JP2018090516A - Inhibitor of melanosome uptake into epidermal cells (keratinocytes), and promoter for excreting taken up melanosomes to outside body - Google Patents
Inhibitor of melanosome uptake into epidermal cells (keratinocytes), and promoter for excreting taken up melanosomes to outside body Download PDFInfo
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Abstract
Description
本発明は、リノール酸誘導体を有効成分とした表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害剤、または取り込まれたメラノソームの体外への排出促進剤に関する。 The present invention relates to an inhibitor of melanosome uptake into epidermal cells (keratinocytes) or an accelerator for exudation of incorporated melanosomes out of the body, which comprises a linoleic acid derivative as an active ingredient.
皮膚の色は、皮膚中に存在する色素細胞（メラノサイト）内において生成されるメラニ
ンによって決定する。メラニンは、細胞核のＤＮＡを破壊する紫外線を吸収し、皮膚ガンのリスクを減らす、医学上重要な因子である。しかしながら、皮膚内でメラニンが過剰に生成される現象はしばしば起こり、これがクスミ、シミ、ソバカスなど、美容上の大きな問題となる。このメラニンは、紫外線をはじめ様々なストレスによって誘導がなされ、色素細胞内のチロシナーゼによってチロシンより酸化生成される。実際には、チロシナーゼによるメラニン生成はメラノソームと呼ばれる小胞体の中で行われる。メラノソーム内でメラニンが生成されながら、メラノソーム自身は色素細胞の樹状突起の先端部分へと局在を変更する。色素細胞の樹状突起先端部に位置したメラノソームは、表皮細胞（ケラチノサイト）へと受け渡される（非特許文献１）。
Skin color is determined by melanin produced in pigment cells (melanocytes) present in the skin. Melanin is a medically important factor that absorbs ultraviolet light that destroys the DNA of the cell nucleus and reduces the risk of skin cancer. However, a phenomenon in which melanin is excessively generated in the skin often occurs, and this becomes a major cosmetic problem such as kusumi, blemishes, and freckles. This melanin is induced by various stresses including ultraviolet rays, and is oxidatively produced from tyrosine by tyrosinase in the pigment cell. In practice, melanin production by tyrosinase occurs in the endoplasmic reticulum called melanosomes. While melanin is produced in melanosomes, melanosomes themselves change their localization to the tip of the pigment cell dendrites. The melanosomes located at the tip of the dendrites of the pigment cells are delivered to epidermal cells (keratinocytes) (Non-patent Document 1).
メラノソームの受け渡し過程は、色素細胞（メラノサイト）からの放出（エキソサイトーシス）過程と、表皮細胞（ケラチノサイト）へ取り込み（ファゴサイトーシス）過程のおおきく二つに分類されるが、皮膚の色は色素細胞（メラノサイト）内のメラニンの量ではなく、表皮細胞（ケラチノサイト）へ受け渡されたメラニン量によって決定する（非特許文献２、３）。
さらに、表皮細胞（ケラチノサイト）へ受け渡されたメラノソームは、通常皮膚（表皮）のターンオーバーと共に垢となって皮膚より剥がれ落ち、体外へと排出されるが、メラノソームを取り込んだ表皮細胞においては、ターンオーバーが遅延することで老人性色素斑など色素沈着の原因となることが知られている（特許文献１）。
つまり、表皮細胞（ケラチノサイト）内のメラノソーム量を制御することは、クスミ、シミ、ソバカスをはじめとする色素沈着の制御に有効である。
The melanosome delivery process is classified into two major processes: the release from melanocytes (exocytosis) and the uptake into keratinocytes (phagocytosis), but the skin color is pigment. It is determined not by the amount of melanin in the cell (melanocyte) but by the amount of melanin delivered to the epidermal cell (keratinocyte) (Non-patent Documents 2 and 3).
In addition, the melanosomes delivered to the epidermal cells (keratinocytes) are usually peeled off from the skin with the turnover of the skin (epidermis) and fall out of the skin, but are discharged outside the body. It is known that delayed turnover causes pigmentation such as senile pigment spots (Patent Document 1).
