JP2007262012A - Hyaluronic acid production promoter, skin external preparation containing the hyaluronic acid production promoter, cosmetic, quasi drug, chapped skin ameliorating agent, and wrinkle ameliorating agent - Google Patents
Hyaluronic acid production promoter, skin external preparation containing the hyaluronic acid production promoter, cosmetic, quasi drug, chapped skin ameliorating agent, and wrinkle ameliorating agent Download PDFInfo
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Description
本発明は、ヒアルロン酸産生促進剤、さらに詳しくは、表皮におけるヒアルロン酸の合成を促進し、ひいては角層でのヒアルロン酸産生量を増大させることで角層の水分量を増やし、角層の硬度を最適にすることによって、荒れ肌、しわの予防および改善が期待される、製剤中で安定なヒアルロン酸産生促進剤、及びそのようなヒアルロン酸産生促進剤を配合した皮膚外用剤、化粧料、医薬部外品、肌荒れ改善剤、しわ改善剤に関する。 The present invention is a hyaluronic acid production promoter, more specifically, promotes the synthesis of hyaluronic acid in the epidermis, and thereby increases the amount of hyaluronic acid production in the stratum corneum, thereby increasing the amount of water in the stratum corneum, the hardness of the stratum corneum , Which is expected to prevent and improve rough skin and wrinkles, is a stable hyaluronic acid production promoter in preparations, and an external preparation for skin, cosmetics and pharmaceuticals containing such hyaluronic acid production promoter It relates to quasi-drugs, rough skin improvers, and wrinkle improvers.
ヒアルロン酸は、皮膚、靱帯、関節液等、生体に広く分布し、たとえば皮膚においては細胞の保護、栄養の運搬、組織水分の保持、柔軟性の維持等に重要な役割を果たしている。このため、ヒアルロン酸は、化粧料等の分野において従来から代表的な保湿剤として使用されている。 Hyaluronic acid is widely distributed in living bodies such as skin, ligaments, and joint fluid, and plays an important role in the skin, for example, cell protection, nutrient transport, tissue moisture retention, and flexibility maintenance. For this reason, hyaluronic acid has been conventionally used as a typical humectant in the field of cosmetics and the like.
このような保湿剤として使用は、従来では皮膚に直接塗布する等によって行われていたが、このように塗布するのみでは、洗浄等によって効果が持続しないおそれがあり、またヒアルロン酸は本来皮膚から吸収され易いものではなく、いずれにしても十分な効果が期待できないものである。 The use as such a moisturizing agent has been conventionally performed by directly applying to the skin, but the effect may not be sustained by washing etc. only by applying in this way, and hyaluronic acid is originally from the skin. It is not easily absorbed, and in any case, a sufficient effect cannot be expected.
そこで、このような点に鑑みて下記特許文献１のような特許出願がなされている。この特許文献１に係る発明は、明細書の［０００４］にも記載されているように、ヒアルロン酸を外部から単に補給するのではなく、生体の自己回復力を利用し、細胞自身のヒアルロン酸合成能を促進することによって生体の機能を根本的に改善することを意図してなされたものである。 In view of this point, a patent application such as the following Patent Document 1 has been filed. As described in [0004] of the specification, the invention according to Patent Document 1 does not simply replenish hyaluronic acid from the outside, but utilizes the self-healing power of the living body, and the cell's own hyaluronic acid. It was made with the intention of fundamentally improving the function of the living body by promoting the synthesis ability.
ところで、このようなヒアルロン酸合成促進剤としては、従来では数多くのものが存在するが、一般には下記特許文献２に示すように、皮膚内の線維芽細胞に作用するもの、つまり真皮におけるヒアルロン酸の合成を促進するものがほとんどである。 By the way, as such a hyaluronic acid synthesis promoter, there are many conventional ones. Generally, as shown in Patent Document 2 below, one acting on fibroblasts in the skin, that is, hyaluronic acid in the dermis. Most of them promote the synthesis of
これに対して、上記特許文献１の［０００５］には、「ヒアルロン酸が表皮基底細胞、線維芽細胞、滑膜細胞などで作られ、中でも表皮基底細胞で合成されるヒアルロン酸は、保水性の向上、細胞の保護、栄養の補給等に関与することにより、皮膚を健康に保ち、張りや色つやを良くし、きめを細かくするのに重要な役割を担っている」ことが開示されている。すなわち、真皮よりも表皮で合成されたヒアルロン酸の重要性が示唆されている。 On the other hand, [0005] of Patent Document 1 states that “hyaluronic acid is produced by epidermal basal cells, fibroblasts, synovial cells, etc., among which hyaluronic acid synthesized by epidermal basal cells is water-retaining. It plays an important role in keeping the skin healthy, improving tension and color, and making the texture finer by being involved in improving skin, protecting cells, and supplementing nutrition. " . That is, the importance of hyaluronic acid synthesized in the epidermis rather than the dermis has been suggested.
しかし、上記特許文献１では、表皮基底細胞におけるヒアルロン酸の合成促進効果が必ずしも試験等によって十分に裏付けられているわけではない。 However, in the said patent document 1, the synthesis | combination promotion effect of the hyaluronic acid in an epidermal basal cell is not necessarily fully supported by the test.
