JP2023110910A - Tight junction formation promoter, epithelial barrier function improver, and pharmaceutical, quasi drug, food and drink, and cosmetic - Google Patents
Tight junction formation promoter, epithelial barrier function improver, and pharmaceutical, quasi drug, food and drink, and cosmetic Download PDFInfo
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- JP2023110910A JP2023110910A JP2023011933A JP2023011933A JP2023110910A JP 2023110910 A JP2023110910 A JP 2023110910A JP 2023011933 A JP2023011933 A JP 2023011933A JP 2023011933 A JP2023011933 A JP 2023011933A JP 2023110910 A JP2023110910 A JP 2023110910A
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Landscapes
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Abstract
Description
本技術は、タイトジャンクション形成促進剤に関する。より詳細には、タイトジャンクション形成促進剤、および上皮バリア機能改善剤、並びに、前記タイトジャンクション形成促進剤、または前記上皮バリア機能改善剤を含有する医薬品、医薬部外品、飲食品および化粧料に関する。 The present technology relates to a tight junction formation promoter. More specifically, it relates to tight junction formation promoters, epithelial barrier function improving agents, and pharmaceuticals, quasi-drugs, food and drink, and cosmetics containing said tight junction formation promoters or said epithelial barrier function improving agents. .
タイトジャンクションは、細胞同士を接着させる細胞間結合のことで、隣り合う上皮細胞をつなぎ、さまざまな分子が細胞間を通過するのを防いでいる。気管、腸管、血管などの細胞ではタイトジャンクションが発達し、管の内外に存在するイオン・水などが細胞間隙を介して透過するのを防ぐためのバリアとして働いている。皮膚の上皮細胞にもタイトジャンクションが存在し、皮膚のバリア機能を担っている。 Tight junctions are the intercellular junctions that hold cells together, connecting adjacent epithelial cells and preventing the passage of various molecules between cells. Tight junctions develop in the cells of the trachea, intestinal tract, blood vessels, etc., and act as a barrier to prevent ions, water, etc. existing inside and outside the tubes from permeating through intercellular spaces. Tight junctions also exist in epithelial cells of the skin and are responsible for the barrier function of the skin.
皮膚のタイトジャンクションは、物理的な皮膚バリアとして働くことのみならず、表皮の分化等についても影響することが明らかになっており、炎症や紫外線などの環境因子によってその構造が損傷を受けることからも、タイトジャンクションの状態を良好に保つことは、健やかな肌状態を保つために重要である。 Tight junctions in the skin not only function as a physical skin barrier, but also have been shown to affect epidermal differentiation, etc., and environmental factors such as inflammation and ultraviolet rays can damage the structure. Also, keeping tight junctions in good condition is important for maintaining healthy skin conditions.
近年、タイトジャンクションの形成を促進するための技術が開発されつつある。例えば、特許文献１には、ユーカリ葉抽出物からなる組成物が、優れたタイトジャンクション形成促進剤として利用することができる技術が開示されている。また、特許文献２には、フェニルエチルアミン誘導体又はシネフリンを有効成分とするタイトジャンクション形成促進剤、タイトジャンクションタンパク質１発現誘導剤、タイトジャンクションタンパク質１細胞膜局在誘導剤及び該物質を含む医薬品、飲食品、皮膚外用剤が開示されている。 In recent years, techniques have been developed to promote the formation of tight junctions. For example, Patent Document 1 discloses a technique in which a composition comprising a eucalyptus leaf extract can be used as an excellent tight junction formation promoter. In addition, Patent Document 2 discloses a tight junction formation promoter, a tight junction protein 1 expression inducer, a tight junction protein 1 cell membrane localization inducer, and pharmaceuticals, foods and beverages containing the substance, which contain a phenylethylamine derivative or synephrine as an active ingredient. , a topical skin preparation is disclosed.
上記のとおり、タイトジャンクションの形成を促進するための技術の開発が進められているが、更なる技術が期待されているのが実情である。そこで、本技術では、タイトジャンクションの形成を促進するための新規な技術を提供することを主目的とする。 As described above, the development of techniques for promoting the formation of tight junctions is progressing, but the actual situation is that further techniques are expected. Therefore, the main object of the present technology is to provide a novel technology for promoting the formation of tight junctions.
本願発明者らは、タイトジャンクションの形成に効果を有する物質の鋭意探求を行ったところ、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物にタイトジャンクション形成を促進させ、上皮バリア機能を改善する効果があることを見出した。また、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物の成分にも着目し、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物にアクテオシド、およびイソアクテオシドが含まれること、および、これらにタイトジャンクション形成を促進させ、上皮バリア機能を改善する効果があることを見出し、本技術を完成させた。 The inventors of the present application have made an intensive search for a substance that has an effect on the formation of tight junctions, and found that the extract of Magnolia champaca (Michelia champaca) has the effect of promoting the formation of tight junctions and improving the epithelial barrier function. found that there is We also focused on the components of the extract of Magnolia champaca (Michelia champaca), and found that the extract of Magnolia champaca (Michelia champaca) contains acteoside and isoacteoside, and that they form tight junctions. and found that it has the effect of improving the epithelial barrier function, and completed this technology.
すなわち、本技術では、まず、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物、アクテオシド、およびイソアクテオシドから選択される１以上の物質を有効成分とする、タイトジャンクション形成促進剤を提供する。
また、本技術では、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物、アクテオシド、およびイソアクテオシドから選択される１以上の物質を有効成分とする、上皮バリア機能改善剤を提供する。
That is, the present technology first provides a tight junction formation accelerator containing, as an active ingredient, one or more substances selected from an extract of Magnolia champaca (Michelia champaca), acteoside, and isoacteoside.
In addition, the present technology provides an epithelial barrier function-improving agent containing, as an active ingredient, one or more substances selected from an extract of Magnolia champaca (Michelia champaca), acteoside, and isoacteoside.
本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤は、医薬品、医薬部外品、飲食品および化粧料に用いることができる。 The tight junction formation promoter and the epithelial barrier function improving agent according to the present technology can be used for pharmaceuticals, quasi-drugs, food and drink, and cosmetics.
本技術によれば、タイトジャンクションの形成を促進するための新規な技術を提供することができる。なお、本技術の効果は、ここに記載された効果に限定されず、本明細書内に記載されたいずれかの効果であってもよい。 According to the present technology, it is possible to provide a novel technology for promoting the formation of tight junctions. Note that the effects of the present technology are not limited to the effects described here, and may be any of the effects described in this specification.
以下、本技術を実施するための好適な形態について説明する。以下に説明する実施形態は、本技術の代表的な実施形態を示したものであり、本技術の範囲がこれらの実施形態のみに限定されることはない。 A preferred embodiment for implementing the present technology will be described below. The embodiments described below show representative embodiments of the present technology, and the scope of the present technology is not limited only to these embodiments.
１．タイトジャンクション形成促進剤、上皮バリア機能改善剤
本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤は、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物、アクテオシド、およびイソアクテオシドから選択される１以上の物質を有効成分とする。
1. Tight Junction Formation Promoting Agent, Epithelial Barrier Function Improving Agent The tight junction formation promoting agent and epithelial barrier function improving agent according to the present technology are selected from an extract of Magnolia champaca (Michelia champaca), acteoside, and isoacteoside One or more substances are used as active ingredients.
（１）キンコウボクの抽出物
キンコウボク（金厚朴）は、モクレン科モクレン属（オガタマノキ属）に属する植物であり、学名はMagnolia champaca（Michelia champaca）である。キンコウボクの抽出物とは、キンコウボク（Magnolia champaca（Michelia champaca））の根、幹、葉、枝、樹皮、花、実などを、適当な溶媒で抽出して得られる抽出物のことであり、通常、抽出した溶媒の濃縮液を使用する。また、当該濃縮液を凍結乾燥させたものも、本技術に用いることが可能である。
(1) Extract of Chrysanthemum Chrysanthemum Chrysanthemum is a plant belonging to the genus Magnolia of the Magnoliaceae family, and its scientific name is Magnolia champaca (Michelia champaca). The extract of ragweed (Magnolia champaca (Michelia champaca)) is an extract obtained by extracting roots, trunks, leaves, branches, bark, flowers, fruits, etc. of ragweed (Magnolia champaca (Michelia champaca)) with an appropriate solvent. , using concentrates of the extracted solvent. A freeze-dried concentrate can also be used in the present technology.
キンコウボクの具体的な抽出部位は、本技術の目的を損なわなければ特に限定されないが、葉または花を選択することが好ましく、花を選択することがより好ましい。また、前記抽出部位は採取直後でもよいし、乾燥させた後に、抽出に用いてもよい。必要に応じて、粉砕、切断、細切、成形等の加工を行ってから抽出に用いることもできる。 A specific extraction part of the sagebrush is not particularly limited as long as it does not impair the purpose of the present technology, but leaves or flowers are preferably selected, and flowers are more preferably selected. In addition, the extraction site may be used immediately after collection, or may be used for extraction after being dried. If necessary, it can be used for extraction after being subjected to processing such as pulverization, cutting, shredding, molding, and the like.
抽出に用いる溶媒も特に限定されず、通常、植物抽出に用いることができる溶媒を１種又は２種以上自由に選択して用いることができる。例えば、水、アルコール類、グリコール類、ケトン類、エステル類、エーテル類、ハロゲン化炭素類、超臨界溶媒（二酸化炭素など）、亜臨界溶媒などを挙げることができる。アルコール類としては、エタノール、メタノール及びプロパノールなどが挙げられる。グリコール類としては、エチレングリコール、ジエチレングリコール、ブチレングリコール及びプロピレングリコールなどが挙げられる。ケトン類としては、アセトン、メチルエチルケトンなどが挙げられる。エステル類としては、酢酸エチル、酢酸プロピル、ギ酸エチルなどが挙げられる。これらの溶媒は、単独或いは水溶液として用いてもよく、任意の２種又は３種以上の混合溶媒として用いてもよい。本技術においては、この中でも特に、水‐アルコール類混合液を用いることが好ましい。 The solvent used for extraction is also not particularly limited, and usually one or more solvents that can be used for plant extraction can be freely selected and used. Examples include water, alcohols, glycols, ketones, esters, ethers, halogenated carbons, supercritical solvents (such as carbon dioxide), and subcritical solvents. Alcohols include ethanol, methanol and propanol. Glycols include ethylene glycol, diethylene glycol, butylene glycol and propylene glycol. Ketones include acetone, methyl ethyl ketone, and the like. Esters include ethyl acetate, propyl acetate, ethyl formate and the like. These solvents may be used alone or as an aqueous solution, or may be used as a mixed solvent of any two or three or more. In the present technology, it is particularly preferable to use a water-alcohol mixture among these.
本技術において、含水エタノールを抽出溶媒として用いる場合、そのエタノール濃度も特に限定されないが、５～９５質量％が好ましく、１５～７０質量％以下がより好ましく、２５～６０質量％が特に好ましい。 In the present technology, when water-containing ethanol is used as an extraction solvent, the ethanol concentration is not particularly limited, but is preferably 5 to 95% by mass, more preferably 15 to 70% by mass or less, and particularly preferably 25 to 60% by mass.
抽出方法も特に限定されず、通常、植物抽出で行う抽出方法を自由に選択して用いることができる。例えば、前記溶媒にキンコウボクの任意の部位を２４時間浸漬した後に濾過する方法、溶媒の沸点以下の温度で加温、攪拌等しながら抽出した後に濾過する方法などが挙げられる。 The extraction method is also not particularly limited, and an extraction method usually used for plant extraction can be freely selected and used. For example, there is a method of immersing an arbitrary part of the sagebrush in the solvent for 24 hours and then filtering, and a method of extracting with heating and stirring at a temperature below the boiling point of the solvent and then filtering.
