JP2015193588A - External composition for skin - Google Patents
External composition for skin Download PDFInfo
- Publication number
- JP2015193588A JP2015193588A JP2015033450A JP2015033450A JP2015193588A JP 2015193588 A JP2015193588 A JP 2015193588A JP 2015033450 A JP2015033450 A JP 2015033450A JP 2015033450 A JP2015033450 A JP 2015033450A JP 2015193588 A JP2015193588 A JP 2015193588A
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- Japan
- Prior art keywords
- skin
- dried
- composition
- external composition
- atopic dermatitis
- 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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Abstract
Description
この発明は、じゃばら乾燥果皮末を有効成分として含む皮膚外用組成物に関する。 The present invention relates to a composition for external use containing dry dried fruit peel as an active ingredient.
アレルギーは発生機序によって大きくI型からV型に分類される(クームス分類)。
そのうち、花粉症やアレルギー性鼻炎は、別名、即時型過敏とも呼ばれるI型アレルギーであることが分かっている。なお、I型アレルギーは、アレルギーの原因となるアレルゲンに特異的に反応するIgEや一部のIgG4などの免疫グロブリン等が関与する液性免疫である(非特許文献1を参照。)。
Allergies are broadly classified from type I to type V (Coombs classification) depending on the mechanism of development.
Among them, hay fever and allergic rhinitis are known to be type I allergies, also called immediate hypersensitivity. Type I allergy is humoral immunity involving IgE that reacts specifically with allergens that cause allergies and some immunoglobulins such as IgG4 (see Non-Patent Document 1).
これに対して、アレルギー性皮膚炎やアトピー性皮膚炎は、I型アレルギーに加えて、アレルゲンに特異的に反応する感作T細胞等が関与する細胞性免疫であるIV型アレルギーと、特定のアレルゲンとは関連しない、非特異的刺激反応が関係していることが分かっている。 In contrast, allergic dermatitis and atopic dermatitis, in addition to type I allergy, type IV allergy, which is a cellular immunity involving sensitized T cells that specifically react to allergens, It has been found that non-specific stimulatory responses that are not associated with allergens are involved.
さらに、I型アレルギーに分類される花粉症や食物アレルギーとアトピー性皮膚炎の違いについて考える。花粉症の場合、花粉アレルゲンの曝露がなくなると症状が寛解する。すなわち、花粉の飛散シーズンが終わると症状はなくなり、花粉飛散期に花粉が飛散しない地域へ避難することで花粉症の発症を回避することができる。食物アレルギーはアレルギーを発症するアレルゲンを摂取・曝露しないことで、食物アレルギーの発症を防ぐことができる。つまり、花粉症や食物アレルギーは、アレルゲン曝露・アレルギー反応と症状とが対応関係にある。 Furthermore, we will consider the differences between hay fever, food allergies and atopic dermatitis, which are classified as type I allergies. In the case of hay fever, symptoms disappear when the pollen allergen exposure is removed. That is, when the pollen scattering season ends, the symptoms disappear, and the onset of hay fever can be avoided by evacuating to an area where pollen does not scatter during the pollen scattering period. Food allergies can prevent the development of food allergies by not taking or exposing allergens that develop allergies. In other words, hay fever and food allergies are associated with allergen exposure / allergic reaction and symptoms.
一方、アトピー性皮膚炎は慢性疾患であり、患者をアレルゲンに曝露されない状態に置いただけで寛解することはない。アトピー性皮膚炎の治療には、症状の発露であるアレルギー反応以外の分部に対処しなければならない。つまり、アトピー性皮膚炎は、アレルギー反応を含む複雑な病態メカニズムをもつ慢性疾患である。以上より、アトピー性皮膚炎の治療は、同じI型アレルギーに分類される花粉症や食物アレルギーの場合とは、大きく異なっている。 On the other hand, atopic dermatitis is a chronic disease and does not ameliorate just by leaving the patient unexposed to allergens. To treat atopic dermatitis, a part other than the allergic reaction that is the manifestation of symptoms must be dealt with. That is, atopic dermatitis is a chronic disease having a complicated pathological mechanism including allergic reaction. From the above, the treatment of atopic dermatitis is very different from the case of hay fever and food allergy, which are classified as the same type I allergy.
ところで、日本皮膚科学会ガイドラインにおいて、アトピー性皮膚炎は「表皮、中でも角層の異常に起因する皮膚の乾燥とバリア機能異常という皮膚の生理学的異常を伴い、多彩な非特異的刺激反応および特異的アレルギー反応が関与して生じる、慢性に経過する炎症と掻痒をその病態とする湿疹・皮膚炎群の一疾患」と定義されている。 By the way, according to the Japanese Dermatological Association guidelines, atopic dermatitis is described as “a variety of non-specific irritation reactions and idiosyncrasies, accompanied by skin abnormalities such as dryness of the epidermis, especially skin caused by abnormalities in the stratum corneum, and abnormal barrier function. It is defined as "a disease of the eczema / dermatitis group that is caused by chronic allergic inflammation and pruritus caused by a positive allergic reaction".
また、日本皮膚科学会のアトピー性皮膚炎の診断基準では、痒み、特徴的な皮疹とその分布、慢性・反復性の経過、の3つすべて当てはまるものをアトピー性皮膚炎と診断している。 In addition, according to the criteria for diagnosis of atopic dermatitis of the Japanese Dermatological Association, it is diagnosed as atopic dermatitis that applies to all three of itching, characteristic rash and its distribution, and chronic / repetitive course.
