JP4675806B2 - Annexin activator - Google Patents
Annexin activator Download PDFInfo
- Publication number
- JP4675806B2 JP4675806B2 JP2006071970A JP2006071970A JP4675806B2 JP 4675806 B2 JP4675806 B2 JP 4675806B2 JP 2006071970 A JP2006071970 A JP 2006071970A JP 2006071970 A JP2006071970 A JP 2006071970A JP 4675806 B2 JP4675806 B2 JP 4675806B2
- Authority
- JP
- Japan
- Prior art keywords
- annexin
- skin
- components
- formulation
- tocopheryl
- 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.)
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Description
本発明は、皮膚老化の防止および不全角化にともなう肌荒れや毛穴の目立ちの防止、改善に関する技術分野の発明であり、化学式(1)で表される化合物のナトリウム塩及びカリウム塩を有効成分とするアネキシン活性化剤に関する。
The present invention is an invention in the technical field relating to the prevention of skin aging and the prevention of skin roughness and pore conspicuousness due to keratinization, and the improvement thereof. The sodium salt and potassium salt of the compound represented by the chemical formula (1) Annexin activator.
太陽紫外線や大気汚染物質による刺激、もしくは他の多くの原因により引き起こされる皮膚障害は急性期の反応と慢性期の反応に分けられる。例えば、炎症は急性期の代表的な皮膚障害の一つであり、表皮では不全角化が起こり、肌荒れや毛穴が目立つ一因となっている。このような皮膚障害を予防、改善するためには炎症を抑えることが重要であり、ヒスタミンなどの炎症性ケミカルメディエーターの遊離抑制作用を有する物質を外用する処置が一般的となっている。しかしながら、このような処置は、必ずしも効果が十分とはいえず、炎症の根本的な解決方法が望まれている。 Skin damage caused by solar ultraviolet radiation, air pollutants, or many other causes can be divided into acute and chronic reactions. For example, inflammation is one of the typical skin disorders in the acute phase, and keratinization occurs in the epidermis, contributing to conspicuous rough skin and pores. In order to prevent and ameliorate such skin disorders, it is important to suppress inflammation, and treatment using a substance having an inhibitory action on the release of inflammatory chemical mediators such as histamine is generally used. However, such treatment is not always effective, and a fundamental solution for inflammation is desired.
一方、慢性期の皮膚障害として皮膚老化を挙げることができる。皮膚老化の一つであるしわは、太陽紫外線によって加速される加齢変化であり、コラーゲンなどの細胞外マトリックス成分の減少および変性により皮膚弾力の低下が原因となって発生する。このような紫外線に曝された皮膚の真皮では、細胞外マトリックス成分を基質として分解能を有するプロテアーゼの活性化が起こっているため、分解酵素の活性化を根本から制御することが皮膚老化を防止するうえで極めて重要となっている。 On the other hand, skin aging can be mentioned as a skin disorder in the chronic phase. Wrinkles, which are one type of skin aging, are aging changes accelerated by solar ultraviolet rays, and are caused by a decrease in skin elasticity due to a decrease and degeneration of extracellular matrix components such as collagen. In the dermis of skin exposed to such ultraviolet rays, protease with high resolution occurs using extracellular matrix components as a substrate, so fundamentally controlling the activation of degrading enzymes prevents skin aging It is extremely important.
本発明者らは紫外線による皮膚障害の根本原因を遺伝子レベルで解析するため、DNAマイクロアレイによる網羅的な解析を行ったところ、カルシウム結合タンパク質ファミリーの一つであるアネキシンの発現が、紫外線を照射した表皮細胞において著しく低下することを見出した。ほとんどすべての細胞がアネキシンファミリーのタンパク質を少なくとも一つは発現しているといわれているが、その皮膚における生理活性は不明である。アネキシンファミリーに共通した性質としてカルシウム濃度に依存したリン脂質結合能を持ち、炎症性メディエーターであるロイコトリエンやプロスタグランジンの前駆体であるアラキドン酸を産生するホスホリパーゼA2の活性を阻害する。また、アネキシン3および5はプロテインキナーゼCの基質と競合的に拮抗することから、プロテインキナーゼC活性阻害作用を持つ。さらにアネキシンは細胞内から細胞表面に現れ、レセプタータンパクとして機能する。例えば、アネキシン5はコラーゲンに対して高い親和性を持ち、基底膜への細胞接着における役割が注目されている(非特許文献1〜3)。 In order to analyze the root cause of skin damage caused by ultraviolet rays at the gene level, the present inventors conducted a comprehensive analysis using a DNA microarray. As a result, the expression of annexin, one of the calcium binding protein families, was irradiated with ultraviolet rays. It was found to be significantly reduced in epidermal cells. Almost all cells are said to express at least one protein of the annexin family, but their physiological activity in the skin is unknown. As a property common to the annexin family, it has a phospholipid-binding ability depending on the calcium concentration, and inhibits the activity of phospholipase A 2 which produces inflammatory mediator leukotriene and prostaglandin precursor arachidonic acid. Annexins 3 and 5 competitively antagonize the protein kinase C substrate, and thus have an activity of inhibiting protein kinase C activity. Furthermore, annexin appears on the cell surface from inside the cell and functions as a receptor protein. For example, Annexin 5 has a high affinity for collagen, and its role in cell adhesion to the basement membrane has attracted attention (Non-Patent Documents 1 to 3).