本発明はこのような点に鑑みてなされたもので、表皮におけるヒアルロン酸量を増大させるという効果、ひいては角層においてもヒアルロン酸の産生促進の効果を示し、また肌荒れやしわの発生を防ぐ効果の実効性を有し、安全性及び使用感に優れた皮膚外用剤、化粧料、医薬部外品、肌荒れ改善剤、しわ改善剤として使用されるヒアルロン酸産生促進剤を提供することを課題とするものである。 The present invention has been made in view of such points, and has the effect of increasing the amount of hyaluronic acid in the epidermis, and thus the effect of promoting hyaluronic acid production in the stratum corneum, and the effect of preventing the occurrence of rough skin and wrinkles. It is an object to provide hyaluronic acid production promoter used as an external preparation for skin, cosmetics, quasi-drugs, rough skin remedy, wrinkle remedy, which has the effectiveness of To do.
角層は皮膚の最も外側に位置し、表皮細胞が分化して角層細胞となった死細胞が層状に堆積した構造体である。また、角層での水分量は角層の柔軟性や外的刺激に対するバリア機能において重要な役割をし、荒れ肌やしわの形成に関与していることが知られている。本発明者等は、このような点に鑑み、上記従来の問題点を改良せんとして鋭意研究を重ねた結果、アスパラガス抽出物、及びブッチャーブルーム抽出物に表皮、特に角層中のヒアルロン酸の産生を促進させ、角層中のヒアルロン酸量を増大させる作用があり、それによって肌荒れやしわを改善しうることを見出し、本発明を完成するに至った。 The stratum corneum is located on the outermost side of the skin, and is a structure in which dead cells, which are differentiated into epidermal cells and become stratum corneum, are deposited in layers. It is known that the amount of water in the stratum corneum plays an important role in the flexibility of the stratum corneum and the barrier function against external stimuli, and is involved in the formation of rough skin and wrinkles. In view of these points, the present inventors have conducted extensive research to improve the conventional problems described above, and as a result, the asparagus extract and the butcher bloom extract have epidermal, particularly hyaluronic acid in the stratum corneum. It has been found that it has the effect of promoting production and increasing the amount of hyaluronic acid in the stratum corneum, thereby improving rough skin and wrinkles, and has completed the present invention.
すなわち、請求項１記載の発明は、ヒアルロン酸産生促進剤に、アスパラガス抽出物、又はブッチャーブルーム抽出物の少なくとも１種を含有させたことである。ここで「アスパラガス抽出物、又はブッチャーブルーム抽出物の少なくとも１種を含有する」とは、ヒアルロン酸産生促進剤がアスパラガス抽出物若しくはブッチャーズブルーム抽出物のみからなる場合、又はこれら双方の抽出物からなる場合の他、アスパラガス抽出物又はブッチャーブルーム抽出物以外の成分を含んでいてもよいことを意味する。 That is, the invention described in claim 1 is that the hyaluronic acid production promoter contains at least one of asparagus extract or butcher bloom extract. Here, “containing at least one of asparagus extract or butcher bloom extract” means that the hyaluronic acid production promoter is composed of only asparagus extract or butcher's bloom extract, or extracts of both It means that components other than the asparagus extract or butcher bloom extract may be included.
また請求項２記載の発明は、請求項１記載のヒアルロン酸産生促進剤を配合したことを特徴とする皮膚外用剤の発明である。さらに請求項３記載の発明は、請求項１記載のヒアルロン酸産生促進剤を配合したことを特徴とする化粧料の発明である。 The invention described in claim 2 is an invention for a topical skin preparation characterized in that the hyaluronic acid production promoter described in claim 1 is blended. Furthermore, the invention described in claim 3 is an invention of a cosmetic characterized in that the hyaluronic acid production promoter described in claim 1 is blended.
さらに請求項４記載の発明は、請求項１記載のヒアルロン酸産生促進剤を配合したことを特徴とする医薬部外品の発明である。さらに請求項５記載の発明は、請求項１記載のヒアルロン酸産生促進剤を配合したことを特徴とする肌荒れ改善剤の発明である。さらに請求項６記載の発明は、請求項１記載のヒアルロン酸産生促進剤を配合したことを特徴とするしわ改善剤の発明である。 Furthermore, the invention described in claim 4 is an quasi-drug invention characterized in that the hyaluronic acid production promoter described in claim 1 is blended. Furthermore, the invention according to claim 5 is an invention for a rough skin improving agent, characterized in that the hyaluronic acid production promoter according to claim 1 is blended. Further, the invention according to claim 6 is an invention of a wrinkle improving agent, characterized in that the hyaluronic acid production promoter according to claim 1 is blended.
本発明のアスパラガス抽出物、ブッチャーブルーム抽出物を含有するヒアルロン酸産生促進剤は、表皮、特に角層でのヒアルロン酸合成を有意に促進し、肌荒れ改善作用、皮膚のバリア機能改善作用およびしわ改善作用を有することが確認された。従って、本発明のヒアルロン酸産生促進剤が配合された組成物は、肌荒れを改善し、皮膚バリア機能を高め、しわを改善する優れた皮膚化粧料、医薬部外品、あるいは皮膚外用剤として好適に使用することができる。 Hyaluronic acid production promoter containing the asparagus extract and butcher bloom extract of the present invention significantly promotes the synthesis of hyaluronic acid in the epidermis, especially in the stratum corneum, and improves skin roughness, improves skin barrier function and wrinkles. It was confirmed to have an improving effect. Therefore, the composition containing the hyaluronic acid production promoter of the present invention is suitable as an excellent skin cosmetic, quasi-drug, or skin external preparation that improves rough skin, enhances skin barrier function, and improves wrinkles. Can be used for
本発明のヒアルロン酸産生促進剤は、上述のようにアスパラガス抽出物、又はブッチャーブルーム抽出物の少なくとも１種を含有したものである。本発明で用いる抽出物とは、アスパラガス又はブッチャーブルームの全草又はそれらの葉、茎、根、果実、種子および花のうち１又は２以上の箇所を乾燥し、又は乾燥することなく粉砕した後、低温又は室温ないし加温下に溶媒により抽出するか、又はソックスレー抽出器などの抽出器具を用いて抽出することにより得られる各種溶媒抽出液、その希釈液、その濃縮液、或いはその乾燥末等を意味するものである。 The hyaluronic acid production promoter of the present invention contains at least one of asparagus extract or butcher bloom extract as described above. The extract used in the present invention is a whole plant of asparagus or butcher bloom, or one or more of the leaves, stems, roots, fruits, seeds and flowers, or dried or pulverized without drying. Subsequently, various solvent extracts obtained by extraction with a solvent at a low temperature or room temperature or under heating, or extraction using an extraction device such as a Soxhlet extractor, a diluted solution thereof, a concentrated solution thereof, or a dried powder thereof And so on.
