JP6904688B2 - Epithelial cell activator - Google Patents
Epithelial cell activator Download PDFInfo
- Publication number
- JP6904688B2 JP6904688B2 JP2016229344A JP2016229344A JP6904688B2 JP 6904688 B2 JP6904688 B2 JP 6904688B2 JP 2016229344 A JP2016229344 A JP 2016229344A JP 2016229344 A JP2016229344 A JP 2016229344A JP 6904688 B2 JP6904688 B2 JP 6904688B2
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- JP
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- Prior art keywords
- extract
- saffron
- keratinocytes
- cells
- skin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
本発明は、上皮細胞賦活剤に関する。 The present invention relates to epithelial cell activators.
上皮細胞は、皮膚や粘膜の上皮組織を構成する細胞を指し、表皮角化細胞、腸管上皮細胞、角膜上皮細胞、口腔粘膜細胞、結膜上皮細胞、食道上皮細胞、気道上皮細胞など、種々の細胞が存在する。 Epithelial cells refer to cells that make up the epithelial tissue of the skin and mucosa, and various cells such as epithelial keratinized cells, intestinal epithelial cells, corneal epithelial cells, oral mucosal cells, conjunctival epithelial cells, esophageal epithelial cells, and airway epithelial cells. Exists.
皮膚表皮は、生体内部からの外部環境への水分喪失を防止して水分を保持するバリア機能を有する。皮膚表皮は、下から基底層、有棘層、顆粒層、角質層(角層)から構成される。表皮に存在する細胞の95%は角化細胞(ケラチノサイトとも呼ばれる)であり、残りの5%は色素細胞(メラノサイトとも呼ばれる)やランゲルハンス細胞である。皮膚の上皮細胞である角化細胞は基底層で分裂し、有棘層、顆粒層と上層に移動しながら分化し、角質層において脱核した角質細胞となる。角質細胞は重層化して約10層の角質層を構成するが、表層から角質細胞はいわゆる垢となって順に剥がれ落ちる。基底層の角化細胞の増殖から表皮表面で角質細胞が脱落するまでを皮膚のターンオーバーという。 The skin epidermis has a barrier function of preventing water loss from the inside of the living body to the external environment and retaining water. The epidermis of the skin is composed of the basal layer, the stratum spinosum, the stratum granulosum, and the stratum corneum (stratum corneum) from the bottom. 95% of the cells present in the epidermis are keratinocytes (also called keratinocytes), and the remaining 5% are pigment cells (also called melanocytes) or Langerhans cells. Keratinocytes, which are epithelial cells of the skin, divide in the basal layer, differentiate while moving to the spinous layer, the stratum granulosum, and the upper layer, and become enucleated keratinocytes in the stratum corneum. The stratum corneum is layered to form about 10 stratum corneum, but the stratum corneum becomes so-called dirt and peels off in order from the surface layer. The process from the proliferation of keratinocytes in the basal layer to the shedding of keratinocytes on the surface of the epidermis is called skin turnover.
加齢やストレスなど種々の原因で角化細胞の機能が低下する場合がある。角化細胞の機能が低下すると、これに伴い皮膚のターンオーバーの時間が遅くなるため、角質肥厚などの分化不全が生じる。かような角質肥厚により、肌色がくすむなどの症状が現れる。 The function of keratinocytes may decrease due to various causes such as aging and stress. When the function of keratinocytes is reduced, the turnover time of the skin is delayed accordingly, resulting in poor differentiation such as hyperkeratosis. Due to such hyperkeratosis, symptoms such as dull skin color appear.
このため、角化細胞を賦活させるための物質の探索がこれまでも行われてきた。例えば、特許文献1には、ヒトリシズカ抽出物が表皮角化細胞を増殖させる機能を有することが記載されている。 For this reason, the search for substances for activating keratinocytes has been carried out. For example, Patent Document 1 describes that the human lizard extract has a function of proliferating epidermal keratinized cells.