アネキシンは皮膚でも同じような機能を持っているものと推測され、ホスホリパーゼA2活性阻害作用を有することから、アラキドン酸カスケードにおける内因性の抑制因子として働いており、皮膚の炎症を制御する重要なタンパク質と考えられる。また、プロテインキナーゼCは細胞外マトリックス成分を分解するプロテアーゼを活性化するなど様々な皮膚障害を誘導するので、その内因性の抑制因子であるアネキシンは紫外線皮膚老化の防御に関わっている可能性が高い。一方、細胞はマトリックス成分のような足場がなければ十分に機能することができないが、アネキシンは細胞とマトリックス成分の接着に必要なタンパク質であり、細胞の機能維持にも重要な調節因子として働いていると考えられる。 Annexin is presumed to have similar functions in the skin, since it has a phospholipase A 2 inhibitory activity, has worked as inhibitors of endogenous in the arachidonic acid cascade, an important to control the inflammation of the skin It is considered a protein. In addition, protein kinase C induces various skin disorders, such as activating proteases that degrade extracellular matrix components, so an annexin that is an endogenous inhibitor may be involved in the protection of ultraviolet skin aging. high. On the other hand, cells cannot function adequately without a scaffold like matrix components, but annexin is a protein necessary for adhesion between cells and matrix components, and acts as an important regulator for maintaining cell functions. It is thought that there is.
本発明者らはヒト表皮細胞において、ほとんどすべてのアネキシンファミリーが発現していることを明らかにし、さらに紫外線によってこれらの遺伝子の発現が低下することを見出した。これらの結果は、肌荒れや毛穴の目立ちなど炎症が原因と考えられる皮膚症状の予防、改善にアネキシンが有用であることを示唆するものであり、アネキシンの老化防止用組成物への応用が期待される。 The present inventors have clarified that almost all annexin families are expressed in human epidermal cells, and further found that the expression of these genes is reduced by ultraviolet rays. These results suggest that annexins are useful for the prevention and improvement of skin symptoms thought to be caused by inflammation such as rough skin and conspicuous pores, and application of annexins to anti-aging compositions is expected. The
しかしながら、アネキシンを直接製剤化することは、安定性や安全性、効果の面から考えても不可能であり、なにより不経済である。このため、皮膚内でアネキシンを活性化もしくは紫外線によって発現低下したアネキシンを回復する方法が良く、特にアネキシン活性化剤の開発が望まれている。 However, it is impossible to formulate annexin directly from the viewpoint of stability, safety, and effect, and it is uneconomical. For this reason, a method for activating annexin in the skin or recovering an annexin whose expression is reduced by ultraviolet rays is good, and development of an annexin activator is particularly desired.
このような事情により、本発明者らは鋭意研究検討した結果、化学式(1)で表される化合物のナトリウム塩及びカリウム塩が安定で、優れたアネキシン活性化効果を示すことを見出し、本発明を完成するに至った。 Under such circumstances, the present inventors have intensively studied and found that the sodium salt and potassium salt of the compound represented by the chemical formula (1) are stable and show an excellent annexin activating effect. It came to complete.
本発明の化学式(1)は、天然由来のものを利用することができるほか、トコフェロールから常法により合成でき、下記の文献も参考にできる。 The chemical formula (1) of the present invention can be naturally derived, or can be synthesized from tocopherol by a conventional method, and the following documents can also be referred to.
また、本発明においては化学式(1)で表される化合物のナトリウム塩及びカリウム塩が用いられる。 In the present invention, the sodium salt and potassium salt of the compound represented by the chemical formula (1) are used.