In other words, controlling the amount of melanosomes in epidermal cells (keratinocytes) is effective in controlling pigmentation including Kusumi, blemishes and buckwheat.
本発明は、表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害、または取り込まれたメラノソームの体外への排出促進を介して表皮細胞（ケラチノサイト）内のメラノソーム量を制御することを課題とする。 It is an object of the present invention to control the amount of melanosomes in epidermal cells (keratinocytes) through inhibition of melanosome uptake into epidermal cells (keratinocytes) or promotion of excretion of the incorporated melanosomes outside the body.
本発明者らは、表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害、または取り込まれたメラノソームの体外への排出促進を介した表皮細胞（ケラチノサイト）内のメラノソーム量の制御について鋭意研究した結果、リノール酸誘導体が顕著な有用性を示すことを見出し、本発明を完成するに至った。 As a result of intensive studies on the control of the amount of melanosomes in epidermal cells (keratinocytes) through inhibition of melanosome uptake into epidermal cells (keratinocytes) or promotion of exudation of the incorporated melanosomes outside the body, the present inventors have conducted linoleic acid. The present inventors have found that the derivatives show remarkable utility and have completed the present invention.
従来の美白剤は、色素細胞におけるメラニン産生、およびメラノソーム輸送に関するものが主体であり、皮膚色決定に寄与する表皮細胞（ケラチノサイト）内のメラノソーム量制御に効果を示すものではなかった。本発明者らは、表皮細胞（ケラチノサイト）の機能に着目し、メラノソーム取り込み阻害、および取り込まれたメラノソームの体外への排出促進を介した表皮細胞（ケラチノサイト）内のメラノソーム量を制御に対し、リノール酸誘導体に顕著な有用性を見出したことから、色素沈着に対して有効な表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害剤、または取り込まれたメラノソームの体外への排出促進剤を提供することができる。 Conventional whitening agents are mainly related to melanin production and melanosome transport in pigment cells, and have no effect on the control of the amount of melanosomes in epidermal cells (keratinocytes) that contribute to skin color determination. The present inventors pay attention to the function of epidermal cells (keratinocytes) and control the amount of melanosomes in epidermal cells (keratinocytes) through inhibition of melanosome uptake and promotion of exudation of the incorporated melanosomes out of the body. The remarkable usefulness of acid derivatives has led to the provision of an inhibitor of melanosome uptake into epidermal cells (keratinocytes) effective for pigmentation, or a promoter of elimination of incorporated melanosomes out of the body. .
本発明に係る表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害剤、または取り込まれたメラノソームの体外への排出促進剤は、リノール酸誘導体を有効成分とするもので、それを配合した化粧料および皮膚外用剤として皮膚表面に適用されることで、皮膚の色素沈着を改善する効果を発現するものである。
本発明で用いるリノール酸誘導体としては、リノール酸エチル、リノール酸イソプロピル等を、それぞれ単独でまたは混合して用いる事ができる。
以下に実施例を挙げて本発明を具体的に説明するが、本発明の技術的範囲がこれらに限定されるものではない。
The inhibitor of melanosome uptake into epidermal cells (keratinocytes) according to the present invention, or the accelerator for exudation of incorporated melanosomes out of the body comprises a linoleic acid derivative as an active ingredient. When applied to the skin surface as an agent, it exhibits the effect of improving skin pigmentation.
As the linoleic acid derivative used in the present invention, ethyl linoleate, isopropyl linoleate and the like can be used alone or in combination.
EXAMPLES The present invention will be specifically described below with reference to examples, but the technical scope of the present invention is not limited to these examples.