一方、サフランは、アヤメ科クロッカス属の多年草であり、そのめしべは香辛料として用いられている。特許文献2では、サフランのめしべの抽出物により、真皮線維芽細胞および毛乳頭細胞が賦活することが記載されている。 On the other hand, saffron is a perennial plant belonging to the genus Crocus of the Iridaceae family, and its pistil is used as a spice. Patent Document 2 describes that saffron pistil extract activates dermal fibroblasts and dermal papilla cells.
上皮細胞を賦活させるための物質の探索は現在も希求されている。したがって、本発明の目的は、上皮細胞の細胞賦活、特に角化細胞の細胞を賦活させる薬剤を提供することである。 The search for substances to activate epithelial cells is still sought after. Therefore, an object of the present invention is to provide a drug that activates cells of epithelial cells, particularly cells of keratinocytes.
本発明者らは、上記目的を達成するために、種々の成分を探索した結果、サフラン抽出物が上皮細胞賦活作用を有することを見出し、本発明を完成させた。 As a result of searching for various components in order to achieve the above object, the present inventors have found that the saffron extract has an epithelial cell activating effect, and completed the present invention.
したがって、本発明は、アヤメ科クロッカス属サフランの抽出物を含有する、上皮細胞賦活剤である。 Therefore, the present invention is an epithelial cell activator containing an extract of Iridaceae Crocus saffron.
本発明によれば、上皮細胞を賦活することで、上皮細胞の機能が低下したことに伴う諸症状の改善が可能となる。 According to the present invention, by activating epithelial cells, it is possible to improve various symptoms associated with a decrease in the function of epithelial cells.
以下、本発明の実施の形態を説明する。なお、本発明は、以下の実施の形態のみには限定されない。本明細書において、範囲を示す「X〜Y」は、XおよびYを含み、「X以上Y以下」を意味する。また、特記しない限り、操作および物性等の測定は室温(20〜25℃)/相対湿度40〜50%RHの条件で行う。 Hereinafter, embodiments of the present invention will be described. The present invention is not limited to the following embodiments. In the present specification, "X to Y" indicating a range includes X and Y and means "X or more and Y or less". Unless otherwise specified, operations and physical properties are measured under the conditions of room temperature (20 to 25 ° C.) / relative humidity of 40 to 50% RH.
本発明の上皮細胞賦活剤は、アヤメ科クロッカス属サフランの抽出物を有効成分とする。有効成分が植物の抽出物であるため、生体、特に皮膚に対する安全性が高い。 The epithelial cell activator of the present invention contains an extract of Iridaceae Crocus saffron as an active ingredient. Since the active ingredient is a plant extract, it is highly safe for living organisms, especially the skin.
上皮細胞としては、例えば、表皮角化細胞、腸管上皮細胞、角膜上皮細胞、口腔粘膜細胞、結膜上皮細胞、食道上皮細胞、気道上皮細胞などが挙げられる。中でも、上皮細胞は(表皮)角化細胞であることが好ましい。 Examples of epithelial cells include epithelial keratinocytes, intestinal epithelial cells, corneal epithelial cells, oral mucosal cells, conjunctival epithelial cells, esophageal epithelial cells, airway epithelial cells and the like. Among them, epithelial cells are preferably (epidermis) keratinocytes.
細胞賦活とは、上皮細胞が本来有する機能の活性化および/または機能の向上を指し、具体的には、細胞増殖、刺激応答性の活性化、外部因子によるストレス耐性の向上などが挙げられる。 Cell activation refers to activation of the function inherent in epithelial cells and / or improvement of function, and specific examples thereof include cell proliferation, activation of stimulus responsiveness, and improvement of stress tolerance by external factors.
細胞賦活剤の適用対象は、特に制限されないが、哺乳動物であることが好ましく、より好ましくは、ヒトである。 The application target of the cell activator is not particularly limited, but is preferably a mammal, and more preferably a human.