本発明のアネキシン活性化剤は、医薬品、医薬部外品、化粧品または食品のいずれにも用いることができ、その剤型としては、例えば、散剤、丸剤、錠剤、注射剤、座剤、乳剤、カプセル剤、顆粒剤、液剤(チンキ剤、流エキス剤、酒精剤、懸濁剤、リモナーデ剤等を含む)、化粧水、クリーム、乳液、ゲル剤、エアゾール剤、パック、洗浄剤、浴用剤、ファンデーション、打粉、口紅、軟膏、パップ剤、ペースト剤、プラスター剤、エッセンス、錠菓、飲料等が挙げられる。また、本発明の効果を損なわない範囲内で、通常の化粧品、医薬部外品、医薬品等に用いられる各種成分、例えば油性成分、乳化剤、保湿剤、増粘剤、薬効成分、防腐剤、顔料、粉体、pH調整剤、紫外線吸収剤、抗酸化剤、香料等を適宜配合することができる。 The annexin activator of the present invention can be used for any of pharmaceuticals, quasi drugs, cosmetics or foods. Examples of the dosage form include powders, pills, tablets, injections, suppositories, and emulsions. , Capsules, granules, liquids (including tinctures, fluid extracts, spirits, suspensions, limonades, etc.), lotions, creams, emulsions, gels, aerosols, packs, cleaning agents, bath preparations , Foundation, powder, lipstick, ointment, poultice, paste, plaster, essence, tablet confectionery, beverage and the like. In addition, various components used for normal cosmetics, quasi drugs, pharmaceuticals, etc., for example, oily ingredients, emulsifiers, moisturizers, thickeners, medicinal ingredients, preservatives, pigments, as long as the effects of the present invention are not impaired. , Powders, pH adjusters, ultraviolet absorbers, antioxidants, fragrances and the like can be appropriately blended.
油性成分としては、例えば流動パラフィン、ワセリン、マイクロクリスタリンワックス、スクワラン、ホホバ油、ミツロウ、カルナウバロウ、ラノリン、オリーブ油、ヤシ油、高級アルコール、脂肪酸、高級アルコールと脂肪酸のエステル、シリコーン油等が挙げられる。乳化剤としては、例えばポリオキシエチレンアルキルエーテル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油等の非イオン界面活性剤、ステアロイル乳酸ナトリウム等のアニオン界面活性剤、大豆リン脂質等の両性界面活性剤、塩化アルキルトリメチルアンモニウム等のカチオン界面活性剤が挙げられる。保湿剤としては、例えばグリセリン、ソルビトール、キシリトール、マルチトール、プロピレングリコール、ポリエチレングリコール、1,3−ブチレングリコールなどが挙げられる。増粘剤としては、例えばカルボキシビニルポリマー、キサンタンガム、メチルセルロース、ポリビニルピロリドン、ゼラチン、ベントナイト等の粘土鉱物等が挙げられる。薬効成分としては、例えば各種ビタミンおよびその誘導体、アラントイン、グリチルリチン酸およびその誘導体、各種動植物抽出物等が挙げられる。 Examples of the oil component include liquid paraffin, petrolatum, microcrystalline wax, squalane, jojoba oil, beeswax, carnauba wax, lanolin, olive oil, coconut oil, higher alcohol, fatty acid, ester of higher alcohol and fatty acid, and silicone oil. Examples of the emulsifier include nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, and polyoxyethylene hydrogenated castor oil. And anionic surfactants such as sodium stearoyl lactate, amphoteric surfactants such as soybean phospholipid, and cationic surfactants such as alkyltrimethylammonium chloride. Examples of the humectant include glycerin, sorbitol, xylitol, maltitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol and the like. Examples of the thickener include clay minerals such as carboxyvinyl polymer, xanthan gum, methyl cellulose, polyvinyl pyrrolidone, gelatin, and bentonite. Examples of medicinal ingredients include various vitamins and derivatives thereof, allantoin, glycyrrhizic acid and derivatives thereof, and various animal and plant extracts.
本発明のアネキシン活性化剤中に配合される化合物の量は、剤型や期待する効果の程度により異なるが、通常0.001重量%以上、好ましくは0.1〜50重量%程度配合するのがよい。0.001重量%未満では十分な効果は望みにくい場合があり、50重量%を超えて配合した場合、効果の増強は認められにくく不経済である。 The amount of the compound to be blended in the annexin activator of the present invention varies depending on the dosage form and the expected effect, but is usually 0.001% by weight or more, preferably about 0.1 to 50% by weight. Is good. If it is less than 0.001% by weight, a sufficient effect may be difficult to expect, and if it exceeds 50% by weight, an increase in the effect is hardly recognized and it is uneconomical.
本発明の新規な薬効成分は、アネキシン活性化効果を有し、皮膚の炎症を制御して、角化不全にともなう肌荒れや毛穴の目立ちを防止、改善する。さらに、プロテアーゼの活性化を抑え、細胞の機能維持効果を持つので、皮膚老化を防止する。 The novel medicinal component of the present invention has an annexin activating effect, controls skin inflammation, and prevents or improves rough skin and conspicuous pores due to keratinization failure. Furthermore, it suppresses the activation of protease and has the effect of maintaining the function of cells, thus preventing skin aging.
次に本発明による効果を具体的な実施例を挙げ説明する。これらの実施例は効果を具体的に説明するもので、発明の範囲を限定するものではない。実施例中の配合量は重量%である。 Next, the effects of the present invention will be described with specific examples. These examples specifically illustrate the effect and do not limit the scope of the invention. The compounding quantity in an Example is weight%.
本発明の薬効成分は、処方例として下記の製剤化を行うことができる。 The medicinal component of the present invention can be formulated as a formulation example as follows.
