JP6818421B2 - Dermal fibroblast activator and its uses - Google Patents
Dermal fibroblast activator and its uses Download PDFInfo
- Publication number
- JP6818421B2 JP6818421B2 JP2016067897A JP2016067897A JP6818421B2 JP 6818421 B2 JP6818421 B2 JP 6818421B2 JP 2016067897 A JP2016067897 A JP 2016067897A JP 2016067897 A JP2016067897 A JP 2016067897A JP 6818421 B2 JP6818421 B2 JP 6818421B2
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- Prior art keywords
- skin
- ceramide
- fibroblasts
- ceramides
- composition
- Prior art date
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Description
本発明は、真皮層にある線維芽細胞を活性化する作用を有する線維芽細胞賦活剤、並びに当該作用に優れた医薬品、医薬部外品、化粧品または飲食品に関する。より詳細には、本発明は真皮層にある線維芽細胞に働きかけ、加齢または紫外線照射によって生じる真皮じわ、肌のたるみ、及び／または肌のハリ低下を予防または改善するために有効な線維芽細胞賦活剤、及びそれを有効成分とする医薬品、医薬部外品、化粧品または飲食品用組成物に関する。 The present invention relates to a fibroblast activator having an action of activating fibroblasts in the dermis layer, and a drug, a quasi drug, a cosmetic or a food or drink having an excellent action. More specifically, the present invention acts on fibroblasts in the dermis layer to prevent or ameliorate dermal wrinkles, sagging skin, and / or reduced skin firmness caused by aging or UV irradiation. The present invention relates to a blast cell activator and a composition for a pharmaceutical product, a quasi drug, a cosmetic product or a food or drink containing the active ingredient.
皮膚（肌）は、外側から順に、表皮、真皮及び皮下組織の三層構造を有している。 The skin (skin) has a three-layer structure of epidermis, dermis, and subcutaneous tissue in this order from the outside.
表皮は、外側から角層、顆粒層、有棘層及び基底層の４つの層からなる厚さ平均約０.２ｍｍの薄い膜であり、外部からの異物の侵入や体内の水分の蒸散を防ぐバリアとなって内部を保護している。表皮の最表面にある「角層」は、角層細胞と細胞間脂質から構成されている。細胞間脂質は「セラミド」等からなる脂質の層と水分子の層が交互に規則正しく何層も重なり合う層構造（ラメラ構造）を有しており、これが角層細胞と角層細胞の隙間を満たして、外部からの刺激の侵入や体内の水分の過剰な蒸散を防ぎ、表皮のバリア機能と保湿機能という重要な役目を果たしている。表皮の９５％は角化細胞（ケラチノサイト）から構成されている。当該細胞は表皮の最も深部にある基底層で作られ、上へ上へと押し上げられ（基底層→有棘層→顆粒層→角層）、やがては最上層になる角層から垢となって剥がれ落ちる。基底細胞が分裂し、娘細胞が産まれて角層で脱落するまでの時間をターンオーバー時間と呼び、約４５日と言われている。 The epidermis is a thin film with an average thickness of about 0.2 mm consisting of four layers, the stratum granulosum, the stratum granulosum, the stratum spinosum, and the stratum basale, from the outside, and prevents the invasion of foreign substances from the outside and the evaporation of water in the body. It acts as a barrier to protect the inside. The "horny layer" on the outermost surface of the epidermis is composed of stratum corneum cells and intercellular lipids. Intercellular lipids have a layered structure (lamellar structure) in which layers of lipids such as "ceramide" and layers of water molecules are alternately and regularly overlapped, and this fills the gap between stratum corneum cells and stratum corneum cells. It prevents the invasion of external stimuli and excessive evaporation of water in the body, and plays an important role of the barrier function and moisturizing function of the epidermis. 95% of the epidermis is composed of keratinocytes (keratinocytes). The cells are made in the deepest basal layer of the epidermis, pushed upwards (basal layer → spinous layer → granular layer → stratum granulosum), and eventually become dirt from the stratum granulosum, which is the uppermost layer. It peels off. The time it takes for basal cells to divide, daughter cells to be born and to shed in the stratum corneum is called the turnover time, which is said to be about 45 days.
一方、真皮は、表皮の内側に存在する平均約２ｍｍの厚みを有する皮膚の本体組織であり、表皮とは基底膜によって隔てられている。真皮は、コラーゲンという線維状のタンパク質がその大部分を占めており、その間をヒアルロン酸等のゼリー状の基質が水分を抱えた状態で満たしている。さらにこれにエラスチンやフィブリリンという線維状のタンパク質も加わって、肌に弾力性を与えている。つまり真皮は、その大部分を占めるコラーゲンやエラスチンなどにより、皮膚（肌）を支え、その形や弾力を保つ働きを担っている。そしてこれらの線維状タンパク質や基質を生成する細胞が線維芽細胞である。 On the other hand, the dermis is the main body tissue of the skin having an average thickness of about 2 mm existing inside the epidermis, and is separated from the epidermis by the basement membrane. The dermis is dominated by a fibrous protein called collagen, which is filled with a jelly-like substrate such as hyaluronic acid in a state of holding water. In addition, fibrous proteins such as elastin and fibrillin are added to give the skin elasticity. In other words, the dermis supports the skin (skin) with collagen and elastin, which occupy most of it, and plays a role in maintaining its shape and elasticity. The cells that produce these fibrous proteins and substrates are fibroblasts.
ところで従来より肌の乾燥等による肌荒れや小じわ対策が求められている。こうした肌荒れや小じわの発生は肌のバリア機能や保湿機能の低下によるところが大きいこと、また表皮角層の細胞間脂質中に存在するセラミド量の減少が当該肌のバリア機能や保湿機能の低下に深く関与していることから、これらを改善する方法として、減少したセラミドを直接的に補給する方法やセラミド合成促進剤等の使用により、角層細胞間脂質内のセラミド量を増加させる方法が種々提案されている（例えば、非特許文献１等）。 By the way, there has been a demand for measures against rough skin and fine wrinkles due to dry skin and the like. The occurrence of such rough skin and fine wrinkles is largely due to the deterioration of the barrier function and moisturizing function of the skin, and the decrease in the amount of ceramide present in the intercellular lipids of the epidermal horny layer is deeply responsible for the deterioration of the barrier function and moisturizing function of the skin. Since they are involved, various methods for improving these have been proposed, such as a method of directly supplementing the decreased ceramide and a method of increasing the amount of ceramide in the intercellular lipid of the stratum corneum by using a ceramide synthesis promoter or the like. (For example, Non-Patent Document 1 and the like).
一方、従来より加齢や長期間の紫外線照射によって、肌のたるみ、ハリ低下、及び／又は真皮じわ（真皮層まで達した深いしわ、大しわ）が生じることが知られている。この原因として、加齢や紫外線照射によって真皮に存在するコラーゲンやエラスチンなどの間質成分が古く脆くなり、その量も減少することが挙げられる。 On the other hand, it has been conventionally known that aging and long-term UV irradiation cause sagging of the skin, reduction of firmness, and / or dermis wrinkles (deep wrinkles reaching the dermis layer, large wrinkles). The cause of this is that the interstitial components such as collagen and elastin present in the dermis become old and brittle due to aging and ultraviolet irradiation, and the amount thereof also decreases.
真皮は、表皮とは異なり、新陳代謝がとてもゆっくりであり、そのサイクルは数年を要するため、加齢や紫外線照射による肌のたるみ、ハリ低下、及び／又は真皮じわの対策としては、紫外線照射からの予防は勿論のこと、真皮層に存在する間質成分の劣化や減少を抑制することが必要であり、その方法としては間質成分（膠原線維（コラーゲン）、弾性線維（エラスチン、フィブリリン）、ムコ多糖（ヒアルロン酸）等）を生成する真皮層にある線維芽細胞を活性化（賦活化）する方法が挙げられる。 Unlike the epidermis, the dermis has a very slow metabolism and the cycle takes several years. Therefore, as a countermeasure against aging and skin sagging due to UV irradiation, reduction of firmness, and / or dermis wrinkles, UV irradiation It is necessary to suppress the deterioration and decrease of the interstitial component existing in the dermis layer as well as the prevention from the dermis component (collagen fiber (collagen), elastic fiber (elastin, fibrillin)). , Mucopolysaccharide (hyaluronic acid), etc.), and a method of activating (activating) fibroblasts in the dermis layer.
線維芽細胞の賦活化方法として従来より知られている方法として、例えば、特許文献１及び２等に記載の方法が知られている。 As a method conventionally known as a method for activating fibroblasts, for example, the methods described in Patent Documents 1 and 2 and the like are known.
本発明の目的は、真皮層にある線維芽細胞を活性化する作用を有する新規な線維芽細胞賦活剤を提供することである。また本発明の目的は、真皮層にある線維芽細胞を活性化して当該層内の間質成分（膠原線維（コラーゲン）、弾性線維（エラスチン、フィブリリン）、ムコ多糖（ヒアルロン酸）等）の少なくとも１種の生成を促してその減少を抑制することで、加齢または紫外線照射等によって生じる真皮じわ、肌のたるみ、及び／または肌のハリ低下を予防または改善することが可能な組成物、具体的には医薬品、医薬部外品、化粧品または飲食品を提供することである。 An object of the present invention is to provide a novel fibroblast activator having an action of activating fibroblasts in the dermis layer. Another object of the present invention is to activate fibroblasts in the dermis layer and at least the stromal components (collagen fibers (collagen), elastic fibers (elastin, fibrillin), mucopolysaccharide (hyaluronic acid), etc.) in the layer. A composition capable of preventing or improving dermis wrinkles, sagging of the skin, and / or reduction of firmness of the skin caused by aging or irradiation with ultraviolet rays, etc. by promoting the production of one type and suppressing the decrease thereof. Specifically, it is to provide pharmaceuticals, non-pharmaceutical products, cosmetics or foods and drinks.