キンコウボクの抽出物は、そのままでも本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤の有効成分として用いることができるが、当該抽出物を、さらに、適当な分離手段（例えば、分配抽出、ゲル濾過法、シリカゲルクロマト法、逆相若しくは順相の高速液体クロマト法など）により活性の高い画分を分画して用いることも可能である。 The extract of the sagebrush can be used as it is as an active ingredient of the tight junction formation promoter and the epithelial barrier function improving agent according to the present technology. , gel filtration, silica gel chromatography, reverse-phase or normal-phase high-performance liquid chromatography, etc.) to fractionate and use a highly active fraction.
本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤に用いるキンコウボクの抽出物の乾燥固形分濃度は、本技術の効果を損なわなければ、用いる抽出溶媒の種類、抽出方法などに応じて自由に設定することが可能である。本技術においては、特に、乾燥固形分濃度の下限値は、例えば、０．０５質量％以上とすることができ、０．１質量％以上が好ましく、０．２質量％以上がより好ましい。０．２質量％以上とすることで、より高いタイトジャンクション形成促進効果および／または上皮バリア機能改善効果を発揮することができる。また、乾燥固形分濃度の上限値は、例えば、１０質量％以下とすることができ、５質量％以下が好ましく、２質量％以下がより好ましい。２質量％以下とすることで、植物に由来する匂いの発生や沈殿の発生を防止することができる。 The dry solid content concentration of the extracts of the Tit Junction Formation Promoter and the epithelial barrier function-improving agent according to the present technology does not impair the effect of the present technology, depending on the type of extraction solvent used, the extraction method, etc. It can be set freely. In the present technology, in particular, the lower limit of the dry solid content concentration can be, for example, 0.05% by mass or more, preferably 0.1% by mass or more, and more preferably 0.2% by mass or more. By making it 0.2% by mass or more, a higher tight junction formation promoting effect and/or an epithelial barrier function improving effect can be exhibited. Moreover, the upper limit of the dry solid content concentration can be, for example, 10% by mass or less, preferably 5% by mass or less, and more preferably 2% by mass or less. By setting the content to 2% by mass or less, it is possible to prevent the generation of plant-derived odors and the generation of precipitation.
（２）アクテオシド、イソアクテオシド
アクテオシド（Acteoside）は、別名ベルバコシド（verbascoside）、クサギニン（Kusaginin）で、分子式：Ｃ２９Ｈ３６Ｏ１５、下記の化学式（１）で表される物質である。
( 2) Acteoside, Isoacteoside Acteoside, also known as verbascoside or Kusaginin , is a substance represented by the following chemical formula (1) with the molecular formula: C29H36O15 .
イソアクテオシド（Isoacteoside）は、別名イソベルバコシド（isoverbascoside）で、分子式：Ｃ２９Ｈ３６Ｏ１５、下記の化学式（２）で表される物質である。 Isoacteoside, also known as isoverbascoside , is a substance represented by the following chemical formula ( 2 ) with the molecular formula: C29H36O15 .
本願発明者らは、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物に、アクテオシド、およびイソアクテオシドが含有されることを見出した。そして、これらの物質に、タイトジャンクション形成を促進させ、上皮バリア機能を改善する効果があることも確認した。即ち、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物には、複数の物質が含まれていると考えられるが、その中でも、アクテオシド、およびイソアクテオシドは、確実にタイトジャンクション形成促進作用および／または上皮バリア機能改善作用を有することを見出した。 The inventors of the present application have found that the extract of Magnolia champaca (Michelia champaca) contains acteoside and isoacteoside. We also confirmed that these substances have the effect of promoting tight junction formation and improving the epithelial barrier function. That is, it is believed that extracts of ragweed (Magnolia champaca (Michelia champaca)) contain a plurality of substances. It was found that it has a barrier function improving action.
より詳細には、後述する実施例に示すように、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物、アクテオシド、およびイソアクテオシドは、タイトジャンクションの構成因子であるオクルディンの発現遺伝子（オクルディン（OCLN）mRNA）、タイトジャンクションの構成因子であるクローディンの発現遺伝子（クローディン－１（CLDN1）mRNA、クローディン－４（CLDN4）mRNA）の発現促進作用を有する。 More specifically, as shown in the examples below, the extract of Magnolia champaca (Michelia champaca), acteoside, and isoacteoside are the components of tight junctions, occludin expression gene (occludin (OCLN) mRNA ), which promotes the expression of claudin expression genes (cladin-1 (CLDN1) mRNA and claudin-4 (CLDN4) mRNA), which are constituent factors of tight junctions.
また、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物、アクテオシド、およびイソアクテオシドは、上皮バリア機能に関わるヒアルロン酸の産生促進作用、ヒアルロン酸合成酵素３（HAS3）mRNA発現促進作用、表皮角化細胞の増殖促進作用、角層タンパク質であるフィラグリンの発現遺伝子（フィラグリン（FLG）mRNA）の発現促進作用、セラミド等のスフィンゴ脂質の生合成に関わるセリンパルミトイルトランスフェラーゼ（SPT）mRNA発現促進作用、および皮膚角化細胞の構成因子であるカスパーゼ１４の発現遺伝子（Caspase-14 mRNA）の発現促進作用を有する。 In addition, the extract of Magnolia champaca (Michelia champaca), acteoside, and isoacteoside promote production of hyaluronic acid, hyaluronic acid synthase 3 (HAS3) mRNA expression, and epidermal keratinocytes, which are involved in the epithelial barrier function. growth-promoting effect, expression-promoting effect of filaggrin expression gene (filagrin (FLG) mRNA), which is a stratum corneum protein, expression-promoting effect of serine palmitoyltransferase (SPT) mRNA expression involved in the biosynthesis of sphingolipids such as ceramide, and skin horn It has the effect of promoting the expression of the expression gene (Caspase-14 mRNA) of caspase 14, which is a constituent factor of metastatic cells.
なお、本技術に用いることができるアクテオシド、およびイソアクテオシドは、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物から精製されたものに限らず、他の植物や生物から精製されたものでもよい。また、化学合成されたものを用いることも可能である。 Acteoside and isoacteoside that can be used in the present technology are not limited to those purified from the extract of Magnolia champaca (Michelia champaca), but may be those purified from other plants or organisms. It is also possible to use a chemically synthesized one.
（３）その他
本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤には、本技術の効果を損なわない限り、その他の成分として、化粧料、飲食品、医薬品及び医薬部外品分野において用いることができるその他の成分を１種又は２種以上、自由に選択して含有させることもできる。例えば、保存剤、乳化剤、ｐＨ調整剤、着色剤、防腐剤、界面活性剤等の成分を用いることができる。
(3) Others The tight junction formation promoter and the epithelial barrier function improving agent according to this technology may be used in the fields of cosmetics, food and drink, pharmaceuticals, and quasi-drugs as other ingredients as long as they do not impair the effects of this technology. One or two or more other components that can be used in can be freely selected and contained. For example, components such as preservatives, emulsifiers, pH adjusters, coloring agents, preservatives, and surfactants can be used.
２．医薬品、医薬部外品および飲食品
本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤は、その優れたタイトジャンクション形成促進効果および／または上皮バリア機能改善効果を利用して、医薬品や医薬部外品および飲食品に好適に用いることができる。医薬品および医薬部外品は、経口投与や非経口投与などの投与方法に応じて、適宜所望の剤形に製剤化することができ、その剤形は特に限定されない。医薬品における経口投与の場合、例えば、散剤、顆粒剤、錠剤、トローチ剤、カプセル剤等の固形製剤；溶液剤、シロップ剤、懸濁剤、乳剤等の液剤等に製剤化することができる。非経口投与の場合、例えば、皮膚外用剤、座剤、膣錠、吸入剤、点鼻剤、注射剤等に製剤化することができる。医薬部外品においては、例えば、散剤、顆粒剤、錠剤、トローチ剤、カプセル剤、液剤、シロップ剤、皮膚外用剤、軟膏剤、エアゾール剤等に製剤化することができる。医薬品および医薬部外品について、本技術では、この中でも特に、皮膚外用剤の剤形に製剤化することが好ましい。皮膚外用剤としては、例えば、外用液剤、外用ゲル剤、クリーム剤、軟膏剤、スプレー剤、リニメント剤、ローション剤、ハップ剤、硬膏剤、噴霧剤、エアゾール剤、貼付剤等が挙げられる。飲食品としては、冷凍飲食品、粉末食品、シート状食品、瓶詰飲食品、缶詰飲食品、レトルト飲食品、カプセル状食品、タブレット状食品等の形態の他、例えば蛋白質、糖類、脂肪、微量元素、ビタミン類、乳化剤、香料等が配合された自然流動食、半消化栄養食および成分栄養食、ドリンク剤等の加工形態等、いずれの形態でもよい。また、飲食品の種類は特に限定するものではなく、例えば、飴、チューインガム、飲料等が挙げられる。
2. Pharmaceuticals, quasi-drugs, and food and drink The tight junction formation promoter and epithelial barrier function improving agent according to the present technology can be It can be suitably used for quasi-drugs and food and drink. Pharmaceuticals and quasi-drugs can be appropriately formulated into desired dosage forms according to administration methods such as oral administration and parenteral administration, and the dosage form is not particularly limited. For oral administration of pharmaceuticals, for example, solid formulations such as powders, granules, tablets, troches and capsules; liquid formulations such as solutions, syrups, suspensions and emulsions can be formulated. In the case of parenteral administration, for example, it can be formulated into skin external preparations, suppositories, vaginal tablets, inhalants, nasal drops, injections, and the like. Quasi-drugs can be formulated into, for example, powders, granules, tablets, troches, capsules, liquids, syrups, external preparations for skin, ointments, aerosols, and the like. Regarding pharmaceuticals and quasi-drugs, in the present technology, it is particularly preferable to formulate them into dosage forms for external skin preparations. Examples of external preparations for skin include liquids for external use, gels for external use, creams, ointments, sprays, liniments, lotions, poultices, plasters, sprays, aerosols, patches and the like. Food and drink include frozen food and drink, powdered food, sheet-like food, bottled food and drink, canned food and drink, retort food and drink, capsule-like food, tablet-like food, as well as proteins, sugars, fats, and trace elements. , natural liquid food containing vitamins, emulsifiers, flavorings, etc., semi-digested nutritional food and component nutritional food, and processed forms such as drinks. Moreover, the type of food and drink is not particularly limited, and examples thereof include candy, chewing gum, and beverages.
本技術に係る医薬品、医薬部外品および飲食品には、薬理学的に許容される添加剤を１種または２種以上自由に選択して含有させることができる。例えば、本技術に係る医薬品および医薬部外品を皮膚外用剤に適用させる場合、基剤、界面活性剤、保存剤、乳化剤、着色剤、矯臭剤、香料、安定化剤、防腐剤、酸化防止剤、潤沢剤、溶解補助剤、懸濁化剤等の、医薬製剤および医薬部外品製剤の分野で通常使用し得る全ての添加剤を含有させることができる。 Pharmaceuticals, quasi-drugs, and food and drink according to the present technology can contain one or more pharmacologically acceptable additives by freely selecting them. For example, when applying the pharmaceuticals and quasi-drugs according to the present technology to external skin preparations, bases, surfactants, preservatives, emulsifiers, coloring agents, flavoring agents, fragrances, stabilizers, preservatives, antioxidants All additives that can be commonly used in the fields of pharmaceutical formulations and quasi-drug formulations, such as agents, lubricants, solubilizers, and suspending agents, can be contained.
