JP6522286B2 - Hyaluronic acid production promoter - Google Patents
Hyaluronic acid production promoter Download PDFInfo
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- JP6522286B2 JP6522286B2 JP2014116845A JP2014116845A JP6522286B2 JP 6522286 B2 JP6522286 B2 JP 6522286B2 JP 2014116845 A JP2014116845 A JP 2014116845A JP 2014116845 A JP2014116845 A JP 2014116845A JP 6522286 B2 JP6522286 B2 JP 6522286B2
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- hyaluronic acid
- acid production
- sdf
- skin
- production promoter
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Description
本発明は、皮膚の荒れ、シワ、弾性低下、関節機能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サプリメント、飲食品及びヒアルロン酸産生促進用化粧料に関する。 The present invention relates to a hyaluronic acid production promoter, a supplement for hyaluronic acid production promotion, a food and a drink, and a cosmetic for promoting hyaluronic acid production, which are useful for preventing roughening of the skin, wrinkles, elasticity reduction, joint function deterioration and the like.
近年、光老化という、長年において肌に紫外線が照射され続けることによる、しみ、皺、たるみなどの肌の障害を防止することに関して、多くの研究がなされている。
皮膚はおおまかに皮膚表面に存在する表皮と表皮の下部に存在する真皮からなる。表皮は主に外部からの異物や病原菌、紫外線から保護するバリアー機能や、生体内からの物質の漏洩を防護する機能を有する。また真皮は表皮の約15〜40倍の厚さを持ち、皮膚の力学的強度を保つ役割を担っている。真皮はその乾燥重量の70%がコラーゲンからなる繊維成分であるが、真皮の線維と皮膚線維芽細胞との間には、糖蛋白質や、プロテオグリカンといった基質が存在する。プロテオグリカンは、糖蛋白質とグリコサミノグリカンといったムコ多糖とが結合した分子量105〜106以上の巨大分子であり、真皮のグリコサミノグリカンは、主にヒアルロン酸やデルマタン硫酸からなるため、ヒアルロン酸は真皮における主要なマトリックス成分であると言える。
老化などの生理的要因や、太陽光などの紫外線、乾燥、酸化等などの外的環境の変化により皮膚の水分含量や真皮のヒアルロン酸量が低下すると、皮膚に皺が発生し、たるんだ状態を引き起こす。ヒアルロン酸は、主に皮膚の水分を保持する機能を有していることから、真皮中のヒアルロン酸含量を高めることによって、皮膚の水分含量の低下を防ぐことができると考えられ、皮膚における水分保持機能の改善剤として、ヒアルロン酸を配合した化粧料が数多く提案されている。しかしながら、これらの皮膚表面に塗布されたヒアルロン酸は、皮膚表面の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い。
また、ヒアルロン酸は、高い相対分子量や低い脂溶性、生体膜障壁の通過困難性、大量の多糖分解酵素の存在といった理由から、経口投与した際の消化管からの吸収が悪いことが報告されている(特許文献1)。したがって、肌の機能低下を本質的に改善するためには、真皮層のヒアルロン酸の生合成を促進させる必要があり、これによって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。
これまで、ヒアルロン酸産生促進剤としては、インシュリン様成長因子−1(IGF-1)や上皮成長因子(EGF)、血漿由来成長因子(PDGF)-BB、インターロイキンン−1(IL-1)、トランスフォーミング増殖因子(TGF)-β1などが知られているが、いずれも飲食品や化粧品、医薬品等として実用化に至っていない。
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。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1)。
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、上記の性状の改善が認められている(非特許文献2)。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3)。
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サプリメント、クリームあるいは飲食品が望まれていた。
ケモカインであるstromal cell derived factor 1 (SDF−1またはCXCL12、PBSF)は、Gタンパク質共役受容体であるCXCR4のリガンドであるが、そのSDF−1/CXCR4シグナル伝達系は、発生過程における造血・血管形成などの生理作用を有することが知られている。また、近年では、SDF−1はマウス背部の真皮に発現していることや、表皮の細胞増殖を促すことが報告されている。しかし、ヒアルロン酸を産生する機能についての報告はない。
In recent years, much research has been conducted on photoaging, for example, to prevent skin disorders such as stains, wrinkles, and sagging caused by continuous irradiation of ultraviolet rays on the skin for many years.