本発明者らは、上記課題を解決すべく鋭意検討を重ねていたところ、後述する実験例に示すように、セラミドに下記の作用があることを見出し、このことからセラミドには真皮層内にある線維芽細胞を活性化（賦活化）する作用があることを確認した。
（1）ヒト線維芽細胞におけるＡＴＰ産生促進作用
（2）膠原線維の引っ張り力を回復／向上する作用（ヒト線維芽細胞のコラーゲンゲル収縮促進作用）
（3）ヒト線維芽細胞において、膠原線維や弾性線維との結合点であるインテグリンの発現を増加する作用（ヒト線維芽細胞におけるインテグリン発現量の増加作用）
（4）ヒト線維芽細胞において、弾性線維構成成分であるフィブリリン-1の発現を増加する作用（ヒト線維芽細胞におけるフィブリリン-1発現量の増加作用）。
As a result of diligent studies to solve the above problems, the present inventors have found that ceramide has the following effects as shown in an experimental example described later, and from this, ceramide is contained in the dermis layer. It was confirmed that it has an action of activating (activating) a certain fibroblast.
(1) ATP production promoting action in human fibroblasts (2) Action to restore / improve the tensile force of collagen fibers (collagen gel contraction promoting action of human fibroblasts)
(3) Action to increase the expression of integrin, which is a binding point with collagen fibers and elastic fibers, in human fibroblasts (action to increase the expression level of integrin in human fibroblasts)
(4) Action to increase the expression of fibrillin-1, which is an elastic fiber component, in human fibroblasts (action to increase the expression level of fibrillin-1 in human fibroblasts).
線維芽細胞は真皮層内の間質成分（膠原線維（コラーゲン）、弾性線維（エラスチン、フィブリリン）、ムコ多糖（ヒアルロン酸）等）の生成に関わっている。また、線維芽細胞はインテグリンを介して膠原線維や弾性線維と結合し、膠原線維や弾性線維を引っ張り、皮膚を引き締めている。このため、線維芽細胞を賦活化することで、上記の間質成分の減少を抑制したり、また膠原線維や弾性線維を引っ張った状態にすること等ができ、当該成分の減少及び／又は膠原線維や弾性線維の引っ張り力の低下を原因とする加齢または紫外線照射等による真皮じわ、肌のたるみ、及び／または肌のハリ低下を予防若しくは改善することが可能になる。 Fibroblasts are involved in the production of interstitial components (collagen fibers (collagen), elastic fibers (elastin, fibrillin), mucopolysaccharides (hyaluronic acid), etc.) in the dermis layer. In addition, fibroblasts bind to collagen fibers and elastic fibers via integrins, pull collagen fibers and elastic fibers, and tighten the skin. Therefore, by activating fibroblasts, it is possible to suppress the decrease of the above-mentioned interstitial component, or to bring the collagen fiber or elastic fiber into a pulled state, and reduce the component and / or the collagen. It is possible to prevent or improve dermis wrinkles, sagging skin, and / or decreased firmness of the skin due to aging or irradiation with ultraviolet rays caused by a decrease in the tensile force of fibers and elastic fibers.
本発明は、これらの知見に基づいて完成したものであり、下記の実施形態を有する。 The present invention has been completed based on these findings, and has the following embodiments.
（Ｉ）真皮線維芽細胞賦活剤
（I-1）セラミド類を有効成分とする線維芽細胞賦活剤。
（I-2）下記（1）〜（4）からなる群から選択される少なくとも１つの作用を有する、（I-1）記載の線維芽細胞賦活剤。
（1）ヒト線維芽細胞におけるＡＴＰ産生促進作用
（2）ヒト線維芽細胞のコラーゲンゲル収縮促進作用
（3）ヒト線維芽細胞におけるインテグリン発現量の増加作用
（4）ヒト線維芽細胞におけるフィブリリン-1発現量の増加作用
（I-3）線維芽細胞を賦活化することで真皮層中において膠原線維や弾性線維の引っ張り力の回復/向上作用、間質成分の生成を促進する作用を有する、（I-1）または（I-2）記載の線維芽細胞賦活剤。
(I) Dermal fibroblast activator (I-1) A fibroblast activator containing ceramides as an active ingredient.
(I-2) The fibroblast activator according to (I-1), which has at least one action selected from the group consisting of the following (1) to (4).
(1) ATP production promoting action in human fibroblasts (2) Collagen gel contraction promoting action in human fibroblasts (3) Integrin expression level increasing action in human fibroblasts (4) Fibrin-1 in human fibroblasts Increased expression level (I-3) By activating fibroblasts, it has the effect of recovering / improving the tensile force of collagen fibers and elastic fibers in the dermis layer, and promoting the production of stromal components (I-3). The fibroblast activator according to I-1) or (I-2).
（II）加齢または紫外線照射による肌劣化症状を予防および／または改善するための組成物
（II-1）セラミド類を有効成分とする、加齢または紫外線照射による肌劣化症状を予防および／または改善するための組成物。なお、当該組成物は、前述する「（I-1）〜（I-3）のいずれかに記載する線維芽細胞賦活剤を有効成分とする、加齢または紫外線照射による肌劣化症状を予防および／または改善するための組成物」と言い換えることができる。
(II) Composition for preventing and / or ameliorating skin deterioration symptoms due to aging or UV irradiation (II-1) Preventing and / or ameliorating skin deterioration symptoms due to aging or UV irradiation containing ceramides as an active ingredient Composition for improvement. The composition comprises the fibroblast activator according to any one of (I-1) to (I-3) described above as an active ingredient to prevent skin deterioration symptoms due to aging or ultraviolet irradiation. / Or a composition for improvement ".
（II-2）上記加齢または紫外線照射による肌劣化症状が、真皮じわ、肌のたるみ及びハリ低下からなる群から選択される少なくとも１つの症状である、（II-1）記載の組成物。（II-3）さらに皮膚吸収促進剤を含有する（II-1）または（II-2）に記載する組成物。
（II-4）セラミド類の皮膚浸透を促進するための形態、例えばリポソーム形態、マイクロエマルション形態、またはマイクロニードル形態を有する、（II-1）〜（II-3）のいずれかに記載する組成物。
（II-5）下記（a）〜（ｄ）のいずれかの皮膚浸透法に適用して用いられるものである、（II-1）〜（II-3）のいずれかに記載する組成物：
（a）閉鎖密封法
（b）エレクトロポレーション
（c）ソノフォレーシス
(d)マイクロニードル。
(II-2) The composition according to (II-1), wherein the skin deterioration symptom due to aging or ultraviolet irradiation is at least one symptom selected from the group consisting of dermis wrinkles, skin sagging and reduced firmness. .. (II-3) The composition according to (II-1) or (II-2), which further contains a skin absorption promoter.
(II-4) The composition according to any one of (II-1) to (II-3), which has a form for promoting skin penetration of ceramides, for example, a liposome form, a microemulsion form, or a microneedle form. Stuff.
(II-5) The composition according to any one of (II-1) to (II-3), which is used by applying to any of the following skin penetration methods (a) to (d):
(A) Closed seal method (b) Electroporation (c) Sonophoresis
(d) Microneedle.
（II-6）医薬品、医薬部外品、化粧品及び飲食品からなる群から選択されるいずれかである（II-1）〜（II-5）のいずれかに記載する組成物。 (II-6) The composition according to any one of (II-1) to (II-5), which is selected from the group consisting of pharmaceuticals, quasi-drugs, cosmetics and foods and drinks.
（III）肌劣化症状を改善する美容方法
（III-1）セラミド類を有効成分とする組成物を、加齢または紫外線照射による肌劣化症状を有する被験者に適用し、当該被験者の上記肌劣化症状を改善する美容方法（ヒトに対する治療方法を除く）。
（III-2）セラミド類を有効成分とする組成物が、上記（II-1）〜（II-5）のいずれかに記載する組成物である（III-1）に記載する美容方法。
（III-3）セラミド類を有効成分とする組成物が、医薬部外品、化粧品及び飲食品からなる群から選択されるいずれかである（III-1）または（III-2）に記載する美容方法。
(III) Beauty method for improving skin deterioration symptoms (III-1) A composition containing ceramides as an active ingredient is applied to a subject who has skin deterioration symptoms due to aging or ultraviolet irradiation, and the above-mentioned skin deterioration symptoms of the subject are applied. Beauty methods to improve (excluding treatment methods for humans).
(III-2) The cosmetological method according to (III-1), wherein the composition containing ceramides as an active ingredient is the composition according to any one of (II-1) to (II-5) above.
(III-3) Describe in (III-1) or (III-2), wherein the composition containing ceramides as an active ingredient is selected from the group consisting of quasi-drugs, cosmetics and foods and drinks. Beauty method.