抽出材料となる各植物の部位は特に限定されるものではないが、アスパラガス（Asparagus officinalis Linneユリ科、別名：ショウビャクブ（小百部）、オランダキジカクシ）は茎、ブッチャーブルーム（Ruscus aculeatus L. ユリ科、別名：ナギイカダ）は根茎を、それぞれ抽出材料として用いることが好ましい。 The part of each plant that is the extraction material is not particularly limited, but the asparagus (Asparagus officinalis Linne lily family, also known as: Shobakubu (small hundred parts), Dutch pheasant) is a stem, butcher bloom (Ruscus aculeatus L It is preferable to use rhizomes as the extraction material in Lilium family, also known as Nagiikada.
抽出に用いる溶媒としては、通常の抽出に用いられる溶媒であれば任意に用いることができる。例えば水、メタノール、エタノールなどの低級１価アルコール、グリセリン、プロピレングリコール、１，３−ブチレングリコール等の液状多価アルコール、含水アルコール類等の１種または２種以上を組み合わせて用いることができる。好ましい抽出方法の例としては、含水濃度２０〜８０容量％のエタノール又は１，３−ブチレングリコールを用い、室温にて１〜５日間抽出を行ったのち、濾過する方法が挙げられる。 As a solvent used for extraction, any solvent can be used as long as it is a solvent used for normal extraction. For example, water, lower monohydric alcohols such as methanol and ethanol, liquid polyhydric alcohols such as glycerin, propylene glycol, and 1,3-butylene glycol, and hydrous alcohols can be used alone or in combination. As an example of a preferable extraction method, there may be mentioned a method in which ethanol or 1,3-butylene glycol having a water content of 20 to 80% by volume is extracted at room temperature for 1 to 5 days and then filtered.
本発明の皮膚外用剤、化粧料、医薬部外品、肌荒れ改善剤、しわ改善剤中のアスパラガス抽出物、ブッチャーブルーム抽出物等の各ヒアルロン酸産生促進剤の配合量は特に限定されるものではないが、乾燥固形物重量（複数の抽出物を含む場合はその合計量）で、総量を基準として０．０００１〜２０．０重量％であることが好ましい。配合量が０．０００１重量％未満であると、本発明の効果が充分に得られず、一方２０．０重量％を超えても、その増量に見合った効果の向上は認められないからである。この観点からは、０．０００５〜５．０重量％であることがより好ましい。 The amount of hyaluronic acid production promoters such as asparagus extract and butcher bloom extract in skin external preparations, cosmetics, quasi drugs, rough skin improvers, wrinkle improvers of the present invention is particularly limited Although it is not, it is preferable that it is 0.0001-20.0 weight% on the basis of the total amount by dry solid weight (the total amount when a plurality of extracts are included). This is because if the blending amount is less than 0.0001% by weight, the effect of the present invention cannot be sufficiently obtained, and if the blending amount exceeds 20.0% by weight, no improvement in the effect commensurate with the increase is observed. . From this viewpoint, the content is more preferably 0.0005 to 5.0% by weight.
本発明のヒアルロン酸産生促進剤は、皮膚外用剤として、たとえばローション類、乳液類、クリーム類、軟膏類、パック類、ファンデーション等の剤型とすることができる。本発明のヒアルロン酸産生促進剤には、形態に応じ、色素、防腐剤、界面活性剤、香料、顔料等を適宜配合することができる。 The hyaluronic acid production promoter of the present invention can be made into dosage forms such as lotions, emulsions, creams, ointments, packs, foundations and the like as external preparations for skin. In the hyaluronic acid production promoter of the present invention, a dye, an antiseptic, a surfactant, a fragrance, a pigment, and the like can be appropriately blended depending on the form.
以下、本発明の実施例について説明する。
（実施例１）
本実施例は、アスパラガス抽出物を含有したヒアルロン酸産生促進剤の実施例である。アスパラガス抽出物の調製は次のようにして行う。すなわち、先ずアスパラガスの茎を乾燥して細かく砕いたもの１０ｇに、含水濃度５０容量％エタノール１００ｍLを加える。次に、室温（２０〜３０℃程度の温度）にて５日間抽出を行った後、濾過することによって、アスパラガス抽出物を得た。このとき、乾燥固形物量は、１．６１重量％であった。
Examples of the present invention will be described below.
Example 1
This example is an example of a hyaluronic acid production promoter containing an asparagus extract. The asparagus extract is prepared as follows. That is, first, 100 mL of ethanol having a water content of 50% by volume is added to 10 g of asparagus stems dried and finely crushed. Next, after extracting for 5 days at room temperature (temperature of about 20-30 degreeC), the asparagus extract was obtained by filtering. At this time, the dry solid content was 1.61% by weight.