このようなアトピー性皮膚炎の定義と病態の実際を考えると、その症状を緩和するためには、アレルゲン特異的刺激反応を抑制するだけでは不十分であり、むしろ、(1)皮膚の乾燥とバリア機能異常を正常に戻すこと、(2)非特異的な刺激反応を抑え炎症を抑えること、(3)痒みを抑えることなどによって、非特異的刺激反応を抑制することのほうが重要である。 Considering the definition of such atopic dermatitis and the actual state of the pathology, it is not sufficient to suppress allergen-specific stimulation responses to alleviate the symptoms. Rather, (1) skin dryness and It is more important to suppress the nonspecific stimulation reaction by returning the abnormal barrier function to normal, (2) suppressing nonspecific stimulation reaction and suppressing inflammation, and (3) suppressing itchiness.
この非特異的刺激反応は、慢性的な炎症と痒みが生じる症状である。なお、非特異的刺激反応の原因は、患者の皮膚が乾燥して、皮膚のバリア機能が損なわれることによって、皮膚の角質直下まで伸びている神経線維を直接刺激すること、及び神経線維の刺激によって発生する神経ペプチド(サブスタンスP)が表皮内のケラチノサイトに結合して、様々な炎症性サイトカインを放出することなどである。 This non-specific stimulus response is a symptom of chronic inflammation and itching. The cause of the nonspecific stimulation reaction is that the skin of the patient is dried and the barrier function of the skin is impaired, thereby directly stimulating nerve fibers extending directly under the skin of the skin, and stimulation of nerve fibers. The neuropeptide (Substance P) generated by the keratinocytes binds to keratinocytes in the epidermis and releases various inflammatory cytokines.
また、非特異的刺激反応は、そのまま放置しておくと、患者が炎症部分を掻き毟ることによって症状がより悪化する。そのため、アレルギー性皮膚炎やアトピー性皮膚炎の治療に、アレルギー反応を抑制する抗アレルギー剤が単独で使用されることは稀であり、非特異的反応を抑えるためにプロピオン酸クロベタゾールなどのステロイド剤が併用されること、又はステロイド剤が単独で使用されることが多い。 In addition, if the non-specific stimulation reaction is left as it is, the symptom is further worsened by the patient scratching the inflamed part. Therefore, antiallergic agents that suppress allergic reactions are rarely used alone in the treatment of allergic dermatitis and atopic dermatitis, and steroids such as clobetasol propionate are used to suppress nonspecific reactions. Are often used in combination, or steroids are often used alone.
ただ、ステロイド剤は、内服薬の場合には高血圧、糖尿病、骨粗鬆症、緑内障、白内障、感染症に罹患し易くなるなどの副作用が生じる懼れがあり、外用薬の場合には軟膏を塗った皮膚がうすくなる(皮膚萎縮)、ニキビやヘルペスなど感染症が悪化する等の副作用が生じる懼れがあるため、その使用が忌避されている。 However, steroids may cause side effects such as high blood pressure, diabetes, osteoporosis, glaucoma, cataracts, and easy infections in the case of internal medicine, and skin with ointment applied in the case of external medicine. Its use is avoided because it may cause side effects such as faintness (skin atrophy), worsening of infections such as acne and herpes.
そこで、ステロイド剤の代わりに生薬、特に柑橘類を原料とする生薬が従来から研究されている。例えば、チンピの抽出物を含む接触皮膚炎抑制剤(特許文献1を参照。)、ユズ又はウンシュウミカンの抽出物を含むRANTES産生阻害剤(特許文献2を参照。)、サンショウ抽出物を含むアトピー性皮膚炎用外用剤(特許文献3を参照。)、陳皮を有効成分とするヒスタミンH1受容体遮断剤(特許文献4を参照。)、ジャバラ抽出物を含む化粧料(特許文献5を参照。)が挙げられる。 Therefore, instead of steroidal drugs, herbal medicines, particularly herbal medicines based on citrus fruits, have been studied. For example, a contact dermatitis inhibitor containing an extract of chimpi (see Patent Document 1), a RANTES production inhibitor containing an extract of Yuzu or Citrus unshiu (see Patent Document 2), and a salamander extract. A topical preparation for atopic dermatitis (see Patent Document 3), a histamine H1 receptor blocker containing Chen as an active ingredient (see Patent Document 4), and a cosmetic containing a bellows extract (see Patent Document 5) .).
また、ウンシュウミカンの花部の抽出物を含む皮膚外用剤(特許文献6を参照。)、柑橘類由来のクリプトキサンチン及び/又はその誘導体を含むヒアルロン酸合成促進剤(特許文献7を参照。)、ジャバラ抽出物を含む局所用スキンケア組成物(特許文献8を参照。)、温州みかん由来のクリプトキサンチン及び/又はその誘導体を含む抗炎症剤(特許文献9を参照。)、八朔、甘夏、夏みかん及びグレープフルーツ等の柑橘類に含まれるオーラプテンを有効成分とするMCP−1の発現抑制剤(特許文献10を参照。)が挙げられる。 Moreover, the external preparation for skin containing the extract of the flower part of Citrus unshiu (refer patent document 6), the hyaluronic acid synthesis promoter containing cryptoxanthin derived from citrus fruits and / or its derivative (refer patent document 7), Topical skin care composition containing bellows extract (see Patent Document 8), anti-inflammatory agent containing Cryptoxanthin and / or its derivatives derived from Wenzhou oranges (see Patent Document 9), Yawata, Kanatsu, Summer oranges And an expression inhibitor of MCP-1 (see Patent Document 10) containing aurapten contained in citrus fruits such as grapefruit as an active ingredient.
しかし、これらの皮膚外用剤等は、ある程度の治療効果を供えてはいるものの、その効果は限定的であり、特に非特異的刺激反応の抑制効果は不十分であった。そのため、これら皮膚外用剤等だけでは、アレルギー性皮膚炎やアトピー性皮膚炎を治療できず、現時点ではステロイド剤を使用しなければならない。 However, although these external preparations for skin and the like provide a certain degree of therapeutic effect, the effect is limited, and in particular, the effect of suppressing non-specific stimulation reaction is insufficient. Therefore, allergic dermatitis and atopic dermatitis cannot be treated with these external preparations for skin alone, and steroids must be used at present.
