が好適である。 In addition, for example, when a heparin-like substance is used as a sulfated glucosaminoglycan, heparin-like substances included in the Japanese Pharmacopoeia pharmaceutical standards are suitable.
本発明のセラミド合成促進剤における硫酸化グルコサミノグリカンの配合量については、当該セラミド合成促進剤の製剤形態等に応じて適宜設定すればよいが、例えば０．０１〜５重量％、好ましくは０．０５〜３重量％、更に好ましくは０．１〜１重量％が挙げられる。
その他の成分
本発明のセラミド合成促進は、前記硫酸化グルコサミノグリカンの他に、必要に応じて、他の薬理成分を含有していてもよい。このような薬理成分としては、例えば、抗ヒスタミン剤（グリチルリチン酸二カリウム、グリチルリチン酸、ジフェンヒドラミン、塩酸ジフェンヒドラミン等）、局所麻酔剤（プロカイン、テトラカイン、ブピパカイン、メピパカイン、クロロプロカイン、プロパラカイン、メプリルカイン又はこれらの塩、オルソカイン、オキセサゼイン、オキシポリエントキシデカン、ロートエキス、ペルカミンパーゼ、テシットデシチン等）、抗炎症剤（アラントイン、インドメタシン、フェルビナク、ジクロフェナクナトリウム、ロキソプロフェンナトリウム等）、皮膚保護剤（コロジオン、ヒマシ油等）、血行促進成分（ノニル酸ワニリルアミド、ニコチン酸ベンジルエステル、カプサイシン、トウガラシエキス等）、清涼化剤（メントール、カンフル等）、ビタミン類（ビタミンＡ等）、ムコ多糖類（コンドロイチン硫酸ナトリウム、グルコサミン等）等が挙げられる。
What is necessary is just to set suitably about the compounding quantity of the sulfated glucosaminoglycan in the ceramide synthesis promoter of this invention according to the formulation form etc. of the said ceramide synthesis promoter, For example, 0.01-5 weight%, Preferably 0.05-3 weight%, More preferably, 0.1-1 weight% is mentioned.
Other Components The ceramide synthesis promotion of the present invention may contain other pharmacological components as necessary in addition to the sulfated glucosaminoglycan. Examples of such pharmacological components include antihistamines (dipotassium glycyrrhizinate, glycyrrhizic acid, diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilucaine or salts thereof. , Orthocaine, oxesasein, oxypolyentoxydecane, funnel extract, percamin ase, tesit decite, etc.), anti-inflammatory agents (allantoin, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promotion Ingredients (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, pepper extract, etc.), cooling agents (menthol, canned Le etc.), vitamins (vitamin A, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.) and the like.
また、本発明のセラミド合成促進剤は、所望の製剤形態にするために、必要に応じて、基剤や添加剤が含まれていてもよい。このような基剤や添加剤については、薬学的に許容されることを限度として特に制限されないが、例えば、水、低級アルコール（エタノール、イソプロパノール等）、多価アルコール（グリセリン、プロピレングリコール、ジプロピレングリコール、１，３−ブチレングリコール等）等の水性基剤；油類（オリーブ油、サフラワー油、大豆油、つばき油、とうもろこし油、なたね油、ひまわり油、綿実油、落花生油、ラード、スクワラン、魚油等）、鉱物油（流動パラフィン、パラフィン、ゲル化炭化水素、ワセリン等）、ワックス類・ロウ類（ミツロウ、カルナウバロウ、キャンデリラロウ、セレシン、ライスワックス、マイクロクリスタリンワックス等）、エステル油（ミリスチン酸イソプロピル、アジピン酸イソプロピル、セバシン酸ジエチル、セバシン酸イソプロピル、パルミチン酸イソプロピル、パルミチン酸セチル、オレイン酸エチル等）、脂肪酸アルキルエステル、脂肪酸（ステアリン酸、オレイン酸、パルミチン酸、ベヘン酸、リノール酸、ラノリン等）、脂肪酸エステル（パルミチン酸セチル、パルミチン酸イソプロピル、リノール酸エチル等）