JP2013234130A - Hyaluronic acid production promotor - Google Patents
Hyaluronic acid production promotor Download PDFInfo
- Publication number
- JP2013234130A JP2013234130A JP2012105511A JP2012105511A JP2013234130A JP 2013234130 A JP2013234130 A JP 2013234130A JP 2012105511 A JP2012105511 A JP 2012105511A JP 2012105511 A JP2012105511 A JP 2012105511A JP 2013234130 A JP2013234130 A JP 2013234130A
- Authority
- JP
- Japan
- Prior art keywords
- lactoperoxidase
- hyaluronic acid
- acid production
- degradation product
- skin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 79
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Description
本発明は、皮膚の荒れ、シワ、弾性低下等を防止するのに有用なヒアルロン酸産生促進剤、ヒアルロン酸産生促進用飲食品及びヒアルロン酸産生促進用化粧料に関する。さらに詳しくは、本発明は、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼをタンパク質分解酵素で分解して得られるラクトパーオキシダーゼ分解物を有効成分とするヒアルロン酸産生促進剤に関する。 The present invention relates to hyaluronic acid production promoters, hyaluronic acid production promoting foods and drinks, and hyaluronic acid production promoting cosmetics that are useful for preventing rough skin, wrinkles, reduced elasticity, and the like. More specifically, the present invention relates to a hyaluronic acid production promoter containing lactoperoxidase and / or lactoperoxidase degradation product obtained by degrading lactoperoxidase with a proteolytic enzyme as an active ingredient.
近年、皮膚のメカニズムに関する研究が進められ、皮膚の乾燥感や肌荒れの原因として、加齢による新陳代謝の減衰によるもののほか、太陽光などの紫外線、乾燥、酸化等の作用が複雑に関与している(非特許文献1、2)。これらの因子は、真皮の主要なマトリックス成分であるヒアルロン酸を顕著に減少させることが明らかとなっている(非特許文献3)。ヒアルロン酸はその分子中に水分を保持することができ、それにより、皮膚をしっとりとした状態に保つ働きを有している。しかし、これらの作用によりヒアルロン酸が破壊され皮膚の水分保持機構が損なわれると、肌は、乾燥し荒れた状態になるとともに、シワやたるみを増した状態になる。 In recent years, research on the mechanism of the skin has been promoted, and the causes of skin dryness and rough skin are not only due to attenuation of metabolism due to aging, but also the effects of ultraviolet rays such as sunlight, drying, oxidation, etc. are involved in a complex manner (Non-Patent Documents 1 and 2). These factors have been shown to significantly reduce hyaluronic acid, which is the main matrix component of the dermis (Non-patent Document 3). Hyaluronic acid can retain moisture in the molecule, thereby keeping the skin moist. However, when hyaluronic acid is destroyed by these actions and the moisture retention mechanism of the skin is impaired, the skin becomes dry and rough, and wrinkles and sagging are increased.
このような皮膚における水分保持機能の改善剤として、ヒアルロン酸やコラーゲンなどを配合した化粧料が数多く提案されているが、これらは皮膚表面における保湿効果を発揮するのみであり、肌の機能低下を本質的に改善し得るものではなかった。その他、皮膚細胞賦活剤としてビタミン類や生薬類が使用されているが、やはり、肌の機能低下を治療するまでには至っていないのが現状である。以上のことから、真皮層の主要な成分の一つであるヒアルロン酸の生合成を促進させることにより、皮膚のシワやたるみを防止でき、しかも安全性の点でも問題のないヒアルロン酸産生促進剤が望まれていた。 Many cosmetics containing hyaluronic acid, collagen, etc. have been proposed as an agent for improving the moisture retention function in the skin, but these only exert a moisturizing effect on the skin surface and reduce the skin function. It could not be improved essentially. In addition, vitamins and herbal medicines are used as skin cell activators, but the current situation is that they have not yet reached the point of treating a decrease in skin function. From the above, by promoting the biosynthesis of hyaluronic acid, which is one of the main components of the dermis layer, it is possible to prevent wrinkles and sagging of the skin, and there is no problem in terms of safety. Was desired.
一方、関節液中のヒアルロン酸は、関節軟骨の表面を覆い、関節機能の円滑な作動に役立っている。正常人関節液中のヒアルロン酸濃度は約2.3mg/mLであるが、例えば、関節リウマチの場合、関節液中のヒアルロン酸濃度は約1.2mg/mLへと低下し、同時に関節液の粘度も著しく低下する(非特許文献4)。また、化膿性関節炎や痛風性関節炎などでも関節リウマチの場合と同様、ヒアルロン酸含量の低下が起こることが知られている(非特許文献5参照)。 On the other hand, hyaluronic acid in synovial fluid covers the surface of articular cartilage and helps smooth operation of joint functions. The concentration of hyaluronic acid in normal human joint fluid is about 2.3 mg / mL. For example, in the case of rheumatoid arthritis, the concentration of hyaluronic acid in joint fluid decreases to about 1.2 mg / mL, and at the same time, The viscosity is also significantly reduced (Non-Patent Document 4). In addition, it is known that hyaluronic acid content decreases in pyogenic arthritis and gouty arthritis as in the case of rheumatoid arthritis (see Non-Patent Document 5).