（実施例１）表皮細胞（ケラチノサイト）への疑似メラノソーム取り込み阻害
１、試験の概要
表皮細胞（ケラチノサイト）への疑似メラノソーム取り込みに対する、リノール酸誘導体の阻害作用を評価した。
２、実験方法
表皮細胞（ケラチノサイト）に対して疑似メラノソームとして蛍光ビーズ（ＦｌｕｏＳｐｈｅｒｅｓ? Ｆｌｕｏｒｅｓｃｅｎｔ Ｍｉｃｒｏｓｐｈｅｒｅｓ， Ｉｎｖｉｔｒｏｇｅｎ）を添加し、２４時間培養した。表皮細胞（ケラチノサイト）をＰＢＳ（Ｐｈｏｓｏｈａｔｅ Ｂｕｆｆｅｒ Ｓａｌｉｎｅ）で洗浄した後、０．５％無蛍光ＴｒｉｔｏｎＸ−１００含有ＰＢＳにて溶解し、破砕液の蛍光強度（Ｅｘ／Ｅｍ＝３６５ｎｍ／４１５ｎｍ）を測定し、蛍光ビーズ取り込み量の指標とした。その後、ウェル当たりのタンパク量を算出し、単位タンパク当たりの蛍光強度として試料未処理コントロールを１００とした相対値で算出した。
(Example 1) Inhibition of pseudo melanosome uptake into epidermal cells (keratinocytes) 1. Outline of test The inhibitory action of linoleic acid derivatives on the uptake of pseudo melanosomes into epidermal cells (keratinocytes) was evaluated.
2. Experimental method Fluorescent beads (FluoSpheres ? Fluorescent Microspheres, Invitrogen) were added to the epidermal cells (keratinocytes) as pseudo melanosomes and cultured for 24 hours. After washing the epidermal cells (keratinocytes) with PBS (Phoshate Buffer Saline), the cells were dissolved in PBS containing 0.5% non-fluorescent Triton X-100, and the fluorescence intensity (Ex / Em = 365 nm / 415 nm) of the disrupted solution was measured. This was used as an index of the amount of fluorescent beads incorporated. Thereafter, the amount of protein per well was calculated, and the fluorescence intensity per unit protein was calculated as a relative value with the sample untreated control taken as 100.
３、結果
結果を表１に示した。試験試料未処理細胞での単位タンパク当たりの蛍光ビーズ取り込み量を比較対象として、各種リノール酸誘導体０．４〜１００μｍｏｌ／Ｌを処理した表皮細胞（ケラチノサイト）の取り込み量は、濃度依存的かつ有意に減少した。リノール酸誘導体の中でも、特にリノール酸エチルはその作用が顕著であった。
3. Results The results are shown in Table 1. Taking the amount of fluorescent beads taken up per unit protein in test sample-untreated cells as a comparison target, the amount of uptake of epidermal cells (keratinocytes) treated with 0.4 to 100 μmol / L of various linoleic acid derivatives is concentration-dependent and significantly Diminished. Among linoleic acid derivatives, ethyl linoleate was particularly effective.
（実施例２）表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害
１、試験の概要
表皮細胞（ケラチノサイト）へのメラノソーム取り込みに対する、リノール酸誘導体の阻害作用を評価した。
２、実験方法
表皮細胞（ケラチノサイト）に対して、非特許文献３に記載の方法で色素細胞（メラノサイト）より単離したメラノソームとリノール酸誘導体を添加し、４８時間培養した。表皮細胞（ケラチノサイト）をＰＢＳで洗浄した後、冷メタノールで固定し、フォンタナ・マッソン染色により、メラノソームの染色を行った。グリセリンで包埋した後、顕微鏡下で観察した。
(Example 2) Inhibition of melanosome uptake into epidermal cells (keratinocytes) 1. Outline of test The inhibitory action of linoleic acid derivatives on the uptake of melanosomes into epidermal cells (keratinocytes) was evaluated.
2. Experimental method To epidermal cells (keratinocytes), melanosomes and linoleic acid derivatives isolated from pigment cells (melanocytes) by the method described in Non-Patent Document 3 were added and cultured for 48 hours. Epidermal cells (keratinocytes) were washed with PBS, fixed with cold methanol, and melanosomes were stained by Fontana-Masson staining. After embedding with glycerin, it was observed under a microscope.