The skin is roughly composed of the epidermis present on the skin surface and the dermis present in the lower part of the epidermis. The epidermis mainly has a barrier function to protect from foreign substances and pathogens from the outside, ultraviolet rays, and a function to protect the leakage of substances from inside the living body. In addition, the dermis has a thickness of about 15 to 40 times that of the epidermis and plays a role in maintaining the mechanical strength of the skin. The dermis is a fiber component in which 70% of its dry weight is collagen, but there are substrates such as glycoproteins and proteoglycans between the fibers of the dermis and the skin fibroblasts. Proteoglycans are macromolecules with a molecular weight of 10 5 to 10 6 or more, in which glycoproteins and mucopolysaccharides such as glycosaminoglycans are bound, and glycosaminoglycans in the dermis are mainly composed of hyaluronic acid and dermatan sulfate. Acid is said to be the main matrix component in the dermis.
When the moisture content of the skin or the amount of hyaluronic acid in the skin decreases due to physiological factors such as aging, UV light such as sunlight, changes in external environment such as dryness, oxidation, etc., wrinkles are generated in the skin, resulting in a sagging condition cause. Since hyaluronic acid mainly has a function to retain skin moisture, it is thought that the reduction of skin moisture content can be prevented by increasing the hyaluronic acid content in the dermis, Many cosmetic compositions containing hyaluronic acid have been proposed as agents for improving the retention function. However, hyaluronic acid applied to these skin surfaces only exerts a moisturizing effect on the skin surface, and can not essentially improve the deterioration of the skin function.
Hyaluronic acid has also been reported to be poorly absorbed from the digestive tract when orally administered due to its high relative molecular weight, low lipid solubility, difficulty in passing through biological membrane barriers, and the presence of a large amount of polysaccharide degrading enzyme (Patent Document 1). Therefore, it is necessary to promote the biosynthesis of hyaluronic acid in the dermal layer in order to essentially improve the decrease in the function of the skin, which can prevent wrinkles and sagging of the skin, and is also a problem in terms of safety. A hyaluronic acid production promoter was desired.
So far, as hyaluronic acid production promoting agents, insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), plasma derived growth factor (PDGF) -BB, interleukin-1 (IL-1) Transforming growth factor (TGF) -β1 and the like are known, but none have been put to practical use as food and drink, cosmetics, medicines and the like.
On the other hand, hyaluronic acid in synovial fluid covers the surface of articular cartilage and helps smooth operation of articular function. Although 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 drops to about 1.2 mg / mL, and at the same time The viscosity also decreases significantly. In addition, it is known that, in the cases of suppurative arthritis, gouty arthritis and the like as well as in the case of rheumatoid arthritis, a decrease in the content of hyaluronic acid occurs (Non-patent Document 1).
In the above-mentioned diseases, in order to improve the lubricating function, coat and protect articular cartilage, to suppress pain and to improve the properties of pathological joint fluid, it has been carried out to increase the amount of hyaluronic acid in the joint fluid. For example, when the joint injection therapy of sodium hyaluronate is performed on a patient with rheumatoid arthritis, the above-mentioned property improvement is observed (Non-patent Document 2). Similarly, in traumatic arthropathy, osteoarthritis and osteoarthritis, an improving effect by joint injection therapy of hyaluronic acid has been reported (Non-patent Document 3).
From the above, promotion of hyaluronic acid production is effective for prevention and treatment of joint diseases such as skin diseases such as rough skin, rheumatoid arthritis, traumatic arthropathy, osteoarthritis and osteoarthritis. However, treatment of the above-mentioned diseases is long-term and requires a doctor's prescription. Therefore, a supplement, a cream or a food / drink product containing a hyaluronic acid production promoter which can be easily treated in daily life has been desired.