本発明の線維芽細胞賦活剤によれば、真皮層内にある線維芽細胞に作用してそれを活性化することが可能となる。その結果、真皮層に存在する間質成分（膠原線維（コラーゲン）、弾性線維（エラスチン、フィブリリン）、ムコ多糖（ヒアルロン酸）等）の少なくとも１種の生成を促進したり、また膠原線維及び／又は弾性線維の引っ張り力を回復／向上することで、加齢や紫外線照射によって生じる当該成分の減少や膠原線維や弾性線維の引っ張り力の減少を原因とする肌のたるみ、肌のハリ低下及び／又は真皮じわを予防または改善することが可能となる。従って、本発明の線維芽細胞賦活剤は、加齢または紫外線照射による上記原因の肌劣化症状を予防および／または改善するための組成物（医薬品、医薬部外品、化粧品または飲食品）の有効成分として有用である。 According to the fibroblast activator of the present invention, it is possible to act on and activate fibroblasts in the dermis layer. As a result, it promotes the production of at least one of the interstitial components (collagen fiber (collagen), elastic fiber (elastin, fibrillin), mucopolysaccharide (hyaluronic acid), etc.) present in the dermis layer, and also promotes the production of collagen fiber and / Alternatively, by recovering / improving the tensile force of the elastic fibers, the sagging of the skin, the decrease of the firmness of the skin caused by the decrease of the relevant component caused by aging and the irradiation of ultraviolet rays, and the decrease of the tensile force of the collagen fibers and the elastic fibers, and / Alternatively, it becomes possible to prevent or improve dermal wrinkles. Therefore, the fibroblast activator of the present invention is effective as a composition (pharmaceutical product, quasi-drug, cosmetic or food or drink) for preventing and / or ameliorating the skin deterioration symptom caused by aging or ultraviolet irradiation. It is useful as an ingredient.
本発明の組成物によれば、線維芽細胞の賦活作用に基づいて、真皮層に存在する間質成分（膠原線維（コラーゲン）、弾性線維（エラスチン、フィブリリン）、ムコ多糖（ヒアルロン酸）等）の少なくとも１種の生成を促進することや膠原線維、弾性線維の引っ張り力の回復/向上ができる。その結果、加齢や紫外線照射によって生じるこれら成分の減少を抑制し、当該成分の減少を原因とする肌のたるみ、肌のハリ低下及び／又は真皮じわを予防または改善することが可能となる。 According to the composition of the present invention, stromal components existing in the dermis layer (collagen fibers (collagen), elastic fibers (elastin, fibrillin), mucopolysaccharide (hyaluronic acid), etc.) based on the activating action of fibroblasts. It is possible to promote the production of at least one of the collagen fibers and to restore / improve the tensile force of collagen fibers and elastic fibers. As a result, it is possible to suppress the decrease of these components caused by aging and ultraviolet irradiation, and to prevent or improve the sagging of the skin, the decrease of the firmness of the skin and / or the dermis wrinkles caused by the decrease of the components. ..
また有効成分であるセラミド類と皮膚吸収促進剤（皮膚浸透促進剤）等を併用した本発明の組成物によれば、セラミド類の真皮層への浸透性を高めることで、より高い線維芽細胞賦活作用を得ることができ、それに伴って加齢または紫外線照射による肌劣化症状をより有効に予防および／または改善することが可能になる。 Further, according to the composition of the present invention in which ceramides which are active ingredients and a skin absorption promoter (skin penetration promoter) are used in combination, higher fibroblasts are obtained by increasing the permeability of ceramides into the dermis layer. An activating effect can be obtained, and accordingly, it becomes possible to more effectively prevent and / or improve skin deterioration symptoms due to aging or ultraviolet irradiation.
（Ｉ）真皮線維芽細胞賦活剤
本発明の線維芽細胞賦活剤は、セラミド類を有効成分とすることを特徴とする。本発明が対象とするセラミド類には、セラミド（天然セラミド、ヒト型セラミド、植物性セラミド等）の他セラミド類縁体（擬似セラミド等）が含まれる。
(I) Dermal fibroblast activator The fibroblast activator of the present invention is characterized by containing ceramides as an active ingredient. The ceramides targeted by the present invention include ceramides (natural ceramides, human ceramides, plant ceramides, etc.) and ceramide analogs (pseudo-ceramides, etc.).
ここでセラミド (ceramide) はスフィンゴ脂質の一種であり、スフィンゴシンのアミノ基に長鎖脂肪酸がアミド結合した化合物群の総称である。スフィンゴシンの構造（Ｎ−アシル基の構造など）及び長鎖脂肪酸の構造の違いにより１１種類に細分化（セラミド１〜１１）されている（例えば、Robson KJ, Stewart ME, Michelsen S, Lazo ND, Downing DT.: 6-Hydroxy-4-sphingenine in human epidermal ceramides. J Lipid Res. 1994 Nov;35(11):2060-8；及び、石田賢哉ら「特集１ 機能性原料としてのセラミドとその応用『天然型セラミドの開発と応用 角層細胞間脂質に着目した光学活性セラミド製剤』」FRAGRANCE JOURNAL 2004-11:23-32）。 Here, ceramide is a kind of sphingolipid, and is a general term for a group of compounds in which a long chain fatty acid is amide-bonded to an amino group of sphingosine. It is subdivided into 11 types (ceramides 1 to 11) depending on the structure of sphingosine (N-acyl group structure, etc.) and the structure of long chain fatty acids (for example, Robson KJ, Stewart ME, Michelsen S, Lazo ND, Downing DT .: 6-Hydroxy-4-sphingenine in human epidermal ceramides. J Lipid Res. 1994 Nov; 35 (11): 2060-8; and Kenya Ishida et al. "Special Feature 1 Ceramides as Functional Ingredients and Their Applications" Development and application of natural ceramide Optically active ceramide preparation focusing on intercellular lipids in the stratum corneum ”” FRAGRANCE JOURNAL 2004-11: 23-32).
本発明においては上記のセラミドの構造を有していれば何れのセラミドでも使用でき、動物または植物由来のセラミドの他、有機合成により得られたセラミドを用いてもよい。またこれらには不斉炭素が存在し、光学活性体、ラセミ体（光学不活性体）が存在するが、本発明ではその何れもが使用できる。好ましいのは光学活性体である。なかでも好ましくは、セラミド１、セラミド２、およびセラミド３である。商業的に入手可能なセラミドとしては、例えば、セラミド１（商品名；CERAMIDE I（エボニックジャパン株式会社製））、セラミド２（商品名：CERAMIDE TIC-001(高砂香料工業株式会社製)）セラミド３（商品名：CERAMIDE III（エボニックジャパン株式会社製））等が挙げられる。 In the present invention, any ceramide having the above-mentioned ceramide structure can be used, and in addition to animal or plant-derived ceramides, ceramides obtained by organic synthesis may be used. In addition, there are asymmetric carbons in these, and there are optically active substances and racemic forms (optically inactive substances), and any of them can be used in the present invention. An optically active substance is preferable. Of these, ceramide 1, ceramide 2, and ceramide 3 are preferable. Commercially available ceramides include, for example, ceramide 1 (trade name; CERAMIDE I (manufactured by Ebonic Japan Co., Ltd.)), ceramide 2 (trade name: CERAMIDE TIC-001 (manufactured by Takasago Fragrance Industry Co., Ltd.)) ceramide 3. (Product name: CERAMIDE III (manufactured by Ebonic Japan Co., Ltd.)) and the like.
セラミド類縁体とは、セラミドと構造及び性質が類似した擬似セラミド及び、それらの成分からの抽出物や誘導体（スフィンゴシン誘導体）も含まれている。当該セラミド類縁体には、特開昭６２−２２８０４８号公報、特開昭６３−２１６８１２号公報、特開昭６３−２２７５１３号公報、特開昭６４−２９３４７号公報、特開昭６４−３１７５２号公報、および特開平８−３１９２６３号公報などに記載されているセラミド類似構造物質が含まれる。具体的には、下記一般式（１）で示される化合物及び一般式（２）で示される化合物から選択される化合物を挙げることができる。 The ceramide analog also includes pseudo-ceramide having a structure and properties similar to those of ceramide, and extracts and derivatives (sphingosine derivatives) from those components. Examples of the ceramide analog include JP-A-62-228048, JP-A-63-216812, JP-A-63-227513, JP-A-64-29347, and JP-A-64-31752. Includes ceramide-like structural substances described in JP-A-8-319263 and the like. Specifically, a compound selected from the compound represented by the following general formula (1) and the compound represented by the general formula (2) can be mentioned.
なお、上記式（１）及び（２）中、炭化水素基としてはアルキル基又はアルケニル基を好適に挙げることができる。 In the above formulas (1) and (2), an alkyl group or an alkenyl group can be preferably mentioned as the hydrocarbon group.
セラミド類は、１種単独で使用してもよいし、また２種以上を任意に組み合わせて使用することもできる。好ましいセラミド類は、ヒト型（光学活性体）セラミドであり、なかでも前述するように、セラミド１、セラミド２、およびセラミド３からなる群から選択される少なくとも１種を挙げることができる。 One type of ceramide may be used alone, or two or more types may be used in any combination. Preferred ceramides are human-type (optically active) ceramides, and as described above, at least one selected from the group consisting of ceramide 1, ceramide 2, and ceramide 3 can be mentioned.
本発明の線維芽細胞賦活剤中に含まれるセラミド類の割合としては、線維芽細胞に対して賦活作用を発揮する量であればよく、その限りにおいて特に制限されるものではない。通常、０．０００１〜１００重量％の範囲から適宜選択することができる。好ましくは０．０１〜１００重量％、より好ましくは０．６３〜１００重量％を例示することができる。 The ratio of ceramides contained in the fibroblast activator of the present invention is not particularly limited as long as it exerts an activating effect on fibroblasts. Usually, it can be appropriately selected from the range of 0.0001 to 100% by weight. Preferably, 0.01 to 100% by weight, more preferably 0.63 to 100% by weight can be exemplified.