本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤は、その有効成分が天然由来成分であるため、他剤との併用を注意する必要性が低い。そのため、既存のあらゆる薬剤を１種または２種以上自由に選択して、合剤とすることもできる。例えば、抗菌剤、消炎鎮痛剤、ステロイド剤、抗真菌剤、鎮咳剤、抗ヒスタミン剤、ビタミン剤、抗腫瘍剤など、あらゆる薬剤を配合することができる。更に、従来公知の又は将来的に見出される疾患や症状の予防、改善及び／又は治療の効果を有する成分を、本技術の効果を損なわない限り、適宜目的に応じて併用することも可能である。 Since the active ingredients of the tight junction formation promoter and the epithelial barrier function improving agent according to the present technology are naturally-derived ingredients, there is little need to be careful when using them in combination with other agents. Therefore, one or two or more of all existing drugs can be freely selected to form a combination drug. For example, any drugs such as antibacterial agents, antiphlogistic analgesics, steroids, antifungals, antitussives, antihistamines, vitamins, and antitumor agents can be blended. Furthermore, it is also possible to use ingredients having preventive, ameliorating and/or therapeutic effects on diseases or symptoms that have been known in the past or will be found in the future, as long as they do not impair the effects of the present technology, depending on the purpose. .
本技術に係る医薬品、医薬部外品および飲食品、において、タイトジャンクション形成促進剤、および上皮バリア機能改善剤の含有量は特に限定されず、目的に応じて自由に設定することが可能である。本技術では、医薬品、医薬部外品および飲食品中におけるキンコウボク抽出物の乾燥固形分、アクテオシド及びイソアクテオシドの含有量は、例えば下限としては０．００００００１質量％以上が好ましく、０．０００００１質量％以上がより好ましく、０．００００１質量％以上が特に好ましい。また、上限としては１質量％以下が好ましく、０．０５質量％以下がより好ましく、０．０１質量％以下が特に好ましい。 In the pharmaceuticals, quasi-drugs, and food/beverage products according to the present technology, the contents of the tight junction formation promoter and the epithelial barrier function-improving agent are not particularly limited, and can be freely set according to the purpose. . In the present technology, the content of the dry solid content of the nutmeg extract, acteoside, and isoacteoside in pharmaceuticals, quasi-drugs, and food and drink is preferably 0.0000001% by mass or more as a lower limit, and 0.000001% by mass or more. is more preferable, and 0.00001% by mass or more is particularly preferable. Moreover, as an upper limit, 1 mass % or less is preferable, 0.05 mass % or less is more preferable, and 0.01 mass % or less is especially preferable.
以上説明した本技術に係る医薬品、医薬部外品および飲食品は、その有効成分が天然由来成分であるため、種々の疾患を罹患した患者に対しても安心して投与できる可能性も高い。また、長期間、連続的に投与しても副作用が生じる可能性も低い。 Since the active ingredients of the pharmaceuticals, quasi-drugs, and food/beverage products according to the present technology described above are naturally-derived ingredients, there is a high possibility that they can be safely administered to patients suffering from various diseases. In addition, even if administered continuously for a long period of time, the possibility of causing side effects is low.
３．化粧料
本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤は、その優れたタイトジャンクション形成促進効果および／または上皮バリア機能改善効果を利用して、あらゆる形態の化粧料に好適に用いることができる。例えば、ローション、乳液、クリーム、美容液、パック化粧料などのスキンケア化粧料、ファンデーション、コンシーラー、化粧下地、口紅、頬紅、アイシャドウ、アイライナーなどのメイクアップ化粧料、日焼け止め化粧料、などに適用することができる。化粧料の剤型として、水系、油系、可溶系、乳化系（Ｏ／Ｗ型、Ｗ／Ｏ型、Ｗ／Ｏ／Ｗ型、Ｏ／Ｗ／Ｏ型）等が挙げられる。
3. Cosmetics Tight junction formation promoters and epithelial barrier function improving agents according to the present technology are suitably used in all forms of cosmetics by utilizing their excellent tight junction formation promoting effects and/or epithelial barrier function improving effects. be able to. For example, skin care cosmetics such as lotions, milky lotions, creams, serums, pack cosmetics, makeup cosmetics such as foundations, concealers, makeup bases, lipsticks, blushers, eye shadows and eyeliners, sunscreen cosmetics, etc. can be applied. Formulations of cosmetics include water-based, oil-based, soluble-based and emulsified-based (O/W type, W/O type, W/O/W type, O/W/O type) and the like.
本技術に係る化粧料には、本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤に加え、通常化粧料に用いることができる成分を、１種または２種以上自由に選択して配合することが可能である。例えば、基材、保存剤、乳化剤、着色剤、防腐剤、界面活性剤、紫外線吸収剤、酸化防止剤、保湿剤、紫外線吸収剤、香料、防腐防黴剤、体質顔料、着色顔料、アルコール、水などの、化粧料分野で通常使用し得る全ての添加剤を含有させることができる。 In the cosmetic according to the present technology, in addition to the tight junction formation promoter and the epithelial barrier function improving agent according to the present technology, one or more components that can be used in ordinary cosmetics are freely selected. It is possible to blend For example, base materials, preservatives, emulsifiers, coloring agents, preservatives, surfactants, ultraviolet absorbers, antioxidants, moisturizing agents, ultraviolet absorbers, fragrances, antiseptic antifungal agents, extender pigments, coloring pigments, alcohols, All additives, such as water, that can normally be used in the field of cosmetics can be included.
また、本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤は、その有効成分が天然由来成分であるため、他の有効成分との併用を注意する必要性が低い。そのため、本技術に係る化粧料には、本技術に係るタイトジャンクション形成促進剤、および上皮バリア機能改善剤に加え、他の有効成分を必要に応じて自由に配合することができる。 In addition, since the active ingredients of the tight junction formation promoter and the epithelial barrier function improving agent according to the present technology are naturally-derived ingredients, there is little need to be careful when using them in combination with other active ingredients. Therefore, in addition to the tight junction formation promoter and the epithelial barrier function improving agent according to the present technology, the cosmetic according to the present technology can be freely blended with other active ingredients as necessary.
本技術に係る化粧料において、タイトジャンクション形成促進剤、および上皮バリア機能改善剤の含有量は特に限定されず、目的に応じて自由に設定することが可能である。本技術では、化粧料中におけるキンコウボク抽出物の乾燥固形分、アクテオシド及びイソアクテオシドの含有量は、例えば下限としては０．００００００１質量％以上が好ましく、０．０００００１質量％以上がより好ましく、０．００００１質量％以上が特に好ましい。また、上限としては１質量％以下が好ましく、０．０５質量％以下がより好ましく、０．０１質量％以下が特に好ましい。 In the cosmetic according to the present technology, the contents of the tight junction formation promoter and the epithelial barrier function improving agent are not particularly limited, and can be freely set according to the purpose. In the present technology, the content of the dry solid content of the extract of Osmanthus japonicum, acteoside, and isoacteoside in the cosmetic is, for example, as a lower limit, preferably 0.0000001% by mass or more, more preferably 0.000001% by mass or more, and 0.00001% by mass or more. More than % by mass is particularly preferred. Moreover, as an upper limit, 1 mass % or less is preferable, 0.05 mass % or less is more preferable, and 0.01 mass % or less is especially preferable.
以上説明した本技術に係る化粧料を用いた化粧料は、その有効成分が天然由来成分であるため、安全性が高く、長期間、連続的な使用が可能である。 A cosmetic using the cosmetic according to the present technology described above is highly safe and can be used continuously for a long period of time because its active ingredient is a naturally-derived component.
４．タイトジャンクション形成促進方法、上皮バリア機能改善方法
本技術に係るタイトジャンクション形成促進方法、および上皮バリア機能改善方法は、キンコウボク（Magnolia champaca（Michelia champaca））の抽出物、アクテオシド、およびイソアクテオシドから選択される１以上の物質を投与する工程を含む方法である。
4. Method for Promoting Tight Junction Formation, Method for Improving Epithelial Barrier Function The method for promoting tight junction formation and method for improving epithelial barrier function according to the present technology is selected from an extract of Magnolia champaca (Michelia champaca), acteoside, and isoacteoside. A method comprising administering one or more substances.
投与方法は、特に限定されず、経口投与や非経口投与のいずれを選択することもできる。非経口投与としては、例えば、経皮投与、経腸投与、経膣投与、舌下投与、口腔投与、吸入投与、経鼻投与、経静脈投与、経動脈投与、筋肉内投与、皮内投与、皮下投与等が挙げられる。 The administration method is not particularly limited, and either oral administration or parenteral administration can be selected. Parenteral administration includes, for example, transdermal administration, enteral administration, vaginal administration, sublingual administration, buccal administration, inhalation administration, nasal administration, intravenous administration, transarterial administration, intramuscular administration, intradermal administration, subcutaneous administration and the like.
以下、実施例に基づいて本技術を更に詳細に説明する。なお、以下に説明する実施例は、本技術の代表的な実施例の一例を示したものであり、これにより本技術の範囲が狭く解釈されることはない。 Hereinafter, the present technology will be described in further detail based on examples. It should be noted that the embodiments described below are examples of representative embodiments of the present technology, and the scope of the present technology should not be interpreted narrowly.
＜キンコウボク抽出物の調製＞
乾燥粉砕したキンコウボクの花を抽出溶媒に入れ、花の成分を抽出した後に濾過で不溶分を取り除き、溶媒で固形分量を調製し、キンコウボク抽出物を得た。なお抽出溶媒としては、含水エタノール（エタノール濃度：５０質量％）を用いた。
<Preparation of Kinkouboku extract>
Dried and pulverized flowers of Osmanthus annuus were put into an extraction solvent to extract the components of the flowers, insoluble matter was removed by filtration, and the solid content was adjusted with the solvent to obtain an Osmanthus extract. Water-containing ethanol (ethanol concentration: 50% by mass) was used as an extraction solvent.
＜実験例１＞
実験例１では、キンコウボク抽出物のタイトジャンクション形成促進効果を、経上皮電気抵抗を測定することで確認した。
<Experimental example 1>
In Experimental Example 1, the tight junction formation-promoting effect of the extract of Osmanthus japonicum was confirmed by measuring the transepithelial electrical resistance.
（１）経上皮電気抵抗の測定
ヒト表皮角化細胞を用いて作製した３次元培養表皮モデルの経上皮電気抵抗（TEER（Trans Epithelial Electrical Resistance））を測定することにより、タイトジャンクション形成促進効果を調べた。表皮モデルの作製過程で、培養液に、前記で調製したキンコウボク抽出物（0, 1, 10μg/mL）を添加し、培養を続けた。キンコウボク抽出物の添加後６日目に、表皮モデルの上下を培地で満たし、Millicell ERS-2（Millipore社製）の電極を用いて、電気抵抗を測定した。
(1) Measurement of transepithelial electrical resistance By measuring the transepithelial electrical resistance (TEER (Trans Epithelial Electrical Resistance)) of a three-dimensional cultured epidermis model prepared using human epidermal keratinocytes, the effect of promoting tight junction formation was evaluated. Examined. During the process of preparing the epidermis model, the above-prepared extracts (0, 1, 10 µg/mL) of the nutmeg extract (0, 1, 10 µg/mL) were added to the culture medium, and the culture was continued. On the 6th day after the addition of the extract, the top and bottom of the epidermis model were filled with medium, and electrical resistance was measured using Millicell ERS-2 (manufactured by Millipore) electrodes.