（実施例２）
本実施例は、ブッチャーブルーム抽出物を含有したヒアルロン酸産生促進剤の実施例である。ブッチャーブルームの全草を乾燥して細かく砕いたもの１０ｇに、含水濃度５０容量％エタノール１００ｍLを加え、室温にて５日間抽出を行った後、濾過し、ブッチャーブルーム抽出物を得た。乾燥固形物量は、１．５７重量％であった。
(Example 2)
This example is an example of hyaluronic acid production promoter containing butcher bloom extract. To 10 g of the butcher bloom whole plant dried and finely crushed, 100 mL ethanol with a water content of 50% by volume was added and extracted at room temperature for 5 days, followed by filtration to obtain a butcher bloom extract. The amount of dry solid was 1.57% by weight.
（試験例１）
本試験例は、正常ヒト新生児包皮皮膚表皮角化細胞（ＮＨＥＫ、クラボウ）を用いたヒアルロン酸産生促進作用試験である。
(Test Example 1)
This test example is a hyaluronic acid production promoting effect test using normal human newborn foreskin skin epidermal keratinocytes (NHEK, Kurabo).
正常ヒト新生児包皮皮膚表皮角化細胞（ＮＨＥＫ、クラボウ）を用い、ＮＨＥＫの培養には、ＮＨＥＫ培養用基礎培地（ＫＢ？２、クラボウ）をベースとし、ハイドロコーチゾン (０．５μｍｏｌ／ｍL)、インシュリン（５μｇ／ｍL）、ＥＧＦ（上皮細胞成長因子:１０ｎｇ／ｍL）、ＢＰＥ(牛脳下垂体抽出液)、及び抗生物質からなる添加剤セット（クラボウ）を添加し、表皮細胞培養用培地（ＫＧ？２）を用いた。 Normal human neonatal foreskin skin epidermal keratinocytes (NHEK, Kurabo) are used, and NHEK culture is based on NHEK culture basal medium (KB-2, Kurabo), hydrocortisone (0.5 μmol / mL), insulin. (5 μg / mL), EGF (epidermal growth factor: 10 ng / mL), BPE (bovine pituitary extract), and an antibiotic additive set (Kurabo) were added, and epidermal cell culture medium (KG) ? 2) was used.
２４ｗｅｌｌ組織培養用プレート（ＩＷＡＫＩ社製）の各ｗｅｌｌに、５×１０-4（ｃｅｌｌ／ｍL）の細胞数でＫＧ−２に懸濁したＮＨＥＫを１ｍＬ播種した。培養は、９５％（v／v）空気−５％（v／v）炭酸ガスの雰囲気下３７℃で行い、培養３日目に実施例１のアスパラガス抽出物（アスパラガス抽出液）を添加し、さらに２４時間培養後の培養上清をサンプルとして、ＥＬＩＳＡ法にてヒアルロン酸（ＨＡ）量を測定した。 Each well of a 24 well tissue culture plate (manufactured by IWAKI) was seeded with 1 mL of NHEK suspended in KG-2 at a cell number of 5 × 10 −4 (cell / mL). Cultivation was performed at 37 ° C. in an atmosphere of 95% (v / v) air-5% (v / v) carbon dioxide, and the asparagus extract (asparagus extract) of Example 1 was added on the third day of cultivation. Then, the amount of hyaluronic acid (HA) was measured by ELISA using the culture supernatant after 24 hours of culture as a sample.
培養上清中のヒアルロン酸量の測定は、次のような方法で行った。すなわち、ヒアルロン酸固相化マイクロプレートに各培養上清（５０μL）を分注し、これにビオチン標識したヒアルロン酸結合タンパク質溶液（５０μL）を加えて１分間震盪混和後、３７℃で６０分間静置した。６０分間静置後、プレート内の溶液を除去した後、０．０２％のツイーン２０を含むリン酸緩衝生理食塩水（４００μL）で３回洗浄した。 The amount of hyaluronic acid in the culture supernatant was measured by the following method. Specifically, each culture supernatant (50 μL) was dispensed onto a hyaluronic acid-immobilized microplate, a biotin-labeled hyaluronic acid-binding protein solution (50 μL) was added thereto, and the mixture was shaken and mixed for 1 minute, and then allowed to stand at 37 ° C. for 60 minutes. I put it. After standing for 60 minutes, the solution in the plate was removed, and the plate was washed 3 times with phosphate buffered saline (400 μL) containing 0.02% Tween 20.
これにパーオキシダーゼ標識ストレプトアビジン溶液（１００μL）を分注した後、３７℃で６０分間静置した。６０分間静置後、プレート内の溶液を除去した後、０．０２％のツイーン２０を含むリン酸緩衝生理食塩水（４００μL）で５回洗浄した。これに酵素基質溶液（１００μL）を分注した後、アルミホイルで遮光し、常温（１５〜２５℃）で３０分間静置した。これに反応停止液（１００μL）を添加した後、４９２ｎｍにおける吸光度を測定した。 A peroxidase-labeled streptavidin solution (100 μL) was dispensed thereto, and then allowed to stand at 37 ° C. for 60 minutes. After standing for 60 minutes, the solution in the plate was removed, and the plate was washed 5 times with phosphate buffered saline (400 μL) containing 0.02% Tween 20. An enzyme substrate solution (100 μL) was dispensed to this, light-shielded with aluminum foil, and allowed to stand at room temperature (15-25 ° C.) for 30 minutes. The reaction stop solution (100 μL) was added thereto, and then the absorbance at 492 nm was measured.