上記疾患において、潤滑機能の改善、関節軟骨の被覆・保護、疼痛抑制及び病的関節液の性状改善をするために、関節液中のヒアルロン酸量を増加させることが行われている。例えば、関節リウマチ患者にヒアルロン酸ナトリウムの関節注入療法を行うと、上記の改善が認められている(非特許文献6)。同様に、外傷性関節症、骨関節炎や変形性関節症においても、ヒアルロン酸の関節注入療法による改善効果が報告されている(非特許文献7)。以上のことから、ヒアルロン酸産生の促進は、肌荒れ等の皮膚疾患、関節リウマチや外傷性関節症、骨関節炎、変形性関節症といった関節疾患の予防、治療に有効である。しかしながら、上記疾患の治療は長期にわたり、しかも医師の処方を必要とする。したがって、日常の生活の中で手軽に治療できるヒアルロン酸産生促進剤を含有するクリームあるいは飲食品が望まれていた。 In the above diseases, the amount of hyaluronic acid in the joint fluid is increased in order to improve the lubrication function, cover / protect articular cartilage, suppress pain, and improve the properties of pathological joint fluid. For example, when rheumatoid arthritis patients are given joint injection therapy with sodium hyaluronate, the above improvement has been observed (Non-patent Document 6). Similarly, in traumatic arthritis, osteoarthritis and osteoarthritis, the improvement effect by the joint injection therapy of hyaluronic acid has been reported (Non-patent Document 7). From the above, promotion of hyaluronic acid production is effective for the prevention and treatment of skin diseases such as rough skin, joint diseases such as rheumatoid arthritis, traumatic arthropathy, osteoarthritis, and osteoarthritis. However, treatment of the above diseases is long-lasting and requires a doctor's prescription. Therefore, a cream or a food or drink containing a hyaluronic acid production promoter that can be easily treated in daily life has been desired.
本発明は、安全性の点で問題のないヒアルロン酸産生促進剤を提供することを課題とする。また、本発明は、そのような物質を配合したヒアルロン酸産生促進用飲食品及びヒアルロン酸産生促進用化粧料を提供することを課題とする。 This invention makes it a subject to provide the hyaluronic acid production promoter which is satisfactory in terms of safety. Moreover, this invention makes it a subject to provide the hyaluronic acid production promotion food-drinks and hyaluronic acid production promotion cosmetics which mix | blended such a substance.
本発明者らは、これらの課題を解決するために、広く食品素材に含まれているヒアルロン酸産生促進作用を示す物質について、鋭意、探索を進めたところ、ラクトパーオキシダーゼあるいはそのラクトパーオキシダーゼをペプシンやパンクレアチンなどのタンパク質分解酵素で分解して得られるラクトパーオキシダーゼ分解物が、皮膚(口唇を含む)、関節等、生体内(表皮細胞や真皮細胞等)におけるヒアルロン酸の産生が促進されることを見出し、本発明を完成するに至った。 In order to solve these problems, the present inventors diligently searched for substances that promote hyaluronic acid production that are widely contained in food materials. As a result, lactoperoxidase or its lactoperoxidase was obtained. Lactoperoxidase degradation products obtained by degrading with proteolytic enzymes such as pepsin and pancreatin promote the production of hyaluronic acid in the skin (including lips), joints, etc. in vivo (epidermal cells, dermal cells, etc.) As a result, the present invention has been completed.
すなわち本発明は、以下の態様を含むものである。
(1)ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を有効成分とするヒアルロン酸産生促進剤。
(2)前記ラクトパーオキシダーゼ分解物が、分子量500以上、8000以下であることを特徴とする(1)に記載のヒアルロン酸産生促進剤。
(3)前記ラクトパーオキシダーゼ分解物が、ラクトパーオキシダーゼをタンパク質分解酵素で分解して得られたものであることを特徴とする(1)記載のヒアルロン酸産生促進剤。
(4)前記タンパク質分解酵素が、トリプシン、パンクレアチン、キモトリプシン、ペプシン、パパイン、カリクレイン、カテプシン、サーモライシン、V8プロテアーゼから選択されるいずれか1種以上であることを特徴とする(3)記載のヒアルロン酸産生促進剤。
(5)ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を有効成分とするスキンケア剤。
(6)前記スキンケアが、肌荒れの予防及び/又は改善であることを特徴とする(5)記載のスキンケア剤。
(7)(1)〜(4)のいずれかに記載のラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を配合したヒアルロン酸産生促進用飲食品。
(8)(1)〜(4)のいずれかに記載のラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を配合したヒアルロン酸産生促進用化粧料。
(9)ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を経口摂取又は塗布することによる肌質の改善方法。
(10)ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を1日あたり9.4μg以上経口摂取するか、又は0.001〜2重量%になるよう配合した組成物を塗布することによる肌質の改善方法。
That is, the present invention includes the following aspects.