サフラン(学名:Crocus sativus)は、アヤメ科クロッカス属の多年草である。抽出物に用いられる部位としては、サフランの植物体全体、葉、茎、芽、花(ガク、花弁、めしべ、おしべ等を含む)、木質部、木皮部(樹皮)、果実(花托(果肉)、子房、果皮(内果皮、中果皮、外果皮)等を含む)、種子等の地上部;根、根茎、塊茎等の地下部などの植物体の一部が挙げられる。上記植物の部分は、単独で抽出に供せられてもあるいは2種以上の混合物の形態で抽出に供せられてもよい。これらのうち、角化細胞の賦活作用を考慮すると、花を用いることが好ましく、めしべであることがより好ましく、柱頭を用いることがさらに好ましい。すなわち、本発明の好適な形態は、アヤメ科クロッカス属サフランの抽出物が柱頭の抽出物である。 Saffron (scientific name: Crocus sativus) is a perennial plant belonging to the genus Crocus in the family Iridaceae. The parts used for the extract include the entire saffron plant, leaves, stems, buds, flowers (including gaku, petals, pistils, oshibe, etc.), woody parts, bark (pericarp), fruits (receptacles (pericarp), etc.). Above-ground parts such as ovaries, pericarps (including inner pericarp, pistil, outer pericarp), seeds; and parts of plants such as roots, rhizomes, and underground parts such as stalks. The plant portion may be subjected to extraction alone or in the form of a mixture of two or more species. Of these, considering the activating effect of keratinocytes, it is preferable to use flowers, more preferably pistils, and even more preferably stigmas. That is, in a preferred form of the present invention, the extract of the genus Saffron of the genus Crocus of the Iridaceae family is the extract of the stigma.
抽出する際に用いられる原料は、そのままの形態で抽出に供されてもよいが、抽出に供される前に、予め乾燥および/または粉砕されてもよい。これにより、原料から所望の有効成分をより効率よく抽出できる。 The raw material used for extraction may be subjected to extraction in its original form, or may be pre-dried and / or ground before being subjected to extraction. This makes it possible to more efficiently extract the desired active ingredient from the raw material.
次に、必要であれば予め乾燥および/または粉砕した原料を、適当な溶媒を用いて抽出する。ここで使用できる溶媒は、原料から有効成分を抽出できるものであれば特に制限されず、使用される植物や植物の部分に応じて適宜選択される。具体的には、水(水道水、工業用水、蒸留水、逆浸透膜水、濾過水、滅菌水、精製水等を含む);メタノール、エタノール、1−プロパノール、2−プロパノール、1−ブタノール、2−ブタノール、プロピレングリコール、1,3−ブチレングリコール等のアルコール;酢酸メチル、酢酸エチル等のエステル;アセトン等のケトン;ジエチルエーテル、ホルムアルデヒド、ジメチルスルホキシドなどが挙げられる。上記溶媒は、単独で用いても、2種以上を併用してもよい。これらのうち、抽出効率、安全性などを考慮すると、水が抽出溶媒として好ましい。すなわち、本発明の好ましい形態では、アヤメ科クロッカス属サフランの抽出物は水抽出物である。 Next, if necessary, the pre-dried and / or pulverized raw material is extracted with a suitable solvent. The solvent that can be used here is not particularly limited as long as it can extract the active ingredient from the raw material, and is appropriately selected depending on the plant to be used and the part of the plant. Specifically, water (including tap water, industrial water, distilled water, back-penetration membrane water, filtered water, sterilized water, purified water, etc.); methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, Alcohols such as 2-butanol, propylene glycol and 1,3-butylene glycol; esters such as methyl acetate and ethyl acetate; ketones such as acetone; diethyl ether, formaldehyde, dimethyl sulfoxide and the like. The above solvent may be used alone or in combination of two or more. Of these, water is preferable as the extraction solvent in consideration of extraction efficiency, safety and the like. That is, in a preferred embodiment of the present invention, the extract of Iridaceae Crocus saffron is a water extract.
抽出は、1回のみ行われても、複数回行われてもよい。後者の場合、各抽出工程は、いずれの溶媒を使用してもよく、また、各工程における抽出条件は同一であってもあるいは異なってもよい。 The extraction may be performed only once or multiple times. In the latter case, any solvent may be used in each extraction step, and the extraction conditions in each step may be the same or different.