処方例−1 飲料
処方 配合量(%)
1.dl−α−トコフェリルリン酸ナトリウム 2.0
2.クエン酸 0.7
3.果糖ブドウ糖液糖 60.0
4.香料 適量
5.精製水にて全量を100とする。
[製法]5に1〜4を加え、攪拌溶解してろ過し、加熱殺菌後、50mLガラス瓶に充填する。
Formulation Example-1 Beverage Formulation Blending amount (%)
1. dl-α-Tocopheryl sodium phosphate 2.0
2. Citric acid 0.7
3. Fructose dextrose liquid sugar 60.0
4). Perfume appropriate amount 5. Bring the total amount to 100 with purified water.
[Production method] Add 1 to 4 to 5, dissolve by stirring, filter, heat sterilize, and fill into a 50 mL glass bottle.
処方例−2 飲料
処方 配合量(%)
1.d−α−トコフェリルリン酸ナトリウム 1.0
2.クエン酸 0.7
3.ショ糖 60.0
4.香料 適量
5.精製水にて全量を100とする。
[製法]5に1〜4を加え、攪拌溶解してろ過し、加熱殺菌後、50mLガラス瓶に充填する。
Formulation Example-2 Beverage Formulation Blending amount (%)
1. d-α-Tocopheryl sodium phosphate 1.0
2. Citric acid 0.7
3. Sucrose 60.0
4). Perfume appropriate amount 5. Bring the total amount to 100 with purified water.
[Production method] Add 1 to 4 to 5, dissolve by stirring, filter, heat sterilize, and fill into a 50 mL glass bottle.
処方例−3 顆粒剤
処方 配合量(%)
1.dl−α−トコフェリルリン酸ジナトリウム 3.0
2.還元麦芽糖水あめ 38.0
3.微結晶セルロース 59.0
[製法]成分1〜3に70%エタノールを適量加えて練和し、押出し造粒した後、乾燥して顆粒剤を得る。
Formulation Example-3 Granule Formulation Blending amount (%)
1. dl-α-Tocopheryl phosphate disodium 3.0
2. Reduced maltose syrup 38.0
3. Microcrystalline cellulose 59.0
[Manufacturing method] An appropriate amount of 70% ethanol is added to components 1 to 3, kneaded, extruded and granulated, and dried to obtain granules.
処方例−4 錠剤
処方 配合量(%)
1.d−α−トコフェリルリン酸カリウム 4.0
2.乾燥コーンスターチ 25.0
3.還元麦芽糖水あめ 20.0
4.粉糖 48.0
5.ショ糖脂肪酸エステル 3.0
[製法]成分1〜4に70%エタノールを適量加えて練和し、押出し造粒した後、乾燥して顆粒を得る。顆粒に成分5を加えて打錠し、1錠0.52gの錠剤を得る。
Formulation Example-4 Tablet Formulation Blending amount (%)
1. d-α-Tocopheryl potassium phosphate 4.0
2. Dried corn starch 25.0
3. Reduced maltose syrup 20.0
4). Powdered sugar 48.0
5. Sucrose fatty acid ester 3.0
[Manufacturing method] An appropriate amount of 70% ethanol is added to components 1 to 4, kneaded, extruded and granulated, and dried to obtain granules. Ingredient 5 is added to the granules and tableted to give 0.52 g tablets.
処方例−5 錠菓
処方 配合量(%)
1.dl−α−トコフェリルリン酸ナトリウム 0.9
2.乾燥コーンスターチ 51.1
3.エリスリトール 39.0
4.クエン酸 5.0
5.ショ糖脂肪酸エステル 3.0
6.香料 1.0
[製法]成分1〜4に水を適量加えて練和し、押出し造粒した後、乾燥して顆粒を得る。顆粒に成分5及び6を加えて打錠し、1個1.0gの錠菓を得る。
Formulation example-5 Tablet confection Formulation amount (%)
1. dl-α-Tocopheryl sodium phosphate 0.9
2. Dried corn starch 51.1
3. Erythritol 39.0
4). Citric acid 5.0
5. Sucrose fatty acid ester 3.0
6). Fragrance 1.0
[Manufacturing method] An appropriate amount of water is added to components 1 to 4, kneading, extrusion granulation, and drying to obtain granules. Ingredients 5 and 6 are added to the granules and tableted to obtain 1.0 g of tablet confectionery.
処方例−6 カプセル剤
処方 配合量(%)
1.dl−α−トコフェリルリン酸ナトリウム 15.0
2.セルロース 85.0
[製法]成分1および2を混合し、2号硬カプセルに250mg充填してカプセル剤を得る。
Formulation Example-6 Capsule Formulation Formulation Amount (%)
1. dl-α-tocopheryl sodium phosphate 15.0
2. Cellulose 85.0
[Manufacturing method] Components 1 and 2 are mixed, and a No. 2 hard capsule is filled with 250 mg to obtain a capsule.