本発明の線維芽細胞賦活剤は、後述する実験例で示すように、下記（1）〜（4）からなる群から選択される少なくとも１つの作用を有する。
（1）ヒト線維芽細胞におけるＡＴＰ産生促進作用
（2）ヒト線維芽細胞のコラーゲンゲル収縮促進作用
（3）ヒト線維芽細胞におけるインテグリン発現量の増加作用
（4）ヒト線維芽細胞におけるフィブリリン-1発現量の増加作用。
The fibroblast activator of the present invention has at least one action selected from the group consisting of the following (1) to (4), as shown in the experimental examples described later.
(1) ATP production promoting action in human fibroblasts (2) Collagen gel contraction promoting action in human fibroblasts (3) Integrin expression level increasing action in human fibroblasts (4) Fibrin-1 in human fibroblasts The effect of increasing the expression level.
前記のとおり、線維芽細胞を賦活化することで、上記の間質成分の減少を抑制する、及び／又は膠原線維や弾性線維を引っ張った状態にすること等ができ、当該成分の減少及び／又は膠原線維や弾性線維の引っ張り力の低下を原因とする加齢または紫外線照射等による真皮じわ、肌のたるみ、及び／または肌のハリ低下を予防若しくは改善することが可能になる。
なお、本発明で「線維芽細胞賦活（活性化）」というときは、正常ヒト真皮線維芽細胞（NHDF）において、前記（1）乃至（4）のいずれか１以上の作用を高めることができることをいう。
As described above, by activating fibroblasts, it is possible to suppress the decrease of the above-mentioned interstitial component and / or to bring the collagen fiber or elastic fiber into a pulled state, and the decrease of the component and / Alternatively, it becomes possible to prevent or improve dermis wrinkles, sagging of the skin, and / or reduction of firmness of the skin due to aging or irradiation with ultraviolet rays caused by a decrease in the tensile force of collagen fibers and elastic fibers.
In the present invention, the term "fibroblast activation (activation)" means that the action of any one or more of (1) to (4) above can be enhanced in normal human dermal fibroblasts (NHDF). To say.
本発明の線維芽細胞賦活剤には、本発明の効果を妨げないことを限度として他の成分を配合することができる。かかる成分は、線維芽細胞賦活剤が医薬品、医薬部外品、化粧品、及び飲食品からなる群から選択されるいずれの組成物に適用されるかによっても異なるが、例えば、線維芽細胞賦活作用を有する物質（セラミド類以外）、抗酸化剤、防腐・殺菌剤、油性成分、界面活性剤（合成系、天然物系）、増粘剤等を挙げることができる。 The fibroblast activator of the present invention may contain other components as long as the effects of the present invention are not impaired. Such components vary depending on which composition the fibroblast activator is applied to selected from the group consisting of pharmaceuticals, quasi-drugs, cosmetics, and foods and drinks, but for example, fibroblast activator action. (Other than ceramides), antioxidants, preservatives / bactericides, oily components, surfactants (synthetic, natural products), thickeners, etc. can be mentioned.
ここで線維芽細胞賦活作用を有する物質（セラミド類以外）としては、ビルベリー葉エキス、ポリアミン、アロエエキス、カッコンエキス、クロレラエキス、プラセンタエキス、サトウカエデ樹液、ローヤルゼリー、酵母エキス、ムコ多糖体液、ヒオウギ抽出液、ダイズエキス、ホエイ等を挙げることができる。 Here, as substances having a fibroblast activating effect (other than ceramides), bilberry leaf extract, polyamine, aloe extract, cucumber extract, chlorella extract, placenta extract, sugar maple sap, royal jelly, yeast extract, mucopolysaccharide solution, and barley extract. Liquids, soybean extract, whey and the like can be mentioned.
また抗酸化剤としては、ビタミンＥ、ブチルヒドロキシトルエン、エリソルビン酸、チオジプロピオン酸ジラウリル、無水亜硫酸ナトリウム、チャエキス、パルミチン酸アスコルビル、ステアリン酸アスコルビル、没食子酸オクチル、アスコルビン酸誘導体等を挙げることができる。 Examples of antioxidants include vitamin E, butylhydroxytoluene, erythorbic acid, dilauryl thiodipropionate, sodium anhydrous sodium sulfite, cha extract, ascorbyl palmitate, ascorbyl stearate, octyl gallate, and ascorbic acid derivatives. ..
さらに防腐・殺菌剤としては、フェノキシエタノール、ヤシ油アルキルPG-ジモニウムクロリドリン酸Na、ブチルカルバミン酸ヨウ化プロピニル、安息香酸、クレゾール、ヒノキチオール、塩化ベンザルコニウム、ソルビン酸、パラオキシ安息香酸ブチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ベンジル等を挙げることができる。 Further, as preservatives and bactericides, phenoxyethanol, coconut oil alkyl PG-dimonium chloriderina Na, propynyl iodide butylcarbamate, benzoic acid, cresol, hinokithiol, benzalkonium chloride, sorbic acid, butyl paraoxybenzoate, paraoxy Examples thereof include propyl benzoate and benzyl paraoxybenzoate.
油性成分としては、高級アルコール、植物油、及び植物ステロール（フィトステロール等）が挙げられる。 Examples of the oily component include higher alcohols, vegetable oils, and vegetable sterols (phytosterols, etc.).
高級アルコールとしては、炭素数６以上、より好ましくは炭素数６〜３０の脂肪族アルコールが挙げられる。当該油性成分は、常温（２５℃）で固形のものが好ましい。具体的には、セタノール、ベヘニルアルコール、ミリスチルアルコール、セチルアルコール、オレイルアルコール、ステアリルアルコール、イソステアリルアルコール、ヘキサデシルアルコール、ラノリンアルコール等が挙げられる。これらの高級アルコールは、１種単独で用いてもよいし、また２種以上を併用してもよい。 Examples of the higher alcohol include fatty alcohols having 6 or more carbon atoms, more preferably 6 to 30 carbon atoms. The oily component is preferably solid at room temperature (25 ° C.). Specific examples thereof include cetanol, behenyl alcohol, myristyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, isostearyl alcohol, hexadecyl alcohol, and lanolin alcohol. These higher alcohols may be used alone or in combination of two or more.
植物油としては、マカデミア種子油、ホホバ種子油、カニナバラ果実油、ヤシ油、アボガド油、オリーブ油、杏仁油、ククイナッツ油、グレープシード油、サフラワー油、スイーツアルモンド油、トウモロコシ胚芽油、ヒマワリ油、ヘーセルナッツ油、ホホバワックス、及びローズヒップ油等が挙げられる。これらの植物油は、１種単独で用いてもよいし、また２種以上を併用してもよい。 Vegetable oils include macadamia seed oil, jojoba seed oil, canina rose fruit oil, palm oil, avocado oil, olive oil, apricot oil, kukui nut oil, grape seed oil, safflower oil, sweets almond oil, corn germ oil, sunflower oil, and hazelnut. Examples include oil, jojoba wax, rose hip oil and the like. These vegetable oils may be used alone or in combination of two or more.
植物ステロール（フィトステロール）は、植物の細胞膜中に存在し、二重結合を持つシトステロールを始め、スチグマステロール、カンペステロール、ブラシカステロール、フコステロールや二重結合を持たないステロール等の混合物である。本発明に使用される植物ステロールは特に限定するものではなく、例えば、大豆、米、小麦、ゴマなどの穀物；大根、キャベツ、リンゴ、レタスなどの果物や野菜；その他ヒマワリ、菜種、ヤシ、棉実、樹木の皮などからの抽出品、精製品などが挙げられる。抽出される植物原料の種類は特に限定するものではないが、好ましくは植物油の脱臭工程により産出されるスカム等より分離して得られる植物ステロール、パルプの製造の際に副産物として得られるステロールを挙げることができる。 Plant sterols (phytosterols) are a mixture of sitosterol, which is present in the cell membrane of a plant and has a double bond, stigmasterol, campesterol, brassicasterol, fucosterol, and sterol which does not have a double bond. The plant sterol used in the present invention is not particularly limited, and for example, grains such as soybean, rice, wheat and sesame; fruits and vegetables such as radish, cabbage, apple and lettuce; and other sunflower, rapeseed, palm and sardine. Examples include products extracted from the bark of trees and refined products. The type of plant raw material to be extracted is not particularly limited, but preferably plant sterols obtained by separating from scum or the like produced in the deodorizing step of vegetable oil, and sterols obtained as a by-product in the production of pulp. be able to.
界面活性剤としては、陽イオン界面活性剤、陰イオン界面活性剤、両性界面活性剤、非イオン界面活性剤が挙げられる。好ましく非イオン界面活性剤である。具体的にはラウリン酸ポリグリセリル−６、ミリスチン酸ポリグリセリル−６、ステアリン酸ポリグリセリル−６、ラウリン酸ポリグリセリル−１０、ミリスチン酸ポリグリセリル−１０、ステアリン酸ポリグリセリル−１０ミリスチン酸グリセリル、ステアリン酸グリセリル、オレイン酸グリセリルが挙げられる。 Examples of the surfactant include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant. It is preferably a nonionic surfactant. Specifically, polyglyceryl laurate-6, polyglyceryl myristate-6, polyglyceryl stearate-6, polyglyceryl laurate-10, polyglyceryl myristate-10, polyglyceryl stearate-10 glyceryl stearate, glyceryl stearate, glyceryl oleate. Can be mentioned.