また、ヒアルロン酸量の測定と同時に細胞数をカウントし、細胞あたりのヒアルロン酸量として評価し、試料を添加していない時の細胞あたりのヒアルロン酸量を１００とした値で表した。尚、このようなヒアルロン酸量の測定は、アスパラガス抽出物の濃度
（容量％）を変えて行った。具体的には、試験容器中での最終濃度がそれぞれ０．１容量％、０．２５容量％、又は０．５容量％となるよう、それぞれアスパラガス抽出物を添加した。その結果を表１に示す。
In addition, the number of cells was counted simultaneously with the measurement of the amount of hyaluronic acid, and evaluated as the amount of hyaluronic acid per cell. The amount of hyaluronic acid per cell when no sample was added was expressed as 100. Such measurement of the amount of hyaluronic acid was performed by changing the concentration (volume%) of the asparagus extract. Specifically, the asparagus extract was added so that the final concentration in the test container was 0.1% by volume, 0.25% by volume, or 0.5% by volume, respectively. The results are shown in Table 1.
表１からも明らかなように、アスパラガス抽出物を添加しないＮＨＥＫの培養上清中のヒアルロン酸量を１００とすると、アスパラガス抽出物を添加したときの培養上清中のヒアルロン酸量は、アスパラガス抽出物濃度が０．１容量％の場合に１０５、０．２５容量％の場合に１１６、０．５容量％の場合に１３１と、アスパラガス抽出物の添加濃度に依存して表皮細胞からのヒアルロン酸の産生量が増加した。このことから、アスパラガス抽出物に、表皮細胞におけるヒアルロン酸の産生促進効果があり、また抽出物の濃度を高めることによって産生促進効果が高くなることがわかった。 As is apparent from Table 1, assuming that the amount of hyaluronic acid in the culture supernatant of NHEK to which no asparagus extract is added is 100, the amount of hyaluronic acid in the culture supernatant when the asparagus extract is added is Epidermal cells depending on the concentration of the added asparagus extract, 105 when the asparagus extract concentration is 0.1% by volume, 116 when the volume is 0.25%, 131 when the volume is 0.5% by volume. The amount of hyaluronic acid produced from the increased. From this, it was found that the asparagus extract has a hyaluronic acid production promoting effect in epidermal cells, and the production promoting effect is enhanced by increasing the concentration of the extract.
（試験例２）
実施例２のブッチャーブルーム抽出物（ブッチャーブルーム抽出液）からなるヒアルロン酸産生促進剤を対象として、上記試験例１と同様にしてＮＨＥＫを用いたヒアルロン酸産生促進試験を行った。アスパラガス抽出物をブッチャーブルーム抽出物に変えたこと以外は、すべて同じ操作で試験を行った。その結果を表２に示す。
(Test Example 2)
A hyaluronic acid production promotion test using NHEK was performed in the same manner as in Test Example 1 above, with the hyaluronic acid production promoter composed of the butcher bloom extract (butcher bloom extract) of Example 2 as the target. All tests were performed in the same manner except that the asparagus extract was replaced with a butcher bloom extract. The results are shown in Table 2.
（試験例３）
本試験例は、正常ヒト新生児包皮皮膚線維芽細胞（ＮＨＤＦ、クラボウ）を用いたヒアルロン酸産生促進作用試験である。
(Test Example 3)
This test example is a hyaluronic acid production promoting action test using normal human newborn foreskin dermal fibroblasts (NHDF, Kurabo).
ＮＨＤＦの培養には、５０容量％の牛胎児血清（ICN製）、１容量％の非必須アミノ酸溶液、１００ｕｎｉｔ／ｍLのペニシリンおよび１００μｇ／ｍLのストレプトマイシンを添加したdulbecco's MEM（SIGMA製）培地を使用した。 For culture of NHDF, dulbecco's MEM (manufactured by SIGMA) medium supplemented with 50 vol% fetal bovine serum (ICN), 1 vol% non-essential amino acid solution, 100 units / mL penicillin and 100 μg / mL streptomycin is used. did.
２４ｗｅｌｌ組織培養用プレート（ＩＷＡＫＩ製）の各ｗｅｌｌに、５×１０-4（ｃｅｌｌ／ｍL）の細胞数で懸濁したＮＨＤＦを１ｍLずつ播種した。培養は、９５％（v／v）空気−５％（v／v）炭酸ガスの雰囲気下３７℃で行い、培養３日目に上記試験例１と同様の各濃度のアスパラガス抽出物を添加し、さらに２４時間培養後の培養上清をサンプルとして、ＥＬＩＳＡ法にてヒアルロン酸（ＨＡ）量を測定した。 Each well of a 24-well tissue culture plate (manufactured by IWAKI) was seeded with 1 mL of NHDF suspended at a cell number of 5 × 10 −4 (cell / mL). Cultivation was carried out at 37 ° C. in an atmosphere of 95% (v / v) air-5% (v / v) carbon dioxide gas, and asparagus extracts having the same concentrations as in Test Example 1 were added on the third day of culture. Then, the amount of hyaluronic acid (HA) was measured by ELISA using the culture supernatant after 24 hours of culture as a sample.
培養上清中のヒアルロン酸量の測定は、次のような方法で行った。すなわち、ヒアルロン酸固相化マイクロプレートに各培養上清（５０μL）を分注し、これにビオチン標識したヒアルロン酸結合タンパク質溶液（５０μL）を加えて１分間震盪混和後、３７℃で６０分間静置した。６０分間静置後、プレート内の溶液を除去した後、０．０２％のツイーン２０を含むリン酸緩衝生理食塩水（４００μL）で３回洗浄した。 The amount of hyaluronic acid in the culture supernatant was measured by the following method. Specifically, each culture supernatant (50 μL) was dispensed onto a hyaluronic acid-immobilized microplate, a biotin-labeled hyaluronic acid-binding protein solution (50 μL) was added thereto, and the mixture was shaken and mixed for 1 minute, and then allowed to stand at 37 ° C. for 60 minutes. I put it. After standing for 60 minutes, the solution in the plate was removed, and the plate was washed 3 times with phosphate buffered saline (400 μL) containing 0.02% Tween 20.