The chemokine stromal cell derived factor 1 (SDF-1 or CXCL12, PBSF) is a ligand for the G protein coupled receptor CXCR4, but its SDF-1 / CXCR4 signaling system It is known to have physiological effects such as formation. Moreover, in recent years, SDF-1 has been reported to be expressed in the dermis of the back of mice and to promote cell proliferation of the epidermis. However, there is no report on the function of producing hyaluronic acid.
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サプリメント、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。 An object of the present invention is to provide a hyaluronic acid production promoter that does not have a problem in terms of safety. Moreover, this invention makes it a subject to provide the supplement for hyaluronic acid production promotion which compounded such a substance, food-drinks, and cosmetics for hyaluronic acid production promotion.
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、SDF−1がヒアルロン酸産生量を増加させることを見出し、本発明を完成するに至った。
すなわち本発明は、以下の態様を含むものである。
(1)SDF−1を有効成分とするヒアルロン酸産生促進剤。
(2)SDF−1を有効成分とするスキンケア剤。
(3)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(2)記載のスキンケア剤。
(4)(1)〜(3)のいずれかに記載のSDF−1を配合したヒアルロン酸産生促進用サプリメント。
(5)(1)〜(3)のいずれかに記載のSDF−1を配合したヒアルロン酸産生促進用飲食品。
(6)(1)〜(3)のいずれかに記載のSDF−1を配合したヒアルロン酸産生促進用化粧料。
(7)SDF−1を経口摂取又は塗布することによる肌質の改善方法。
(8)SDF−1を1日あたり10μg以上経口摂取するか、又は0.05〜0.5重量%になるよう調整した物を塗布することによる肌質の改善方法。
In order to solve these problems, the present inventors have intensively searched for substances having a hyaluronan production promoting action widely contained in food materials, and as a result, SDF-1 produces a quantity of hyaluronan produced. It has been found to increase, and the present invention has been completed.
That is, the present invention includes the following aspects.
(1) A hyaluronic acid production promoter containing SDF-1 as an active ingredient.
(2) A skin care agent containing SDF-1 as an active ingredient.
(3) The skin care agent according to (2), wherein the skin care is the prevention and / or improvement of rough skin.
(4) The supplement for hyaluronic acid production promotion which mix | blended SDF-1 in any one of (1)-(3).
(5) Food-drinks for hyaluronic acid production promotion which mix | blended SDF-1 in any one of (1)-(3).
(6) A cosmetic for promoting hyaluronic acid production, which contains SDF-1 according to any one of (1) to (3).
(7) A method of improving skin quality by orally taking or applying SDF-1.
(8) A method for improving skin quality by orally ingesting 10 μg or more of SDF-1 per day, or applying a product adjusted to 0.05 to 0.5% by weight.
本発明により、SDF−1を有効成分とするヒアルロン酸産促進剤、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サプリメント、飲食品及びヒアルロン酸産生促進用化粧料は、皮膚のヒアルロン酸産生を促進させる作用を有し、皮膚のシワやたるみ、乾燥感や肌荒れの予防や治療に有用である。 According to the present invention, a hyaluronic acid production accelerator, a food / beverage product for hyaluronic acid production promotion, and a hyaluronic acid production promotion cosmetic comprising SDF-1 as an active ingredient are provided. The hyaluronic acid production promoter of the present invention, the supplement for hyaluronic acid production promotion, the food and drink, and the cosmetic for promoting hyaluronic acid production have an action to promote the hyaluronic acid production of the skin, and the wrinkles and slackness of the skin, the feeling of dryness and It is useful for prevention and treatment of rough skin.