そこで、この発明は、ステロイド剤を使用しなくても、アレルギー性皮膚炎やアトピー性皮膚炎の症状を軽減・治療する効果が高く、アレルゲン特異的刺激反応の抑制に加えて、非特異的刺激反応についても抑制でき、環境にも優しい皮膚外用組成物を提供することを課題とする。 Therefore, the present invention is highly effective in alleviating and treating symptoms of allergic dermatitis and atopic dermatitis without using a steroid, and in addition to suppressing allergen-specific stimulation reactions, non-specific stimulation An object of the present invention is to provide a composition for external use on the skin which can suppress the reaction and is friendly to the environment.
発明者は、鋭意検討の結果、じゃばらの乾燥果皮末を皮膚外用組成物に使用することによって、ステロイド剤を使用せずとも、アレルギー性皮膚炎やアトピー性皮膚炎の症状を充分軽減・治療できること、特にアレルゲン特異的刺激反応の抑制に加えて、非特異的刺激反応についても抑制できること、及びこれらの効果がナリルチンによって生じることを見出し、この発明を完成させた。 As a result of intensive studies, the inventor has been able to sufficiently reduce and treat symptoms of allergic dermatitis and atopic dermatitis without using steroids by using dried dry skin powder in the composition for external use. In particular, in addition to the suppression of allergen-specific stimulation responses, it was found that non-specific stimulation responses can also be suppressed, and that these effects are produced by nariltin, and the present invention has been completed.
すなわち、この出願の請求項1に記載の皮膚外用組成物は、じゃばら乾燥果皮末を有効成分として含むものである。また、請求項2に記載の皮膚外用組成物は、請求項1に記載の皮膚外用組成物であって、じゃばら果皮を熱乾燥法、フリーズドライ法、スプレードライ法の何れかによって乾燥するものである。また、請求項3に記載の皮膚外用組成物は、請求項2に記載の皮膚外用組成物であって、じゃばら果皮をフリーズドライ法によって乾燥したのち、熱乾燥法によって乾燥するものである。さらに、請求項4に記載の皮膚外用組成物は、請求項3に記載の皮膚外用組成物であって、80℃で熱乾燥するものである。
That is, the external composition for skin according to
この発明の皮膚外用組成物は、アトピー性皮膚炎やアレルギー性皮膚炎の症状を軽減する効果に優れている。また、従来は焼却廃棄されていたじゃばら果皮が利用できるため、環境にも優しい。 The external composition for skin of this invention is excellent in the effect of reducing the symptoms of atopic dermatitis and allergic dermatitis. In addition, it is environmentally friendly because it can use the peels that had been discarded by incineration.
この発明の皮膚外用組成物は、じゃばら乾燥果皮末を有効成分として含むものである。そこで、この発明の構成要素であるじゃばら乾燥果皮末、他の構成要素及び調製方法などについて以下に詳説する。 The composition for external use of the skin of the present invention contains dry dried fruit skin powder as an active ingredient. Then, the dry rose peel powder which is a component of this invention, another component, a preparation method, etc. are explained in full detail below.
1.じゃばら乾燥果皮末
(1)じゃばら果実
この発明で使用するじゃばら果実は、特に限定することなく使用できる。中でも、単位重量当たりのナリルチンの含有量が多いことから、摘果された果実や果皮が黄変する以前の未成熟段階の果実が好ましい。ここで、未成熟段階の果実とは、具体的には、着果から3月〜4月後に摘果した果実が好ましい。なお、じゃばらは、一般的に6月ごろに着果することから、9月〜10月ごろに収穫された果実が好ましい。
1. Jabal dried fruit powder (1) Jabal fruit Jabal fruit used in the present invention can be used without any particular limitation. Especially, since there is much content of the narirutin per unit weight, the fruit of the immature stage before yellowing of the fruit and fruit peel which were picked is preferable. Here, specifically, the immature stage fruit is preferably a fruit that has been harvested three to four months after fruit set. In addition, since potatoes generally fruit around June, fruits harvested around September to October are preferable.
(2)じゃばら果皮
じゃばら果皮は、じゃばら果実から手で剥いたもの、公知の自動皮むき機により剥いたもの、果汁圧搾機により果汁を搾った後に残る残渣などが使用できるが、手間を考えると果汁圧搾機の残渣が好ましい。
(2) Jara pericarp Jara pericarp can be peeled off by hand from the perilla fruit, peeled off by a known automatic peeler, or residue left after squeezing the fruit juice from the fruit juice press. The residue of a fruit juice press is preferred.
(3)乾燥方法
じゃばら乾燥果皮末は、一般的な方法、すなわち、果皮をそのまま又は細切したのち、日陰、陽干しする自然乾燥法、乾燥機によって乾燥する熱乾燥法、フリーズドライ法、スプレードライ法又はこれらの方法を組み合わせて製造したものが、例示できる。
(3) Drying method Jabara dried skin powder is a general method, that is, after the skin has been cut or shredded, shaded, dried naturally, dried by a dryer, freeze dried, spray dried, spray Examples thereof include those produced by a dry method or a combination of these methods.
中でも、フリーズドライ法で乾燥したのち、熱乾燥法によって乾燥することによって製造したものが好ましく、80℃で熱乾燥したものがより好ましい。このようにして製造したじゃばら乾燥果皮は、高いナリルチン濃度を維持したまま、酸化されるとアレルギー誘発物質になるリモネンが完全に除去されている。そのため、この発明の皮膚外用組成物自身によるアレルギー等が発症する可能性をほぼ完全に無くすことができる。 Among these, those produced by drying by freeze drying and then drying by heat drying are preferred, and those produced by heat drying at 80 ° C. are more preferred. Limonene, which is an allergen when it is oxidized, is completely removed from the dried dry peel of the rose thus produced while maintaining a high concentration of naliltin. Therefore, the possibility of developing allergies or the like due to the external composition for skin of the present invention can be almost completely eliminated.