これにパーオキシダーゼ標識ストレプトアビジン溶液（１００μL）を分注した後、３７℃で６０分間静置した。６０分間静置後、プレート内の溶液を除去した後、０．０２％のツイーン２０を含むリン酸緩衝生理食塩水（４００μL）で５回洗浄した。これに酵素基質溶液（１００μL）を分注した後、アルミホイルで遮光し、常温（１５〜２５℃）で３０分間静置した。これに反応停止液（１００μL）を添加した後、４９２ｎｍにおける吸光度を測定した。 A peroxidase-labeled streptavidin solution (100 μL) was dispensed thereto, and then allowed to stand at 37 ° C. for 60 minutes. After standing for 60 minutes, the solution in the plate was removed, and the plate was washed 5 times with phosphate buffered saline (400 μL) containing 0.02% Tween 20. An enzyme substrate solution (100 μL) was dispensed to this, light-shielded with aluminum foil, and allowed to stand at room temperature (15-25 ° C.) for 30 minutes. The reaction stop solution (100 μL) was added thereto, and then the absorbance at 492 nm was measured.
また、ヒアルロン酸量の測定と同時に細胞数をカウントし、細胞あたりのヒアルロン酸量として評価し、試料を添加していない時の細胞あたりのヒアルロン酸量を１００とした値で表した。尚、各抽出物は上記試験例１と同様、試験容器中に最終濃度０．１容量％、０．２５容量％、又は０．５容量％となるようそれぞれ添加した。その結果を表３に示す。 In addition, the number of cells was counted simultaneously with the measurement of the amount of hyaluronic acid, and evaluated as the amount of hyaluronic acid per cell. The amount of hyaluronic acid per cell when no sample was added was expressed as 100. In addition, each extract was added to the test container so that the final concentration was 0.1% by volume, 0.25% by volume, or 0.5% by volume, as in Test Example 1. The results are shown in Table 3.
表３からも明らかなように、アスパラガス抽出物を添加しないＮＨＤＦの培養上清中のヒアルロン酸量を１００とすると、アスパラガス抽出物を添加したときの培養上清中のヒアルロン酸量は、アスパラガス抽出物濃度が０．１容量％の場合に１０２、０．２５容量％の場合に１１０、０．５容量％の場合に１３１と、アスパラガス抽出物の添加濃度に依存して表皮細胞からのヒアルロン酸の産生量が増加した。このことから、アスパラガス抽出物に、線維芽細胞におけるヒアルロン酸の産生促進効果があり、また抽出物の濃度を高めることによって産生促進効果が高くなることがわかった。 As is apparent from Table 3, assuming that the amount of hyaluronic acid in the culture supernatant of NHDF to which no asparagus extract is added is 100, the amount of hyaluronic acid in the culture supernatant when the asparagus extract is added is Epidermis cells depending on the concentration of the added asparagus extract, 102 when the concentration of asparagus extract is 0.1%, 110 when the concentration is 0.25%, 131 when the concentration is 0.5%. The amount of hyaluronic acid produced from the plant increased. From this, it was found that the asparagus extract has an effect of promoting hyaluronic acid production in fibroblasts, and that the production promoting effect is enhanced by increasing the concentration of the extract.
そして、この試験例３の線維芽細胞での試験と、上記試験例１の表皮細胞での試験結果から、実施例１のアスパラガス抽出物は、表皮におけるヒアルロン酸の産生量を増加するだけでなく、真皮におけるヒアルロン酸の産生量も増加することがわかった。 And from the test with the fibroblasts of Test Example 3 and the test results with the epidermal cells of Test Example 1, the asparagus extract of Example 1 only increased the amount of hyaluronic acid produced in the epidermis. It was also found that hyaluronic acid production in the dermis also increased.
（試験例４）
本試験例は、肌荒れ改善作用試験の試験例である。上記実施例の肌荒れに対する改善効果を評価するため、肌荒れモデルを作成したモルモットを使用し、試料の適用試験を実施した。尚、試料は実施例１、２にて得られた各抽出物を含水濃度５０容量％エタノールで希釈して、固形分濃度０．１％となるように調製した。また比較例として含水濃度５０容量％エタノールのみについても実施した。
(Test Example 4)
This test example is a test example of the rough skin improvement test. In order to evaluate the improvement effect with respect to the rough skin of the said Example, the application test of the sample was implemented using the guinea pig which created the rough skin model. The sample was prepared by diluting each extract obtained in Examples 1 and 2 with ethanol having a water content of 50% by volume to obtain a solid content of 0.1%. In addition, as a comparative example, only a water content concentration of 50% by volume ethanol was used.
背部を除毛したハートレー系モルモット（雌性、５週齢、１群３匹）に、白色ワセリンにて３重量％に調整したラウリル硫酸ナトリウム（０．２ｇ）を３日間連続解放塗布して肌荒れを作成した。肌荒れ作成部位を４分し、各試料（１．０ｍL）を１日３回、３日間連続塗布し、肌荒れの状態を観察した。肌荒れの度合いは定められた判定基準（スコア）に従って評価した。結果を表４に示す。 Hartley guinea pigs (female, 5 weeks old, 3 mice per group) with hair removed on the back were coated with white petrolatum adjusted to 3% by weight with sodium lauryl sulfate (0.2 g) for 3 days to apply rough skin. Created. The rough skin preparation site was divided into 4 minutes, and each sample (1.0 mL) was applied three times a day for three consecutive days to observe the rough skin state. The degree of rough skin was evaluated according to a predetermined criterion (score). The results are shown in Table 4.