３、結果
結果を表２に示した。リノール酸誘導体処理により、表皮細胞（ケラチノサイト）へのメラノソーム取り込みが抑制された。
3. Results The results are shown in Table 2. The linoleic acid derivative treatment suppressed melanosome uptake into epidermal cells (keratinocytes).
（実施例３）表皮細胞（ケラチノサイト）へ取り込まれたメラノソームの体外への排出促進
１、試験の概要
メラノソームを取り込んだ表皮細胞（ケラチノサイト）のターンオーバー遅延を改善することによるメラノソームの体外への排出促進に対する、リノール酸誘導体の作用を評価した。
２、実験方法
表皮細胞（ケラチノサイト）に対して、非特許文献３に記載の方法で色素細胞（メラノサイト）より単離したメラノソームを添加し、２４時間培養することで表皮細胞（ケラチノサイト）にメラノソームを取り込ませた。ＰＢＳで洗浄した後、リノール酸誘導体を添加し、７２時間培養した。その後、ＮＲ（ニュートラルレッド）法により、細胞数を簡易的に評価し、ターンオーバーの指標とした。試料未処理コントロールを１００とした相対値で算出した。
(Example 3) Promotion of melanosome uptake into epidermal cells (keratinocytes) to the outside of the body 1. Outline of the test. The effect of linoleic acid derivatives on acceleration was evaluated.
2. Experimental method To the epidermal cells (keratinocytes), add melanosomes isolated from pigment cells (melanocytes) by the method described in Non-Patent Document 3, and culture for 24 hours to transform the melanosomes into the epidermal cells (keratinocytes). I took it in. After washing with PBS, a linoleic acid derivative was added and cultured for 72 hours. Thereafter, the number of cells was simply evaluated by the NR (neutral red) method and used as an index of turnover. The relative value was calculated with the sample untreated control as 100.
３、結果
結果を表３に示した。メラノソーム添加によりターンオーバーが遅延し、リノール酸誘導体処理によりターンオーバーが促進され、このことより表皮細胞（ケラチノサイト）に取り込まれたメラノソームを皮膚のターンオーバーを促進することでの体外への排出を促進した。
3. Results The results are shown in Table 3. Addition of melanosomes delays turnover, and treatment with linoleic acid derivative promotes turnover, and this promotes excretion of melanosomes taken up by epidermal cells (keratinocytes) by promoting skin turnover. did.
以下に、本発明の表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害剤、または取り込まれたメラノソームの体外への排出促進剤を配合した化粧料及び皮膚外用剤の応用例を示す。配合量は質量％である。 Hereinafter, application examples of cosmetics and external preparations for skin that incorporate an inhibitor of melanosome uptake into epidermal cells (keratinocytes) of the present invention, or an agent for promoting the elimination of incorporated melanosomes outside the body will be shown. A compounding quantity is the mass%.
本表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害剤、または取り込まれたメラノソームの体外への排出促進剤の、化粧料および皮膚外用剤における配合量は、用途、剤型、配合目的等によって異なり、特に限定されるものではないが、一般的には、リノール酸誘導体として、化粧料及び皮膚外用剤中０．００１〜１０．０質量％が好ましく、より好ましくは０．０１〜５．０質量％である。 The amount of the melanosome uptake inhibitor in the epidermal cells (keratinocytes) or the exudation promoter of the incorporated melanosome outside the body varies depending on the use, dosage form, formulation purpose, etc. Although it is not limited, in general, the linoleic acid derivative is preferably 0.001 to 10.0% by mass, more preferably 0.01 to 5.0% by mass in cosmetics and skin external preparations. is there.
本表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害剤、または取り込まれたメラノソームの体外への排出促進剤を配合した化粧料および皮膚外用剤には、既存の抗炎症剤、肌荒れ予防／改善剤、色素沈着予防／改善剤を配合することができる。これらの成分を併用することは、本効果の相乗効果をもたらし、本効果を損なうものではない。 Cosmetics and external preparations for skin that contain an inhibitor of melanosome uptake into the epidermal cells (keratinocytes), or an expelling promoter for incorporated melanosomes outside the body include existing anti-inflammatory agents, rough skin prevention / improving agents, pigments An anti-deposition / improving agent can be added. The combined use of these components brings about a synergistic effect of this effect and does not impair this effect.