(1) Hyaluronic acid production promoter containing lactoperoxidase and / or lactoperoxidase degradation product as an active ingredient.
(2) The hyaluronic acid production promoter according to (1), wherein the lactoperoxidase degradation product has a molecular weight of 500 or more and 8000 or less.
(3) The hyaluronic acid production promoter according to (1), wherein the lactoperoxidase degradation product is obtained by degrading lactoperoxidase with a proteolytic enzyme.
(4) The hyaluron according to (3), wherein the proteolytic enzyme is at least one selected from trypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, and V8 protease. Acid production promoter.
(5) A skin care agent containing lactoperoxidase and / or lactoperoxidase degradation product as an active ingredient.
(6) The skin care agent according to (5), wherein the skin care is prevention and / or improvement of rough skin.
(7) A food and drink for promoting hyaluronic acid production, wherein the lactoperoxidase and / or lactoperoxidase degradation product according to any one of (1) to (4) is blended.
(8) A hyaluronic acid production promoting cosmetic comprising the lactoperoxidase and / or the lactoperoxidase degradation product according to any one of (1) to (4).
(9) A method for improving skin quality by orally ingesting or applying lactoperoxidase and / or lactoperoxidase degradation product.
(10) Ingestion of lactoperoxidase and / or lactoperoxidase degradation product orally 9.4 μg or more per day, or application of a composition formulated so as to be 0.001 to 2% by weight How to improve.
本発明により、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を有効成分とするヒアルロン酸産生促進剤、ヒアルロン酸産生促進用飲食品及びヒアルロン酸産生促進用化粧料が提供される。本発明のヒアルロン酸産生促進剤、ヒアルロン酸産生促進用飲食品及びヒアルロン酸産生促進用化粧料は、ヒアルロン酸産生を促進させる作用を有する。 According to the present invention, hyaluronic acid production promoters, hyaluronic acid production promoting foods and drinks and hyaluronic acid production promoting cosmetics containing lactoperoxidase and / or lactoperoxidase degradation products as active ingredients are provided. The hyaluronic acid production promoter, the hyaluronic acid production promoting food and drink and the hyaluronic acid production promoting cosmetic of the present invention have an action of promoting hyaluronic acid production.
本発明のヒアルロン酸産生促進剤の特徴は、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を有効成分とすることにある。 A feature of the hyaluronic acid production promoter of the present invention is that lactoperoxidase and / or a degradation product of lactoperoxidase is used as an active ingredient.
本発明のラクトパーオキシダーゼは哺乳動物の乳から調製する。給源としては、ウシ、水牛、ヒト、ブタ、ヒツジ、ヤギ、ウマ等の乳があげられる。ラクトパーオキシダーゼは、公知の物質であって、市販されているものであるが、それを製造するには、公知の方法、例えばスルホン化担体を用いてラクトパーオキシダーゼを精製する方法(特開平3−109400号公報)を工業的に有利に利用することができる。また、本発明では、遺伝子工学的手法により生産されたラクトパーオキシダーゼも使用し得る。 The lactoperoxidase of the present invention is prepared from mammalian milk. Examples of the source include milk such as cows, buffalos, humans, pigs, sheep, goats and horses. Lactoperoxidase is a known substance and is commercially available. To produce it, a known method, for example, a method for purifying lactoperoxidase using a sulfonated carrier (Japanese Patent Laid-Open No. Hei 3). -109400) can be advantageously used industrially. In the present invention, lactoperoxidase produced by genetic engineering techniques can also be used.
ラクトパーオキシダーゼ分解物は、上記のラクトパーオキシダーゼをトリプシン、パンクレアチン、キモトリプシン、ペプシン、パパイン、カリクレイン、カテプシン、サーモライシン、V8プロテアーゼ等のタンパク質分解酵素で分子量が8,000以下となるように限定分解したペプチド混合物を使用することが可能である。但し、分子量の下限は500以上であることが好ましい。 The lactoperoxidase degradation product is a limited degradation of the above-mentioned lactoperoxidase with a proteolytic enzyme such as trypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, V8 protease and the like so that the molecular weight is 8,000 or less. It is possible to use a mixture of peptides. However, the lower limit of the molecular weight is preferably 500 or more.