、高級アルコール（ステアリルアルコール、セタノール、ベヘニルアルコール、ミリスチルアルコール、オレイルアルコール、ヘキサデシルアルコール、ラノリンアルコール等）、コレステロール、トリ２−エチルヘキサン酸グリセリル、２−エチルヘキサン酸セチル、シリコーンオイル（ジメチルポリシロキサン、環状シリコーン等）等の油性基剤；ＰＯＥ（１０〜５０モル）フィトステロールエーテル、ＰＯＥ（１０〜５０モル）ジヒドロコレステロールエーテル、ＰＯＥ（１０〜５０モル）２−オクチルドデシルエーテル、ＰＯＥ（１０〜５０モル）デシルテトラデシルエーテル、ＰＯＥ（１０〜５０モル）オレイルエーテル、ＰＯＥ（２〜５０モル）セチルエーテル、ＰＯＥ（５〜５０モル）ベヘニルエーテル、ＰＯＥ（５〜３０モル）ポリオキシプロピレン（５〜３０モル）２−デシルテトラデシルエーテル、ＰＯＥ（１０〜５０モル）ポリオキシプロピレン（２〜３０モル）セチルエーテルなどのポリオキシエチレンアルキルエーテル、これらのリン酸・リン酸塩（ＰＯＥセチルエーテルリン酸ナトリウムなど）、ＰＯＥ（２０〜６０モル）ソルビタンモノオレート、ＰＯＥ（１０〜６０モル）ソルビタンモノイソステアレート、ＰＯＥ（１０〜８０モル）グリセリルモノイソステアレート、ＰＯＥ（１０〜３０モル）グリセリルモノステアレート、ＰＯＥ（２０〜１００モル）・ポリオキシプロピレン変性シリコーン、ＰＯＥ・アルキル変性シリコーン、モノラウリン酸ポリエチレングリコール、モノパルミチ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、ジラウリン酸ポリエチレングリコール、ジパルミチン酸ポリエチレングリコール、ジステアリン酸ポリエチレングリコール、ジオレイン酸ポリエチレングリコール、ジリシノレイン酸ポリエチレングリコール、ポリオキシエチレン硬化ヒマシ油（５〜１００）、ポリソルベート（２０〜８５）、グリセリン脂肪酸エステル（モノステアリン酸グリセリン等）、水素添加大豆リン脂質、水素添加ラノリンアルコール等の界面活性剤；清涼化剤（メントール、カンフル、ボルネオール、ハッカ水、ハッカ油等）、防腐剤（メチルパラベン、プロピルパラベン、安息香酸、安息香酸ナトリウム、ソルビン酸等）、着香剤（シトラール、１，８−シオネール、シトロネラール、ファルネソール等）、着色剤（タール色素（褐色２０１号、青色２０１号、黄色４号、黄色４０３号等）、カカオ色素、クロロフィル、酸化アルミニウム等）、粘稠剤（カルボキシビニルポリマー、ヒプロメロース、ポリビニルピロリドン、アルギン酸ナトリウム、エチルセルロース、カルボキシメチルセルロースナトリウム、キサンタンガム、カラギーナン等）、ｐＨ調整剤（リン酸、塩酸、クエン酸、クエン酸ナトリウム、コハク酸、酒石酸、水酸化ナトリウム、水酸化カリウム、トリエタノールアミン、トリイソプロパノールアミン等）、湿潤剤（ｄｌ−ピロリドンカルボン酸ナトリウム液、Ｄ−ソルビトール液、マクロゴール等）、安定化剤（ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エデト酸ナトリウム、メタリン酸ナトリウム、Ｌ−アルギニン、Ｌ−アスパラギン酸、ＤＬ−アラニン、グリシン、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム、二酸化硫黄、クロロゲン酸、カテキン、ローズマリー抽出物等）、酸化防止剤、紫外線吸収剤、キレート剤、粘着剤、緩衝剤、溶解補助剤、可溶化剤、保存剤等の添加剤が挙げられる。 Moreover, in order to make the ceramide synthesis promoter of this invention into a desired formulation form, the base and the additive may be contained as needed. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. For example, water, lower alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propylene glycol, dipropylene) Aqueous bases such as glycol and 1,3-butylene glycol; oils (olive oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil, lard, squalane, fish oil, etc. ), Mineral oil (liquid paraffin, paraffin, gelled hydrocarbon, petroleum jelly, etc.), waxes and waxes (honey bees, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oil (isopropyl myristate) , Isopropyl adipate, sebacic acid Ethyl, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc., fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (palmitic acid) Cetyl, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, 2-ethyl Oily bases