(4)果皮末化
じゃばら乾燥果皮は、ボールミル等を使用する公知の粉砕方法により果皮末に加工して使用する。なお、果皮末に加工する際の粉末の大きさは、200〜1000メッシュのものが好ましい。粉末が200メッシュの篩を通らないほど大きければ、乾燥果皮末から溶出するナリルチン量が限定され、粉末が1000メッシュの篩を通り抜けるほど小さければ粉砕に手間が掛かるからである。
(4) Peeling of fruit peel The dried dry peel is processed into a powdered powder by a known grinding method using a ball mill or the like. In addition, as for the magnitude | size of the powder at the time of processing into a pericarp powder, the thing of 200-1000 mesh is preferable. This is because if the powder is so large that it does not pass through a 200-mesh sieve, the amount of nariltin eluted from the dried pericarp is limited, and if the powder is so small that it passes through a 1000-mesh sieve, it will take time to grind.
(5)含有量
皮膚外用組成物におけるじゃばら乾燥果皮末の含有量は、0.01〜10%(重量%、特に記載がなければ以下同じ。)であり、1〜5%が好ましい。1%以上であれば充分な効果が得られ、5%以下であれば塗り心地、安定性、色味がよいからである。
(5) Content The content of the dried dry skin powder in the composition for external use of skin is 0.01 to 10% (% by weight, the same shall apply hereinafter unless otherwise specified), and preferably 1 to 5%. This is because if it is 1% or more, a sufficient effect is obtained, and if it is 5% or less, the coating comfort, stability, and color are good.
(6)その他の成分
この発明の皮膚外用組成物は、この発明の効果を損なわない範囲において、一般に化粧料、医薬部外品、医薬品等の皮膚外用組成物に使用される公知の任意成分を必要に応じて加えてもよい。
(6) Other components The composition for external use of the skin of the present invention is a known optional component that is generally used for compositions for external use of skin such as cosmetics, quasi-drugs, and pharmaceuticals as long as the effects of the present invention are not impaired. You may add as needed.
具体的には、例えば、陰イオン(高級脂肪酸アルカリ金属塩、高級脂肪酸アミン塩、アミノ酸系界面活性剤)、非イオン界面活性剤、リン脂質ステロールエステルなどの界面活性剤、炭化水素(流動パラフィン、スクワラン、ワセリンなど)、油脂(動植物油、トリグリセリド、ワックスエステル、高級アルコール、高級脂肪酸、シリコーン、エステル油、ロウ類など)など、湿潤剤(グリセリン等の多価アルコール、糖類、生体高分子、アミノ酸、ペプチド類など)、アルコール(エチルアルコール)、皮膜形成剤(ポリビニルアルコール、ぺクチン)、水溶性、油溶性高分子、エチルヘキサン酸セチル等の保湿剤、紫外線吸収剤、防腐剤(メチルパラベン、フェノキシエタノール)、抗酸化剤、増粘剤(ポリアクリルアミド、ラウレス-7、水添ポリイソブテン)、金属封鎖剤、着色剤(天然色素、合成色素)、各種香料、各種植物抽出物及び動物抽出物、ビタミン剤(油溶性ビタミン、水溶性ビタミン)、アルブチン、コウジ酸、エラグ酸、尿素、アラントイン、抗炎症剤(グルチルレチン酸、グリチルリチン酸、アズレン)、収斂剤(パラフェノールスルホン酸亜鉛)、クエン酸を含む有機酸類とその塩等、及び粉体(有機粉体、無機系粉体)などが挙げられる。 Specifically, for example, anions (higher fatty acid alkali metal salts, higher fatty acid amine salts, amino acid surfactants), nonionic surfactants, surfactants such as phospholipid sterol esters, hydrocarbons (liquid paraffin, Wetting agents (polyhydric alcohols such as glycerin, saccharides, biopolymers, amino acids) such as squalane and petrolatum), fats and oils (animal and vegetable oils, triglycerides, wax esters, higher alcohols, higher fatty acids, silicones, ester oils, waxes, etc.) , Peptides, etc.), alcohol (ethyl alcohol), film forming agents (polyvinyl alcohol, pectin), water-soluble, oil-soluble polymers, humectants such as cetyl ethylhexanoate, UV absorbers, preservatives (methylparaben, phenoxyethanol) ), Antioxidants, thickeners (polyacrylamide, laureth-7) Hydrogenated polyisobutene), sequestering agents, coloring agents (natural pigments, synthetic pigments), various fragrances, various plant extracts and animal extracts, vitamins (oil-soluble vitamins, water-soluble vitamins), arbutin, kojic acid, ellagic acid , Urea, allantoin, anti-inflammatory agents (glutyl retinoic acid, glycyrrhizic acid, azulene), astringents (zinc paraphenol sulfonate), organic acids and salts thereof including citric acid, and powders (organic powders, inorganic powders) Body).
(7)調製方法
この発明の皮膚外用組成物は、化粧料、医薬部外品、医薬品等を調製する公知の方法により調製できる。具体的には、高速ホモミキサー、プラネタリーミキサー、流動式混合機などにより、皮膚外用組成物の構成成分を混合することによって調製することができる。なお、加える成分に応じて、加温や冷却しながら混合してもよい。
(7) Preparation Method The external composition for skin of the present invention can be prepared by a known method for preparing cosmetics, quasi drugs, pharmaceuticals and the like. Specifically, it can be prepared by mixing the components of the composition for external use with a high-speed homomixer, a planetary mixer, a fluid mixer, or the like. In addition, you may mix, heating or cooling according to the component to add.