本発明のヒアルロン酸産生促進剤は、経口投与あるいは塗布することにより、ヒアルロン酸産生促進効果を発揮する。本発明のヒアルロン酸産生促進剤を経口投与するに際しては、有効成分であるラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物をそのままの状態で用いることもできるが、常法に従い、粉末剤、顆粒剤、錠剤、カプセル剤、ドリンク剤等に製剤化して用いることもできる。本発明において、粉末剤、顆粒剤、錠剤、カプセル剤等の経口剤は、例えば、澱粉、乳糖、白糖、マンニット、カルボキシメチルセルロース、コーンスターチ、無機塩類等の賦形剤を用いて常法によって製剤化される。この種の製剤には、前記賦形剤の他に、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、着色料、香料等を適宜使用することが出来る。より具体的には、結合剤としては、例えば、澱粉、デキストリン、アラビアガム、ゼラチン、ヒドロキシプロピルスターチ、カルボキシメチルセルロースナトリウム、メチルセルロース、結晶性セルロース、エチルセルロース、ポリビニルピロリドンが挙げられる。また、崩壊剤としては、例えば、澱粉、ヒドロキシプロピルスターチ、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、架橋カルボキシメチルセルロースナトリウム、結晶性セルロース等が挙げられる。界面活性剤としては、大豆レシチン、蔗糖脂肪酸エステル等が、滑沢剤としては、タルク、ロウ、蔗糖脂肪酸エステル、水素添加植物油等が、流動性促進剤としては無水ケイ酸、乾燥水酸化アルミニウム、ケイ酸マグネシウム等が挙げられる。 The hyaluronic acid production promoter of the present invention exhibits hyaluronic acid production promoting effect by oral administration or application. When the hyaluronic acid production promoter of the present invention is orally administered, the active ingredient lactoperoxidase and / or lactoperoxidase degradation product can be used as it is, but according to conventional methods, powders and granules In addition, it can be formulated into tablets, capsules, drinks and the like. In the present invention, oral preparations such as powders, granules, tablets and capsules are formulated by conventional methods using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts. It becomes. In this type of preparation, in addition to the above-mentioned excipients, binders, disintegrants, surfactants, lubricants, fluidity promoters, colorants, fragrances and the like can be appropriately used. More specifically, examples of the binder include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, sodium carboxymethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, and polyvinylpyrrolidone. Examples of the disintegrant include starch, hydroxypropyl starch, carboxymethylcellulose, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, and crystalline cellulose. As surfactant, soybean lecithin, sucrose fatty acid ester, etc., as lubricant, talc, wax, sucrose fatty acid ester, hydrogenated vegetable oil, etc., as fluidity promoter, anhydrous silicic acid, dry aluminum hydroxide, Examples include magnesium silicate.
さらには、これらのラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物をそのままあるいは製剤化した後、これを栄養剤や飲食品等に配合することも可能である。また、N-アセチルグルコサミンやN-メチル-L-セリン等の従来からヒアルロン酸産生に有効な作用を持つと考えられている成分とともにラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を配合すれば、一層のヒアルロン酸産生促進作用が期待できる。なお、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物は、比較的熱に対して安定であるので、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を含む原料を通常行われるような条件で加熱殺菌することも可能である。 Furthermore, these lactoperoxidases and / or lactoperoxidase degradation products can be used as they are or after preparation, and then blended with nutrients, foods and drinks, and the like. In addition, if a lactoperoxidase and / or a lactoperoxidase degradation product is combined with components that are conventionally considered to have an effective action for hyaluronic acid production, such as N-acetylglucosamine and N-methyl-L-serine, Further hyaluronic acid production promoting action can be expected. In addition, since lactoperoxidase and / or lactoperoxidase degradation products are relatively stable to heat, heat sterilization is performed under conditions such that a raw material containing lactoperoxidase and / or lactoperoxidase degradation products is usually used. It is also possible to do.