本発明のヒアルロン酸産生促進剤の特徴は、SDF−1を有効成分とすることにある。本発明のSDF−1はどのような由来のものであっても使用可能である。たとえば、ヒト及びウシ由来のSDF−1はすでにその遺伝子配列が明らかになっており、遺伝子組換えによる生産が可能であるが、本発明では、遺伝子工学的手法により生産されたSDF−1も使用可能であり、細胞培養の培養液から回収した細胞由来のものも使用可能である。また、SDF−1はウシ初乳中に含有されており、乳から回収したものであっても良く、生乳や粉乳、脱脂乳、還元乳等から、加熱処理、加塩処理、エタノール処理、イオン交換クロマトグラフィーやゲル濾過クロマトグラフィー等の各種クロマト処理、限外濾過処理等によって取得することも可能である。 The feature of the hyaluronic acid production promoter of the present invention is that SDF-1 is an active ingredient. The SDF-1 of the present invention may be of any origin. For example, SDF-1 derived from human and bovine has already been clarified its gene sequence, and recombinant production is possible, but in the present invention, SDF-1 produced by genetic engineering techniques is also used It is also possible to use those derived from cells recovered from cell culture broth. In addition, SDF-1 is contained in bovine colostrum and may be recovered from milk, and raw milk, milk powder, skimmed milk, reduced milk, etc., heat treatment, salting treatment, ethanol treatment, ion exchange It is also possible to obtain by various chromatography processes such as chromatography and gel filtration chromatography, ultrafiltration process and the like.
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SDF−1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することが可能である。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、香料等を適宜使用してもよい。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、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。また、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、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、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 exerts a hyaluronic acid production promoting effect by oral administration or application. When orally administering the hyaluronic acid production promoter of the present invention, SDF-1 which is an active ingredient can be used as it is, but according to a conventional method, powders, granules, tablets, capsules, drinks It can also be formulated and used. In the present invention, oral preparations such as powders, granules, tablets, capsules and the like are formulated by a conventional method using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like. It is possible to In this type of preparation, in addition to the above-mentioned excipients, binders, disintegrants, surfactants, lubricants, flow promoters, colorants, perfumes and the like may be used as appropriate. Binders include, for example, starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, carboxymethylcellulose sodium, methylcellulose, crystalline cellulose, ethylcellulose, polyvinyl pyrrolidone, and disintegrants include, for example, starch, hydroxypropyl starch And carboxymethylcellulose, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, crystalline cellulose and the like. Further, as a surfactant, soybean lecithin, sucrose fatty acid ester, etc., as a lubricant, talc, wax, sucrose fatty acid ester, hydrogenated vegetable oil, etc., as a fluidity promoter, anhydrous silicic acid, dry aluminum hydroxide, Magnesium silicate etc. are mentioned.
さらには、これらのSDF−1をそのままあるいは製剤化した後、これをサプリメント、栄養剤や飲食品等に配合することも可能である。なお、SDF−1は、比較的熱に対して安定であるので、SDF−1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, it is also possible to mix | blend these SDF-1 with a supplement, a nutrient agent, food-drinks, etc., after preparing as it is or formulation. In addition, since SDF-1 is relatively stable to heat, it is also possible to heat-sterilize the raw material containing SDF-1 on the conditions normally performed.
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, it may be prepared into various dosage forms such as liquid agent, solid agent, semi-solid agent, etc. by blending with known components generally used depending on the purpose of use. Possible compositions and ointments, gels, creams, sprays, patches, lotions, powders and the like as preferred compositions. For example, the hyaluronic acid production promoter of the present invention may be a hydrocarbon such as vaseline, a higher fatty acid lower alkyl ester such as stearyl alcohol and isopropyl myristate, an animal oil and fat such as lanolin, a polyhydric alcohol such as glycerin, glycerin fatty acid ester, mono Cosmetics for promoting hyaluronic acid production by mixing with surfactants such as stearic acid and polyethylene glycol, inorganic salts, waxes, resins, water and preservatives such as methyl parahydroxybenzoate and butyl parahydroxybenzoate if necessary. 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、SDF−1は、ラット体重1kg当たり10μg以上摂取させることでヒアルロン酸産生促進作用を示すことが明らかとなった。したがって、外挿法によると、通常、成人一人当たり一日10μg以上のSDF−1を摂取すればヒアルロン酸産生促進効果が期待できるため、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 dose of the hyaluronic acid production promoter of the present invention by oral administration is appropriately determined depending on the formulation form, administration method, purpose of use and age, weight and medical condition of the patient to which it is applied. As a result of animal experiments, it was revealed that SDF-1 exhibits a hyaluronic acid production promoting action by taking 10 μg or more per kg of rat body weight. Therefore, according to the extrapolation method, the hyaluronic acid production promoting effect can usually be expected by taking in 10 μg or more of SDF-1 per adult per day, so it should be added to the food or drink so that the necessary amount can be secured or It may be administered as a medicine. In addition, it is also possible to divide administration into several times a day, as needed.