(8)剤型
この発明の皮膚外用組成物は、皮膚に使用するものであれば特に限定しない。具体的には、溶液系、可溶化系、乳化系、粉末分散系、水―油二層系、水―油―粉末系、水―油―シリコーン系の三層系や親水性軟膏や吸水性軟膏、ゲル系、エアゾール系など任意の剤型でよい。
(8) Dosage form The external composition for skin of the present invention is not particularly limited as long as it is used on the skin. Specifically, solution system, solubilization system, emulsification system, powder dispersion system, water-oil two-layer system, water-oil-powder system, water-oil-silicone three-layer system, hydrophilic ointment and water absorption Any dosage form such as an ointment, a gel system, and an aerosol system may be used.
(9)用途
この発明の皮膚外用組成物は、外皮に使用される化粧料、医薬部外品、医薬品等に広範囲に使用できる。具体的には、洗顔料、乳液、クリーム、化粧水、パック、美容液等のスキンケア化粧料、ファンデーションなどのベースメイクアップや口紅、アイシャドウ、アイライナーなどのポイントメークやシャンプー、リンス、コンディショナーや頭皮ケア剤などを含むヘアケア製品、浴用剤、芳香性化粧料等にも使用でき、分野別では、サンケア商品、ボディケア商品、美白商品や抗老化用商品にも使用できる。
(9) Applications The external composition for skin of the present invention can be used in a wide range of cosmetics, quasi-drugs, pharmaceuticals and the like used for the outer skin. Specifically, skin care cosmetics such as facial cleansers, milky lotions, creams, lotions, packs, beauty essences, base makeup such as foundations, point makeup such as lipsticks, eye shadows, eyeliners, shampoos, rinses, conditioners, etc. It can also be used in hair care products including scalp care agents, bath preparations, aromatic cosmetics, etc., and can also be used in sun care products, body care products, whitening products and anti-aging products.
以下に、実施例に基づいてこの発明をより具体的に説明する。ただし、これらの実施例は如何なる意味においても特許請求の範囲に記載の発明を限定するものではない。 Hereinafter, the present invention will be described more specifically based on examples. However, these examples do not limit the invention described in the claims in any way.
1.皮膚外洋性組成物アレルギー性皮膚炎等に与える影響
(1)じゃばら乾燥果皮末の調製
和歌山県和歌山市松江北のじゃばら果樹からじゃばら果実を10月末頃に採取して、その果皮を手で剥ぎ取った。剥ぎ取った果皮を-70℃のフリーズドライ法で乾燥したのち、80℃で8時間熱乾燥して乾燥果皮を得た。乾燥果皮をボールミルで粉砕して、200メッシュの篩に掛け、200メッシュの篩を通過したじゃばら乾燥果皮末を得た。
1. Effects on outer skin composition allergic dermatitis, etc. (1) Preparation of dried dried fruit skin Jabara fruits were collected from the grown fruit trees of Matsue-kita in Wakayama City, Wakayama Prefecture at the end of October and peeled off by hand. . The peeled peel was dried by a freeze-drying method at -70 ° C and then heat-dried at 80 ° C for 8 hours to obtain a dried peel. The dried pericarp was pulverized with a ball mill, passed through a 200 mesh sieve, and a dried dried pericarp powder that passed through the 200 mesh sieve was obtained.
(2)皮膚外用組成物の調製
この発明に係る皮膚外用組成物を調製した。具体的には、表1に記載の成分をビーカーに入れ、ホモミキサーや攪拌機で攪拌して調製した。
(2) Preparation of external composition for skin The external composition for skin according to the present invention was prepared. Specifically, the components listed in Table 1 were put in a beaker and prepared by stirring with a homomixer or a stirrer.
(3)皮膚外用組成物の性能試験
(2)で製造した皮膚外用組成物を、成人男女各10名(20代〜50代)の顔及び皮膚に塗布して、その性能を「使用感試験」、「刺激試験」、「肌質改善試験」により評価した。その結果を表2から表4に示す。
(3) Performance test of composition for external use on skin The composition for external use in skin prepared in (2) was applied to the face and skin of 10 adult men and women (20s to 50s). ”,“ Irritation test ”, and“ Skin quality improvement test ”. The results are shown in Tables 2 to 4.
なお、「使用感試験」は、塗布直後の肌馴染みや塗布直後及び翌日の保湿感を被験者へのアンケートによって評価する試験である。また、「刺激試験」は塗布直後に塗布部分に感じた刺激を被験者へのアンケートによって評価する試験である。さらに、「肌質改善試験」は、1日2回30日間塗布したのち、塗布部分の症状の変化を目視により評価する試験である。 The “use feeling test” is a test for evaluating skin familiarity immediately after application and moisturizing feeling immediately after application and the next day by a questionnaire to the subject. Further, the “stimulus test” is a test for evaluating a stimulus felt in the application part immediately after application by a questionnaire to the subject. Furthermore, the “skin quality improvement test” is a test in which after applying twice a day for 30 days, a change in symptoms of the applied part is visually evaluated.
表2は「使用感試験」の結果を示しており、この表から、この発明の皮膚外用組成物は、皮膚の乾燥とバリア機能異常を正常に戻し、肌馴染みや、保湿感などの使用感の点で優れことが分かった。また、表3は「刺激試験」の結果を示しており、この表から、この発明の皮膚外用組成物は塗布しても皮膚に有害な刺激を与えないことが分かった。さらに、表4は「肌質改善試験」の結果を示しており、この表から、この発明の皮膚外用組成物は、皮膚の乾燥とバリア機能異常を正常に戻して、肌質を改善する能力に優れ、少なくとも塗布しても症状を悪化はしないことが分かった。 Table 2 shows the results of the “use feeling test”. From this table, the composition for external use of the present invention returns the skin dryness and abnormal barrier function to normal, and the feeling of use such as skin familiarity and moisturizing feeling. It turned out that it was excellent in the point. Table 3 shows the results of the “stimulation test”. From this table, it was found that the external composition for skin of the present invention does not give harmful irritation to the skin even when applied. Furthermore, Table 4 shows the results of the “skin quality improvement test”. From this table, the composition for external use of the skin of the present invention has the ability to improve skin quality by returning skin dryness and abnormal barrier function to normal. It was found that the symptoms were not worsened even when applied.