（２）結果
経上皮電気抵抗の測定結果を図１に示す。図１に示す通り、キンコウボク抽出物を添加することにより、タイトジャンクション形成が促進されることが確認できた。特に、キンコウボク抽出物を10μg/mLを添加した表皮モデルのTEERは、未添加の表皮モデルのTEERに対して、有意差をもって高い数値を示した。
(2) Results FIG. 1 shows the measurement results of transepithelial electrical resistance. As shown in FIG. 1, it was confirmed that the addition of the extract of Osmanthus japonicum promoted the formation of tight junctions. In particular, the TEER of the epidermis model to which 10 μg/mL of the extract was added showed a significantly higher value than the TEER of the epidermis model to which the extract was not added.
＜実験例２＞
実験例２では、キンコウボク抽出物のタイトジャンクション形成促進効果を、タイトジャンクションの構造を観察することで確認した。
<Experimental example 2>
In Experimental Example 2, the effect of promoting the formation of tight junctions by the extract of Osmanthus japonicum was confirmed by observing the structure of tight junctions.
（１）タイトジャンクションの観察
ヒト表皮角化細胞を用いて作製した３次元培養表皮モデルに対し、タイトジャンクションの構成因子であるオクルディンを抗体染色することによって、タイトジャンクションを観察した。表皮モデルの作製過程で、培養液に、前記で調製したキンコウボク抽出物（0,1, 10μg/mL）を添加し、培養を続けた。キンコウボク抽出物の添加後６日目に、表皮モデルを固定し、固定した試料を１次抗体の抗オクルディン抗体と反応させ、さらに蛍光標識２次抗体と反応させた。抗体染色した試料の観察像は、共焦点レーザースキャン顕微鏡（ZEISS社製）を用いて得た。
(1) Observation of Tight Junctions A three-dimensional cultured epidermis model prepared using human epidermal keratinocytes was subjected to antibody staining for occludin, which is a constituent of tight junctions, to observe tight junctions. During the process of preparing the epidermis model, the above-prepared extracts (0, 1, 10 µg/mL) of the nutmeg extract (0, 1, 10 µg/mL) were added to the culture medium, and the culture was continued. Six days after the addition of the extract of Osmanthus annuus, the epidermis model was fixed, and the fixed sample was reacted with an anti-occludin antibody as a primary antibody, and further reacted with a fluorescence-labeled secondary antibody. An observation image of the antibody-stained sample was obtained using a confocal laser scanning microscope (manufactured by ZEISS).
（２）結果
顕微鏡画像を図２に示す。図２に示す通り、キンコウボク抽出物未添加の表皮モデルではオクルディン集積が不十分な箇所が多く存在するが、キンコウボク抽出物添加群では、オクルディンがほとんどの細胞－細胞境界に集積していることが確認された。この結果から、キンコウボク抽出物によって、タイトジャンクション形成が促進されたことが確認された。
(2) Results A microscopic image is shown in FIG. As shown in Fig. 2, in the epidermis model to which the extract was not added, there were many places where occludin accumulation was insufficient, but in the group to which the extract was added, occludin accumulated at most of the cell-cell boundaries. confirmed. From this result, it was confirmed that tight junction formation was promoted by the extract of Osmanthus chinensis.
＜実験例３＞
実験例３では、キンコウボク抽出物に含有される物質（アクテオシド、イソアクテオシド）のタイトジャンクション形成促進作用を調べた。
<Experimental example 3>
In Experimental Example 3, the tight junction formation-promoting action of substances (acteoside, isoacteoside) contained in the Osmanthus japonicum extract was investigated.
（１）定量的PCR
ヒト表皮角化細胞を、コラーゲンコートプレート（Corning社製、#356400）に播種し、サブコンフルエントとなった時点で、キンコウボク抽出物（0, 12.5, 25, 50μg/mL）、アクテオシド（0, 5, 25μg/mL）、イソアクテオシド（0, 25μg/mL）を培地に添加し、培養を行った。薬剤添加２４時間後に、細胞からtotal RNAをTRIzol Reagent（Invitrogen社製）を用いて抽出し、High-Capacity cDNA Reverse Transcription Kit（Thermo Fisher社製）を用いて逆転写を行った。合成したcDNAを鋳型とし、オクルディン遺伝子を増幅させるプライマーを用いて定量的PCRを行った。各試料の遺伝子発現量はハウスキーピング遺伝子グリセルアルデヒド３－リン酸脱水素酵素の発現量で標準化した。
(1) Quantitative PCR
Human epidermal keratinocytes were seeded on a collagen-coated plate (Corning, #356400), and when they became sub-confluent, they were added with extracts (0, 12.5, 25, 50 μg/mL), acteoside (0, 5 , 25 μg/mL) and isoacteoside (0, 25 μg/mL) were added to the medium and cultured. Twenty-four hours after addition of the drug, total RNA was extracted from the cells using TRIzol Reagent (manufactured by Invitrogen) and reverse-transcribed using a High-Capacity cDNA Reverse Transcription Kit (manufactured by Thermo Fisher). Quantitative PCR was performed using the synthesized cDNA as a template and primers that amplify the occludin gene. The gene expression level of each sample was standardized by the expression level of the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase.
（２）結果
結果を図３に示す。図３に示す通り、キンコウボク抽出物、アクテオシド、イソアクテオシドは、濃度依存的にオクルディンの遺伝子発現を亢進することが確認された。これらの結果から、キンコウボク抽出物に含有される少なくともアクテオシド、イソアクテオシドは、タイトジャンクション形成促進作用をもたらす活性成分であることが確認された。
(2) Results The results are shown in FIG. As shown in FIG. 3, it was confirmed that the extract of Osmanthus japonicum, acteoside, and isoacteoside enhanced the gene expression of occludin in a concentration-dependent manner. From these results, it was confirmed that at least acteoside and isoacteoside contained in the Osmanthus chinensis extract are active ingredients that promote the formation of tight junctions.
＜実験例４＞
実験例４では、タイトジャンクションの構成因子であるオクルディンの発現遺伝子（オクルディン（OCLN）mRNA）の発現促進作用について、検証した。
<Experimental example 4>
In Experimental Example 4, the effect of promoting the expression of the expression gene of occludin (occludin (OCLN) mRNA), which is a component of tight junctions, was examined.
（１）試験方法
正常ヒト新生児表皮角化細胞（NHEK）を正常ヒト表皮角化細胞増殖培地（KGM）を用いて培養した後、トリプシン処理により回収した。回収した細胞を6 well プレートに播種し、37℃、5％CO2 下で一晩培養した。
(1) Test Method Normal human neonatal epidermal keratinocytes (NHEK) were cultured using normal human epidermal keratinocyte growth medium (KGM) and then collected by trypsinization. Collected cells were seeded in a 6-well plate and cultured overnight at 37°C under 5% CO 2 .
24時間後に被験試料を各 well に添加し、37℃、5％CO2 下で24時間培養後、培養液を捨て、ISOGEN II（NIPPON GENE）にて total RNA を調製した。 After 24 hours, the test sample was added to each well, cultured at 37°C, 5% CO 2 for 24 hours, the culture medium was discarded, and total RNA was prepared using ISOGEN II (NIPPON GENE).
この total RNA を鋳型とし、OCLNおよび内部標準であるGAPDHのmRNAの発現量を測定した。検出はリアルタイムPCR装置 Thermal Cycler Dice（登録商標） Real Time SystemIII（TaKaRa）を用いて、リアルタイム RT-PCR 反応により行った。 Using this total RNA as a template, the expression levels of OCLN and internal standard GAPDH mRNAs were measured. Detection was performed by real-time RT-PCR reaction using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (TaKaRa).
OCLNの発現量は、GAPDH mRNA の発現量で補正し算出した。OCLN mRNA 発現促進率の計算方法は以下の通りである。
OCLN mRNA 発現促進率（％）＝（Ａ／Ｂ）×１００
Ａ：被験試料添加時の補正値
Ｂ：被験試料無添加時の補正値
The expression level of OCLN was corrected and calculated with the expression level of GAPDH mRNA. The method for calculating the OCLN mRNA expression promotion rate is as follows.
OCLN mRNA expression promotion rate (%) = (A/B) x 100
A: Correction value when test sample is added B: Correction value when test sample is not added
（２）結果
結果を下記の表１に示す。
（３）考察
表１に示すように、キンコウボク抽出液、アクテオサイド、およびイソアクテオサイドの全てにおいて、有意なOCLN mRNA 発現促進作用が認められた。
(3) Discussion As shown in Table 1, significant OCLN mRNA expression-enhancing effects were observed in all of the extract, acteoside, and isoacteoside.
＜実験例５＞
実験例５では、タイトジャンクションの構成因子であるクローディンの発現遺伝子（クローディン－１（CLDN1）mRNA）の発現促進作用について、検証した。
<Experimental example 5>
In Experimental Example 5, the effect of promoting the expression of claudin expression gene (claudin-1 (CLDN1) mRNA), which is a constituent factor of tight junctions, was examined.
（１）試験方法
正常ヒト新生児表皮角化細胞（NHEK）を正常ヒト表皮角化細胞増殖培地（KGM）を用いて培養した後、トリプシン処理により回収した。回収した細胞を6 well プレートに播種し、37℃、5％CO2 下で一晩培養した。
(1) Test Method Normal human neonatal epidermal keratinocytes (NHEK) were cultured using normal human epidermal keratinocyte growth medium (KGM) and then collected by trypsinization. Collected cells were seeded in a 6-well plate and cultured overnight at 37°C under 5% CO 2 .
24時間後に被験試料を各 well に添加し、37℃、5％CO2 下で24時間培養した。培養後、培養液を捨て、ISOGEN II（NIPPON GENE）にて total RNA を調製した。 After 24 hours, the test sample was added to each well and cultured at 37°C, 5% CO 2 for 24 hours. After culturing, the culture medium was discarded, and total RNA was prepared using ISOGEN II (NIPPON GENE).
このtotal RNA を鋳型とし、CLDN1 および内部標準であるGAPDHのmRNA の発現量を測定した。検出はリアルタイムPCR装置 Thermal Cycler Dice（登録商標） Real Time SystemIII（TaKaRa） を用いて、リアルタイム RT-PCR 反応により行った。 Using this total RNA as a template, the expression levels of CLDN1 and internal standard GAPDH mRNA were measured. Detection was performed by real-time RT-PCR reaction using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (TaKaRa).
CLDN1 の発現量は、GAPDH mRNA の発現量で補正し算出した。CLDN1 mRNA 発現促進率の計算方法は以下の通りである。
CLDN1 mRNA 発現促進率（％）＝（Ａ／Ｂ）×１００
Ａ：被験試料添加時の補正値
Ｂ：被験試料無添加時の補正値
The expression level of CLDN1 was calculated after correcting it with the expression level of GAPDH mRNA. The method for calculating the CLDN1 mRNA expression promotion rate is as follows.
CLDN1 mRNA expression promotion rate (%) = (A/B) x 100
A: Correction value when test sample is added B: Correction value when test sample is not added
（２）結果
結果を下記の表２に示す。
（３）考察
キンコウボク抽出液、アクテオサイド、およびイソアクテオサイドの全てにおいて、有意なCLDN1 mRNA 発現促進作用が認められた。
(3) Discussion A significant CLDN1 mRNA expression-enhancing effect was observed in all of the extract, acteoside, and isoacteoside.