such as cetyl hexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); POE (10-50 mol) phytosterol ether, POE ( 0-50 mol) Dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) ) Cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2- 30 mol) polyoxyethylene alkyl ethers such as cetyl ether, phosphoric acid / phosphate thereof (such as POE cetyl ether sodium phosphate), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan Monoisostearate, POE (10 80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100 mol) polyoxypropylene-modified silicone, POE alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene monopalmitate Glycol, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20 -85), glycerin fatty acid ester (glyceryl monostearate, etc.), hydrogenated soybean phospholipid, hydrogenated lanoli Surfactants such as alcohol; refreshing agents (menthol, camphor, borneol, mint water, mint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral) , 1,8-shioner, citronellal, farnesol, etc.), coloring agent (tar pigment (brown 201, blue 201, yellow 4, yellow 403, etc.), cacao pigment, chlorophyll, aluminum oxide, etc.), thickener (Carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, etc.), pH adjuster (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, Hydroxy Potassium, triethanolamine, triisopropanolamine, etc.), wetting agents (sodium dl-pyrrolidonecarboxylate, D-sorbitol, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, metalin) Acid sodium, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidant, UV absorption Additives such as agents, chelating agents, pressure-sensitive adhesives, buffers, solubilizers, solubilizers, preservatives, etc.
製剤形態
本発明のセラミド合成促進剤は、皮膚外用剤、内服剤等のいずれの剤型であってもよいが、セラミド合成をより一層効果的に促進させるという観点から、好ましくは皮膚外用剤が挙げられる。
Formulation Form The ceramide synthesis promoter of the present invention may be in any dosage form such as an external preparation for skin and an internal preparation, but from the viewpoint of further effectively promoting ceramide synthesis, an external preparation for skin is preferred. Can be mentioned.
本発明のセラミド合成促進剤を皮膚外用剤として使用する場合、その形状については、経皮適用できることを限度として特に制限されないが、例えば、液状、固形状、半固形状（ゲル状、軟膏状、ペースト状）等が挙げられる。 When the ceramide synthesis promoter of the present invention is used as a skin external preparation, its shape is not particularly limited as long as it can be applied transdermally. For example, liquid, solid, semi-solid (gel, ointment, Paste) and the like.