本発明のヒアルロン酸産生促進剤を塗布するに際しては、その使用目的に応じて、通常用いられる公知の成分に配合することによって、液剤、固形剤、半固形剤等の各種剤形に調製することが可能で、好ましい組成物として軟膏、ゲル、クリーム、スプレー剤、貼付剤、ローション、粉末等が挙げられる。例えば、本発明のヒアルロン酸産生促進剤をワセリン等の炭化水素、ステアリルアルコール、ミリスチン酸イソプロピル等の高級脂肪酸低級アルキルエステル、ラノリン等の動物性油脂、グリセリン等の多価アルコール、グリセリン脂肪酸エステル、モノステアリン酸、ポリエチレングリコール等の界面活性剤、無機塩、ロウ、樹脂、水及び、要すればパラオキシ安息香酸メチル、パラオキシ安息香酸ブチル等の保存料に混合することによって、ヒアルロン酸産生促進用化粧料や医薬品を製造することができる。 When applying the hyaluronic acid production promoter of the present invention, various dosage forms such as liquids, solids, semisolids, etc. are prepared by blending with commonly known components according to the purpose of use. Preferred compositions include ointments, gels, creams, sprays, patches, lotions, powders and the like. For example, the hyaluronic acid production promoter of the present invention is a hydrocarbon such as petrolatum, higher fatty acid lower alkyl esters such as stearyl alcohol, isopropyl myristate, animal fats such as lanolin, polyhydric alcohols such as glycerin, glycerin fatty acid esters, mono Cosmetics for promoting hyaluronic acid production by mixing with surfactants such as stearic acid and polyethylene glycol, inorganic salts, waxes, resins, water and, if necessary, preservatives such as methyl paraoxybenzoate and butyl paraoxybenzoate And can produce medicines.
本発明のヒアルロン酸産生促進剤の経口投与による有効量は、その製剤形態、投与方法、使用目的、及びこれを適用される患者の年齢、体重、病状により適宜規定され一定でないが、ラットを用いた動物実験の結果によると、ヒアルロン酸産生促進作用を示すためには、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物をラット体重1kg当たり9.4μg以上摂取する必要があることが判った。したがって、外挿法によると、通常、成人一人当たり一日9.4μg以上のラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を摂取すれば効果が期待できるので、この必要量を確保できるよう飲食品に配合するか、あるいは、医薬として投与すれば良い。なお、投与は必要に応じて一日数回に分けて行うことも可能である。 The effective amount of the hyaluronic acid production promoter of the present invention by oral administration is appropriately defined by the formulation form, administration method, purpose of use, and age, weight, and medical condition of the patient to which it is applied. According to the results of animal experiments, it was found that in order to show hyaluronic acid production promoting action, it is necessary to ingest 9.4 μg or more of lactoperoxidase and / or lactoperoxidase degradation product per kg of rat body weight. Therefore, according to the extrapolation method, an effect can normally be expected by ingesting 9.4 μg or more of lactoperoxidase and / or lactoperoxidase degradation product per adult per day. Or may be administered as a medicine. The administration can be divided into several times a day as necessary.
本発明のヒアルロン酸産生促進剤の塗布による有効量は、剤形により異なるが、適用する組成物全量を基準として、好ましくは、0.001〜2重量%となるように、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を配合すれば良い。ただし、入浴剤のように使用時に希釈されるものは、さらに配合量を増やすことができる。 The effective amount by application of the hyaluronic acid production promoter of the present invention varies depending on the dosage form, but preferably based on the total amount of the applied composition, lactoperoxidase and / or so as to be 0.001 to 2% by weight. Or a lactoperoxidase degradation product may be blended. However, what is diluted at the time of use like a bath agent can increase a compounding quantity further.
以下に、実施例及び試験例を示して本発明を詳細に説明するが、これらは単に本発明の実施態様を例示するのみであり、本発明はこれらによって何ら限定されるものではない。 EXAMPLES Hereinafter, the present invention will be described in detail with reference to examples and test examples. However, these are merely examples of the present invention, and the present invention is not limited to these examples.
陽イオン交換樹脂のスルホン化キトパール(富士紡績株式会社製)400gを充填したカラム(直径5cm×高さ30cm)を脱イオン水で十分洗浄した後、このカラムに未殺菌脱脂乳40リットル(pH 6.7)を流速25ml/minで通液した。通液後、このカラムを脱イオン水で十分洗浄し、2.0M塩化ナトリウムを含む0.02M炭酸緩衝液(pH 7.0)で溶出した。そしてラクトパーオキシダーゼを含有する溶出画分をS-Sepharose FFカラム(アマシャムバイオサイエンス社製)に吸着させ、脱イオン水で十分洗浄し、10mMリン酸緩衝液(pH7.0)で平衡化した後、0〜2.0M塩化ナトリウムのリニアグラジエントで吸着した画分を溶出し、ラクトパーオキシダーゼを含む画分を回収した。そしてその画分をHiLoad 16/60 Superdex 75 pg(アマシャムバイオサイエンス社製)を用いたゲル濾過クロマトグラフィーで処理し、ラクトパーオキシダーゼ3.0g(試料A)を得た。なお、このようにして得られたラクトパーオキシダーゼの純度は94%であり、そのままヒアルロン酸産生促進剤として使用可能である。 A column (5 cm in diameter x 30 cm in height) packed with 400 g of a cation exchange resin sulfonated chitopearl (Fujibo Co., Ltd.) was thoroughly washed with deionized water, and then 40 liters of unsterilized skim milk (pH 6) was added to this column. 7) was passed at a flow rate of 25 ml / min. After passing through the column, the column was thoroughly washed with deionized water and eluted with 0.02 M carbonate buffer (pH 7.0) containing 2.0 M sodium chloride. The elution fraction containing lactoperoxidase is adsorbed on an S-Sepharose FF column (Amersham Biosciences), washed thoroughly with deionized water, and equilibrated with 10 mM phosphate buffer (pH 7.0). The fraction adsorbed with a linear gradient of 0 to 2.0 M sodium chloride was eluted, and the fraction containing lactoperoxidase was recovered. Then, the fraction was treated by gel filtration chromatography using HiLoad 16/60 Superdex 75 pg (manufactured by Amersham Biosciences) to obtain 3.0 g of lactoperoxidase (sample A). The purity of the lactoperoxidase thus obtained is 94% and can be used as it is as a hyaluronic acid production promoter.