増粘剤としては、カルボキシビニルポリマー、アクリル酸／アクリル酸ステアリル）コポリマー、（アクリレーツ／アクリル酸アルキル（Ｃ１０−３０））クロスポリマー、カルボキシメチルセルロースＣａ、キサンタンガム、タマリンドガム等が挙げられる。 Examples of the thickener include carboxyvinyl polymer, acrylic acid / stearyl acrylate) copolymer, (Acrylate / alkyl acrylate (C10-30)) crosspolymer, carboxymethyl cellulose Ca, xanthan gum, tamarind gum and the like.
本発明の線維芽細胞賦活剤は、医薬品、医薬部外品、化粧品、及び飲食品に適用することができるが、好ましくは外用の医薬品、医薬部外品、及び化粧品等の外用組成物に配合して用いられる。こうした医薬品、医薬部外品、化粧品、及び飲食品への配合割合としては、これらの製品が経口投与（経口摂取）されるものであるか、または皮膚に塗布または貼付して使用されるものであるか（外用用途）によって異なり、一概に定めることはできないが、経口投与（経口摂取）される組成物に対しては、通常、セラミド類が最終製品に０．０００１〜１００重量％の割合で含まれるように配合することができ、外用組成物に対しては、通常、セラミド類が最終製品に０．０００１〜２０重量％の割合で含まれるように配合することができる。 The fibroblast activator of the present invention can be applied to pharmaceuticals, quasi-drugs, cosmetics, and foods and drinks, but is preferably blended in external compositions such as external pharmaceuticals, quasi-drugs, and cosmetics. Is used. The proportion of these products in pharmaceuticals, quasi-drugs, cosmetics, and foods and drinks is that these products are orally administered (orally ingested) or applied or affixed to the skin. Depending on the presence (for external use), it cannot be unequivocally determined, but for compositions to be orally administered (orally ingested), ceramides are usually added to the final product at a ratio of 0.0001 to 100% by weight. It can be blended so as to be contained, and for external compositions, ceramides can be usually blended so as to be contained in the final product in a proportion of 0.0001 to 20% by weight.
（II）加齢または紫外線照射による肌劣化症状を予防および／または改善するための組成物
本発明の組成物は、加齢または紫外線照射による肌劣化症状を予防および／または改善するのに適しており、もっぱらこの目的のために使用される組成物であって、セラミド類を有効成分とすることを特徴とする。
なお、加齢または紫外線照射による肌劣化症状としては、真皮じわ、肌のたるみ及びハリ低下からなる群から選択される少なくとも１つの症状を挙げることができる。ここで肌のたるみ及びハリ低下は、真皮層に存在する膠原線維（コラーゲン）、弾性線維（エラスチン、フィブリリン）、及びムコ多糖（ヒアルロン酸）等（本明細書では、「真皮層内に存在する間質成分」または単に「間質成分」とも称する。）からなる群から選択される少なくとも１種の量の低下、及び／又は膠原線維や弾性線維の引っ張り力の低下に伴って生じる「肌のたるみ及びハリ低下」を意味し、「真皮じわ」は当該間質成分の減少に起因して生じるしわ（大しわ、深いしわ）を意味する。
(II) Composition for Preventing and / or Ameliorating Skin Deterioration Symptoms Due to Aging or UV Irradiation The composition of the present invention is suitable for preventing and / or ameliorating skin deterioration symptoms due to aging or UV irradiation. It is a composition used exclusively for this purpose, and is characterized by containing ceramides as an active ingredient.
As the skin deterioration symptom due to aging or ultraviolet irradiation, at least one symptom selected from the group consisting of dermis wrinkles, sagging skin and decreased firmness can be mentioned. Here, the sagging and reduced firmness of the skin are caused by collagen fibers (collagen), elastic fibers (elastin, fibrillin), mucopolysaccharide (hyaluronic acid), etc. existing in the dermis layer (in the present specification, "existing in the dermis layer". A decrease in the amount of at least one selected from the group consisting of "interstitial components" or simply "interstitial components") and / or a decrease in the tensile force of collagen fibers and elastic fibers "of the skin". It means "reduced sagging and firmness", and "dermis wrinkle" means wrinkles (large wrinkles, deep wrinkles) caused by the decrease of the interstitial component.
本発明の組成物中に含まれるセラミド類の割合としては、線維芽細胞に対する賦活作用を有し、その作用に基づいて加齢または紫外線照射による肌劣化症状が予防および／または改善できる量であればよく、その限りにおいて特に制限されるものではない。通常、０．０００１〜１００重量％の範囲から適宜選択することができる。好ましくは０．０１〜２０重量％、より好ましくは０．６３〜２０重量％を例示することができる。 The proportion of ceramides contained in the composition of the present invention is such that it has an activating effect on fibroblasts and can prevent and / or improve skin deterioration symptoms due to aging or ultraviolet irradiation based on the effect. As long as it is sufficient, there are no particular restrictions. Usually, it can be appropriately selected from the range of 0.0001 to 100% by weight. Preferably, 0.01 to 20% by weight, more preferably 0.63 to 20% by weight can be exemplified.
本発明の組成物には、本発明の効果を妨げないことを限度として他の成分を配合することができる。かかる成分は、本発明の組成物が医薬品、医薬部外品、化粧品、及び飲食品からなる群から選択されるいずれの組成物であるか、またその剤型（固形状、半固形状、液状、乳液状等）によっても異なり、各種の態様に応じて、適宜選択し設定することができる。 Other components can be added to the composition of the present invention as long as the effects of the present invention are not impaired. Such an ingredient is a composition selected from the group consisting of pharmaceuticals, quasi-drugs, cosmetics, and foods and drinks, and the dosage form (solid, semi-solid, liquid) thereof. , Emulsion, etc.), and can be appropriately selected and set according to various aspects.
例えば、セラミド類以外の線維芽細胞賦活作用を有する物質を組み合わせて配合することもできる。ここで使用できる物質としては、（Ｉ）において説明した線維芽細胞賦活作用を有する物質を同様に挙げることができる。 For example, substances other than ceramides having a fibroblast activating effect can be combined and blended. As the substance that can be used here, the substance having the fibroblast activating action described in (I) can be similarly mentioned.
また本発明の組成物が外用の医薬品、医薬部外品または化粧品である場合、さらに皮膚吸収促進剤（皮膚浸透促進剤）を配合してもよい。皮膚吸収促進剤（皮膚浸透促進剤）としては、セラミド類の経皮浸透性を高め、皮膚への吸収を促進する作用を有するものを使用することができる。かかるものとして、例えば、各種の界面活性剤（アニオン性、カチオン性、ノニオン性界面活性剤）、脂肪酸・脂肪酸エステル（オレイン酸、ミリスチン酸イソプロピル、中鎖脂肪酸トリグリセライド等）、生分解性促進剤（アルキルエステル、アミノカプロン酸）、その他、アミノ酸、テルペン類、ピロリドン類、尿素、リン脂質、各種の溶媒（ポリオール、低級アルコール、高級アルコール、ジメチルフルスルフォキシド等）を制限なく例示することができる。 When the composition of the present invention is a pharmaceutical product, quasi-drug or cosmetic product for external use, a skin absorption promoter (skin penetration promoter) may be further added. As the skin absorption promoter (skin penetration promoter), those having an action of enhancing the percutaneous permeability of ceramides and promoting their absorption into the skin can be used. Such as, for example, various surfactants (anionic, cationic, nonionic surfactants), fatty acid / fatty acid esters (oleic acid, isopropyl myristate, medium chain fatty acid triglyceride, etc.), biodegradability accelerators ( Alkyl esters (aminocaproic acid), other amino acids, terpenes, pyrrolidones, urea, phospholipids, various solvents (polyols, lower alcohols, higher alcohols, dimethylflusulfoxide, etc.) can be exemplified without limitation.
セラミド類をかかる皮膚吸収促進剤（皮膚浸透促進剤）と併用することで、セラミド類を効率的に真皮層に到達させることができ、当該真皮層においてより有効に線維芽細胞賦活効果を発揮させることができる。制限されないものの、本発明の組成物中、当該皮膚吸収促進剤（皮膚浸透促進剤）は、０．５〜７０重量％の範囲で配合することができる。 By using ceramides in combination with such a skin absorption promoter (skin penetration promoter), the ceramides can reach the dermis layer efficiently, and the fibroblast activation effect is more effectively exerted in the dermis layer. be able to. Although not limited, the skin absorption promoter (skin penetration promoter) in the composition of the present invention can be blended in the range of 0.5 to 70% by weight.
本発明の組成物は、その使用目的（医薬品、医薬部外品、化粧品、飲食品）及び投与経路等に応じて、固形剤、半固形剤、液剤、乳液剤等の各種剤形の組成物に調製することが可能である。 The composition of the present invention is a composition in various dosage forms such as a solid preparation, a semi-solid preparation, a liquid preparation, and a milky lotion preparation, depending on the purpose of use (pharmaceutical products, quasi-drugs, cosmetics, foods and drinks), administration route, and the like. It is possible to prepare in.
外用の医薬品または医薬部外品としての形態としては、例えば、硬膏剤、軟膏剤、クリーム剤、パップ剤、リニメント剤、ローション剤、乳液剤、液剤、エアゾール剤を挙げることができる。 Examples of the form of an external drug or quasi-drug include a plaster, an ointment, a cream, a poultice, a liniment, a lotion, a milky lotion, a liquid, and an aerosol.