また、本発明のセラミド合成促進剤を皮膚外用剤として使用する場合、その製剤形態については、経皮適用できることを限度として特に制限されないが、例えば、皮膚外用医薬品、皮膚外用医薬部外品、化粧料、皮膚洗浄料等が挙げられる。本発明のセラミド合成促進剤を皮膚外用剤にする場合の製剤形態として、具体的には、クリーム剤、ローション剤、ジェル剤、乳液剤、液剤、貼付剤、エアゾール剤、軟膏剤、パック剤等の皮膚外用医薬品；クリーム剤、ローション剤、ジェル剤、乳液剤、液剤、貼付剤、エアゾール剤、軟膏剤、パック剤等の皮膚外用医薬部外品；クリーム剤、ローション剤、ジェル剤、乳液剤、液剤、軟膏剤、パック剤等の化粧料；ボディーシャンプー、ヘアシャンプー、リンス等の皮膚洗浄料等が挙げられる。これらの製剤形態の中でも、好ましくは皮膚外用医薬品、更に好ましくはクリーム剤、ローション剤、ジェル剤、乳液剤、パック剤が挙げられる。 In addition, when the ceramide synthesis promoter of the present invention is used as a skin external preparation, the formulation form is not particularly limited as long as it can be applied transdermally. For example, skin external pharmaceuticals, skin external quasi drugs, cosmetics And skin cleansing materials. As a preparation form when the ceramide synthesis promoter of the present invention is used as an external preparation for skin, specifically, creams, lotions, gels, emulsions, solutions, patches, aerosols, ointments, packs, etc. Skin external medicines: creams, lotions, gels, emulsions, solutions, patches, aerosols, ointments, packs, etc .; external quasi-drugs such as creams, lotions, gels, emulsions And cosmetics such as liquids, ointments and packs; and skin cleansing agents such as body shampoos, hair shampoos and rinses. Among these preparation forms, preferably a skin external medicine, more preferably a cream, a lotion, a gel, an emulsion, or a pack.
用途・用量
本発明のセラミド合成促進剤は、表皮細胞(特に、表皮の上層に存在する細胞)においてセリンパルミトイルトランスフェラーゼの発現を促進できるので、表皮におけるセラミドの合成を促進させるために使用される。また、表皮におけるセラミドの合成促進は、アトピー性皮膚炎、魚鱗癬、ニキビ、皮膚免疫異常、ウイルスや細菌による皮膚感染症等の皮膚障害の予防又は治療に有効であることが知られているので、本発明のセラミド合成促進剤は、これらの皮膚障害の予防又は治療目的で使用できる。
Use / Dose Since the ceramide synthesis promoter of the present invention can promote the expression of serine palmitoyltransferase in epidermal cells (particularly, cells present in the upper layer of the epidermis), it is used to promote the synthesis of ceramide in the epidermis. Furthermore, it is known that the promotion of ceramide synthesis in the epidermis is effective for the prevention or treatment of skin disorders such as atopic dermatitis, ichthyosis, acne, skin immune abnormalities, and skin infections caused by viruses and bacteria. The ceramide synthesis promoter of the present invention can be used for the purpose of preventing or treating these skin disorders.
また、本発明のセラミド合成促進剤の用量については、剤形、製剤形態、適用する症状の程度等に応じて適宜設定すればよい。例えば、本発明のセラミド合成促進剤を皮膚外用剤として使用する場合であれば、その用量の一例として、１回当たり、皮膚１ｃｍ2当たり、硫酸化グルコサミノグリカンが０．１〜３ｍｇ程度となる量で、１日１〜数回程度の頻度が挙げられる。 In addition, the dose of the ceramide synthesis promoter of the present invention may be appropriately set according to the dosage form, formulation form, degree of symptoms to be applied, and the like. For example, when the ceramide synthesis promoter of the present invention is used as an external preparation for skin, as an example of its dosage, per 1 cm 2 of skin, sulfated glucosaminoglycan is about 0.1 to 3 mg per dose. The amount is about 1 to several times a day.
２．セリンパルミトイルトランスフェラーゼ発現促進剤
前述するように、硫酸化グルコサミノグリカンには、セリンパルミトイルトランスフェラーゼの発現を促進する作用があるので、本発明は、更に、硫酸化グルコサミノグリカンを含有することを特徴とするセリンパルミトイルトランスフェラーゼ発現促進剤を提供する。本発明のセリンパルミトイルトランスフェラーゼ発現促進剤において、使用される硫酸化グルコサミノグリカン、配合可能な他の成分、製剤形態、用途、用量等については、前記「１．セラミド合成促進剤」の欄に記載の通りである。
2. Serine palmitoyltransferase expression promoter As described above, since sulfated glucosaminoglycan has an action of promoting the expression of serine palmitoyltransferase, the present invention further comprises sulfated glucosaminoglycan. A serine palmitoyltransferase expression promoter characterized by the above is provided. In the serine palmitoyltransferase expression promoter of the present invention, the sulfated glucosaminoglycan used, other components that can be blended, formulation forms, uses, doses, etc. are described in the column of “1. Ceramide synthesis promoter”. As described.