実施例1で得られたラクトパーオキシダーゼ25mgを、水100mlに懸濁し、最終濃度が1%となるようにパンクレアチンを加え、37℃で5分から6時間、酵素処理を行った。そして、90℃で5分間加熱処理して酵素を失活させた後、凍結乾燥して、ラクトパーオキシダーゼ分解物24mg(試料B、C、D)を得た。なお、このようにして得られたラクトパーオキシダーゼ分解物の平均分子量は、Bが約3,000、Cが約500、Dが約300であった。画分B、C、Dは、そのままヒアルロン酸産生促進剤として使用可能である。 25 mg of lactoperoxidase obtained in Example 1 was suspended in 100 ml of water, pancreatin was added to a final concentration of 1%, and enzyme treatment was performed at 37 ° C. for 5 minutes to 6 hours. And after heat-processing at 90 degreeC for 5 minute (s) and deactivating an enzyme, it freeze-dried and 24 mg (samples B, C, and D) of lactoperoxidase degradation products were obtained. The average molecular weight of the lactoperoxidase degradation product thus obtained was about 3,000 for B, about 500 for C, and about 300 for D. Fractions B, C, and D can be used as hyaluronic acid production promoters as they are.
[試験例1]
実施例1で得られた試料A及び実施例2で得られた試料B乃至Dについて、ラットを用いた動物実験によりヒアルロン酸産生促進作用を調べた。7週齢のWistar系雄ラットを、生理食塩水投与群(コントロール群)、実施例1で得られた試料Aをラット体重1kg当たり10μg投与する群(A−1群)、実施例1で得られた試料Aをラット体重1kg当たり100μg投与する群(A−2群)、実施例2で得られた試料B乃至Dをラット体重1kg当たり10μg投与する群(B−1〜D−1群)、実施例2で得られた試料B乃至Dをラット体重1kg当たり100μg投与する群(B−2〜D−2群)の9試験群(n=6)に分け、それぞれを毎日1回ゾンデで経口投与して10週間飼育した。皮膚のヒアルロン酸量については、試験前日に剃毛したラットを屠殺後速やかに回収した皮膚組織(各300mg)を測定に供した。加熱によりタンパク変性させた皮膚組織をアクチナーゼによりタンパク質を分解し、さらにヒアルロニダーゼにて分解したヒアルロン酸をHPLC法にて測定した。その結果を表1に示す。
[Test Example 1]
About the sample A obtained in Example 1, and the samples B thru | or D obtained in Example 2, the hyaluronic acid production promotion effect was investigated by the animal experiment using a rat. A 7-week-old Wistar male rat was obtained in Example 1 with a physiological saline administration group (control group), a group (Example A-1) in which 10 μg of sample A obtained in Example 1 was administered per kg of rat body weight. Group (A-2 group) administered with 100 μg of the obtained sample A per kg body weight of the rat, group (B-1 to D-1 group) administered with 10 μg of the samples B to D obtained in Example 2 per kg of the rat body weight The samples B to D obtained in Example 2 were divided into 9 test groups (n = 6) in a group (B-2 to D-2 group) administered with 100 μg / kg of the rat body weight, and each was sampled once a day with a sonde. Orally administered and reared for 10 weeks. Regarding the amount of hyaluronic acid in the skin, skin tissues (each 300 mg) collected immediately after sacrifice of the shaved rat on the day before the test were subjected to measurement. The skin tissue denatured by heating was subjected to protein degradation with actinase, and hyaluronic acid degraded with hyaluronidase was measured by HPLC. The results are shown in Table 1.