処方例−7 クリーム 配合量(%)
処方
1.dl−α−トコフェリルリン酸ナトリウム 2.0
2.スクワラン 5.5
3.オリーブ油 3.0
4.ステアリン酸 2.0
5.ミツロウ 2.0
6.ミリスチン酸オクチルドデシル 3.5
7.ポリオキシエチレンセチルエーテル(20E.O.)3.0
8.ベヘニルアルコール 1.5
9.モノステアリン酸グリセリン 2.5
10.香料 0.1
11.1,3−ブチレングリコール 8.5
12.パラオキシ安息香酸エチル 0.05
13.パラオキシ安息香酸メチル 0.2
14.精製水にて全量を100とする
[製法]成分2〜9を加熱溶解して混合し、70℃に保ち油相とする。成分1および11〜14を加熱溶解して混合し、75℃に保ち水相とする。油相に水相を加えて乳化して、かき混ぜながら冷却し、45℃で成分10を加え、さらに30℃まで冷却して製品とする。
Formulation Example-7 Cream Amount (%)
Formula 1. dl-α-Tocopheryl sodium phosphate 2.0
2. Squalane 5.5
3. Olive oil 3.0
4). Stearic acid 2.0
5. Beeswax 2.0
6). Octyldodecyl myristate 3.5
7). Polyoxyethylene cetyl ether (20E.O.) 3.0
8). Behenyl alcohol 1.5
9. Glycerol monostearate2.5
10. Fragrance 0.1
11.1,3-butylene glycol 8.5
12 Ethyl paraoxybenzoate 0.05
13. Methyl paraoxybenzoate 0.2
14 Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 9 are heated and dissolved and mixed, and kept at 70 ° C to obtain an oil phase. Ingredients 1 and 11 to 14 are dissolved by heating and mixed, and kept at 75 ° C. to obtain an aqueous phase. The aqueous phase is added to the oil phase to emulsify, and the mixture is cooled while stirring. The component 10 is added at 45 ° C., and further cooled to 30 ° C. to obtain a product.
比較例−1 従来のクリーム
処方例−7において、dl−α−トコフェリルリン酸ナトリウムを精製水に置き換えたものを従来のクリームとした。
Comparative Example-1 Conventional Cream In Formulation Example-7, a product obtained by replacing dl-α-tocopheryl phosphate with purified water was used as a conventional cream.
処方例−8 化粧水 配合量(%)
処方
1.d−α−トコフェリルリン酸ナトリウム 0.1
2.1,3−ブチレングリコール 8.0
3.グリセリン 2.0
4.キサンタンガム 0.02
5.クエン酸 0.01
6.クエン酸ナトリウム 0.1
7.エタノール 5.0
8.パラオキシ安息香酸メチル 0.1
9.ポリオキシエチレン硬化ヒマシ油(40E.O.) 0.1
10.香料 適量
11.精製水にて全量を100とする
[製法]成分1〜6および11と、成分7〜10をそれぞれ均一に溶解し、両者を混合し濾過して製品とする。
Formulation example-8 lotion amount (%)
Formula 1. d-α-Tocopheryl sodium phosphate 0.1
2. 1,3-butylene glycol 8.0
3. Glycerin 2.0
4). Xanthan gum 0.02
5. Citric acid 0.01
6). Sodium citrate 0.1
7). Ethanol 5.0
8). Methyl paraoxybenzoate 0.1
9. Polyoxyethylene hydrogenated castor oil (40E.O.) 0.1
10. Perfume proper amount11. Make the total volume 100 with purified water
[Production method] Components 1 to 6 and 11 and components 7 to 10 are uniformly dissolved, mixed and filtered to obtain a product.
処方例−9 乳液 配合量(%)
処方
1.dl−α−トコフェリルリン酸ジナトリウム 0.5
2.スクワラン 5.0
3.オリーブ油 5.0
4.ホホバ油 5.0
5.セタノール 1.5
6.モノステアリン酸グリセリン 2.0
7.ポリオキシエチレンセチルエーテル(20E.O.)3.0
8.ポリオキシエチレンソルビタン
モノオレエート(20E.O.) 2.0
9.香料 0.1
10.プロピレングリコール 1.0
11.グリセリン 2.0
12.パラオキシ安息香酸メチル 0.2
13.精製水にて全量を100とする
[製法]成分2〜8を加熱溶解して混合し、70℃に保ち油相とする。成分1および10〜13を加熱溶解して混合し、75℃に保ち水相とする。油相に水相を加えて乳化して、かき混ぜながら冷却し、45℃で成分9を加え、さらに30℃まで冷却して製品とする。
Formulation Example-9 Emulsion Formulation Amount (%)
Formula 1. dl-α-Tocopheryl phosphate disodium 0.5
2. Squalane 5.0
3. Olive oil 5.0
4). Jojoba oil 5.0
5. Cetanol 1.5
6). Glycerol monostearate 2.0
7). Polyoxyethylene cetyl ether (20E.O.) 3.0
8). Polyoxyethylene sorbitan monooleate (20E.O.) 2.0
9. Fragrance 0.1
10. Propylene glycol 1.0
11. Glycerin 2.0
12 Methyl paraoxybenzoate 0.2
13. Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 8 are dissolved by heating and mixed, and kept at 70 ° C to obtain an oil phase. Ingredients 1 and 10-13 are dissolved by heating and mixed, and kept at 75 ° C. to form an aqueous phase. The aqueous phase is added to the oil phase to emulsify, and the mixture is cooled while stirring.