溶媒の添加量は、原料から有効成分を抽出できるものであれば特に制限されない。具体的には、溶媒を、原料10gに対して、10〜1000mlの量、より好ましくは50〜500mlの量で添加することが好ましい。 The amount of the solvent added is not particularly limited as long as the active ingredient can be extracted from the raw material. Specifically, it is preferable to add the solvent in an amount of 10 to 1000 ml, more preferably 50 to 500 ml, with respect to 10 g of the raw material.
抽出条件もまた、原料から有効成分を抽出できるものであれば特に制限されず、例えば、冷浸法であっても熱水抽出などの温浸法であってもよい。具体的には、抽出温度は、好ましくは1〜150℃、より好ましくは5〜120℃である。また、抽出時間は、好ましくは30分〜48時間、より好ましくは1〜24時間である。このような条件であれば、原料から有効成分を効率よく抽出できる。 The extraction conditions are also not particularly limited as long as the active ingredient can be extracted from the raw material, and may be, for example, a cold dipping method or a hot dipping method such as hot water extraction. Specifically, the extraction temperature is preferably 1 to 150 ° C, more preferably 5 to 120 ° C. The extraction time is preferably 30 minutes to 48 hours, more preferably 1 to 24 hours. Under such conditions, the active ingredient can be efficiently extracted from the raw material.
上記抽出工程後は、原料及び溶媒の混合液から、固形物(原料残渣)を除去して、抽出液を分離することが好ましい。ここで、分離方法としては、特に制限されないが、濾過、遠心分離などが挙げられる。さらに、この抽出液は、そのまま使用してもよいが、必要であれば、希釈液による希釈形態、濃縮によるエキス、ペースト若しくは固体形態、凍結による凍結物形態、凍結乾燥による乾燥粉末物形態など、様々な形態(抽出物)にしてもよい。 After the extraction step, it is preferable to remove the solid matter (raw material residue) from the mixture of the raw material and the solvent to separate the extract. Here, the separation method is not particularly limited, and examples thereof include filtration and centrifugation. Further, this extract may be used as it is, but if necessary, a diluted form by a diluted solution, an extract by concentration, a paste or solid form, a frozen product form by freezing, a dried powder form by freeze-drying, etc. It may be in various forms (extracts).
また、抽出液または抽出物はさらに精製してもよい。ここで、精製方法としては、特に制限されず、公知の精製方法が使用できる。精製方法としては、活性炭処理、吸着樹脂処理、イオン交換樹脂処理などが挙げられる。 In addition, the extract or extract may be further purified. Here, the purification method is not particularly limited, and a known purification method can be used. Examples of the refining method include activated carbon treatment, adsorption resin treatment, ion exchange resin treatment and the like.
サフラン抽出物は、市販品であってもよい。 The saffron extract may be a commercially available product.
本実施形態の上皮細胞賦活剤を用いることで、活性が低下した上皮細胞を賦活することができる。具体的には、上皮細胞が腸管細胞である場合には、例えば、上皮細胞を増加させることにより、腸管機能を改善することで、栄養素の吸収を向上させることができる。また、上皮細胞が角化細胞である場合には、例えば、角質肥厚が抑制され、肌のくすみが改善されるという効果がある。ここで、好適な実施形態である角化細胞賦活剤は、角化細胞の活性が低下することに起因するくすみを改善するものであり、「くすみ」であっても、例えば、しわの凹凸によって物理的に生じるくすみを、真皮細胞に作用してしわの生成を抑制することによって改善する剤とは異なるものである。さらに、角化細胞の賦活を促進することで、皮膚の再生が促進され、例えば、創傷の治療などが期待できる。 By using the epithelial cell activator of the present embodiment, epithelial cells having reduced activity can be activated. Specifically, when the epithelial cells are intestinal cells, the absorption of nutrients can be improved by improving the intestinal function by increasing the number of epithelial cells, for example. Further, when the epithelial cells are keratinocytes, for example, there is an effect that hyperkeratosis is suppressed and dullness of the skin is improved. Here, the keratinocyte activator, which is a preferred embodiment, improves dullness caused by a decrease in the activity of keratinocytes, and even if it is "dullness", for example, due to the unevenness of wrinkles. It is different from agents that improve physically occurring dullness by acting on dermal cells and suppressing the formation of wrinkles. Furthermore, by promoting the activation of keratinocytes, skin regeneration is promoted, and for example, treatment of wounds can be expected.