＜実験例６＞
実験例６では、タイトジャンクションの構成因子であるクローディンの発現遺伝子（クローディン－４（CLDN4）mRNA）の発現促進作用について、検証した。
<Experimental example 6>
In Experimental Example 6, the effect of promoting the expression of claudin expression gene (claudin-4 (CLDN4) mRNA), which is a constituent factor of tight junctions, was verified.
（１）試験方法
正常ヒト新生児表皮角化細胞（NHEK）を正常ヒト表皮角化細胞増殖培地（KGM）を用いて培養した後、トリプシン処理により回収した。回収した細胞を6 well プレートに播種し、37℃、5％CO2 下で一晩培養した。
(1) Test Method Normal human neonatal epidermal keratinocytes (NHEK) were cultured using normal human epidermal keratinocyte growth medium (KGM) and then collected by trypsinization. Collected cells were seeded in a 6-well plate and cultured overnight at 37°C under 5% CO 2 .
24時間後に被験試料を各well に添加し、37℃、5％CO2 下で 24 時間培養した。培養後、培養液を捨て、ISOGEN II （NIPPON GENE）にてtotal RNA を調製した。 After 24 hours, the test sample was added to each well and cultured at 37°C, 5% CO 2 for 24 hours. After culturing, the culture medium was discarded, and total RNA was prepared using ISOGEN II (NIPPON GENE).
この total RNA を鋳型とし、CLDN4および内部標準であるGAPDH のmRNA の発現量を測定した。検出はリアルタイムPCR 装置 Thermal Cycler Dice（登録商標）Real Time SystemIII（TaKaRa）を用いて、リアルタイム RT-PCR 反応により行った。 Using this total RNA as a template, the expression levels of CLDN4 and internal standard GAPDH mRNA were measured. Detection was performed by real-time RT-PCR reaction using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (TaKaRa).
CLDN4 の発現量は、GAPDH mRNA の発現量で補正し算出した。CLDN4 mRNA 発現促進率の計算方法は以下の通りである。
CLDN4 mRNA 発現促進率（％）＝（Ａ／Ｂ）×１００
Ａ：被験試料添加時の補正値
Ｂ：被験試料無添加時の補正値
The expression level of CLDN4 was calculated after correcting it with the expression level of GAPDH mRNA. The method for calculating the CLDN4 mRNA expression promotion rate is as follows.
CLDN4 mRNA expression promotion rate (%) = (A/B) x 100
A: Correction value when test sample is added B: Correction value when test sample is not added
（２）結果
結果を下記の表３に示す。
（３）考察
キンコウボク抽出液、アクテオサイド、およびイソアクテオサイドの全てにおいて、有意なCLDN4 mRNA 発現促進作用が認められた。
(3) Discussion A significant CLDN4 mRNA expression-enhancing effect was observed in all of the extract, acteoside, and isoacteoside.
＜実験例７＞
実験例７では、ヒアルロン酸産生促進率について、検討した。
<Experimental example 7>
In Experimental Example 7, the promotion rate of hyaluronic acid production was examined.
（１）実験方法
正常ヒト新生児表皮角化細胞（NHEK）を正常ヒト表皮角化細胞増殖培地（KGM）を用いて培養した後、トリプシン処理により回収した。回収した細胞を96 well プレートに被験試料を添加し培養した。培養後、各well の培地中のヒアルロン酸量をヒアルロン酸結合タンパク（HABP）を用いたサンドイッチ法により測定した。
(1) Experimental method After culturing normal human neonatal epidermal keratinocytes (NHEK) using normal human epidermal keratinocyte growth medium (KGM), they were collected by trypsinization. The recovered cells were cultured in a 96-well plate with the test sample added. After culturing, the amount of hyaluronic acid in the medium of each well was measured by the sandwich method using hyaluronic acid binding protein (HABP).
ヒアルロン酸産生促進率の計算方法は以下のとおりである。
ヒアルロン酸産生促進率（％）＝（Ａ／Ｂ）×１００
Ａ：被験試料添加時のヒアルロン酸量
Ｂ：被験試料無添加時のヒアルロン酸量
The calculation method of the hyaluronic acid production promotion rate is as follows.
Hyaluronic acid production promotion rate (%) = (A / B) × 100
A: Amount of hyaluronic acid when the test sample is added B: Amount of hyaluronic acid when the test sample is not added
（２）結果
（３）考察
キンコウボク抽出液、およびイソアクテオサイドにおいて、有意なヒアルロン酸産生促進作用が認められた。
(3) Consideration A significant hyaluronic acid production-promoting action was observed in the extract of Osmanthus japonicum and isoacteoside.
＜実験例８＞
実験例８では、ヒアルロン酸の発現遺伝子であるヒアルロン酸合成酵素３（HAS3）mRNA発現促進作用について、検討した。
<Experimental Example 8>
In Experimental Example 8, the effect of promoting the expression of hyaluronic acid synthase 3 (HAS3) mRNA, which is an expression gene of hyaluronic acid, was examined.
（１）実験方法
正常ヒト新生児表皮角化細胞（NHEK）を正常ヒト表皮角化細胞増殖培地 （KGM）を用いて培養した後、トリプシン処理により回収した。回収した細胞を6 well プレートに播種し、37℃、5％CO2 下で一晩培養した。
(1) Experimental method After culturing normal human neonatal epidermal keratinocytes (NHEK) using normal human epidermal keratinocyte growth medium (KGM), they were collected by trypsinization. Collected cells were seeded in a 6-well plate and cultured overnight at 37°C under 5% CO 2 .
24時間後に被験試料を各well に添加し、37℃、5％CO2 下で24 時間培養した。培養後、培養液を捨て、ISOGEN II （NIPPON GENE）にてtotal RNA を調製した。 After 24 hours, the test sample was added to each well and cultured at 37°C, 5% CO 2 for 24 hours. After culturing, the culture medium was discarded, and total RNA was prepared using ISOGEN II (NIPPON GENE).
このtotal RNA を鋳型とし、HAS3 および内部標準である GAPDH のmRNA の発現量を測定した。検出はリアルタイム PCR 装置 Thermal Cycler Dice（登録商標） Real Time SystemIII（TaKaRa） を用いて、リアルタイム RT-PCR 反応により行った。 Using this total RNA as a template, the expression levels of HAS3 and internal standard GAPDH mRNAs were measured. Detection was performed by real-time RT-PCR reaction using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (TaKaRa).
HAS3の発現量は、GAPDH mRNAの発現量で補正し算出した。HAS3 mRNA発現促進率の計算方法は以下の通りである。 The expression level of HAS3 was calculated after correcting it with the expression level of GAPDH mRNA. The method for calculating the HAS3 mRNA expression promotion rate is as follows.
HAS3 mRNA 発現促進率（％）＝（Ａ／Ｂ）×１００
Ａ：被験試料添加時の補正値
Ｂ：被験試料無添加時の補正値
HAS3 mRNA expression promotion rate (%) = (A/B) x 100
A: Correction value when test sample is added B: Correction value when test sample is not added
（２）結果
結果を下記の表５に示す。
（３）考察
キンコウボク抽出液、アクテオサイド、およびイソアクテオサイドの全てにおいて、有意なHAS3発現促進作用が認められた。
(3) Consideration A significant HAS3 expression-enhancing effect was observed in all of the extract, acteoside, and isoacteoside.
＜実験例９＞
実験例９では、表皮角化細胞増殖促進作用について検証した。
<Experimental example 9>
In Experimental Example 9, the effect of promoting proliferation of epidermal keratinocytes was verified.
（１）実験方法
正常ヒト新生児表皮角化細胞（NHEK）を正常ヒト表皮角化細胞増殖培地（KGM）を用いて培養した後、トリプシン処理により回収した。回収した細胞をコラーゲンコートした96 well プレートに播種し、一晩培養した。培養終了後、被験試料を添加し、培養した。表皮角化細胞増殖促進作用は、MTTアッセイ法を用いて測定した。
(1) Experimental method After culturing normal human neonatal epidermal keratinocytes (NHEK) using normal human epidermal keratinocyte growth medium (KGM), they were collected by trypsinization. Collected cells were seeded on a collagen-coated 96-well plate and cultured overnight. After culturing, the test sample was added and cultured. Epidermal keratinocyte proliferation-promoting activity was measured using the MTT assay method.
表皮角化細胞増殖促進率の計算方法は以下のとおりである。
表皮角化細胞増殖促進率（％）＝（Ａ／Ｂ）×１００
Ａ：被験試料を添加した細胞でのブルーホルマザン生成量
Ｂ：被験試料を添加しない細胞でのブルーホルマザン生成量
The calculation method of the epidermal keratinocyte proliferation promotion rate is as follows.
Epidermal keratinocyte proliferation promotion rate (%) = (A/B) x 100
A: Amount of blue formazan produced in cells to which the test sample was added B: Amount of blue formazan produced in cells to which no test sample was added
（２）結果
結果を下記の表６に示す。
（３）考察
キンコウボク抽出液、アクテオサイド、およびイソアクテオサイドの全てにおいて、表皮角化細胞増殖促進作用が認められた。
(3) Consideration It was found that all of the extract, acteoside, and isoacteoside have the effect of promoting proliferation of epidermal keratinocytes.
＜実験例１０＞
実験例１０では、角層タンパク質であるフィラグリンの発現遺伝子（フィラグリン（FLG）mRNA）の発現促進作用について、検証した。
<Experimental example 10>
In Experimental Example 10, the effect of promoting the expression of filaggrin expression gene (filagrin (FLG) mRNA), which is a stratum corneum protein, was verified.
（１）実験方法
正常ヒト新生児表皮角化細胞（NHEK）を正常ヒト表皮角化細胞増殖培地（KGM）を用いて培養した後、トリプシン処理により回収した。回収した細胞を6 well プレートに播種し、37℃、5％CO2 下で一晩培養した。
(1) Experimental method After culturing normal human neonatal epidermal keratinocytes (NHEK) using normal human epidermal keratinocyte growth medium (KGM), they were collected by trypsinization. Collected cells were seeded in a 6-well plate and cultured overnight at 37°C under 5% CO 2 .
24時間後に被験試料を各well に添加し、37℃、5％CO2 下で 24 時間培養した。培養後、培養液を捨て、ISOGEN II （NIPPON GENE）にてtotal RNA を調製した。 After 24 hours, the test sample was added to each well and cultured at 37°C, 5% CO 2 for 24 hours. After culturing, the culture medium was discarded, and total RNA was prepared using ISOGEN II (NIPPON GENE).
この total RNA を鋳型とし、FLGおよび内部標準であるGAPDH のmRNA の発現量を測定した。検出はリアルタイムPCR 装置 Thermal Cycler Dice（登録商標） Real Time SystemIII（TaKaRa） を用いて、リアルタイムRT-PCR 反応により行った。 Using this total RNA as a template, the expression levels of FLG and internal standard GAPDH mRNA were measured. Detection was performed by real-time RT-PCR reaction using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (TaKaRa).
FLGの発現量は、GAPDH mRNA の発現量で補正し算出した。FLG mRNA 発現促進率の計算方法は以下の通りである。
FLG mRNA 発現促進率（％）＝（Ａ／Ｂ）×１００
Ａ：被験試料添加時の補正値
Ｂ：被験試料無添加時の補正値
The expression level of FLG was calculated after correcting it with the expression level of GAPDH mRNA. The method for calculating the FLG mRNA expression promotion rate is as follows.
FLG mRNA expression promotion rate (%) = (A/B) x 100
A: Correction value when test sample is added B: Correction value when test sample is not added
（２）結果
結果を下記の表７に示す。
（３）考察
キンコウボク抽出液、アクテオサイド、およびイソアクテオサイドの全てにおいて、有意なFLG mRNA発現促進作用が認められた。
(3) Consideration A significant FLG mRNA expression-enhancing effect was observed in all of the extract, acteoside, and isoacteoside.