処方例−10 ゲル剤 配合量(%)
処方
1.d−α−トコフェリルリン酸カリウム 0.1
2.エタノール 5.0
3.パラオキシ安息香酸メチル 0.1
4.ポリオキシエチレン硬化ヒマシ油 0.1
5.香料 適量
6.1,3−ブチレングリコール 5.0
7.グリセリン 5.0
8.キサンタンガム 0.1
9.カルボキシビニルポリマー 0.2
10.水酸化カリウム 0.2
11.精製水にて全量を100とする
[製法]成分2〜5と、成分1および6〜11をそれぞれ均一に溶解し、両者を混合して製品とする。
Formulation Example -10 Gel formulation (%)
Formula 1. d-α-Tocopheryl potassium phosphate 0.1
2. Ethanol 5.0
3. Methyl paraoxybenzoate 0.1
4). Polyoxyethylene hydrogenated castor oil 0.1
5. Perfume appropriate amount 6.1,3-butylene glycol 5.0
7). Glycerin 5.0
8). Xanthan gum 0.1
9. Carboxyvinyl polymer 0.2
10. Potassium hydroxide 0.2
11. Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 5 and components 1 and 6 to 11 are uniformly dissolved and mixed to obtain a product.
処方例−11 軟膏 配合量(%)
処方
1.dl−α−トコフェリルリン酸ナトリウム 1.0
2.ポリオキシエチレンセチルエーテル(30E.O.)2.0
3.モノステアリン酸グリセリン 10.0
4.流動パラフィン 5.0
5.セタノール 6.0
6.パラオキシ安息香酸メチル 0.1
7.プロピレングリコール 10.0
8.精製水にて全量を100とする
[製法]成分2〜5を加熱溶解して混合し、70℃に保ち油相とする。成分1および6〜8を加熱溶解して混合し、75℃に保ち水相とする。油相に水相を加えて乳化し、かき混ぜながら30℃まで冷却して製品とする。
Formulation Example-11 Ointment Amount (%)
Formula 1. dl-α-tocopheryl sodium phosphate 1.0
2. Polyoxyethylene cetyl ether (30E.O.) 2.0
3. Glycerol monostearate 10.0
4). Liquid paraffin 5.0
5. Cetanol 6.0
6). Methyl paraoxybenzoate 0.1
7). Propylene glycol 10.0
8). Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 5 are dissolved by heating and mixed, and kept at 70 ° C to obtain an oil phase. Ingredients 1 and 6 to 8 are dissolved by heating and mixed, and kept at 75 ° C. to form an aqueous phase. The aqueous phase is added to the oil phase to emulsify, and the product is cooled to 30 ° C. with stirring to obtain a product.
処方例−12 パック 配合量(%)
処方
1.dl−α−トコフェリルリン酸カリウム 0.1
2.ポリビニルアルコール 12.0
3.エタノール 5.0
4.1,3−ブチレングリコール 8.0
5.パラオキシ安息香酸メチル 0.2
6.パラオキシエチレン硬化ヒマシ油(20E.O.) 0.5
7.クエン酸 0.1
8.クエン酸ナトリウム 0.3
9.香料 適量
10.精製水にて全量を100とする
[製法]成分1〜10を均一に溶解し製品とする。
Formulation example -12 pack compounding amount (%)
Formula 1. dl-α-Tocopheryl potassium phosphate 0.1
2. Polyvinyl alcohol 12.0
3. Ethanol 5.0
4.1,3-Butylene glycol 8.0
5. Methyl paraoxybenzoate 0.2
6). Paraoxyethylene hydrogenated castor oil (20 EO) 0.5
7). Citric acid 0.1
8). Sodium citrate 0.3
9. Perfume appropriate amount10. Make the total volume 100 with purified water
[Production Method] Components 1 to 10 are uniformly dissolved to obtain a product.