上皮細胞賦活剤は、使用形態に応じて、他の添加剤を配合してもよい。 The epithelial cell activator may be blended with other additives depending on the mode of use.
本実施形態の細胞賦活剤の使用形態は、特に限定されず、経皮、経口、経鼻、局所(口内および舌下を含む)、直腸、膣投与等の様々な剤形で使用できる。 The form of use of the cell activator of the present embodiment is not particularly limited, and can be used in various dosage forms such as transdermal, oral, nasal, topical (including intraoral and sublingual), rectal, and vaginal administration.
上皮細胞賦活剤を皮膚に適用する場合には、他の添加剤としては、水、アルコール、油剤、界面活性剤、増粘剤、粉体、キレート剤、pH調整剤、保湿剤、美白剤、抗炎症剤、細胞賦活剤等の各種薬効剤、動植物・微生物由来の抽出物、香料などが挙げられる。また、上皮細胞賦活剤を皮膚に適用する場合には、その剤形は特に限定されず、剤形としては、乳液、クリーム、水性液剤、ゲル剤、パック、分散液、軟膏、液剤、粉剤(成形体も含む)、スプレー、貼付剤などが挙げられる。 When applying epithelial cell activators to the skin, other additives include water, alcohol, oils, surfactants, thickeners, powders, chelating agents, pH regulators, moisturizers, whitening agents, etc. Examples include various medicinal agents such as anti-inflammatory agents and cell activators, extracts derived from animals, plants and microorganisms, and fragrances. When the epithelial cell activator is applied to the skin, its dosage form is not particularly limited, and the dosage forms include emulsions, creams, aqueous liquids, gels, packs, dispersions, ointments, liquids, and powders ( (Including molded bodies), sprays, patches, etc.
乳液、クリームなどの乳化製剤は、水系抽出物を、脂肪、脂肪油、ラノリン、ワセリン、パラフィン、蝋、高級アルコールなどの油剤、多価アルコール類、水および乳化剤などの添加剤を用いて適宜製造することができる。 For emulsified preparations such as emulsions and creams, aqueous extracts are appropriately produced by using oils such as fat, fatty oil, lanolin, petrolatum, paraffin, wax and higher alcohol, polyhydric alcohols, water and emulsifiers. can do.
粉末およびスプレーは、有効成分に加えて、ラクトース、タルク、ケイ酸、水酸化アルミニウム、ケイ酸カルシウムおよびポリアミド粉末、またはこれらの物質の混合物のような補形薬を含んでもよい。スプレーは、塩化フッ化炭化水素や、ブタンおよびプロパンのような揮発性非置換炭化水素のような通例の高圧ガスをさらに含んでもよい。 In addition to the active ingredients, the powders and sprays may contain prostheses such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders, or mixtures of these substances. The spray may further include fluorinated hydrocarbons and conventional high pressure gases such as volatile unsubstituted hydrocarbons such as butane and propane.
貼付剤は、本実施形態の有効成分を体に制御して配送するという更なる利点を有する。このような適用形態は、適当な媒質に本実施形態の有効成分を溶解または分散させることによってなされうる。吸収増進剤を用いて、皮膚を横切る有効成分のフラックスを上昇させることも可能である。このようなフラックスの速さは、速さ制御膜を設けるか、またはポリマーマトリックスもしくはゲル中に化合物を分散させるかのいずれかによって制御することができる。 The patch has the additional advantage of controlling and delivering the active ingredient of the present embodiment to the body. Such an application can be made by dissolving or dispersing the active ingredient of the present embodiment in a suitable medium. Absorption enhancers can also be used to increase the flux of the active ingredient across the skin. The speed of such a flux can be controlled either by providing a speed control membrane or by dispersing the compound in a polymer matrix or gel.