尚、本試験例における判定基準（スコア）は次のとおりである。
紅斑、落屑ともほとんどみられない １点
紅斑を伴わない軽度の落屑 ２点
紅斑を伴わない中等度の落屑 ３点
弱い紅斑を伴った落屑 ４点
中等度の紅斑を伴った落屑 ５点
著しい紅斑を伴った落屑 ６点
In addition, the criterion (score) in this test example is as follows.
There is almost no erythema or desquamation. 1-point mild desquamation without erythema 2-moderate desquamation without erythema 3-point desquamation with weak erythema 4-point desquamation with moderate erythema 5-point significant erythema Accompanying desquamation 6 points
表４からも明らかなように、実施例１及び２のヒアルロン酸産生促進剤ともに、比較例に比べてスコアの合計が小さく、肌荒れ改善作用が優れていることがわかった。 As is clear from Table 4, it was found that both the hyaluronic acid production promoters of Examples 1 and 2 had a smaller total score than the comparative examples, and were excellent in rough skin improvement.
（処方例１）
本処方例は、上記実施例１のヒアルロン酸産生促進剤であるアスパラガス抽出物を化粧料の一例としてのクリームに配合した場合の処方例である。
(Prescription Example 1)
This prescription example is a prescription example when the asparagus extract which is the hyaluronic acid production promoter of Example 1 is blended in a cream as an example of a cosmetic.
クリームの調製は次のようにして行った。すなわち、スクワレン、セチルイソオクタノエートおよびマイクロクリスタリンワックスを加熱溶解後、粘土鉱物およびPOEグリセロールトリイソステアリン酸エステル(界面活性剤)を加え、７０℃に調整し、これらを均一に分散・溶解させて油性ゲルを得た。 次に、アスパラガス抽出物を所定濃度精製水に溶解し、油性ゲルの中へ、十分に攪拌しながらゆっくりと添加した。ホモミキサーで均一に混合した後、脱気、ろ過し、３０℃まで冷却し、クリームを得た。得られた処方例１のクリームの組成および配合比は以下の通りである。 The cream was prepared as follows. That is, squalene, cetylisooctanoate and microcrystalline wax are heated and dissolved, and then clay mineral and POE glycerol triisostearate (surfactant) are added, adjusted to 70 ° C., and uniformly dispersed and dissolved. An oily gel was obtained. Next, the asparagus extract was dissolved in a predetermined concentration of purified water and slowly added into the oily gel with sufficient stirring. After uniformly mixing with a homomixer, deaeration, filtration, and cooling to 30 ° C. gave a cream. The composition and blending ratio of the obtained cream of Formulation Example 1 are as follows.
組成 配合比（重量％）
スクワレン ２０．０％
セチルイソオクタノエート ８．５％
マイクロクリスタリンワックス １．０％
粘土鉱物 １．３％
ＰＯＥグリセロールトリイソステリン酸エステル ０．２％
アスパラガス抽出物 １．０％
水 残量
Composition ratio (wt%)
Squalene 20.0%
Cetyl isooctanoate 8.5%
Microcrystalline wax 1.0%
Clay mineral 1.3%
POE glycerol triisosterate 0.2%
Asparagus extract 1.0%
Water remaining
（処方例２）
本処方例は、上記実施例２のヒアルロン酸産生促進剤であるブッチャーブルーム抽出物を化粧料の一例としてのクリームに配合した場合の処方例である。クリームの調製は上記処方例１と同様に行った。得られた処方例２のクリームの組成および配合比は以下の通りである。
(Prescription example 2)
This prescription example is a prescription example when the butcher bloom extract which is the hyaluronic acid production promoter of Example 2 is blended in a cream as an example of a cosmetic. The cream was prepared in the same manner as in Formulation Example 1 above. The composition and blending ratio of the obtained cream of Formulation Example 2 are as follows.
組成 配合比（重量％）
スクワレン ２０．０％
セチルイソオクタノエート ８．５％
マイクロクリスタリンワックス １．０％
粘土鉱物 １．３％
ＰＯＥグリセロールトリイソステリン酸エステル ０．２％
ブッチャーブルーム抽出物 １．０％
水 残量
Composition ratio (wt%)
Squalene 20.0%
Cetyl isooctanoate 8.5%
Microcrystalline wax 1.0%
Clay mineral 1.3%
POE glycerol triisosterate 0.2%
Butcher Bloom Extract 1.0%
Water remaining
（試験例５）
上記のように調製した処方例１及び２のクリームを用いて、皮膚バリア機能改善試験を行った。すなわち、処方例１及び２のクリームを、それぞれ女子被験者(２５から４５歳)２５人を対象にして、顔に１日２回３ヶ月間連続塗布した。
(Test Example 5)
Using the creams of Formulation Examples 1 and 2 prepared as described above, a skin barrier function improvement test was conducted. That is, the creams of Formulation Examples 1 and 2 were continuously applied twice a day for 3 months to 25 female subjects (25 to 45 years old).
一方、クリーム基剤の組成および配合比は処方例１及び２と同じであって、ヒアルロン酸産生促進剤であるアスパラガス抽出物又はブッチャーブルーム抽出物が配合されていないクリームを調製した。得られたクリームについて、比較例として上記処方例と同様の試験を行った。皮膚バリア機能改善試験の評価は、連続塗布前の経皮水分蒸散量を１００とし、連続塗布後の経皮水分蒸散量変化率の平均で示した。試験結果を表５に示す。 On the other hand, the cream base composition and blending ratio were the same as those in Formulation Examples 1 and 2, and a cream containing no asparagus extract or butcher bloom extract as a hyaluronic acid production promoter was prepared. About the obtained cream, the test similar to the said prescription example was done as a comparative example. In the evaluation of the skin barrier function improvement test, the amount of transdermal moisture transpiration before continuous application was taken as 100, and the average rate of change in the amount of transdermal moisture transpiration after continuous application was shown. The test results are shown in Table 5.