処方例−13 ファンデーション 配合量(%)
処方
1.d−α−トコフェリルリン酸ジナトリウム 1.0
2.ステアリン酸 2.4
3.ポリオキシエチレンソルビタン
モノステアレート(20E.O.) 1.0
4.ポリオキシエチレンセチルエーテル(20E.O.)2.0
5.セタノール 1.0
6.液状ラノリン 2.0
7.流動パラフィン 3.0
8.ミリスチン酸イソプロピル 6.5
9.パラオキシ安息香酸ブチル 0.1
10.カルボキシメチルセルロースナトリウム 0.1
11.ベントナイト 0.5
12.プロピレングリコール 4.0
13.トリエタノールアミン 1.1
14.パラオキシ安息香酸メチル 0.2
15.二酸化チタン 8.0
16.タルク 4.0
17.ベンガラ 1.0
18.黄酸化鉄 2.0
19.香料 適量
20.精製水にて全量を100とする
[製法]成分2〜9を加熱溶解し、80℃に保ち油相とする。成分20に成分10をよく膨潤させ、続いて、成分1および11〜14を加えて均一に混合する。これに粉砕機で粉砕混合した成分15〜18を加え、冷却し、45℃で成分19を加え、かき混ぜながら30℃まで冷却して製品とする。
Formulation Example-13 Foundation Formulation (%)
Formula 1. d-α-Tocopheryl phosphate disodium 1.0
2. Stearic acid 2.4
3. Polyoxyethylene sorbitan monostearate (20E.O.) 1.0
4). Polyoxyethylene cetyl ether (20E.O.) 2.0
5. Cetanol 1.0
6). Liquid lanolin 2.0
7). Liquid paraffin 3.0
8). Isopropyl myristate 6.5
9. Butyl paraoxybenzoate 0.1
10. Sodium carboxymethylcellulose 0.1
11. Bentonite 0.5
12 Propylene glycol 4.0
13. Triethanolamine 1.1
14 Methyl paraoxybenzoate 0.2
15. Titanium dioxide 8.0
16. Talc 4.0
17. Bengala 1.0
18. Yellow iron oxide 2.0
19. Perfume proper amount20. Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 9 are heated and dissolved and kept at 80 ° C to obtain an oil phase. Swell component 10 well with component 20, then add components 1 and 11-14 and mix uniformly. To this, components 15 to 18 pulverized and mixed with a pulverizer are added, cooled, component 19 is added at 45 ° C., and cooled to 30 ° C. with stirring to obtain a product.
処方例−14 浴用剤 配合量(%)
処方
1.dl−α−トコフェリルリン酸ナトリウム 1.0
2.炭酸水素ナトリウム 50.0
3.黄色202号 適量
4.香料 適量
5.無水硫酸ナトリウムにて全量を100とする
[製法]成分1〜5を均一に混合し製品とする。
Formulation Example-14 Bath Agent Formulation (%)
Formula 1. dl-α-tocopheryl sodium phosphate 1.0
2. Sodium bicarbonate 50.0
3. Yellow 202 No. 4 Perfume appropriate amount 5. Make the total amount 100 with anhydrous sodium sulfate
[Production method] Components 1 to 5 are uniformly mixed to obtain a product.
次に、本発明の効果を詳細に説明するため、実験例を挙げる。 Next, experimental examples will be given to explain the effects of the present invention in detail.
実験例−1 アネキシン5mRNAの発現解析
コンフルエントな状態の正常ヒト角化細胞に、試料を50μMとなるように添加し、24時間後に総RNAの抽出を行った。総RNAを基にRT−PCR法によりアネキシン5mRNA発現量の測定を行った。RT−PCR法はTaKaRa RNA PCR Kit(AMV)Ver.2.1を用いた。また、内部標準としてはGAPDHを用いた。その他の操作は定められた方法に従い、PCR反応液をアガロースゲル電気泳動に供し、アネキシン5、GAPDHのmRNA発現をバンドとして確認した。これらのバンドをポラロイドカメラにて撮影してデンシトメーターを用いて定量化し、アネキシン5mRNAの発現量を内部標準であるGAPDHmRNA発現量に対する割合として求め、対照を1とした場合の発現比で表した。その結果、表1に示すように、化学式(1)で表される化合物のナトリウム塩及びカリウム塩はアネキシン5mRNAの発現を亢進した。
Experimental Example 1 Expression Analysis of Annexin 5 mRNA A sample was added to normal human keratinocytes in a confluent state so as to be 50 μM, and total RNA was extracted 24 hours later. Annexin 5 mRNA expression level was measured by RT-PCR method based on total RNA. The RT-PCR method is described in TaKaRa RNA PCR Kit (AMV) Ver. 2.1 was used. GAPDH was used as an internal standard. Other operations were carried out according to a predetermined method, and the PCR reaction solution was subjected to agarose gel electrophoresis, and the mRNA expression of annexin 5 and GAPDH was confirmed as a band. These bands were photographed with a polaroid camera and quantified using a densitometer, and the expression level of annexin 5 mRNA was determined as a ratio with respect to the GAPDH mRNA expression level as an internal standard, and expressed as an expression ratio when the control was 1. . As a result, as shown in Table 1, the sodium salt and potassium salt of the compound represented by the chemical formula (1) enhanced the expression of annexin 5 mRNA.