また、上皮細胞賦活剤を経口で摂取する場合には、他の添加剤としては、賦形剤、基剤、乳化剤、安定剤、溶解助剤、矯味剤、保存剤、芳香剤、着色剤、コーティング剤などを適宜配合することができる。また、上皮細胞賦活剤を経口で摂取する場合には、その剤形は特に限定されず、錠剤、丸剤、散剤、粉剤、顆粒剤などの固体剤形;液剤、ゲル剤、などいずれの剤形であってもよい。 When the epithelial cell activator is taken orally, other additives include excipients, bases, emulsifiers, stabilizers, solubilizers, flavoring agents, preservatives, air fresheners, colorants, etc. A coating agent or the like can be appropriately blended. In addition, when the epithelial cell activator is taken orally, the dosage form is not particularly limited, and any solid dosage form such as tablets, pills, powders, powders, granules; liquids, gels, etc. It may be in shape.
経口投与のための固体剤形(錠剤、丸剤、散剤、粉剤、顆粒剤等)では、有効成分は、クエン酸ナトリウムまたはリン酸二カルシウムのような1つまたは複数の製薬上許容できる担体、および/または以下のもののいずれかと混合される:デンプン、ラクトース、スクロース、グルコース、マンニトール、および/またはケイ酸のような充填剤または増量剤;例えばカルボキシメチルセルロース、アルギン酸塩、ゼラチン、ポリビニルピロリドン、スクロースおよび/またはアラビアゴムのような粘結剤;グリセロールのような保湿剤;寒天、炭酸カルシウム、バレイショまたはタピオカデンプン、アルギン酸、ある特定のケイ酸塩、および炭酸ナトリウムのような崩壊剤;パラフィンのような溶解遅延剤;4級アンモニウム化合物のような吸収促進剤;セチルアルコールおよびモノステアリン酸グリセロールのような湿潤剤;カオリンおよびベントナイト粘土のような吸収剤;タルク、ステアリン酸カルシウム、ステアリン酸マグネシウム、固体ポリエチレングリコール、ラウリル硫酸ナトリウム、およびそれらの混合物のような潤滑剤;ならびに着色剤。錠剤および丸薬の場合、緩衝剤を含んでもよい。 In solid dosage forms for oral administration (tablets, rounds, powders, powders, granules, etc.), the active ingredient is one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate. And / or mixed with any of the following: fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; eg, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / Or a binder such as gum arabic; a moisturizer such as glycerol; a disintegrant such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; such as paraffin Dissolution retarders; Absorption enhancers such as quaternary ammonium compounds; Wetting agents such as cetyl alcohol and glycerol monostearate; Absorbents such as kaolin and bentonite clay; Starch, calcium stearate, magnesium stearate, solid polyethylene glycol , Lubricants such as sodium lauryl sucrose, and mixtures thereof; and colorants. In the case of tablets and pills, a buffer may be included.
このような適用形態は、本実施形態の上皮細胞賦活剤が標的とする上皮細胞を考慮して適宜選択される。上皮細胞が角化細胞である場合、皮膚に適用することで、標的とする角化細胞に直接的に作用するという点で有利である。また、有効成分が植物抽出物であるため、皮膚への安全性が高いという点でも有利である。皮膚に適用する場合、化粧料、医薬品、医薬部外品などの皮膚外用剤の使用形態で用いることができる。この場合、皮膚外用剤への有効成分の含有量は、効果の発現を考慮すると、固形分換算で、0.000001質量%以上であることが好ましく、効果の飽和性を考慮すると、50質量%以下であることが好ましく、0.00001〜50質量%であることがより好ましく、0.0001〜30質量%であることがさらに好ましい。なお、ここでいう固形分換算における固形分とは、サフラン抽出物の抽出溶媒(例えば、水)を揮発させた場合の残渣を指し、例えば、高粘性成分なども含む概念である。 Such an application form is appropriately selected in consideration of the epithelial cells targeted by the epithelial cell activator of the present embodiment. When the epithelial cells are keratinocytes, application to the skin is advantageous in that they act directly on the target keratinocytes. In addition, since the active ingredient is a plant extract, it is also advantageous in that it is highly safe for the skin. When applied to the skin, it can be used in the form of use of external preparations for skin such as cosmetics, pharmaceuticals, and quasi-drugs. In this case, the content of the active ingredient in the external preparation for skin is preferably 0.000001% by mass or more in terms of solid content in consideration of the manifestation of the effect, and 50% by mass in consideration of the saturation of the effect. It is preferably the following, more preferably 0.00001 to 50% by mass, and even more preferably 0.0001 to 30% by mass. The solid content in terms of solid content referred to here refers to a residue when the extraction solvent (for example, water) of the saffron extract is volatilized, and is a concept including, for example, a highly viscous component.