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、SDF−1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。 Although the effective amount by application of the hyaluronic acid production promoter of the present invention varies depending on the dosage form, it is preferable to blend SDF-1 so as to be 0.001 to 2% by weight based on the total amount of the composition to be applied. Just do it. However, what is diluted at the time of use like a bathing agent can further increase a compounding quantity.
[試験例1]
Biolegend社より購入したRecombinant Human CXCL12 (SDF-1α) (carrier-free)を試料Aとし、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(対照群)、試料Aをラット体重1kg当たり10μg投与する群(A−1群)、試料Aをラット体重1kg当たり100μg投与する群(A−2群)、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分解した。得られた分解物を、更にヒアルロニダーゼにてヒアルロン酸に分解した。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]
A sample of Recombinant Human CXCL12 (SDF-1α) (carrier-free) purchased from Biolegend was used as sample A, and its hyaluronic acid production promoting action was examined by animal experiments using rats. Seven-week-old Wistar male rats in the saline administration group (control group), a group to which 10 μg of sample A is administered per kg of rat weight (group A-1), a group to which 100 μg of sample A is administered per kg of rat weight Group A-2), each was orally administered once daily with a sonde and bred for 10 weeks. Regarding the amount of hyaluronic acid in the skin, skin tissues (300 mg each) collected immediately after slaughtering of the shaved rat on the day before the test were subjected to measurement. The heat-denatured skin tissue was proteolytically degraded by actinase. The resulting degradation product was further degraded into hyaluronic acid with hyaluronidase. Hyaluronic acid was measured by HPLC method.
The results are shown in Table 1.
※は対照群と比較して有意差があることを示す(p<0.05)。
※ indicates that there is a significant difference compared to the control group (p <0.05).
この結果、10週間後の可溶性画分中ヒアルロン酸量は、対照群に比べ、すべての試験群で有意に高い値を示した。このことから、SDF−1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SDF−1をラット体重1kg当たり少なくとも10.0μg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 showed significantly higher values in all test groups compared to the control group. From this, it became clear that SDF-1 has hyaluronic acid production promoting action, and it was shown that it is useful as a hyaluronic acid production promoting agent. In addition, it was revealed that this hyaluronic acid production promoting action was observed when SDF-1 was administered at least 10.0 μg / kg of rat body weight.
[試験例2]
試料A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、試料A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中の、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、SDF−1を添加せずに同様の試験を行った。その結果を表2に示す。
[Test Example 2]
Sample A was examined for its hyaluronic acid production promoting effect by an experiment using a normal human fibroblast cell line (CCD45SK (ATCCRL 1506) collected from the skin of a white female). Using a modified Eagle's medium (MEM, 10-101, manufactured by Dainippon Pharmaceutical Co., Ltd.) containing 10% by volume of fetal bovine serum (hereinafter abbreviated as FBS), 4 × 10 4 normal human fibroblast cell lines / well / 0 The cells were seeded in a 24-well plate to 4 ml, cultured for 24 hours at 37 ° C. under 5% carbon dioxide gas, saturated steam, and then replaced with MEM medium containing 0.6% by volume of FBS. Then, the sample A was added to each well to a volume of 0.1% by volume (n = 6), and cultured for 72 hours to obtain a culture solution. The amount of hyaluronic acid (Biotech Trading Partners, Inc.) in the culture solution thus obtained was measured. As a control, the same test was performed without adding SDF-1. The results are shown in Table 2.
数値は、平均値±標準偏差(n=6)を示す。
※は対照と比較して有意差があることを示す(p<0.05)。
Numerical values indicate mean value ± standard deviation (n = 6).
※ indicates that there is a significant difference compared to the control (p <0.05).