(4)アトピー性皮膚炎に対する効果の確認
(2)で製造した皮膚外用組成物をアトピー性皮膚炎の患者10人の患部に朝晩2回塗布して、症状の変化を目視により調べた。なお、患者の年齢、性別、及び症状の変化を表5に示す。
(4) Confirmation of effect on atopic dermatitis The topical skin composition produced in (2) was applied twice in the morning and evening to the affected area of 10 patients with atopic dermatitis, and changes in symptoms were examined visually. Table 5 shows changes in age, sex, and symptoms of patients.
表5から、この発明の皮膚外用組成物を患部に塗布することによって、赤い腫れ・痒みの症状(I型アレルギー)は塗布後1〜5日で改善し、好酸球の湿潤による患部の湿潤(IV型アレルギー、アトピー性皮膚炎)も塗布後5〜14日で改善した。なお、前記のように皮膚の赤い腫れ、痒み、患部の湿潤は、非特異的反応に関係しているので、この発明の皮膚外用組成物は非特異的反応の抑制にも貢献すると考えられる。 From Table 5, by applying the composition for external use of the skin of the present invention to the affected area, the symptoms of red swelling and itching (type I allergy) were improved 1 to 5 days after application, and the affected area was moistened by wetting of eosinophils. (Type IV allergy, atopic dermatitis) also improved 5-14 days after application. As described above, red swelling of the skin, itching, and wetness of the affected area are related to non-specific reactions. Therefore, it is considered that the external composition for skin of the present invention also contributes to suppression of non-specific reactions.
さて、一般的に、ステロイド剤は、即効性はあるものの、長期使用による弊害と副作用があり、反対に、生薬は、即効性は期待できないものの、体質改善などの体に穏やかな方法で作用するので副作用が少ない。 Well, in general, steroids have immediate effects, but there are adverse effects and side effects of long-term use. On the other hand, herbal medicines can not be expected to be effective immediately, but they act on the body in a gentle manner such as improving the constitution. So there are few side effects.
それにもかかわらず、この発明の皮膚外用組成物は、生薬にしては、即効性が極めて高く、かつ症状の改善効果も高かった。すなわち、この発明の皮膚外用組成物は生薬の安全性と、ステロイド剤の高い即効性及び薬効を備えていることが分かった。 Nevertheless, the composition for external use of the present invention has a very high immediate effect and a high symptom improving effect as a crude drug. That is, it was found that the composition for external use of the skin of the present invention has the safety of herbal medicine and the high immediate effect and medicinal effect of the steroid.
2.ナリルチンがアレルギー性皮膚炎等に関連する遺伝子の転写量に与える影響
じゃばら乾燥果皮末に含まれるナリルチンA及びナリルチンBが、抗アレルギー・抗炎症に関与する遺伝子の転写量に与える影響を、実験動物を使用して調べた。その詳細を以下に示す。
2. Effect of Nariltin on Transcription of Genes Related to Allergic Dermatitis, etc. Investigated using. Details are shown below.
(1)実験動物と材料
ナリルチンは、大阪薬科大学生薬学教室谷口教授が精製したものを使用した。なお、ナリルチンは、分子式C27H32O14のS体の化合物であり、立体構造的に区別する場合、2S-ナリルチンと表記される。また、精製法によっては、ナリルチン(2S-ナリルチン)の単離過程で、R体に異性化した2R-ナリルチンが20重量%程含まれる。
(1) Experimental animals and materials Nariltine used was purified by Prof. Taniguchi, Osaka University of Pharmacy. Nallutin is an S-form compound having a molecular formula of C 27 H 32 O 14 , and is expressed as 2S-nariltin when distinguishing three-dimensionally. Further, depending on the purification method, 2R-nariltin isomerized to R form in the isolation process of naryltin (2S-nariltin) is contained in an amount of about 20% by weight.
そこで、本実施例では、「ナリルチン精製品(2S-ナリルチン100重量%、以下、ナリルチンAと省略する。)」及び「2R-ナリルチンを除去していない粗精製品(2S-ナリルチン80重量%及び2R-ナリルチン20重量%の混合物、以下、ナリルチンBと省略する。)」の両方を使用した。 Therefore, in this example, “nariltin purified product (2S-nariltin 100% by weight, hereinafter abbreviated as“ nariltin A ”)” and “crude product from which 2R-nariltin has not been removed (2S-nariltin 80% by weight and A mixture of 20% by weight of 2R-nariltin, hereinafter abbreviated as “nariltin B”) ”was used.
実験動物は、NC/Ngaマウスの雌、7週齢を使用し、動物飼育施設にて1ケージあたり5匹で飼育した。飼育中の給餌は固型飼料CRF-1を給餌器に入れて自由摂取により行い、飼育中の給水は水道水を給水瓶に入れて自由摂取により行った。 The experimental animals were female NC / Nga mice, 7 weeks old, and were bred at 5 animals per cage in an animal breeding facility. Feeding during breeding was performed by free intake of solid feed CRF-1 in a feeder, and water during breeding was performed by free intake of tap water in a water bottle.