本発明は、さらに、表皮角化細胞にサフラン抽出物を接触させて表皮角化細胞を増殖させる、表皮角化細胞の増殖方法をも提供する。具体的には、サフラン抽出物を含む培地に表皮角化細胞を接触させて表皮角化細胞を増殖させる、表皮角化細胞の増殖方法である。 The present invention also provides a method for proliferating epidermal keratinocytes, in which epidermal keratinocytes are brought into contact with a saffron extract to proliferate the epidermal keratinocytes. Specifically, it is a method for proliferating epidermal keratinocytes, in which epidermal keratinocytes are brought into contact with a medium containing a saffron extract to proliferate the epidermal keratinocytes.
培養のための単離されたヒト表皮細胞(ケラチノサイト)は、それ自体公知の各種方法により調製することができる。その培養は初代培養及び継代培養のいずれも、同様にして行なうことができ、培養は、基本的には常法に従い、例えば37℃、5%炭酸ガス気相下に実施することができる。培養皿のサイズ、培養基材、播種時の細胞密度、培地交換時期等にも制限はない。 Isolated human epidermal cells (keratinocytes) for culturing can be prepared by various methods known per se. Both the primary culture and the subculture can be carried out in the same manner, and the culture can be carried out basically according to a conventional method, for example, at 37 ° C. under a 5% carbon dioxide gas phase. There are no restrictions on the size of the culture dish, the culture substrate, the cell density at the time of seeding, the time of medium replacement, and the like.
基礎培地としては、特に制限されず、公知のものを使用することができる。具体的には、DMEM、MEM、F12、DME、RPMI1640、MCDB(MCDB102、104、107、131、153、199など)、L15、SkBM、RITC80−7、DMEM/F12、CnT−Prime等が挙げられる。 The basal medium is not particularly limited, and known ones can be used. Specific examples thereof include DMEM, MEM, F12, DME, RPMI1640, MCDB (MCDB102, 104, 107, 131, 153, 199, etc.), L15, SkBM, RITC80-7, DMEM / F12, CnT-Prime and the like. ..
基礎培地に添加されるサフラン抽出物の濃度は、増殖作用が効果的に現れることから、固形分で15μg/mL以上であることがより好ましく、30μg/mL以上であることがさらに好ましい。基礎培地に添加されるサフラン抽出物の培地中の濃度の上限は特に限定されるものではないが、効果の飽和を考慮すると、300μg/mL以下であることが好ましく、200μg/mL以下であることがより好ましく、100μg/mL以下であることがさらに好ましい。 The concentration of the saffron extract added to the basal medium is more preferably 15 μg / mL or more, and further preferably 30 μg / mL or more in terms of solid content, since the proliferative effect is effectively exhibited. The upper limit of the concentration of the saffron extract added to the basal medium in the medium is not particularly limited, but in consideration of the saturation of the effect, it is preferably 300 μg / mL or less, and 200 μg / mL or less. Is more preferable, and 100 μg / mL or less is further preferable.
サフラン抽出物を含む培地を用いることで、表皮細胞(特にヒト由来の表皮細胞)の優れた増殖が達成される。このように増殖させた皮膚片は、表皮細胞シートとして、既に知られているこの種のシートと同様にして培養皮膚移植に利用できる。 Excellent proliferation of epidermal cells (particularly human-derived epidermal cells) is achieved by using a medium containing saffron extract. The skin piece thus grown can be used as an epidermal cell sheet for skin grafting in the same manner as a sheet of this type already known.