以下に実施例を示して本発明をより具体的に説明するが、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 more specifically with reference to the following examples, but the present invention is not limited to these examples.
試験例１：硫酸化グルコサミノグリカンによるセラミド合成への影響
硫酸化グルコサミノグリカンが表皮細胞のセラミド合成能に与える影響を評価するために以下の実験を行った。
Test Example 1: Effect of sulfated glucosaminoglycan on ceramide synthesis The following experiment was conducted to evaluate the effect of sulfated glucosaminoglycan on ceramide synthesis ability of epidermal cells.
１．実験材料
（細胞）
本試験例において細胞は以下の２種類を使用した。
（Ａ）通常表皮モデル細胞（ＨａＣａＴ細胞）
通常表皮モデル細胞として、ＨａＣａＴ細胞（ヒト表皮角化細胞（Ｄｅｕｔｓｃｈｅｓ Ｋｒｅｂｓｆｏｒｓｃｈｕｎｇｓｚｅｎｔｒｕｍ，Ｓｔｉｆｔｕｎｇ ｄｅｓoｆｆｅｎｔｌｉｃｈｅｎ Ｒｅｃｈｔｓ（ＤＫＦＺ），Ｈｅｉｄｅｌｂｅｒｇ，Ｇｅｒｍａｎｙ））を使用した。
（Ｂ）表皮上層モデル細胞（シンタキシン４高発現ＨａＣａＴ細胞）
ある程度分化が進んだ表皮上層部の細胞モデルを作製し、試験に使用した。（i）表皮細胞は角化すると基底層から有棘層・顆粒層に移動すること、（ii）上層に移動するに従い、細胞外にシンタキシン４が多く分泌されること、及び（iii）ＨａＣａＴ細胞においてシンタキシン４を高発現させると角化が進行すること（Ｋａｄｏｎｏ Ｎ．ｅｔ ａｌ．，Ｍｏｌ Ｍｅｄ ２０１５）が知られている。そこで、表皮上層モデル細胞として、シンタキシン４が高発現しているＨａＣａＴ細胞を作製し、本試験例において使用した。作製方法は、以下の通りである。
先ず、細胞外に強制的に提示させるために２１アミノ酸残基からなるマウス由来ＩＬ−２シグナルペプチドをコードする遺伝子をマウスシンタキシン４遺伝子のＮ末端に付加し、これをｐＱＣＸＩＮレトロウイルスベクターのマルチクローニングサイトに挿入した。次に、これをトランスフェクション試薬Ｌｉｐｏｆｅｃｔａｍｉｎｅ ＰＬＵＳ（サーモフィッシャーサイエンティフィック株式会社製）を用いて、パッケージング細胞ＰＴ６７に導入した。得られた細胞の培養上清からレトロウイルスを得た。得られたウイルスをＨａＣａＴ細胞に感染させることにより、細胞外にシンタキシン４を強制発現したＨａＣａＴ細胞（表皮上層モデル細胞）を作製した。
1. Experimental material (cell)
In this test example, the following two types of cells were used.
(A) Normal epidermis model cell (HaCaT cell)
As normal epidermal model cells, HaCaT cells (human epidermis keratinocytes (Deutsches Krebsforschungszentrum, Stiftung desoffentilicen Rechts (DKFZ), Heidelberg, Germany)) were used.