表2の結果、SDF−1を添加した群は、SDF−1を添加していない群(対照)に比べて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、SDF−1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。 As a result of Table 2, the group which added SDF-1 showed 2 times or more hyaluronan production promotion ability compared with the group (control) which does not add SDF-1. From this, it became clear that SDF-1 acts on skin fibroblasts and has an action of promoting hyaluronic acid production, and it was shown that it is useful as a hyaluronic acid production promoter.
[試験例3]
SDF−1がヒアルロン酸合成酵素遺伝子(Has2)のmRNA発現へ及ぼす影響について、正常ヒト新生児包皮皮膚線維芽細胞(NHDF(NB))を用いた細胞実験及びリアルタイムPCR法を用いて確認した。具体的には、NHDF(NB)細胞を24穴プレートに0.5×105cells/wellになる様に播種し、MEDIUM106培地(GIBCO社製)にて37℃、5%CO2環境下にて7日間培養した。7日間の培養期間のうち最終の24時間について、試料Aをそれぞれ100nM、500nM、1μMになるようにMEDIUM106培地に溶解したものを細胞に添加した後、total RNAを回収しcDNAを合成した。培養した細胞にRNA抽出剤であるISOGEN(ニッポンジーン社製)を0.5ml添加し5分間静置した後、ピペッティングにて可溶化させた細胞液を1.5ml容チューブに回収した。細胞液に0.1mlのクロロホルムを添加し、十分に攪拌した後、二層に分離した上層(水層)を新たな1.5ml容チューブに回収した。回収液に0.25mlの2−プロピルアルコールを添加し、10分間静置後、15,000rpm、4℃にて15分間遠心し、total RNAの沈殿物を得た。得られた沈殿物は、70%エタノールにて洗浄した後、DEPC水に溶解しRNA液とした。1μg分のRNAからTakara PrimeScriptTM RT reagent Kit を用いてcDNAを合成した。得られたcDNAをテンプレートとして、SYBR Green (Takara SYBR Prime Ex Taq II)を使用したリアルタイムPCRを行った。反応条件は、95℃、30秒の初期変性後、95℃、5秒の変性、57℃、15秒のアニーリング、72℃、20秒の伸張であり、合計40サイクル反応させた。プライマーは表3に記載のHas2遺伝子発現確認用プライマーを使用した。結果を図1に示す。
[Test Example 3]
The effect of SDF-1 on the mRNA expression of the hyaluronic acid synthetase gene (Has2) was confirmed using cell experiments using normal human neonatal foreskin skin fibroblasts (NHDF (NB)) and a real-time PCR method. Specifically, NHDF (NB) cells are seeded at 0.5 × 10 5 cells / well in a 24-well plate, and are used at 5 ° C. in a 5% CO 2 environment at 37 ° C. in MEDIUM 106 medium (GIBCO). Culture for 7 days. For the final 24 hours of the 7-day culture period, after dissolving the sample A in MEDIUM 106 medium so as to be 100 nM, 500 nM and 1 μM, respectively, total RNA was recovered and cDNA was synthesized. 0.5 ml of ISOGEN (manufactured by Nippon Gene Co., Ltd.), which is an RNA extraction agent, was added to the cultured cells and allowed to stand for 5 minutes, and then the solubilized cell solution was collected by pipetting in a 1.5 ml tube. After 0.1 ml of chloroform was added to the cell solution and thoroughly stirred, the upper layer (aqueous layer) separated into two layers was collected into a new 1.5 ml tube. To the collected solution, 0.25 ml of 2-propyl alcohol was added, and after standing for 10 minutes, it was centrifuged at 15,000 rpm and 4 ° C. for 15 minutes to obtain a precipitate of total RNA. The obtained precipitate was washed with 70% ethanol and then dissolved in DEPC water to prepare an RNA solution. CDNA was synthesized from 1μg amount of RNA using a Takara PrimeScript TM RT reagent Kit. Real-time PCR using SYBR Green (Takara SYBR Prime Ex Taq II) was performed using the obtained cDNA as a template. The reaction conditions were initial denaturation at 95 ° C. for 30 seconds, denaturation at 95 ° C. for 5 seconds, annealing at 57 ° C. for 15 seconds, and elongation at 72 ° C. for 20 seconds, for a total of 40 cycles of reaction. The primers used were the Has2 gene expression confirmation primers described in Table 3. The results are shown in FIG.