実験例−2 紫外線照射に対するアネキシン5の防御効果
コンフルエントな状態の正常ヒト角化細胞に、試料を10μMとなるように添加した。24時間後に、培養液をPBSに置換し、UVBを30mJ/cm2照射した。照射3時間後に総RNAを抽出し、総RNAを基にRT−PCR法によりアネキシン5mRNA発現量の測定を行った。RT−PCR法はTaKaRa RNA PCR Kit(AMV)Ver.2.1を用いた。また、内部標準としてはGAPDHを用いた。その他の操作は定められた方法に従い、PCR反応液をアガロースゲル電気泳動に供し、アネキシン5、GAPDHのmRNA発現をバンドとして確認した。これらのバンドをポラロイドカメラにて撮影してデンシトメーターを用いて定量化し、アネキシン5mRNAの発現量を内部標準であるGAPDHmRNA発現量に対する割合として求め、対照を1とした場合の発現比で表した。その結果、表2に示すように、化学式(1)で表される化合物のナトリウム塩及びカリウム塩は、紫外線によるアネキシン5mRNAの発現低下を抑制し、防御効果を示した。
Experimental Example-2 Protective effect of Annexin 5 against ultraviolet irradiation A sample was added to a normal human keratinocyte in a confluent state so as to be 10 μM. After 24 hours, the culture medium was replaced with PBS, and UVB was irradiated with 30 mJ / cm 2 . Total RNA was extracted 3 hours after irradiation, and the expression level of annexin 5 mRNA was measured by RT-PCR based on the total RNA. The RT-PCR method is described in TaKaRa RNA PCR Kit (AMV) Ver. 2.1 was used. GAPDH was used as an internal standard. Other operations were carried out according to a predetermined method, and the PCR reaction solution was subjected to agarose gel electrophoresis, and the mRNA expression of annexin 5 and GAPDH was confirmed as a band. These bands were photographed with a polaroid camera and quantified using a densitometer, and the expression level of annexin 5 mRNA was determined as a ratio with respect to the GAPDH mRNA expression level as an internal standard, and expressed as an expression ratio when the control was 1. . As a result, as shown in Table 2, the sodium salt and potassium salt of the compound represented by the chemical formula (1) suppressed the decrease in the expression of annexin 5 mRNA due to ultraviolet rays and exhibited a protective effect.
実験例−3 使用試験
処方例−7のクリームおよび比較例−1のクリームを用いて、各々女性30人(21−47才)を対象に2ヶ月間の使用試験を行った。使用後、皮膚の乾燥状態、肌のキメの乱れ、くすみ、毛穴の目立ちの改善効果についてアンケート調査を行って、美容効果を判定した。アンケートの評価基準は、有効なものを「優」、やや有効なものを「良」、わずかに有効なものを「可」、無効なものを「不可」として評価した。
Experimental Example-3 Use Test Using the cream of Prescription Example-7 and the cream of Comparative Example-1, a use test for 2 months was conducted for 30 women (21-47 years old). After use, a questionnaire survey was conducted on the effect of improving the dryness of the skin, skin irregularities, dullness, and conspicuous pores to determine the cosmetic effect. The evaluation criteria of the questionnaire were evaluated as “excellent” for valid, “good” for slightly effective, “good” for slightly effective, and “impossible” for invalid.
これらの結果を表3に示した。本発明のアネキシン活性化剤を含有した組成物は、肌荒れや毛穴の目立ち等の防止、改善効果に優れていた。なお、試験期間中皮膚トラブルは一人もなく、安全性においても問題なかった。 These results are shown in Table 3. The composition containing the annexin activator of the present invention was excellent in preventing and improving rough skin and conspicuous pores. During the test period, there was no skin problem and there was no problem with safety.
処方例1〜6、8〜14についても同様な試験を行ったところ、いずれも安全で優れた皮膚の老化防止効果を示した。 When similar tests were conducted on Formulation Examples 1 to 6 and 8 to 14, all showed safe and excellent skin aging prevention effects.
本発明の化学式(1)で表される化合物のナトリウム塩及びカリウム塩は、皮膚における優れたアネキシン活性化効果を有し、皮膚の不全角化にともなう乾燥、キメの乱れ、くすみ、毛穴の目立ちなどの症状の防止、改善を目的とする医薬品、医薬部外品、化粧品または食品に配合することが可能である。 The sodium salt and potassium salt of the compound represented by the chemical formula (1) of the present invention have an excellent annexin activating effect on the skin, and dryness, texture disorder, dullness, and conspicuous pores associated with skin keratinization. It can be incorporated into pharmaceuticals, quasi-drugs, cosmetics or foods for the purpose of preventing or improving the symptoms.
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JP4446010B1 (en) | 2008-12-24 | 2010-04-07 | 株式会社ファンケル | Evaluation method of resistance to skin sunburn by ultraviolet rays. |
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