表５から明らかなように、処方例１及び２では、比較例と比べて、被験者の経皮水分蒸散量を大きく低下させ、皮膚バリア機能改善効果が高いことが分かった。 As is apparent from Table 5, it was found that in the prescription examples 1 and 2, the amount of transdermal water transpiration of the subject was greatly reduced and the effect of improving the skin barrier function was high as compared with the comparative example.
（試験例６）
上記処方例１及び２、並びに比較例のそれぞれのクリームを用いて、前記被験者２５人に対して皮膚のしわ改善試験を行った。被験者２５人のうち、しわが改善されたと回答した人数を表６に示した。
(Test Example 6)
A skin wrinkle improvement test was performed on the 25 test subjects using the creams of the above Formulation Examples 1 and 2 and Comparative Example. Table 25 shows the number of the 25 subjects who answered that wrinkles were improved.
表６から明らかなように、処方例１及び２では、比較例と比較して、しわが改善されたと回答した人数が２倍もしくはそれ以上あり、皮膚のしわ改善効果が大きいことがわかった。 As is clear from Table 6, in the prescription examples 1 and 2, the number of people who answered that wrinkles were improved was twice or more compared to the comparative example, and it was found that the effect of improving skin wrinkles was great.
Claims (6)
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| JP2009040757A (en) * | 2007-08-10 | 2009-02-26 | Maruzen Pharmaceut Co Ltd | Agent promoting laminin 5 production, agent normalizing dermal basement membrane, and agent promoting recovery of skin lesion |
| JP2009132662A (en) * | 2007-11-30 | 2009-06-18 | Maruzen Pharmaceut Co Ltd | Glutathione production promoter |
| WO2009110205A1 (en) | 2008-03-04 | 2009-09-11 | ナガセケムテックス株式会社 | Agent for increasing the quantity of hyaluronic acid |
| JP2009235044A (en) * | 2008-03-28 | 2009-10-15 | Maruzen Pharmaceut Co Ltd | ENDOTHELIN-1 mRNA EXPRESSION INHIBITOR, MATRIX METALLOPROTEASE-9 mRNA EXPRESSION INHIBITOR, COLLAGEN PRODUCTION PROMOTER, PROFILAGGRIN PRODUCTION PROMOTER, FILAGGRIN PRODUCTION PROMOTER AND AQUAPORIN 3 mRNA EXPRESSION PROMOTER |
| JP2009298723A (en) * | 2008-06-12 | 2009-12-24 | Maruzen Pharmaceut Co Ltd | Type iv collagen production promoter |
| EP2316417A3 (en) * | 2009-09-03 | 2014-08-06 | Henkel AG & Co. KGaA | Non-therapeutic use to prevent skin aging |
| JP2016037453A (en) * | 2014-08-06 | 2016-03-22 | 花王株式会社 | Skin moisturizing agent |
| JP2016088930A (en) * | 2014-10-31 | 2016-05-23 | 日光ケミカルズ株式会社 | FINE WRINKLE IMPROVER FORMING α GEL STRUCTURE, AND FINE WRINKLE IMPROVING COSMETIC OR FINE WRINKLE IMPROVING SKIN EXTERNAL PREPARATION INCLUDING THE SAME |
| WO2016111310A1 (en) * | 2015-01-06 | 2016-07-14 | 国立研究開発法人理化学研究所 | Novel angiotensin converting enzyme inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2009040757A (en) * | 2007-08-10 | 2009-02-26 | Maruzen Pharmaceut Co Ltd | Agent promoting laminin 5 production, agent normalizing dermal basement membrane, and agent promoting recovery of skin lesion |
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| WO2009110205A1 (en) | 2008-03-04 | 2009-09-11 | ナガセケムテックス株式会社 | Agent for increasing the quantity of hyaluronic acid |
| JP2009235044A (en) * | 2008-03-28 | 2009-10-15 | Maruzen Pharmaceut Co Ltd | ENDOTHELIN-1 mRNA EXPRESSION INHIBITOR, MATRIX METALLOPROTEASE-9 mRNA EXPRESSION INHIBITOR, COLLAGEN PRODUCTION PROMOTER, PROFILAGGRIN PRODUCTION PROMOTER, FILAGGRIN PRODUCTION PROMOTER AND AQUAPORIN 3 mRNA EXPRESSION PROMOTER |
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| EP2316417A3 (en) * | 2009-09-03 | 2014-08-06 | Henkel AG & Co. KGaA | Non-therapeutic use to prevent skin aging |
| JP2016037453A (en) * | 2014-08-06 | 2016-03-22 | 花王株式会社 | Skin moisturizing agent |
| JP2016088930A (en) * | 2014-10-31 | 2016-05-23 | 日光ケミカルズ株式会社 | FINE WRINKLE IMPROVER FORMING α GEL STRUCTURE, AND FINE WRINKLE IMPROVING COSMETIC OR FINE WRINKLE IMPROVING SKIN EXTERNAL PREPARATION INCLUDING THE SAME |
| WO2016111310A1 (en) * | 2015-01-06 | 2016-07-14 | 国立研究開発法人理化学研究所 | Novel angiotensin converting enzyme inhibitor |
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