この結果、10週間後の可溶性画分中ヒアルロン酸量は、コントロール群に比べ、すべての試験群で有意に高い値を示した。このことから、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物には、ヒアルロン酸産生促進作用があることが明らかとなり、ヒアルロン酸産生促進剤として有用であることが示された。また、このヒアルロン酸産生促進作用はラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物をラット体重1kg当たり最低9.4μg投与した場合に認められることが明らかとなった。 As a result, the amount of hyaluronic acid in the soluble fraction after 10 weeks was significantly higher in all test groups than in the control group. From this, it was revealed that lactoperoxidase and / or a degradation product of lactoperoxidase has a hyaluronic acid production promoting action, and it was shown that it is useful as a hyaluronic acid production promoter. It was also revealed that this hyaluronic acid production promoting action was observed when lactoperoxidase and / or lactoperoxidase degradation product was administered at a minimum of 9.4 μg / kg of rat body weight.
[試験例2]
実施例1で得られた試料A及び実施例2で得られた試料B、C、Dについて、正常ヒト線維芽細胞株〔白人女性の皮膚より採取されたCCD45SK(ATCCRL 1506)〕を用いた実験によりヒアルロン酸産生促進作用を調べた。10容量%ウシ胎児血清(以下FBSと略記)含有変法イーグル培地(MEM、10‐101、大日本製薬社製)を用いて、正常ヒト線維芽細胞株を4×104個/ウエル/0.4mlとなるように24ウエルプレートに播種して、5%炭酸ガス、飽和水蒸気下、37℃で24時間培養した後、0.6容量%FBS含有MEM培地に置換した。そして、実施例1で得られた試料A及び実施例2で得られた試料B、C、Dを、各ウエルに0.1容量%となるように添加(n=6)して、72時間培養して培養液を得た。このようにして得られた培養液より、ヒアルロン酸量(バイオテック トレーディング パートナーズ社製)を測定した。なお、対照として、ラクトパーオキシダーゼ又はラクトパーオキシダーゼ分解物を添加しないで同様の試験を行った。その結果を表2に示す。
[Test Example 2]
Experiments using sample A obtained in Example 1 and samples B, C, and D obtained in Example 2 using a normal human fibroblast cell line [CCD45SK (ATCCRL 1506) collected from white female skin] The hyaluronic acid production promoting effect was examined by the above. Using a modified Eagle's medium (MEM, 10-101, manufactured by Dainippon Pharmaceutical Co., Ltd.) containing 10% by volume fetal bovine serum (hereinafter abbreviated as FBS), 4 × 10 4 normal human fibroblast cell lines / well / 0 After seeding in a 24-well plate so as to be 4 ml and culturing at 37 ° C. under 5% carbon dioxide gas and saturated steam for 24 hours, the medium was replaced with a 0.6 volume% FBS-containing MEM medium. Then, the sample A obtained in Example 1 and the samples B, C, and D obtained in Example 2 were added to each well so as to be 0.1% by volume (n = 6), and 72 hours Culture was obtained by culturing. The amount of hyaluronic acid (manufactured by Biotech Trading Partners) was measured from the culture solution thus obtained. As a control, the same test was performed without adding lactoperoxidase or a lactoperoxidase degradation product. The results are shown in Table 2.
これによると、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を添加した群は、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を添加していない群(対照)に比べていずれも2倍以上のヒアルロン酸産生促進能を示した。このことから、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物には、皮膚線維芽細胞に働きかけ、ヒアルロン酸産生を促進する作用があることが明らかとなり、ヒアルロン酸産生促進剤として有用であることが示された。 According to this, the group to which lactoperoxidase and / or lactoperoxidase degradation product was added was at least twice as much as the group to which lactoperoxidase and / or lactoperoxidase degradation product was not added (control). It showed the ability to promote hyaluronic acid production. This reveals that lactoperoxidase and / or lactoperoxidase degradation products act on skin fibroblasts and promote hyaluronic acid production, and are useful as hyaluronic acid production promoters. Indicated.
表3に示す配合のヒアルロン酸産生促進用飲料を常法により製造した。製造した飲料の風味は良好で、常温1年間保存によっても風味が劣化することはなく、沈殿等の問題もなかった。 Beverages for promoting hyaluronic acid production with the formulation shown in Table 3 were produced by conventional methods. The flavor of the manufactured beverage was good, and the flavor did not deteriorate even after storage at room temperature for 1 year, and there was no problem such as precipitation.
表4に示す配合のドウを常法により作製し、成形した後、焙焼してヒアルロン酸産生促進用ビスケットを製造した。 A dough having the composition shown in Table 4 was produced by a conventional method, molded, and then baked to produce hyaluronic acid production promoting biscuits.
表5に示す配合のヒアルロン酸産生促進剤を常法により製造した。 Hyaluronic acid production promoters having the composition shown in Table 5 were produced by a conventional method.