(2)アレルギーモデルマウスの作製
アレルギーモデルマウスは、Yamamoto(下記の参考文献1を参照。)らの方法に従って作製した。)。具体的には、まずNC/Ngaマウスの背部及び耳介部をバリカン、電気シェーバーにて毛刈りしたのち、除毛剤エピラットを適量塗布し除毛した。除毛剤をふき取ったのち、ビオスタAD(株式会社ビオスタ製)100mgをマイクロピペットのチップ裏部で背部及び耳介部に均一に塗布した(初回惹起)。
(2) Preparation of allergy model mouse The allergy model mouse was prepared according to the method of Yamamoto (see the following Reference 1). ). Specifically, first, the back and auricle of NC / Nga mice were shaved with a clipper and an electric shaver, and then an appropriate amount of a depilatory epirat was applied to remove the hair. After wiping off the hair remover, 100 mg of Biosta AD (manufactured by Biosta Co., Ltd.) was uniformly applied to the back and auricle on the back of the tip of the micropipette (initial induction).
初回惹起から3日後、7日後、10日後、14日後、17日後に再惹起を行った。具体的には、シェーバーで除毛のち、4% SDS水溶液 150μlをマイクロピペットで背部、耳介部に滴下しながらマイクロピペットのチップ裏部で均一に塗布後約2〜3時間自然に乾燥させた。乾燥させたのち、ビオスタAD 100mgをマイクロピペットのチップ裏部で背部及び耳介部に均一に塗布し、ダニアレルゲンによるアトピー性皮膚炎モデルを作製した。モデルを作製したのち、アトピー性皮膚炎の症状をスコア化し、麻酔下にてヘパリン採血により全採血した。
Re-induction was performed 3 days, 7 days, 10 days, 14 days, and 17 days after the initial induction. Specifically, after removing hair with a shaver, 150 μl of 4% SDS aqueous solution was dripped onto the back and auricle with a micropipette and uniformly applied on the back of the tip of the micropipette, and then naturally dried for about 2-3 hours. . After drying,
参考文献1:A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in NC/Nga mice. Yamamoto M, Haruna T, Yasui K, Takahashi H, Iduhara M, Takaki S, Deguchi M, Arimura A. Allergol Int. 2007. 56: 139-148. Reference 1: A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in NC / Nga mice. Yamamoto M, Haruna T, Yasui K, Takahashi H, Iduhara M, Takaki S, Deguchi M, Arimura A. Allergol Int. 2007. 56: 139-148.
(3)生体外刺激(ex vivo simulation)法によるmRNA転写量の測定
アレルギーモデルマウスの白血球でしている細胞性免疫関連遺伝子のmRNA転写量をex vivo simulation法により測定した。具体的には、以下のようにして測定した。
(3) Measurement of mRNA transcription amount by ex vivo simulation method The mRNA transcription amount of cellular immunity-related genes in leukocytes of allergic model mice was measured by ex vivo simulation method. Specifically, it measured as follows.
なお、細胞性免疫関連遺伝子として、好中球走化性を促進し、皮膚の非特異的な刺激反応及び炎症に関係するケモカインCXCL1遺伝子及びケモカインCCL4遺伝子、アトピー性皮膚炎の特異的刺激反応に関連するマーカーIL-16遺伝子、痒みの原因となるヒスタミンの合成に関与するL-ヒスチジン脱炭酸酵素HDC遺伝子の転写量を測定した。 As a cellular immunity-related gene, it promotes neutrophil chemotaxis, nonspecific stimulation reaction of skin and chemokine CXCL1 gene and chemokine CCL4 gene related to inflammation, specific stimulation reaction of atopic dermatitis The amount of transcription of the related marker IL-16 gene and L-histidine decarboxylase HDC gene involved in the synthesis of histamine causing itchiness was measured.
(3a)アレルゲン混合液とナリルチン溶液の調製
ダニアレルゲンDer f1及びDer f2(アサヒフードアンドヘルスケア株式会社製)を、それぞれ濃度が100μg/mlとなるように溶解・懸濁してアレルゲン混合溶液を調製した。また、ナリルチンAとナリルチンBを、血液との反応時の濃度が100μM、10μM、1μMになるようにDMSOにて溶解し、ナリルチン溶液を調製した。なお、ナリルチンを含まない溶液を実験対照として使用するため調製した。
(3a) Preparation of allergen mixed solution and narilutin solution Prepared allergen mixed solution by dissolving and suspending mite allergens Der f1 and Der f2 (Asahi Food and Healthcare Co., Ltd.) to a concentration of 100 μg / ml. did. In addition, Nariltin A and Nariltin B were dissolved in DMSO so that the concentration at the time of reaction with blood was 100 μM, 10 μM, and 1 μM to prepare a Nariltin solution. A solution containing no nariltin was prepared for use as an experimental control.
(3b)ex vivo simulation法によるmRNA転写量の測定
ヘパリン採血したマウス全血60μlに、アレルゲン混合溶液1.2μl、及びナリルチン溶液1.2μlを添加し、37℃で4時間反応させた。このナリルチン添加マウス全血中の各遺伝子のmRNAの転写量を、Mitsuhashiの方法(下記の参考文献2を参照。)に従って測定した。具体的には次のようにして行った。
(3b) Measurement of mRNA transcription amount by ex vivo simulation method To 60 μl of mouse whole blood collected from heparin, 1.2 μl of an allergen mixed solution and 1.2 μl of a nariltin solution were added and reacted at 37 ° C. for 4 hours. The amount of transcription of mRNA of each gene in the whole blood of this naliltin-added mouse was measured according to the method of Mitsuhashi (see Reference Document 2 below). Specifically, it was performed as follows.
まず、ナリルチン添加マウス全血を、全血から白血球だけを捕獲する96ウェルのフィルタープレートに通過させた。細胞溶解液をフィルタープレートの各ウェルに加え、フィルタープレートに捕獲された白血球を溶解した。なお、細胞溶解液は、測定対象となる遺伝子のmRNAアンチセンスプライマーの何れかを一つを含んでいる。 First, the whole blood of mice with naliltin was passed through a 96-well filter plate that captures only white blood cells from the whole blood. Cell lysate was added to each well of the filter plate to lyse leukocytes captured on the filter plate. The cell lysate contains one of the mRNA antisense primers for the gene to be measured.