化粧品としての形態は特に限定されるものではないが、例えばスキンケア化粧品として化粧水、美容液、パック、マッサージクリーム、乳液、モイスチャークリーム、リップクリーム等；メーキャップ化粧品としてファンデーション、白粉、口紅、ほほ紅、アイシャドウ等とすることができる。上記化粧品には、一般に化粧品に用いられている各種化粧品成分を適宜配合することができる。 The form as a cosmetic is not particularly limited, but for example, as a skin care cosmetic, a lotion, a beauty essence, a pack, a massage cream, a milky lotion, a moisture cream, a lip cream, etc .; as a makeup cosmetic, a foundation, white powder, lipstick, blush, etc. It can be an eye shadow or the like. Various cosmetic ingredients generally used in cosmetics can be appropriately blended into the above cosmetics.
本発明の組成物には、所望の効果を損なわない範囲で、通常の外用組成物に用いられる成分である油脂類、ロウ類、炭化水素類、脂肪酸類、アルコール類、エステル類、アミノ酸類、ビタミン類、界面活性剤、ｐＨ調整剤、防腐剤、香料、保湿剤、粉体、紫外線吸収剤、増粘剤、色素、酸化防止剤、美白剤、抗炎症剤、抗しわ剤、肌荒れ改善剤、ニキビ用薬剤、アルカリ類、キレート剤の成分を配合することもできる。 The composition of the present invention includes fats and oils, waxes, hydrocarbons, fatty acids, alcohols, esters, amino acids, which are components used in ordinary external composition, as long as the desired effect is not impaired. Vitamins, surfactants, pH regulators, preservatives, fragrances, moisturizers, powders, UV absorbers, thickeners, pigments, antioxidants, whitening agents, anti-inflammatory agents, anti-wrinkle agents, rough skin improvers , Acne agents, alkalis, and chelating agents can also be added.
また本発明の組成物は皮膚の深部（真皮層）にまでセラミド類が効率的に浸透するような形態を有していてもよい。かかる形態としては、制限されないものの、リポソーム形態、マイクロエマルション形態、またはマイクロニードル形態を例示することができる（例えば、最新・化粧品の機能創製・素材開発・応用技術（技術教育出版社発行）288-293頁、及び日本香粧品学会誌（40周年記念誌）39巻, 2015, 112-115頁等参照）。本発明の組成物を例えばリン脂質でできたナノカプセルに封入して調製してリポソーム形態に調製したり、また各種の界面活性剤を利用することでW/O型、O/W型またはW/O/W型のマイクロエマルション形態にすることで、本発明の組成物を皮膚への浸透（吸収）を高め、セラミド類を真皮層にまで到達しやすくすることができる。また本発明の組成物そのものをマイクロニードル形態に調製しそれを皮膚に貼付するか、または本発明の組成物を例えばシリコン、金属、または生分解性高分子により形成された長さ15μm程度の微細な針を用いて皮膚に適用することで、本発明の組成物に含まれるセラミド類を皮膚の深部（真皮層）にまで効率的に浸透（到達）させることが可能になる（例えば、COSME TECH JAPAN, Vol.1, No.5(2011), 20-24等参照）。 Further, the composition of the present invention may have a form in which ceramides efficiently permeate deep into the skin (dermis layer). Examples of such a form include, but are not limited to, a liposome form, a microemulsion form, or a microneedle form (for example, the latest / functional creation of cosmetics / material development / applied technology (published by Technical Education Publishing Co., Ltd.) 288- See page 293 and Journal of the Japanese Society of Cosmetics (40th Anniversary), Volume 39, 2015, pp. 112-115). The composition of the present invention is prepared by encapsulating it in nanocapsules made of phospholipid, for example, to prepare it in a liposome form, or by using various surfactants, W / O type, O / W type or W. By forming the / O / W type microemulsion form, the composition of the present invention can be enhanced in penetration (absorption) into the skin, and ceramides can be easily reached to the dermis layer. Further, the composition of the present invention itself is prepared in the form of microneedles and attached to the skin, or the composition of the present invention is formed of, for example, silicon, metal, or a biodegradable polymer and has a fine length of about 15 μm. By applying it to the skin using a needle, the ceramides contained in the composition of the present invention can be efficiently penetrated (reached) into the deep part (dermis layer) of the skin (for example, COSME TECH). See JAPAN, Vol.1, No.5 (2011), 20-24, etc.).
さらにまた本発明の組成物は、皮膚の深部（真皮層）にまでセラミド類が効率的に浸透するような物理的方法を用いて、皮膚に適用することもできる。かかる方法としては、制限されないものの、閉鎖密封法（ODT：Occulusive Dressing Therapy）、エレクトロポレーション、及びソノフォレーシスを例示することができる（例えば、ファルマシア,49巻,5号,(2013),pp.400-404；および「皮膚科学 考え方学び方」金原出版株式会社、平成2年6月10日発行,p.29等）。なお、閉鎖密封法は外用剤の塗布部分をプラスチックやラップなどで覆うことにより（半日〜２日）、角質層をふやけさせ、これにより角質細胞を膨潤、角質細胞間脂質の水分量を増加させることにより角質バリア機能を低下させ、経皮吸収性を増加させる方法である。またこの際、加温すると温熱効果により血流が増加しさらに経皮吸収性を増加させることができる。また、エレクトロポレーションは、高い電圧を短時間に適用し、可逆的な穴を皮膚に形成させることで、皮膚に適用した組成物の経皮吸収を促進する方法である。また、ソノフォレーシスは、超音波振動を利用して皮膚に微細な穴を空けて皮膚に適用した組成物の経皮吸収を促進する方法である。 Furthermore, the composition of the present invention can also be applied to the skin by using a physical method such that ceramides efficiently penetrate deep into the skin (dermis layer). Examples of such methods include, but are not limited to, closed sealing (ODT: Occulusive Dressing Therapy), electroporation, and sonophoresis (eg, Pharmacia, Vol. 49, No. 5, (2013), pp.400). -404; and "Dermatology Thinking and Learning" Kanahara Publishing Co., Ltd., published on June 10, 1990, p.29, etc.). In the closed sealing method, the area to which the external preparation is applied is covered with plastic or wrap (half a day to two days) to soothe the stratum corneum, thereby swelling the stratum corneum and increasing the water content of the intercellular lipids. This is a method of lowering the keratin barrier function and increasing transdermal absorbability. At this time, when heated, blood flow is increased due to the thermal effect, and transdermal absorbability can be further increased. Electroporation is also a method of promoting transdermal absorption of a composition applied to the skin by applying a high voltage in a short time to form reversible holes in the skin. In addition, sonophoresis is a method of promoting percutaneous absorption of a composition applied to the skin by making fine holes in the skin using ultrasonic vibration.
（III）肌劣化症状を改善する美容方法
また本発明は、加齢または紫外線照射による肌劣化症状を有する被験者に対して、セラミド類を有効成分とする組成物を適用し、当該被験者の上記肌劣化症状を改善する美容方法に関する。なお、本発明が対象とする方法は、美容方法であり、ヒトに対する治療方法ではない。
(III) Beauty Method for Improving Skin Deterioration Symptoms The present invention also applies a composition containing ceramides as an active ingredient to a subject who has skin deterioration symptoms due to aging or ultraviolet irradiation, and the skin of the subject. Regarding beauty methods to improve deterioration symptoms. The method targeted by the present invention is a cosmetic method, not a therapeutic method for humans.
加齢または紫外線照射による肌劣化症状としては、真皮じわ、肌のたるみ及びハリ低下からなる群から選択される少なくとも１つの症状を挙げることができる。ここで肌のたるみ及びハリ低下は、真皮層に存在する間質成分の量の低下及び／又は膠原線維や弾性線維の引っ張り力の低下に伴って生じる肌のたるみ及びハリ低下を意味し、真皮じわは当該間質成分の減少に起因して生じるしわ（大しわ、深いしわ）を意味する。 As the skin deterioration symptom due to aging or ultraviolet irradiation, at least one symptom selected from the group consisting of dermis wrinkles, skin sagging and reduced firmness can be mentioned. Here, the decrease in skin sagging and firmness means a decrease in the amount of interstitial components present in the dermis layer and / or a decrease in the pulling force of collagen fibers and elastic fibers, which means a decrease in skin sagging and firmness. Wrinkles mean wrinkles (large wrinkles, deep wrinkles) caused by the decrease of the interstitial component.
対象とする被験者は、加齢または紫外線照射による肌劣化症状を有する者、好ましくは加齢による肌劣化症状（肌老化症状）を有する者である。通常、男女ともに３０歳を超えると当該該当の被験者になる可能性がある。好ましくは４０歳以上、より好ましくは４５歳以上、さらに好ましくは５０歳以上である。 The target subjects are those who have skin deterioration symptoms due to aging or ultraviolet irradiation, preferably those who have skin deterioration symptoms due to aging (skin aging symptoms). Usually, both men and women may become the subject if they are over 30 years old. It is preferably 40 years or older, more preferably 45 years or older, and even more preferably 50 years or older.
ここで、セラミド類を有効成分とする組成物としては、上記（II）で説明した本発明の組成物を好適に挙げることができる。これらの組成物には医薬部外品、化粧品及び飲食品が含まれる。 Here, as the composition containing ceramides as an active ingredient, the composition of the present invention described in (II) above can be preferably mentioned. These compositions include quasi-drugs, cosmetics and food and drink.