表6に示す配合の化粧水を常法により製造した。 A lotion having the composition shown in Table 6 was produced by a conventional method.
表7に示す配合のクリームを常法により製造した。 A cream having the composition shown in Table 7 was produced by a conventional method.
[試験例3]
実施例6で得られた化粧水及び実施例7で得られたクリームを用いて、実使用テストを行った。比較品としては、ラクトパーオキシダーゼ及び/又はラクトパーオキシダーゼ分解物を除いた以外は実施例6及び7と同じ配合のものを用いた。顔面のたるみや小ジワが認められる乾燥肌を有する成人女性20人を、それぞれ10人ずつ無作為に2群(A、B群)に、また、手に肌荒れが認められる女性20人を、それぞれ10人ずつ無作為に2群(C、D群)に分け、A群の顔面には本発明品の化粧水2gを、B群の顔面には比較品の化粧水2gを、C群の手指には本発明品のクリーム2gを、D群の手指には比較品のクリーム2gを、それぞれ1日2回通常の使用状態と同様に10日間塗布した。結果を表8に示す。
[Test Example 3]
Using the lotion obtained in Example 6 and the cream obtained in Example 7, an actual use test was conducted. As a comparative product, the same product as in Examples 6 and 7 was used except that lactoperoxidase and / or a lactoperoxidase degradation product were removed. 20 adult women with dry skin where facial sagging and fine wrinkles are recognized, 10 people each randomly into 2 groups (Groups A and B), and 20 women with rough skin on the hands, respectively 10 people randomly divided into 2 groups (Group C, D), 2g of the product of the present invention was applied to the face of Group A, 2g of the comparison product was applied to the face of Group B, and fingers of Group C 2 g of the product of the present invention and 2 g of the comparative product were applied to the fingers of group D twice a day for 10 days in the same manner as in normal use. The results are shown in Table 8.
表8の結果より、本発明品の化粧水は、比較品の化粧水に比べて、乾燥感の改善、肌荒れ等の改善が顕著であり、ヒアルロン酸産生促進効果に優れていることが実証された。また、本発明品のクリームについても、比較品のクリームに比べて、乾燥感の改善、肌荒れに顕著な改善がみられ、肌荒れ等の自然増悪抑制効果を有することが明らかとなった。 From the results of Table 8, it was demonstrated that the lotion of the product of the present invention is significantly improved in dry feeling, rough skin and the like, and excellent in hyaluronic acid production promoting effect compared with the comparative lotion. It was. In addition, the cream of the present invention also has an improvement in dry feeling and a marked improvement in rough skin, as compared with the comparative cream, and has been found to have an effect of suppressing natural deterioration such as rough skin.
[試験例4]
変形性関節炎による軽度の痛みを有する患者20名を対象に、実施例3に示す被験食を1日1回飲用し、1年間の臨床試験を行った。関節の疼痛および機能の評価を、疼痛に対するビジュアルアナログスケール(VAS)、及び、関節炎の関節における疼痛、機能、および硬直に関するWestern Ontario and McMaster Universities(WOMAC)指標にて変形性関節症の評価を行った。結果を表9に示す。
[Test Example 4]
For 20 patients with mild pain due to osteoarthritis, the test diet shown in Example 3 was drunk once a day and a one-year clinical trial was conducted. Assess joint pain and function with visual analog scale (VAS) for pain and with the Western Ontario and McMaster Universities (WOMAC) index for pain, function and stiffness in arthritic joints It was. The results are shown in Table 9.
表9の結果より、本発明品の被験食は、比較品の被験食に比べて、関節の疼痛および機能の改善が顕著であり、ヒアルロン酸産生促進効果に優れていることが実証された。
From the results shown in Table 9, it was demonstrated that the test food of the present invention was significantly improved in joint pain and function and superior in hyaluronic acid production promoting effect as compared to the test food of the comparative product.
Claims (10)
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JPH05124980A (en) * | 1991-10-30 | 1993-05-21 | Snow Brand Milk Prod Co Ltd | Aging preventing agent |
JPH11240817A (en) * | 1998-02-23 | 1999-09-07 | Spirulina Kenkyusho:Kk | Beauty culture pack |
JP2004331565A (en) * | 2003-05-07 | 2004-11-25 | Snow Brand Milk Prod Co Ltd | Skin collagen production enhancer |
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JPH05124980A (en) * | 1991-10-30 | 1993-05-21 | Snow Brand Milk Prod Co Ltd | Aging preventing agent |
JPH11240817A (en) * | 1998-02-23 | 1999-09-07 | Spirulina Kenkyusho:Kk | Beauty culture pack |
JP2004331565A (en) * | 2003-05-07 | 2004-11-25 | Snow Brand Milk Prod Co Ltd | Skin collagen production enhancer |
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