＜実験例１１＞
実験例１１では、セラミド等のスフィンゴ脂質の生合成に関わるセリンパルミトイルトランスフェラーゼ（SPT）mRNA発現促進作用について、検証した。
<Experimental example 11>
In Experimental Example 11, the effect of promoting serine palmitoyltransferase (SPT) mRNA expression involved in the biosynthesis of sphingolipids such as ceramide was verified.
（１）実験方法
正常ヒト新生児表皮角化細胞（NHEK）を正常ヒト表皮角化細胞増殖培地（KGM）を用いて培養した後、トリプシン処理により回収した。回収した細胞を6 well プレートに播種し、37℃、5％CO2 下で一晩培養した。
(1) Experimental method After culturing normal human neonatal epidermal keratinocytes (NHEK) using normal human epidermal keratinocyte growth medium (KGM), they were collected by trypsinization. Collected cells were seeded in a 6-well plate and cultured overnight at 37°C under 5% CO 2 .
24時間後に培養液を捨て、被験試料を各well に 2 mL ずつ添加し、37℃、5％CO2 下で24 時間培養した。培養後、培養液を捨て、ISOGEN II （NIPPON GENE）にてtotal RNA を調製した。 After 24 hours, the culture medium was discarded, 2 mL of the test sample was added to each well, and cultured at 37°C under 5% CO 2 for 24 hours. After culturing, the culture medium was discarded, and total RNA was prepared using ISOGEN II (NIPPON GENE).
このtotal RNA を鋳型とし、SPTおよび内部標準である GAPDH の mRNA の発現量を測定した。検出はリアルタイムPCR 装置 Thermal Cycler Dice（登録商標） Real Time SystemIII（TaKaRa） を用いて、リアルタイム RT-PCR 反応により行った。 Using this total RNA as a template, the expression levels of SPT and internal standard GAPDH mRNA were measured. Detection was performed by real-time RT-PCR reaction using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (TaKaRa).
SPTの発現量は、GAPDH mRNA の発現量で補正し算出した。SPT mRNA 発現促進率の計算方法は以下の通りである。
SPT mRNA 発現促進率（％）＝（Ａ／Ｂ）×１００
Ａ：被験試料添加時の補正値
Ｂ：被験試料無添加時の補正値
The expression level of SPT was calculated after correcting it with the expression level of GAPDH mRNA. The method for calculating the SPT mRNA expression promotion rate is as follows.
SPT mRNA expression promotion rate (%) = (A/B) x 100
A: Correction value when test sample is added B: Correction value when test sample is not added
（２）結果
結果を下記の表８に示す。
（３）考察
キンコウボク抽出液、アクテオサイド、およびイソアクテオサイドの全てにおいて、有意なSPT mRNA発現促進作用が認められた。
(3) Consideration A significant SPT mRNA expression-enhancing effect was observed in all of the extract, acteoside, and isoacteoside.
＜実験例１２＞
実験例１２では、皮膚角化細胞の構成因子であるカスパーゼ１４の発現遺伝子（Caspase-14 mRNA）の発現促進作用について、検証した。
<Experimental example 12>
In Experimental Example 12, the effect of promoting expression of the expression gene (Caspase-14 mRNA) of caspase 14, which is a constituent factor of skin keratinocytes, was verified.
（１）実験方法
正常ヒト新生児表皮角化細胞（NHEK）を正常ヒト表皮角化細胞増殖培地（KGM）を用いて培養した後、トリプシン処理により回収した。回収した細胞を6 well プレートに播種し、37℃、5％CO2 下で一晩培養した。
(1) Experimental method After culturing normal human neonatal epidermal keratinocytes (NHEK) using normal human epidermal keratinocyte growth medium (KGM), they were collected by trypsinization. Collected cells were seeded in a 6-well plate and cultured overnight at 37°C under 5% CO 2 .
24時間後に培養液を捨て、被験試料を各well に添加し、37℃、5％CO2 下で24時間培養した。培養後、培養液を捨て、ISOGEN II （NIPPON GENE）にてtotal RNA を調製した。 After 24 hours, the culture medium was discarded, the test sample was added to each well, and cultured at 37°C under 5% CO 2 for 24 hours. After culturing, the culture medium was discarded, and total RNA was prepared using ISOGEN II (NIPPON GENE).
このtotal RNA を鋳型とし、Caspase-14および内部標準であるGAPDH のmRNA の発現量を測定した。検出はリアルタイム PCR 装置 Thermal Cycler Dice（登録商標） Real Time SystemIII（TaKaRa） を用いて、リアルタイムRT-PCR 反応により行った。 Using this total RNA as a template, the expression levels of Caspase-14 and internal standard GAPDH mRNA were measured. Detection was performed by real-time RT-PCR reaction using a real-time PCR device Thermal Cycler Dice (registered trademark) Real Time System III (TaKaRa).
Caspase-14の発現量は、GAPDH mRNA の発現量で補正し算出した。Caspase-14 mRNA 発現促進率の計算方法は以下の通りである。
Caspase-14 mRNA 発現促進率（％）＝（Ａ／Ｂ）×１００
Ａ：被験試料添加時の補正値
Ｂ：被験試料無添加時の補正値
The expression level of Caspase-14 was calculated after correcting it with the expression level of GAPDH mRNA. The method for calculating the caspase-14 mRNA expression promotion rate is as follows.
Caspase-14 mRNA expression promotion rate (%) = (A/B) x 100
A: Correction value when test sample is added B: Correction value when test sample is not added
（２）結果
結果を下記の表９に示す。
（３）考察
キンコウボク抽出液、アクテオサイド、およびイソアクテオサイドの全てにおいて、有意なCaspase14 mRNA発現促進作用が認められた。Caspase-14 は表皮細胞を脱核させて正常な表皮分化を誘導し肌を健康に保つ他、フィラグリンからNMFへの分解やセラミドの合成系に関与することも報告されており、NMFの供給や細胞間脂質の調節においても重要な役割を担うと考えられている。すなわち Caspase-14 の発現を高めることは肌荒れの予防や保湿効果の増強につながると考えられる。
(3) Discussion A significant Caspase14 mRNA expression-enhancing effect was observed in all of the extract, acteoside, and isoacteoside. Caspase-14 enucleates epidermal cells and induces normal epidermal differentiation to keep the skin healthy. It is also believed to play an important role in the regulation of intercellular lipids. In other words, increasing the expression of caspase-14 is thought to lead to prevention of rough skin and enhancement of moisturizing effect.
＜実施例１～１１＞
実施例１～１１では、キンコウボク抽出物、アクテオシドまたはイソアクテオシドを含有する医薬品、医薬部外品、飲食品および化粧料を調製した。
<Examples 1 to 11>
In Examples 1 to 11, pharmaceuticals, quasi-drugs, foods and beverages, and cosmetics containing the extract of Osmanthus japonicum, acteoside or isoacteoside were prepared.
［実施例１：外用液剤］
以下の製法により、外用液剤を調製した。
（製法）
Ａ．下記成分（１）～（７）を混合溶解した。
Ｂ．下記成分（８）～（１１）を混合溶解した。
Ｃ．ＡにＢを加え混合し、実施例１に係る外用液剤を得た。
[Example 1: External solution]
A liquid preparation for external use was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (7) were mixed and dissolved.
B. The following components (8) to (11) were mixed and dissolved.
C. B was added to A and mixed to obtain a liquid preparation for external use according to Example 1.
（１）クエン酸：０．０５質量％
（２）クエン酸ナトリウム：０．２質量％
（３）ピロリドンカルボン酸ナトリウム（５０％）液：０．５質量％
（４）グリセリン：３．０質量％
（５）１，３－ブチレングリコール：８．０質量％
（６）キンコウボク抽出物：０．５質量％
（７）精製水：残量
（８）エタノール：１０．０質量％
（９）香料：０．１質量％
（１０）フェノキシエタノール：０．１質量％
（１１）モノオレイン酸ポリオキシエチレン（２０Ｅ．Ｏ．）ソルビタン：０．５質量％
(1) Citric acid: 0.05% by mass
(2) Sodium citrate: 0.2% by mass
(3) Sodium pyrrolidonecarboxylate (50%) liquid: 0.5% by mass
(4) Glycerin: 3.0% by mass
(5) 1,3-butylene glycol: 8.0% by mass
(6) Kinkouboku extract: 0.5% by mass
(7) Purified water: Remaining amount (8) Ethanol: 10.0% by mass
(9) Perfume: 0.1% by mass
(10) Phenoxyethanol: 0.1% by mass
(11) Polyoxyethylene monooleate (20E.O.) sorbitan: 0.5% by mass
［実施例２：乳液］
下記の製法により、乳液を調製した。
（製法）
Ａ．下記成分（１）～（１０）を加熱溶解し、７０℃に保った。
Ｂ．下記成分（１１）～（１７）を加熱溶解し、７０℃に保った。
Ｃ．ＡにＢを加え乳化し、更に下記成分（１８）を加え混合した。
Ｄ．Ｃを冷却し、下記成分（１９）を加え混合し、実施例２に係る乳液を得た。
[Example 2: Emulsion]
A milky lotion was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (10) were dissolved by heating and kept at 70°C.
B. The following components (11) to (17) were dissolved by heating and kept at 70°C.
C. B was added to A and emulsified, and then the following component (18) was added and mixed.
D. C was cooled, and the following component (19) was added and mixed to obtain a milky lotion according to Example 2.
（１）ステアリン酸：１．０質量％
（２）セタノール：０．５質量％
（３）親油型モノステアリン酸グリセリン：０．５質量％
（４）流動パラフィン：２．０質量％
（５）スクワラン：３．０質量％
（６）ホホバ油：３．０質量％
（７）パルミチン酸セチル：０．２質量％
（８）パラオキシ安息香酸メチル：０．１質量％
（９）モノステアリン酸ソルビタン：０．３質量％
（１０）モノオレイン酸ポリオキシエチレン（２０Ｅ．Ｏ．）ソルビタン：０．５質量％（１１）トリエタノールアミン：０．５質量％
（１２）１，３－ブチレングリコール：１５．０質量％
（１３）グリセリン：３．０質量％
（１４）ポリエチレングリコール６０００：０．５質量％
（１５）キンコウボク抽出物：０．１質量％
（１６）アスコルビン酸リン酸マグネシウム：０．５質量％
（１７）精製水：残量
（１８）カルボキシルビニルポリマー１％溶液：８．０質量％
（１９）香料：０．１質量％
(1) stearic acid: 1.0% by mass
(2) Cetanol: 0.5% by mass
(3) Lipophilic glyceryl monostearate: 0.5% by mass
(4) Liquid paraffin: 2.0% by mass
(5) Squalane: 3.0% by mass
(6) Jojoba oil: 3.0% by mass
(7) Cetyl palmitate: 0.2% by mass
(8) Methyl paraoxybenzoate: 0.1% by mass
(9) Sorbitan monostearate: 0.3% by mass
(10) Polyoxyethylene monooleate (20E.O.) sorbitan: 0.5% by mass (11) Triethanolamine: 0.5% by mass
(12) 1,3-butylene glycol: 15.0% by mass
(13) Glycerin: 3.0% by mass
(14) Polyethylene glycol 6000: 0.5% by mass
(15) Kinkouboku extract: 0.1% by mass
(16) Magnesium ascorbic acid phosphate: 0.5% by mass
(17) Purified water: Remaining amount (18) Carboxyl vinyl polymer 1% solution: 8.0% by mass
(19) Perfume: 0.1% by mass
［実施例３：軟膏］
以下の製法により軟膏を調製した。
（製法）
Ａ．下記成分（１）～（１３）を加熱溶解し、７０℃に保った。
Ｂ．下記成分（１４）～（１９）を加熱溶解し、７０℃に保った。
Ｃ．ＡにＢを加え乳化し、更に下記成分（２０）を加え混合した。
Ｄ．Ｃを冷却し、下記成分（２１）を加え混合し、実施例３に係るクリームを得た。
[Example 3: Ointment]
An ointment was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (13) were dissolved by heating and kept at 70°C.