外用の医薬部外品及び化粧品は、その形態によっても異なるが、硬膏、軟膏、クリーム、リニメント、ローション、乳液、液、エアゾール等の形態を有する場合、当該外用医薬部外品及び化粧品を被験者の所望の部位の皮膚に塗布または噴霧することによって使用することができる。また外用医薬部外品及び化粧品がパップ剤の形態を有する場合、当該外用の医薬部外品及び化粧品を被験者の所望の部位の皮膚に貼付することによって使用することができる。皮膚への適用は、１日１回または複数回行ってよく、例えば朝と晩（寝る前）に適用する方法を挙げることができる。 The topical quasi-drugs and cosmetics differ depending on the form, but if they have the form of plaster, ointment, cream, liniment, lotion, milky lotion, liquid, aerosol, etc., the subject will use the topical quasi-drug and cosmetics. It can be used by applying or spraying on the skin of a desired site. When the external quasi-drug and cosmetics have the form of a poultice, they can be used by attaching the external quasi-drug and cosmetics to the skin of a desired site of the subject. The application to the skin may be performed once or multiple times a day, and examples thereof include a method of applying in the morning and evening (before going to bed).
飲食品には、錠剤、カプセル剤、顆粒剤、散剤、及び液剤（ドリンク剤）など製剤形態を有するサプリメント、並びに機能性表示食品及び特定保健用食品が含まれる。服用は、１日に１回または複数回行ってよく、例えば朝と晩（寝る前）に服用する方法を挙げることができる。
斯くして加齢または紫外線照射による肌劣化症状（特に肌老化症状）の発生を抑制し（予防）、また改善することが可能になる。
Foods and drinks include supplements having formulation forms such as tablets, capsules, granules, powders, and liquids (drinks), as well as foods with functional claims and foods for specified health uses. It may be taken once or multiple times a day, and examples thereof include a method of taking it in the morning and evening (before going to bed).
In this way, it becomes possible to suppress (prevent) or improve the occurrence of skin deterioration symptoms (particularly skin aging symptoms) due to aging or ultraviolet irradiation.
以下、実験例及び実施例に基づいて、本発明を具体的に説明する。但し、本発明はこれらによって何ら限定されるものではない。 Hereinafter, the present invention will be specifically described based on Experimental Examples and Examples. However, the present invention is not limited thereto.
実験例１ ヒト真皮線維芽細胞におけるＡＴＰ産生促進作用の評価
（１）被験試料の調製
被験試料として下記のものを準備した。なお、被験試料１及び２は、９６wellマイクロプレートの１well中のセラミド濃度（複数のセラミドを含む場合はそれらの総濃度）が２５μｇ／ｍｌになるように調製した。なお、以下「ＤＭＳＯ」は和光純薬工業株式会社製を使用した。
被験試料１：セラミド２のＤＭＳＯ溶液
被験試料２：セラミド１、２及び３の混合ＤＭＳＯ溶液
コントロール：ＤＭＳＯ溶液（なお、被験試料１及び２のＤＭＳＯと同量に調整）
なお、被験試料２中のセラミド１、２及び３の組成（重量比）は下記の通りである。
セラミド１：セラミド２：セラミド３＝０．０２：８０：１
Experimental Example 1 Evaluation of ATP production promoting action in human dermal fibroblasts
(1) Preparation of test sample The following test samples were prepared . The test samples 1 and 2 were prepared so that the ceramide concentration in 1 well of the 96-well microplate (the total concentration thereof when a plurality of ceramides were contained) was 25 μg / ml. Hereinafter, "DMSO" used was manufactured by Wako Pure Chemical Industries, Ltd.
Test sample 1: DMSO solution of ceramide 2 Test sample 2: Mixed DMSO solution of ceramides 1, 2 and 3 Control: DMSO solution (adjusted to the same amount as DMSO of test samples 1 and 2)
The composition (weight ratio) of ceramides 1, 2 and 3 in the test sample 2 is as follows.
Ceramide 1: Ceramide 2: Ceramide 3 = 0.02: 80: 1
（２）試験方法
ＤＭＥＭ（Thermo Fischer Scientific Inc製）で予め培養しておいたヒト真皮線維芽細胞を９６wellマイクロプレートに播種（10４個／well）した。これを３７℃で１日間培養した後、被験試料またはコントロールを１μL添加した。次いで３７℃で３日間培養した後に、細胞数とＡＴＰを測定し、下式に基づいて１細胞あたりのＡＴＰ量を産出した。なお、被験試料、コントロールそれぞれの試験数は３であった（ｎ：３）。
(2) was tested how DMEM seeding human dermal fibroblasts which had been preincubated with (Thermo Fischer Scientific Inc, Ltd.) in 96well microplates (104 cells / well). After culturing this at 37 ° C. for 1 day, 1 μL of the test sample or control was added. Then, after culturing at 37 ° C. for 3 days, the number of cells and ATP were measured, and the amount of ATP per cell was produced based on the following formula. The number of tests for each of the test sample and the control was 3 (n: 3).
（ａ）細胞数の測定
細胞を含む測定対象のwellに、Cell counting kit-8溶液（タカラバイオ(株)製）を１０μLずつ添加し、３７℃で２時間インキュベートした。次いで、上清を４５０ｎｍの波長で吸光度を測定して、細胞数を測定した。
(A) Measurement of cell number To a well to be measured containing cells, 10 μL of Cell counting kit-8 solution (manufactured by Takara Bio Inc.) was added and incubated at 37 ° C. for 2 hours. Then, the absorbance of the supernatant was measured at a wavelength of 450 nm, and the number of cells was measured.
（ｂ）ＡＴＰの測定
被験試料（ヒト真皮線維芽細胞）のＡＴＰ量の測定には、ルシフェラーゼ発光法を用いたＡＴＰ測定試薬（「『細胞の』ＡＴＰ測定試薬」、和光純薬工業(株)製）を使用した。具体的にはＡＴＰ測定試薬を各wellに１００μLずつ加えた。次いで、マイクロプレートシェーカーで１分間攪拌した後、１０分間静置し（室温）、マイクロプレートリーダーで発光強度を測定した。
(B) Measurement of ATP For the measurement of the amount of ATP in the test sample (human dermal fibroblasts), an ATP measurement reagent using the luciferase luminescence method ("" Cellular "ATP measurement reagent", Wako Pure Chemical Industries, Ltd. Made) was used. Specifically, 100 μL of ATP test reagent was added to each well. Then, after stirring with a microplate shaker for 1 minute, the mixture was allowed to stand for 10 minutes (room temperature), and the emission intensity was measured with a microplate reader.
（３）試験結果
試験結果を表１に記載する。なお、値はコントロールの結果（平均値）を１００とした相対値（平均値）である。
この結果から、セラミドはヒト真皮線維芽細胞におけるＡＴＰ産生を有意に促進することがわかる。ＡＴＰは生物のエネルギー源というべきものであり細胞の各種の働きに介在するものであるので、セラミドの添加によりヒト線維芽細胞１細胞あたりのＡＴＰ産生が促進されたことは、すなわち細胞が賦活化されたものと考えられる。 From this result, it can be seen that ceramide significantly promotes ATP production in human dermal fibroblasts. Since ATP is an energy source for living organisms and intervenes in various functions of cells, the addition of ceramide promoted ATP production per human fibroblast, that is, cell activation. It is probable that it was done.
実験例２ ヒト真皮線維芽細胞のコラーゲンゲル収縮促進作用の評価
（１）被験試料の調製
被験試料として、実験例１で調製した被験試料１及び２、並びにコントロールを同様に用いた。なお、被験試料１及び２は、１２wellプレートの１well中のセラミド濃度（複数のセラミドを含む場合はそれらの総濃度）が２５μｇ／ｍｌになるように調製した。
Experimental Example 2 Evaluation of collagen gel contraction promoting effect of human dermal fibroblasts
(1) Preparation of test sample As the test sample, the test samples 1 and 2 prepared in Experimental Example 1 and the control were similarly used. The test samples 1 and 2 were prepared so that the ceramide concentration in 1 well of a 12-well plate (the total concentration thereof when a plurality of ceramides were contained) was 25 μg / ml.
（２）試験方法
（a）氷上に１２wellプレートを置き、各wellにＤＭＥＭ１０倍濃縮溶液（ＤＭＥＭを通常濃度の１０倍となるように調整したもの。以下、同じ。）１００μL、ＦＢＳ１００μL、コラーゲン溶液（３μｇ／ｍL）７００μL、ＮａＨＣＯ３(１mol/L)２０μL、及びヒト真皮線維芽細胞培養液７５μL(125万個/well)を加えた。
（b）次いで各wellに被験試料（被験試料１、２またはコントロール）５μLを添加し、３７℃で１時間インキュベートしてゲル化させた。
（c）ゲルをプレートからはがし、プレート上に置いた状態で１０％ＦＢＳ含有ＤＭＥＭを１ｍLを加えた。
（d）各wellに被験試料（被験試料１、２またはコントロール）５μLを添加し、室温で攪拌した。
（e）４日間３７℃の条件で培養した後、ゲルの長さを測定し、下式に基づいて収縮前後（セラミド添加前後）でのコラーゲンゲルの直径の差（cm）を産出した。なお、被験試料、コントロールそれぞれの試験数は３であった（ｎ：３）。
(2) Test method (a) A 12-well plate was placed on ice, and DMEM 10-fold concentrated solution (DMEM adjusted to 10 times the normal concentration. The same applies hereinafter) 100 μL, FBS 100 μL, collagen solution (the same applies hereinafter) in each well. 700 μL (3 μg / mL), 20 μL of NaHCO 3 (1 mol / L), and 75 μL (1.25 million cells / well) of human dermal fibroblast culture solution were added.
(B) Next, 5 μL of the test sample (test sample 1, 2 or control) was added to each well, and the mixture was incubated at 37 ° C. for 1 hour to gel.
(C) The gel was peeled off from the plate, and 1 mL of DMEM containing 10% FBS was added while the gel was placed on the plate.
(D) 5 μL of the test sample (test sample 1, 2 or control) was added to each well, and the mixture was stirred at room temperature.