(B) Epidermis upper layer model cell (Syntaxin 4 highly expressing HaCaT cell)
A cell model of the upper layer of the epidermis that has been differentiated to some extent was prepared and used in the test. (I) When epidermal cells are keratinized, they move from the basal layer to the spinous / granular layer, (ii) secretion of more syntaxin 4 as they move to the upper layer, and (iii) HaCaT cells It is known that keratinization proceeds when syntaxin 4 is highly expressed in Kadono N. et al., Mol Med 2015. Therefore, HaCaT cells in which syntaxin 4 is highly expressed were produced as upper epidermis model cells and used in this test example. The manufacturing method is as follows.
First, a gene encoding a mouse-derived IL-2 signal peptide consisting of 21 amino acid residues is added to the N-terminus of the mouse syntaxin 4 gene in order to force it to be presented outside the cell, and this is added to the multi-site of pQCXIN retroviral vector. Inserted into the cloning site. Next, this was introduced into the packaging cell PT67 using a transfection reagent Lipofectamine PLUS (manufactured by Thermo Fisher Scientific Co., Ltd.). A retrovirus was obtained from the culture supernatant of the obtained cells. By infecting the obtained virus with HaCaT cells, HaCaT cells (upper epidermis model cells) in which syntaxin 4 was forcibly expressed outside the cells were prepared.
（培地）
Ｄ−ＭＥＭ／Ｈａｍ’ｓ Ｆ−１２（和光純薬工業株式会社）／１０％ＦＣＳ添加
(Culture medium)
D-MEM / Ham's F-12 (Wako Pure Chemical Industries, Ltd.) / 10% FCS added
（被験物質）
ヘパリン類似物質
(Test substance)
Heparin analog
２．実験方法
（１）通常表皮モデル細胞におけるセリンパルミトイルトランスフェラーゼｍＲＮＡの発現量
１２ウェルプレートの各ウェルにモデル細胞を１×１０5個／ウェルの濃度でそれぞれ播種し、３７℃、５％ＣＯ2条件下で培養した。翌日に、各ウェルにヘパリン類似物質を０．５ｍｇ／ｍＬとなるように添加し、３７℃、５％ＣＯ2条件下で培養した。その翌日に、モデル細胞を回収しＲＮｅａｓｙ ｍｉｎｉ ｋｉｔ（株式会社キアゲン製）を用いて全ＲＮＡを抽出した。その後、ＲｅｖｅｒＴｒａ Ａｃｅ（東洋紡株式会社製）を用いて逆転写を行い、ｃＤＮＡを合成した。次いで、Ｆａｓｔ Ｓｔａｒｔ Ｅｓｓｅｎｔｉａｌ ＤＮＡ Ｇｒｅｅｎ Ｍａｓｔｅｒ ｏｎ ＬｉｇｈｔＣｙｃｌｅｒ Ｎａｎｏ ｓｙｓｔｅｍ（ロシュ・ダイアグノスティックス株式会社製）を用いて、ｑＲＴ−ＰＣＲにてセリンパルミトイルトランスフェラーゼ遺伝子（ＳＰＴＬＣ１及びＳＰＴＬＣ３）の増幅を行った。β−アクチンを内部標準として使用し、セリンパルミトイルトランスフェラーゼｍＲＮＡの発現量を標準化した。このｍＲＮＡの発現量を、ヘパリン類似物質を添加しなかった以外は前記と同様にして確認したｍＲＮＡの発現量（コントロール）で除算した。
2. Experimental method (1) Expression level of serine palmitoyltransferase mRNA in normal epidermal model cells Model cells were seeded at a concentration of 1 × 10 5 cells / well in each well of a 12-well plate at 37 ° C. under 5% CO 2 condition. In culture. On the next day, heparin-like substance was added to each well so as to be 0.5 mg / mL, and cultured at 37 ° C. under 5% CO 2 condition. On the next day, model cells were collected and total RNA was extracted using RNeasy mini kit (Qiagen). Thereafter, reverse transcription was performed using RiverTra Ace (Toyobo Co., Ltd.) to synthesize cDNA. Subsequently, serine palmitoyltransferase genes (SPTLC1 and SPTLC3) were amplified by qRT-PCR using Fast Start Essential DNA Green Master on LightCycler Nano system (manufactured by Roche Diagnostics). β-actin was used as an internal standard, and the expression level of serine palmitoyltransferase mRNA was normalized. This mRNA expression level was divided by the mRNA expression level (control) confirmed in the same manner as described above except that no heparin-like substance was added.