B. The following components (14) to (19) were dissolved by heating and kept at 70°C.
C. B was added to A and emulsified, and then the following component (20) was added and mixed.
D. C was cooled, and the following component (21) was added and mixed to obtain a cream according to Example 3.
（１）ステアリン酸：２．５質量％
（２）セタノール：２．５質量％
（３）親油型モノステアリン酸グリセリン：２．０質量％
（４）ワセリン：２．０質量％
（５）ジペンタエリトリット脂肪酸エステル：２．０質量％
（６）ミリスチン酸イソトリデシル：５．０質量％
（７）流動パラフィン：８．０質量％
（８）スクワラン：５．０質量％
（９）ミツロウ：１．０質量％
（１０）パルミチン酸セチル：２．０質量％
（１１）セスキオレイン酸ソルビタン：０．５質量％
（１２）モノオレイン酸ポリオキシエチレン（２０Ｅ．Ｏ．）ソルビタン：１．５質量％（１３）フェノキシエタノール：０．２質量％
（１４）トリエタノールアミン：１．２質量％
（１５）１，３－ブチレングリコール：８．０質量％
（１６）グリセリン：２．０質量％
（１７）ポリエチレングリコール２００００：０．５質量％
（１８）キンコウボク抽出物：１．０質量％
（１９）精製水：残量
（２０）カルボキシルビニルポリマー１％溶液：１０．０質量％
（２１）香料：０．０５質量％
(1) stearic acid: 2.5% by mass
(2) Cetanol: 2.5% by mass
(3) Lipophilic glyceryl monostearate: 2.0% by mass
(4) Vaseline: 2.0% by mass
(5) Dipentaerythritol fatty acid ester: 2.0% by mass
(6) isotridecyl myristate: 5.0% by mass
(7) Liquid paraffin: 8.0% by mass
(8) Squalane: 5.0% by mass
(9) Beeswax: 1.0% by mass
(10) Cetyl palmitate: 2.0% by mass
(11) Sorbitan sesquioleate: 0.5% by mass
(12) Polyoxyethylene monooleate (20E.O.) sorbitan: 1.5% by mass (13) Phenoxyethanol: 0.2% by mass
(14) Triethanolamine: 1.2% by mass
(15) 1,3-butylene glycol: 8.0% by mass
(16) Glycerin: 2.0% by mass
(17) Polyethylene glycol 20000: 0.5% by mass
(18) Kinkouboku extract: 1.0% by mass
(19) Purified water: Remaining amount (20) Carboxyl vinyl polymer 1% solution: 10.0% by mass
(21) Perfume: 0.05% by mass
［実施例４：美容液］
下記の製法により、美容液を調製した。
（製法）
Ａ．下記成分（１）～（８）を混合溶解した。
Ｂ．下記成分（９）～（１８）を混合溶解した。
Ｃ．ＢにＡを加え混合し、実施例４に係る美容液を得た。
[Example 4: Essence]
A beauty essence was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (8) were mixed and dissolved.
B. The following components (9) to (18) were mixed and dissolved.
C. A was added to B and mixed to obtain a beauty essence according to Example 4.
（１）トリ２－エチルヘキサン酸グリセリル：０．１質量％
（２）メドウホーム油：０．０５質量％
（３）ホホバ油：０．０５質量％
（４）パラオキシ安息香酸メチル：０．０５質量％
（５）香料：０．０５質量％
（６）モノオレイン酸ポリオキシエチレン（２０Ｅ．Ｏ．）ソルビタン：０．５質量％
（７）イソステアリン酸ポリオキシエチレン硬化ヒマシ油（５０Ｅ．Ｏ．）：１．５質量％
（８）エタノール：５．０質量％
（９）グリセリン：４．０質量％
（１０）ジプロピレングリコール：８．０質量％
（１１）１，３－ブチレングリコール：８．０質量％
（１２）乳酸ナトリウム：０．５質量％
（１３）ピロリドンカルボン酸ナトリウム（５０％）液：０．５質量％
（１４）キンコウボク抽出物：１０．０質量％
（１５）アルブチン：０．２質量％
（１６）ヒドロキシエチルセルロース：０．０８質量％
（１７）アルギン酸ナトリウム：０．０５質量％
（１８）精製水：残量
(1) Glyceryl tri-2-ethylhexanoate: 0.1% by mass
(2) Meadowhome oil: 0.05% by mass
(3) Jojoba oil: 0.05% by mass
(4) Methyl paraoxybenzoate: 0.05% by mass
(5) Perfume: 0.05% by mass
(6) Polyoxyethylene monooleate (20E.O.) sorbitan: 0.5% by mass
(7) polyoxyethylene hydrogenated castor oil isostearate (50 E.O.): 1.5% by mass
(8) Ethanol: 5.0% by mass
(9) Glycerin: 4.0% by mass
(10) Dipropylene glycol: 8.0% by mass
(11) 1,3-butylene glycol: 8.0% by mass
(12) Sodium lactate: 0.5% by mass
(13) Sodium pyrrolidonecarboxylate (50%) liquid: 0.5% by mass
(14) Kinkouboku extract: 10.0% by mass
(15) Arbutin: 0.2% by mass
(16) Hydroxyethyl cellulose: 0.08% by mass
(17) Sodium alginate: 0.05% by mass
(18) Purified water: remaining amount
［実施例５：パック］
以下の製法により、パックを調製した。
（製法）
Ａ．下記成分（１）～（６）を加熱溶解した。
Ｂ．下記成分（７）～（１１）を混合溶解した。
Ｃ．Ａを冷却後、Ｂを加え混合し、実施例５に係るパックを得た。
[Example 5: Pack]
A pack was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (6) were heated and dissolved.
B. The following components (7) to (11) were mixed and dissolved.
C. After cooling A, B was added and mixed to obtain a pack according to Example 5.
（１）ポリビニルアルコール：１２．０質量％
（２）メチルセルロース：０．１質量％
（３）グリセリン：３．０質量％
（４）１，３－ブチレングリコール：５．０質量％
（５）キンコウボク抽出物：５．０質量％
（６）精製水：残量
（７）香料：０．０２質量％
（８）パラオキシ安息香酸メチル：０．０５質量％
（９）トリ２－エチルヘキサン酸グリセリル：０．１質量％
（１０）モノオレイン酸ポリオキシエチレン（２０Ｅ．Ｏ．）ソルビタン：１．０質量％（１１）エタノール：１３．０質量％
(1) Polyvinyl alcohol: 12.0% by mass
(2) Methylcellulose: 0.1% by mass
(3) Glycerin: 3.0% by mass
(4) 1,3-butylene glycol: 5.0% by mass
(5) Kinkouboku extract: 5.0% by mass
(6) Purified water: Remaining amount (7) Perfume: 0.02% by mass
(8) Methyl paraoxybenzoate: 0.05% by mass
(9) Glyceryl tri-2-ethylhexanoate: 0.1% by mass
(10) Polyoxyethylene monooleate (20E.O.) sorbitan: 1.0% by mass (11) Ethanol: 13.0% by mass
［実施例６：リキッドファンデーション（Ｏ／Ｗ型）］
以下の製法により、リキッドファンデーションを調製した。
（製法）
Ａ．下記成分（１）～（７）を加熱溶解した。
Ｂ．Ａに下記成分（８）～（１１）を加え、均一に混合し、７０℃に保った。
Ｃ．下記成分（１２）～（１６）を加熱溶解し、７０℃に保った。
Ｄ．ＣにＢを加えて乳化した。
Ｅ．Ｄを冷却後、下記成分（１７）を加え混合し、実施例６に係るリキッドファンデーション（Ｏ／Ｗ型）を得た。
[Example 6: Liquid foundation (O/W type)]
A liquid foundation was prepared by the following method.
(Manufacturing method)
A. The following components (1) to (7) were heated and dissolved.
B. The following components (8) to (11) were added to A, uniformly mixed, and kept at 70°C.
C. The following components (12) to (16) were dissolved by heating and kept at 70°C.
D. B was added to C and emulsified.
E. After cooling D, the following component (17) was added and mixed to obtain a liquid foundation (O/W type) according to Example 6.
（１）ステアリン酸：２．０質量％
（２）セタノール：０．５質量％
（３）ベヘニルアルコール：１．０質量％
（４）ワセリン：２．５質量％
（５）流動パラフィン：５．０質量％
（６）自己乳化型モノステアリン酸グリセリン：１．０質量％
（７）パラオキシ安息香酸メチル：０．１５質量％
（８）酸化チタン：６．０質量％
（９）着色顔料：４．０質量％
（１０）マイカ：２．０質量％
（１１）タルク：４．０質量％
（１２）カルボキシメチルセルロース：０．２質量％
（１３）ベントナイト：０．４質量％
（１４）キンコウボク抽出物：０．０１質量％
（１５）１，３－ブチレングリコール：８．０質量％
（１６）精製水：残量
（１７）香料：０．２質量％
(1) stearic acid: 2.0% by mass
(2) Cetanol: 0.5% by mass
(3) behenyl alcohol: 1.0% by mass
(4) Vaseline: 2.5% by mass
(5) Liquid paraffin: 5.0% by mass
(6) Self-emulsifying glyceryl monostearate: 1.0% by mass
(7) Methyl paraoxybenzoate: 0.15% by mass
(8) Titanium oxide: 6.0% by mass
(9) Coloring pigment: 4.0% by mass
(10) Mica: 2.0% by mass
(11) Talc: 4.0% by mass
(12) Carboxymethylcellulose: 0.2% by mass
(13) Bentonite: 0.4% by mass
(14) Kinkouboku extract: 0.01% by mass
(15) 1,3-butylene glycol: 8.0% by mass
(16) Purified water: Remaining amount (17) Perfume: 0.2% by mass
［実施例７：乳液（Ｏ／Ｗ型）］
以下の製法により、乳液を調製した。
（製法）
Ａ：下記成分（１）～（２）を７０℃で均一に溶解混合した。
Ｂ：下記成分（３）～（１１）を８０℃で均一に溶解混合した
Ｃ：ＡにＢを添加し７０℃で乳化した。
Ｄ：Ｃに下記成分（１２）～（１７）を添加混合した後、４０℃まで冷却して、
Ｅ：Ｄにあらかじめ混合した下記成分（１８）～（２４）を混合し、乳液（Ｏ／Ｗ型）を得た。
[Example 7: Emulsion (O/W type)]
A milky lotion was prepared by the following method.
(Manufacturing method)
A: The following components (1) and (2) were uniformly dissolved and mixed at 70°C.
B: Components (3) to (11) below were uniformly dissolved and mixed at 80°C. C: B was added to A and emulsified at 70°C.
D: After adding and mixing the following components (12) to (17) to C, cool to 40°C,
E: The following ingredients (18) to (24) that had been mixed in advance with D were mixed to obtain an emulsion (O/W type).