図1により、SDF−1をNHDF(NB)細胞に添加した時に、Has2遺伝子のmRNA発現量は、SDF−1の濃度に依存して有意に亢進された。 According to FIG. 1, when SDF-1 was added to NHDF (NB) cells, the mRNA expression level of the Has2 gene was significantly enhanced depending on the concentration of SDF-1.
表4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沈殿等の問題もなかった。 The hyaluronic acid production promoting beverage formulated as shown in Table 4 was produced by a conventional method. The flavor of the produced beverage was good and there was no problem such as precipitation.
表5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。 Doughs having the formulations shown in Table 5 were produced by the usual method, and then molded and roasted to produce biscuits for promoting hyaluronic acid production.
表6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。 The hyaluronic acid production promoter of the composition shown in Table 6 was manufactured by a conventional method.
表7に示す配合の化粧水を常法により製造した。 The lotion of the composition shown in Table 7 was manufactured by a conventional method.
表8に示す配合のクリームを常法により製造した。 The cream of the composition shown in Table 8 was manufactured by a conventional method.
[試験例5]
実施例4で得られた化粧水及び実施例5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、SDF−1を除いた以外は実施例4及び5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、なおかつ乾燥感を有する成人女性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9に示す。
[Test Example 5]
An actual use test was conducted using the lotion obtained in Example 4 and the cream obtained in Example 5. As a comparative product, the thing of the same composition as Example 4 and 5 was used except having removed SDF-1. Ten adult females with sagging face and small wrinkles and with a sense of dryness are randomly placed in 2 groups (groups A and B), and 20 females with rough skin in their hands. 10 people each randomly divided into 2 groups (C, D groups), 2 g of the lotion of the present invention on the face of group A, 2 g of the lotion of the comparative product on the face of group B, C group 2 g of the cream of the present invention was applied to the fingers of the present invention, and 2 g of the comparative cream was 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 9.
+;10日間塗布後に改善効果あり。
±;10日間塗布後に改善効果なし(10日前と変わらない)。
+; Improves after 10 days application.
±; no improvement after application for 10 days (same as 10 days before).
表9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、シワ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 9, it is demonstrated that the cosmetic lotion of the present invention has remarkable improvement in dryness, wrinkles and the like as compared with the cosmetic lotion of the comparative product, and is excellent in the hyaluronic acid production promoting effect. The In addition, the cream of the present invention also has an improvement in the feeling of dryness, a remarkable improvement in skin roughening, and a natural exacerbation suppressing effect such as skin roughening, as compared with the cream of the comparative product.
[試験例6]
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の飲料を1日1回100g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10に示す。
[Test Example 6]
The beverage of Example 3 was taken 100 g once a day for 20 patients having mild pain caused by osteoarthritis, and a one-year clinical trial was conducted. Joint pain and function are evaluated using the Visual Analog Scale for Pain (VAS) and the Western Ontario and McMaster Universities (WOMAC) Index of Pain, Function, and Stiffness in Arthritic Joints for osteoarthritis. The The results are shown in Table 10.
数値は、平均値±標準偏差(n=20)を示す。
※ は初期値と比較して有意差があることを示す(p<0.05)。
Numerical values indicate mean value ± standard deviation (n = 20).
※ indicates that there is a significant difference compared to the initial value (p <0.05).
本発明は、皮膚の荒れ、シワ、弾性低下、関節機能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サプリメント、飲食品及びヒアルロン酸産生促進用化粧料に関する。 The present invention relates to a hyaluronic acid production promoter, a supplement for hyaluronic acid production promotion, a food and a drink, and a cosmetic for promoting hyaluronic acid production, which are useful for preventing roughening of the skin, wrinkles, elasticity reduction, joint function deterioration and the like.
Claims (4)
The said food-drinks are for food-drinks for hyaluronic acid production promotion of Claim 3 which are for joint function fall prevention.
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