本発明の効果を、以下の実施例および比較例を用いて説明する。ただし、本発明の技術的範囲が以下の実施例のみに制限されるわけではない。また、特記しない限り、各操作は、室温(20〜25℃)で行われる。 The effects of the present invention will be described with reference to the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. Unless otherwise specified, each operation is performed at room temperature (20 to 25 ° C.).
<製造例1>サフラン抽出物の製造方法
サフランの柱頭1kgに精製水20Lを加え、室温(25℃)にて1日(24時間)撹拌した。その後、ろ過してサフランの柱頭の水抽出物を得た。固形分濃度は2.0質量%であった。
<Production Example 1> Method for producing saffron extract 20 L of purified water was added to 1 kg of the stigma of saffron, and the mixture was stirred at room temperature (25 ° C.) for 1 day (24 hours). Then, it was filtered to obtain a water extract of the stigma of saffron. The solid content concentration was 2.0% by mass.
<製造例2>ニンジン抽出物の製造方法
オタネニンジンの根10gに100mLのエタノールを添加し、撹拌、ろ過後、精製水を添加し、50体積%エタノール水溶液に調製することでニンジン抽出物を得た。固形分濃度は2.0質量%であった。
<Production Example 2> Method for producing carrot extract A carrot extract was obtained by adding 100 mL of ethanol to 10 g of otane carrot root, stirring and filtering, and then adding purified water to prepare a 50% by volume ethanol aqueous solution. .. The solid content concentration was 2.0% by mass.
<試験例1>
ヒト由来の角化細胞(HPEKs:CellnTec社製)の細胞増殖率を測定した。
<Test Example 1>
The cell proliferation rate of human-derived keratinocytes (HPEKs: manufactured by CellnTech) was measured.
24ウェルマイクロプレートにCnt−PR(CnT−Prime, Epithelial Culture Medium:CellnTecs社製)培地を適量とり、角化細胞を1ウェルあたり1×104個になるように播種し、37℃、二酸化炭素濃度5%中にて1日静置した。 An appropriate amount of Cnt-PR (CnT-Prime, Epithelium Culture Medium: manufactured by CellnTechs) medium was placed on a 24-well microplate, and keratinized cells were seeded at 1 × 10 4 cells per well at 37 ° C. and carbon dioxide. The mixture was allowed to stand at a concentration of 5% for 1 day.
その後、サフラン抽出物の固形分最終濃度が50μg/ml、100μg/mlとなるように、サフラン抽出物を培地に添加した。 Then, the saffron extract was added to the medium so that the final solid content concentration of the saffron extract was 50 μg / ml and 100 μg / ml.
培養7日後、Cell Titer 96(登録商標) Aqueous One solution Cell Proliferation Assay(Promega社製)を各ウェルにそれぞれ培地中20体積%となるように1mLずつ添加した。1時間培養したのち、マイクロプレートリーダーを用いてリファレンスを490nmとし650nmで吸光度を測定した(n=3)。測定値の平均をとり、(抽出物添加の平均値/コントロールの平均値)×100を算出した。なお、通常の培地にて培養したものをコントロールとして用いた。 After 7 days of culturing, 1 mL of Cell Titer 96 (registered trademark) Aqueous One solution Cell Proliferation Assay (manufactured by Promega) was added to each well so as to be 20% by volume in the medium. After culturing for 1 hour, the absorbance was measured at 650 nm with a reference of 490 nm using a microplate reader (n = 3). The measured values were averaged, and (average value of extract addition / average value of control) × 100 was calculated. In addition, what was cultured in a normal medium was used as a control.
また、別途、ニンジン抽出物についても同様の試験を行った。 Separately, the same test was conducted on the carrot extract.
結果を下記表1および図1に示す。 The results are shown in Table 1 and FIG. 1 below.
上記結果より、サフラン抽出物が、顕著に表皮角化細胞の増殖を促進することができ、サフラン抽出物を有効成分として角化細胞増殖剤の用途を提供できることがわかる。 From the above results, it can be seen that the saffron extract can remarkably promote the proliferation of epidermal keratinocytes, and the saffron extract can be used as an active ingredient to provide the use of a keratinocyte proliferating agent.
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