(E) After culturing at 37 ° C. for 4 days, the length of the gel was measured, and the difference (cm) in the diameter of the collagen gel before and after shrinkage (before and after the addition of ceramide) was produced based on the following formula. The number of tests for each of the test sample and the control was 3 (n: 3).
（３）試験結果
試験結果を表２に記載する。なお、値はコントロールの結果（平均値）を１００とした相対値（平均値）である。
(3) Test results The test results are shown in Table 2. The value is a relative value (average value) with the control result (average value) as 100.
この結果から、セラミドはヒト真皮線維芽細胞のコラーゲンゲルの収縮を有意に促進することがわかる。これは、セラミドの添加により線維芽細胞が膠原線維をより引っ張り引き締めていることを示しており、当該機能の向上はセラミドが線維芽細胞を賦活化した結果生じたものと考えられる From this result, it can be seen that ceramide significantly promotes the contraction of collagen gel in human dermal fibroblasts. This indicates that the addition of ceramide causes the fibroblasts to pull and tighten the collagen fibers more, and it is considered that the improvement in the function was caused by the activation of the fibroblasts by the ceramide.
実験例３ ヒト真皮線維芽細胞におけるインテグリン発現量増加作用の評価
（１）被験試料の調製
被験試料として、実験例１で調製した被験試料２、及びコントロールを同様に用いた。なお、インテグリンとして、インテグリンα２及びインテグリンβ１の発現量を評価した。インテグリンα２の発現量評価には、被験試料２は、１２wellプレートの１well中のセラミドの総濃度が６.２５μｇ／ｍｌになるように調製して使用した。一方、インテグリンβ１の発現量評価には、被験試料２は、１well中のセラミドの総濃度が２５μｇ／ｍｌになるように調製して使用した。
Experimental Example 3 Evaluation of integrin expression increasing effect in human dermal fibroblasts
(1) Preparation of test sample As the test sample, the test sample 2 prepared in Experimental Example 1 and the control were similarly used. The expression levels of integrin α2 and integrin β1 were evaluated as integrin. For the evaluation of the expression level of integrin α2, the test sample 2 was prepared and used so that the total concentration of ceramide in 1 well of a 12-well plate was 6.25 μg / ml. On the other hand, in the evaluation of the expression level of integrin β1, the test sample 2 was prepared and used so that the total concentration of ceramide in 1 well was 25 μg / ml.
（２）試験方法
（a）氷上に１２wellプレートを置き、各wellにＤＭＥＭ１０倍濃縮溶液１００μL、ＦＢＳ１００μL、コラーゲン溶液（３μｇ／ｍL）７００μL、ＮａＨＣＯ３(１mol/L)２０μL、ヒト真皮線維芽細胞培養液７５μL(125万個/well)を加えた。
（b）次いで各wellに被験試料５μLを添加し、３７℃で１時間インキュベートしてゲル化させた。
（c）ゲルをプレートからはがし、プレート上に置いた状態で１０％ＦＢＳ含有ＤＭＥＭを１ｍL加えた。
（d）各wellに被験試料５μLを添加し、室温で攪拌した。
（e）１日培養した後にＲＮＡ抽出キットを用いてＲＮＡを抽出し、One Step SYBRR PrimerScript RT-PCR kit II（タカラバイオ(株)製）を用いてインテグリンα２とインテグリンβ１のｍＲＮＡの発現量を測定した。なお、被験試料、コントロールそれぞれの試験数は３であった（ｎ：３）。
(2) Test method (a) Place a 12-well plate on ice, and in each well, DMEM 10-fold concentrated solution 100 μL, FBS 100 μL, collagen solution (3 μg / mL) 700 μL, NaHCO 3 (1 mol / L) 20 μL, human dermal fibroblast culture. 75 μL (1.25 million pieces / well) of the solution was added.
(B) Next, 5 μL of the test sample was added to each well and incubated at 37 ° C. for 1 hour for gelation.
(C) The gel was peeled off from the plate, and 1 mL of DMEM containing 10% FBS was added while the gel was placed on the plate.
(D) 5 μL of the test sample was added to each well, and the mixture was stirred at room temperature.
(E) After culturing for 1 day, RNA was extracted using an RNA extraction kit, and the expression levels of integrin α2 and integrin β1 mRNA were measured using One Step SYBRR PrimerScript RT-PCR kit II (manufactured by Takara Bio Co., Ltd.). It was measured. The number of tests for each of the test sample and the control was 3 (n: 3).
（３）試験結果
試験結果を表３に記載する。なお、値はコントロールの結果（平均値）を１００とした相対値（平均値）である。
(3) Test results The test results are shown in Table 3. The value is a relative value (average value) with the control result (average value) as 100.
この結果から、セラミドはヒト真皮線維芽細胞中のインテグリン（インテグリンα２及びβ１）の発現量を有意に増加させることがわかる。インテグリンは線維芽細胞と膠原線維や弾性線維との結合点であり、その結合点の数は前記線維の引っ張り力と関係する。当該発現量の増加は、セラミドが線維芽細胞を賦活化した結果生じたものと考えられる From this result, it can be seen that ceramide significantly increases the expression level of integrins (integrin α2 and β1) in human dermal fibroblasts. Integrins are the binding points between fibroblasts and collagen fibers or elastic fibers, and the number of binding points is related to the tensile force of the fibers. The increase in the expression level is considered to be the result of ceramide activating fibroblasts.
実験例４ ヒト真皮線維芽細胞におけるフィブリリン-1発現量増加作用の評価
（１）被験試料の調製
被験試料として、実験例１で調製した被験試料２、及びコントロールを同様に用いた。被験試料２は、１２wellプレートの１well中のセラミドの総濃度が１２.５μｇ／ｍｌになるように調製して使用した。
Experimental Example 4 Evaluation of the effect of increasing the expression level of fibrillin-1 in human dermal fibroblasts
(1) Preparation of test sample As the test sample, the test sample 2 prepared in Experimental Example 1 and the control were similarly used. Test sample 2 was prepared and used so that the total concentration of ceramide in 1 well of a 12-well plate was 12.5 μg / ml.
（２）試験方法
（a）氷上に１２wellプレートを置き、各wellにＤＭＥＭ１０倍濃縮溶液１００μL、ＦＢＳ１００μL、コラーゲン溶液（３μｇ／ｍL）７００μL、ＮａＨＣＯ３(１mol/L)２０μL、ヒト真皮線維芽細胞培養液７５μL(125万個/well)を加えた。
（b）次いで各wellに被験試料５μLを添加し、３７℃で１時間インキュベートしてゲル化させた。
（c）ゲルをプレートからはがし、プレート上に置いた状態で１０％ＦＢＳ含有ＤＭＥＭを１ｍLを加えた。
（d）各wellに被験試料５μLを添加し、室温で攪拌した。
（e）１日培養した後にＲＮＡ抽出キットを用いてＲＮＡを抽出し、One Step SYBRR PrimerScript RT-PCR kit II（タカラバイオ(株)製）を用いてフィブリリン-1のｍＲＮＡの発現量を測定した。
なお、被験試料、コントロールそれぞれの試験数は３であった（ｎ：３）。
(2) Test method (a) Place a 12-well plate on ice, and in each well, DMEM 10-fold concentrated solution 100 μL, FBS 100 μL, collagen solution (3 μg / mL) 700 μL, NaHCO 3 (1 mol / L) 20 μL, human dermal fibroblast culture. 75 μL (1.25 million pieces / well) of the solution was added.
(B) Next, 5 μL of the test sample was added to each well and incubated at 37 ° C. for 1 hour for gelation.
(C) The gel was peeled off from the plate, and 1 mL of DMEM containing 10% FBS was added while the gel was placed on the plate.
(D) 5 μL of the test sample was added to each well, and the mixture was stirred at room temperature.
(E) After culturing for 1 day, RNA was extracted using an RNA extraction kit, and the expression level of fibrillin-1 mRNA was measured using One Step SYBRR PrimerScript RT-PCR kit II (manufactured by Takara Bio Inc.). ..
The number of tests for each of the test sample and the control was 3 (n: 3).
（３）試験結果
試験結果を表４に記載する。なお、値はコントロールの結果（平均値）を１００とした相対値（平均値）である。
この結果から、セラミドはヒト真皮線維芽細胞中のフィブリリン-1の発現量を有意に増加させることがわかる。フィブリリン-1は間質成分の弾性線維を構成するものであり、弾性線維は線維芽細胞により引っ張り引き締められる。当該発現量の増加は、セラミドが線維芽細胞を賦活化した結果生じたものと考えられる。 From this result, it can be seen that ceramide significantly increases the expression level of fibrillin-1 in human dermal fibroblasts. Fibrillin-1 constitutes the elastic fibers of the stromal component, and the elastic fibers are pulled and tightened by fibroblasts. The increase in the expression level is considered to be the result of ceramide activating fibroblasts.
Claims (5)
（1）ヒト線維芽細胞におけるＡＴＰ産生促進作用
（2）ヒト線維芽細胞のコラーゲンゲル収縮促進作用
（3）ヒト線維芽細胞におけるインテグリン発現量の増加作用
（4）ヒト線維芽細胞におけるフィブリリン-1発現量の増加作用。 A fibroblast utilization composition containing human (optically active) ceramide as an active ingredient and having at least one action selected from the group consisting of the following (1) to (4):
(1) ATP production promoting action in human fibroblasts (2) Collagen gel contraction promoting action in human fibroblasts (3) Integrin expression level increasing action in human fibroblasts (4) Fibrin-1 in human fibroblasts The effect of increasing the expression level.
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