（２）表皮上層モデル細胞におけるセリンパルミトイルトランスフェラーゼｍＲＮＡの発現量
通常表皮モデル細胞に代えて表皮上層モデル細胞を使用した以外は、前記（１）と同様に操作し、セリンパルミトイルトランスフェラーゼｍＲＮＡの発現量を確認し、コントロール（ヘパリン類似物質を添加しなかった場合のｍＲＮＡ発現量）で除算した。
(2) Expression level of serine palmitoyltransferase mRNA in the epidermis model cell Except for using the epidermis model cell instead of the normal epidermis model cell, the expression level of serine palmitoyltransferase mRNA was changed in the same manner as in (1) above. Confirmed and divided by control (mRNA expression level when heparin-like substance was not added).
得られた結果を図１及び２に示す。図１及び２から分かるように、通常表皮モデル細胞及び表皮上層モデル細胞のいずれも、ヘパリン類似物質を添加した条件では、セリンパルミトイルトランスフェラーゼｍＲＮＡの発現量の増加が認められ、特に、表皮上層モデル細胞ではその発現量の増加が著しかった。即ち、本結果から、ヘパリン類似物質等の硫酸化グルコサミノグリカンは、表皮細胞、特に表皮上層の細胞（投与された硫酸化グルコサミノグリカンが直接影響する細胞）のセリンパルミトイルトランスフェラーゼｍＲＮＡの発現量を増大させる作用があり、セラミドの合成を促進できることが明らかとなった。なお、通常表皮モデル細胞におけるコントロールと、表皮上層モデル細胞におけるコントロールとでは、ｍＲＮＡの発現量に大きな差はなかった。 The obtained results are shown in FIGS. As can be seen from FIGS. 1 and 2, both the normal epidermal model cell and the upper epidermis model cell showed an increase in the expression level of serine palmitoyltransferase mRNA under the condition that heparin-like substance was added. The increase in the expression level was remarkable. That is, from this result, sulfated glucosaminoglycans such as heparin-like substances are expressed in serine palmitoyltransferase mRNA in epidermal cells, especially cells in the upper epidermis (cells directly affected by the administered sulfated glucosaminoglycan). It has been found that it has the effect of increasing the amount and can promote the synthesis of ceramide. In addition, there was no big difference in the expression level of mRNA between the control in the normal epidermis model cell and the control in the upper epidermis model cell.
処方例
表１〜２に示す組成のクリーム剤（処方例１〜８）、表３に示すローション剤（処方例９〜１４）、表４に示すジェル剤（処方例１５〜１９）、及び表５〜６に示す乳液剤（処方例２０〜２９）を調製した。これらの製剤は、いずれも、前記試験例１の場合と同様に、表皮細胞のセリンパルミトイルトランスフェラーゼｍＲＮＡの発現量を増大させる効果が期待され、セラミドの合成促進に有効である。
Formulation Examples Creams with the composition shown in Tables 1-2 (Prescription Examples 1-8), Lotions (Prescription Examples 9-14) shown in Table 3, Gels (Prescription Examples 15-19) shown in Table 4, and Tables Emulsions (Prescription Examples 20 to 29) shown in 5 to 6 were prepared. Each of these preparations is expected to have an effect of increasing the expression level of serine palmitoyltransferase mRNA in epidermal cells, as in Test Example 1, and is effective in promoting the synthesis of ceramide.
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