（１）１，３－ブチレングリコール：１２．０質量％
（２）精製水：残量
（３）モノステアリン酸ポリエチレングリコール（４０Ｅ．Ｏ．）：０．５質量％
（４）セスキオレイン酸ソルビタン：０．１質量％
（５）水添レシチン：０．１
（６）ヒドロキシステアリン酸コレステリル （注１）：３．０質量％
（７）ワセリン：２．０質量％
（８）α－オレフィンオリゴマー：５．０質量％
（９）シアバター：２．０質量％
（１０）ジメチルポリシロキサン（１０ＣＳ）：１．０質量％
（１１）セラミド３：０．１質量％
（１２）セトステアリルアルコール：２．０質量％
（１３）ベヘニルアルコール：１．０質量％
（１４）パラオキシ安息香酸メチル：０．１質量％
（１５）アクリル酸・メタクリル酸アルキル共重合体 （注２）：０．１質量％
（１６）キサンタンガム：０．１質量％
（１７）水酸化ナトリウム：０．０３質量％
（１８）ヒアルロン酸ナトリウム：０．０００５質量％
（１９）ポリメタクロイルオキシエチルホスホリルコリン液：０．００２５質量％
（２０）アクテオシド：０．０００１質量％
（２１）エタノール：５％
（２２）アスタキサンチン：０．１質量％
（２３）トコフェロール：０．０１質量％
（２４）香料：０．２質量％
注１）サラコスＨＳ（日清オイリオ社製）
注２）ＣＡＲＣＯＰＯＡＬ ＵＬＴＲＥＺ２１（ＬＵＢＲＩＺＯＬ社製）
(1) 1,3-butylene glycol: 12.0% by mass
(2) Purified water: remaining amount (3) Polyethylene glycol monostearate (40E.O.): 0.5% by mass
(4) Sorbitan sesquioleate: 0.1% by mass
(5) Hydrogenated lecithin: 0.1
(6) Cholesteryl hydroxystearate (Note 1): 3.0% by mass
(7) Vaseline: 2.0% by mass
(8) α-olefin oligomer: 5.0% by mass
(9) Shea butter: 2.0% by mass
(10) Dimethylpolysiloxane (10CS): 1.0% by mass
(11) Ceramide 3: 0.1% by mass
(12) cetostearyl alcohol: 2.0% by mass
(13) behenyl alcohol: 1.0% by mass
(14) Methyl paraoxybenzoate: 0.1% by mass
(15) Acrylic acid-alkyl methacrylate copolymer (Note 2): 0.1% by mass
(16) xanthan gum: 0.1% by mass
(17) Sodium hydroxide: 0.03% by mass
(18) Sodium hyaluronate: 0.0005% by mass
(19) Polymethacryloyloxyethylphosphorylcholine liquid: 0.0025% by mass
(20) Acteoside: 0.0001% by mass
(21) Ethanol: 5%
(22) Astaxanthin: 0.1% by mass
(23) Tocopherol: 0.01% by mass
(24) Perfume: 0.2% by mass
Note 1) Saracos HS (manufactured by Nisshin OilliO Co., Ltd.)
Note 2) CARCOPOAL ULTREZ21 (manufactured by LUBRIZOL)
［実施例８：美容液（Ｏ／Ｗ型）］
以下の製法により、美容液を調製した。
（製法）
Ａ：下記成分（１）～（３）を７０℃で均一に溶解混合した。
Ｂ：下記成分（４）～（１１）を８０℃で均一に溶解混合した。
Ｃ：ＡにＢを添加し７０℃で乳化した。
Ｄ：Ｃに下記成分（１２）～（１８）を添加混合した後、４０℃まで冷却して、
Ｅ：Ｄにあらかじめ混合した下記成分（１９）～（２１）を添加し水中油型乳化美容液を得た。
[Example 8: Essence (O/W type)]
A beauty essence was prepared by the following method.
(Manufacturing method)
A: The following components (1) to (3) were uniformly dissolved and mixed at 70°C.
B: The following components (4) to (11) were uniformly dissolved and mixed at 80°C.
C: B was added to A and emulsified at 70°C.
D: After adding and mixing the following components (12) to (18) to C, cool to 40°C,
E: The premixed components (19) to (21) below were added to D to obtain an oil-in-water emulsified beauty essence.
（１）１，３－ブチレングリコール：５．０質量％
（２）トリプロピレングリコール：３．０質量％
（３）精製水：残量
（４）モノオレイン酸ポリオキシエチレンソルビタン（２０Ｅ．Ｏ．）：０．１質量％
（５）モノステアリン酸ポリエチレングリコール（５５Ｅ．Ｏ．）：０．２５質量％
（６）マカデミアナッツ油脂肪酸フィトステリル （注３）：２．０質量％
（７）軽質流動イソパラフィン （注４）：３．０質量％
（８）ジメチルポリシロキサン（６ＣＳ）：３．０質量％
（９）コレステロール：０．１質量％
（１０）トコフェロール：０．０１質量％
（１１）セトステアリルアルコール：０．５質量％
（１２）パラオキシ安息香酸メチル：０．１質量％
（１３）カルボマー （注５）：０．１５質量％
（１４）（アクリル酸Ｎａ／アクリロイルジメチルタウリンＮａ）コポリマー （注６）：０．１質量％
（１５）水酸化ナトリウム：０．０５質量％
（１６）コラーゲン：０．１質量％
（１７）エラスチン：０．１質量％
（１８）ヒアルロン酸：０．１質量％
（１９）エタノール：５．０質量％
（２０）アクテオシド：０．００５質量％
（２１）香料：０．０５質量％
注３）ＰＬＡＮＤＯＯＬ－ＭＡＳ（日本精化社製）
注４）クロラータムＬＥＳ（クローダ社製）
注５）ＣＡＲＣＯＰＯＡＬ ９８０（ＬＵＢＲＩＺＯＬ社製）
注６）ＳＩＭＵＬＧＥＬ ＥＧ（ＳＥＰＩＣ社製）
(1) 1,3-butylene glycol: 5.0% by mass
(2) Tripropylene glycol: 3.0% by mass
(3) Purified water: Remaining amount (4) Polyoxyethylene sorbitan monooleate (20 E.O.): 0.1% by mass
(5) Polyethylene glycol monostearate (55E.O.): 0.25% by mass
(6) Macadamia nut oil fatty acid phytosteryl (Note 3): 2.0% by mass
(7) Light liquid isoparaffin (Note 4): 3.0% by mass
(8) Dimethylpolysiloxane (6CS): 3.0% by mass
(9) Cholesterol: 0.1% by mass
(10) Tocopherol: 0.01% by mass
(11) cetostearyl alcohol: 0.5% by mass
(12) Methyl paraoxybenzoate: 0.1% by mass
(13) Carbomer (Note 5): 0.15% by mass
(14) (Na acrylate/Na acryloyldimethyltaurate) copolymer (Note 6): 0.1% by mass
(15) Sodium hydroxide: 0.05% by mass
(16) Collagen: 0.1% by mass
(17) Elastin: 0.1% by mass
(18) hyaluronic acid: 0.1% by mass
(19) Ethanol: 5.0% by mass
(20) Acteoside: 0.005% by mass
(21) Perfume: 0.05% by mass
Note 3) PLANDOOL-MAS (manufactured by Nippon Fine Chemical Co., Ltd.)
Note 4) Chloratum LES (manufactured by Croda)
Note 5) CARCOPOAL 980 (manufactured by LUBRIZOL)
Note 6) SIMULGEL EG (manufactured by SEPIC)
［実施例９：軟膏］
以下の製法により、軟膏を調製した。
（製法）
Ａ．下記成分（５）～（１１）を７５℃で均一に溶解した。
Ｂ．下記成分（１）～（４）を７５℃で均一に溶解した。
Ｃ．ＡにＢを徐々に加え、７５℃で乳化し、室温に冷却して軟膏を得た。
[Example 9: Ointment]
An ointment was prepared by the following method.
(Manufacturing method)
A. Components (5) to (11) below were uniformly dissolved at 75°C.
B. The following components (1) to (4) were uniformly dissolved at 75°C.
C. B was gradually added to A, emulsified at 75°C, and cooled to room temperature to obtain an ointment.
（１）トリエタノールアミン：２．０質量％
（２）グリセリン：８．０質量％
（３）精製水：残量
（４）ヒアルロン酸ナトリウム：０．００３質量％
（５）イソアクテオシド：０．０００００５質量
（６）ポリクオタニウム－６４：０．００４質量％
（７）セタノール：４．０質量％
（８）ワセリン：３０．０質量％
（９）トコフェロール：０．０１質量％
（１０）ステアリン酸：１８．０質量％
（１１）セスキオレイン酸ソルビタン：１．５質量％
(1) Triethanolamine: 2.0% by mass
(2) Glycerin: 8.0% by mass
(3) Purified water: Remaining amount (4) Sodium hyaluronate: 0.003% by mass
(5) Isoacteoside: 0.000005 mass (6) Polyquaternium-64: 0.004 mass%
(7) Cetanol: 4.0% by mass
(8) Vaseline: 30.0% by mass
(9) Tocopherol: 0.01% by mass
(10) stearic acid: 18.0% by mass
(11) Sorbitan sesquioleate: 1.5% by mass
［実施例１０：タブレット］
以下の製法により、タブレットを調製した。
（製法）
Ａ．下記成分（１）～（７）を均一に混合し、常法に従ってタブレットを得た。
[Example 10: Tablet]
Tablets were prepared by the following method.
(Manufacturing method)
A. The following components (1) to (7) were uniformly mixed to obtain tablets according to a conventional method.
（１）乳糖：２４．０質量％
（２）結晶セルロース：２０．０質量％
（３）コーンスターチ：１５．０質量％
（４）キンコウボク抽出物：０．１質量％
（５）グリセリン脂肪酸エステル：５．０質量％
（６）二酸化ケイ素：１．０質量％
（７）デキストリン：残量
(1) Lactose: 24.0% by mass
(2) Crystalline cellulose: 20.0% by mass
(3) Cornstarch: 15.0% by mass
(4) Kinkouboku extract: 0.1% by mass
(5) Glycerin fatty acid ester: 5.0% by mass
(6) Silicon dioxide: 1.0% by mass
(7) Dextrin: remaining amount
［実施例１１：清涼飲料］
以下の製法により、清涼飲料を調製した。
（製法）
Ａ．下記成分（１）～（５）を均一に混合し、常法に従って清涼飲料を得た。
[Example 11: Soft drink]
A soft drink was prepared by the following method.
(Manufacturing method)
A. The following ingredients (1) to (5) were uniformly mixed to obtain a soft drink according to a conventional method.
（１）果糖ブドウ糖液：３０．０質量％
（２）乳化剤：０．５質量％
（３）キンコウボク抽出物：０．０１質量％
（４）香料：０．０１質量％
（５）精製水：残量
(1) fructose glucose solution: 30.0% by mass
(2) Emulsifier: 0.5% by mass
(3) Kinkouboku extract: 0.01% by mass
(4) Perfume: 0.01% by mass
(5) Purified water: remaining amount
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2022012073 | 2022-01-28 | ||
| JP2022012073 | 2022-01-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2023110910A true JP2023110910A (en) | 2023-08-09 |
Family
ID=87546537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2023011933A Pending JP2023110910A (en) | 2022-01-28 | 2023-01-30 | Tight junction formation promoter, epithelial barrier function improver, and pharmaceutical, quasi drug, food and drink, and cosmetic |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2023110910A (en) |
-
2023
- 2023-01-30 JP JP2023011933A patent/JP2023110910A/en active Pending
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