つぎに、遠心操作によって、フィルタープレート上の細胞溶解液を96ウェルのオリゴ(dT)プレートに移して、細胞溶溶解液中のmRNAとウェル中のオリゴdTとをハイブリダイゼーションさせたのち、オリゴ(dT)プレートの各ウェルを吸引ノズルで洗浄してmRNAを精製した。 Next, the cell lysate on the filter plate is transferred to a 96-well oligo (dT) plate by centrifugation, and the mRNA in the cell lysate and the oligo dT in the well are hybridized. dT) Each well of the plate was washed with a suction nozzle to purify mRNA.
各ウェルに直接逆転写酵素とdNTPを加えて、既にmRNAにハイブリダイゼーションしているオリゴ(dT)とアンチセンスプライマーを起点として、2個所から同時にcDNAを合成した。各ウェルにDNAポリメラーゼを加えて、リアルタイムPCRによりmRNAの転写量の変化を測定し、ナリルチンの濃度の違いがmRNAの転写量に与える影響を比べた。その結果を図1から図4に示す。なお、図1から図4の縦軸は、ナリルチンの投与量が0μMの場合のmRNAの転写量を1.0としたときの相対値である。 Reverse transcriptase and dNTP were added directly to each well, and cDNA was synthesized simultaneously from two sites starting from oligo (dT) and antisense primer that had already hybridized to mRNA. DNA polymerase was added to each well, and changes in the amount of mRNA transcription were measured by real-time PCR, and the effects of differences in the concentration of nariltin on the amount of mRNA transcription were compared. The results are shown in FIGS. The vertical axis in FIGS. 1 to 4 is a relative value when the transcription amount of mRNA when the dose of narilutin is 0 μM is 1.0.
参考文献2:Mitsuhashi M. Ex vivo simulation of leukocyte function: stimulation of specific subset of leukocytes in whole blood followed by the measurement of function-associated mRNAs. J Immunol Methods. 2010, 363: 95-100. Reference 2: Mitsuhashi M. Ex vivo simulation of leukocyte function: stimulation of specific subset of leukocytes in whole blood followed by the measurement of function-associated mRNAs. J Immunol Methods. 2010, 363: 95-100.
(4)実験結果
図1は、ナリルチンの投与量が、ケモカインCXCL1遺伝子の転写量に与える影響を示すグラフである。また、図2は、ナリルチンの投与量が、ケモカインCCL4遺伝子の転写量に与える影響を示すグラフである。さらに、図3は、ナリルチンの投与量が、インターロイキンIL-16遺伝子の転写量に与える影響を示すグラフである。加えて、図4は、ナリルチンの投与量がL-ヒスチジン脱炭酸酵素HDC遺伝子の転写量に与える影響を示すグラフである。
(4) Experimental Results FIG. 1 is a graph showing the influence of the dose of narilutin on the transcription amount of the chemokine CXCL1 gene. FIG. 2 is a graph showing the influence of the dose of nariltin on the transcription amount of the chemokine CCL4 gene. Further, FIG. 3 is a graph showing the effect of the dose of nariltin on the transcription amount of the interleukin IL-16 gene. In addition, FIG. 4 is a graph showing the effect of the dose of narilutin on the transcription amount of the L-histidine decarboxylase HDC gene.
図1から図3に示すように、ナリルチンの血中濃度が1μMという低濃度でも細胞性免疫に係る遺伝子の転写が充分低下しており、特に、ケモカインCXCL1遺伝子(図1)は1μMでも殆どしていないといえる程度まで転写量が低下していることが分かった。 As shown in FIGS. 1 to 3, the transcription of the gene related to cellular immunity is sufficiently reduced even when the blood concentration of nariltin is as low as 1 μM. In particular, the chemokine CXCL1 gene (FIG. 1) is hardly even at 1 μM. It was found that the transfer amount was reduced to such an extent that it was not.
また、図4に示すように、痒みの原因であるヒスタミンの合成と関連するL-ヒスチジン脱炭酸酵素HDC遺伝子の転写量も低下していた。このことから、ナリルチンの投与によってアトピー性皮膚炎での痒み症状が抑制され、患者のQOLを向上できると考えられる。以上の結果から、この発明の皮膚外用組成物はアレルギー皮膚炎やアトピー性皮膚炎に対して高い効果を有すると推測できる。 In addition, as shown in FIG. 4, the amount of transcription of the L-histidine decarboxylase HDC gene associated with the synthesis of histamine that causes itchiness was also reduced. From this, it is considered that the itching symptom in atopic dermatitis is suppressed by administration of nariltin, and the QOL of the patient can be improved. From the above results, it can be presumed that the external composition for skin of the present invention has a high effect on allergic dermatitis and atopic dermatitis.
以上のように、この発明の皮膚外用組成物は、(1)皮膚の乾燥とバリア機能異常を正常に戻し(表2及び表4を参照。)、(2)皮膚の非特異的な刺激反応及び炎症を抑え(表5、図1及び図2を参照。)、(3)痒みを抑える(表5及び図4を参照。)ことによって、アトピー性皮膚炎の特異的刺激と非特異的刺激の何れも抑制できることが明らかになった。すなわち、この発明の皮膚外用組成物は生薬の安全性と、ステロイド剤の高い即効性及び薬効を備えていることが分かった。 As described above, the composition for external use of skin of the present invention (1) restores normal skin dryness and abnormal barrier function (see Tables 2 and 4), and (2) non-specific skin irritation reaction And by suppressing inflammation (see Table 5, FIG. 1 and FIG. 2) and (3) by suppressing itching (see Table 5 and FIG. 4), specific and non-specific stimulation of atopic dermatitis It became clear that any of these can be suppressed. That is, it was found that the composition for external use of the skin of the present invention has the safety of herbal medicine and the high immediate effect and medicinal effect of the steroid.
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