本表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害剤、または取り込まれたメラノソームの体外への排出促進剤を配合した化粧料および皮膚外用剤には、本発明の効果を損なわない範囲で化粧品、医薬部外品等に配合される成分として流動パラフィンなどの炭化水素油、植物油脂、ロウ類、合成エステル油、シリコーン系の油相成分、フッ素系の油相成分、高級アルコール類、脂肪酸類、増粘剤、紫外線吸収剤、粉体、顔料、色材、陰イオン性界面活性剤、陽イオン性界面活性剤、非イオン性界面活性剤、両性界面活性剤、多価アルコール、糖、高分子化合物、生理活性成分、経皮吸収促進剤、溶媒、酸化防止剤、香料、防腐剤等を配合することができる。 The cosmetics and pharmaceutical preparations containing the inhibitor of melanosome uptake into the epidermal cells (keratinocytes) or the exogenous promoter of the incorporated melanosomes to the outside of the body are within the scope of not impairing the effects of the present invention. Hydrocarbon oils such as liquid paraffin, vegetable oils and fats, waxes, synthetic ester oils, silicone oil phase components, fluorine oil phase components, higher alcohols, fatty acids, thickening Agent, ultraviolet absorber, powder, pigment, color material, anionic surfactant, cationic surfactant, nonionic surfactant, amphoteric surfactant, polyhydric alcohol, sugar, polymer compound, Physiologically active ingredients, transdermal absorption promoters, solvents, antioxidants, fragrances, preservatives, and the like can be blended.
本表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害剤、または取り込まれたメラノソームの体外への排出促進剤を配合した化粧料および皮膚外用剤に係る剤型は任意であり、化粧水、ローション、乳液、クリーム、パック、軟膏、分散液、固形物、ムース等の任意の剤型をとることができる。また、用途としては、化粧料の他、皮膚外用剤、医薬用軟膏等に好適に使用できる。 The dosage form for cosmetics and skin external preparations containing an inhibitor of melanosome uptake into the epidermal cells (keratinocytes), or an accelerator for exudation of the incorporated melanosomes outside the body is arbitrary, lotion, lotion, emulsion, Arbitrary dosage forms such as creams, packs, ointments, dispersions, solids, mousses and the like can be taken. In addition to cosmetics, it can be suitably used for skin external preparations, pharmaceutical ointments and the like.
（応用例１）表皮細胞（ケラチノサイト）へのメラノソーム取り込み阻害剤を配合した化粧水
Ａ １，３−ブチレングリコール １．００（質量％）
グリセリン ５．００
ジプロピレングリコール １．００
ペンチレングリコール ２．５０
クエン酸 ０．０３
クエン酸ナトリウム ０．０４
精製水 残部
Ｂ リノール酸エチル １．００
ＰＥＧ−２０水添ヒマシ油 １．００
ジプロピレングリコール ０．３０
Ｃ 精製水 １０．００
（調製方法）Ｂ、Ｃを８０℃に加温後、ＢにＣを徐々に添加して室温まで冷却する。室温で均一混合したＡに（Ｂ＋Ｃ）を添加して撹拌する。
(Application Example 1) Lotion A 1,3-butylene glycol 1.00 (mass%) containing an inhibitor of melanosome uptake into epidermal cells (keratinocytes)
Glycerin 5.00
Dipropylene glycol 1.00
Pentylene glycol 2.50
Citric acid 0.03
Sodium citrate 0.04
Purified water Remainder B Ethyl linoleate 1.00
PEG-20 hydrogenated castor oil 1.00
Dipropylene glycol 0.30
C Purified water 10.00
(Preparation method) After heating B and C to 80 ° C, C is gradually added to B and cooled to room temperature. Add (B + C) to A uniformly mixed at room temperature and stir.
本発明品を美白化粧料に配合することで、より優れた効果を提供することができる。 By blending the product of the present invention into a whitening cosmetic, a more excellent effect can be provided.
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