JPWO2004085486A1 - Skin external composition - Google Patents

Skin external composition Download PDF

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JPWO2004085486A1
JPWO2004085486A1 JP2005504099A JP2005504099A JPWO2004085486A1 JP WO2004085486 A1 JPWO2004085486 A1 JP WO2004085486A1 JP 2005504099 A JP2005504099 A JP 2005504099A JP 2005504099 A JP2005504099 A JP 2005504099A JP WO2004085486 A1 JPWO2004085486 A1 JP WO2004085486A1
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chitosan
composition
skin
chitin
weight
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清水　達丈
達丈 清水
栗山　澄
澄 栗山
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Sekisui Chemical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/736—Chitin; Chitosan; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin

Abstract

本発明の目的は、極めて優れた皮膚乾燥トラブル改善効果を有する皮膚外用組成物を提供することである。本発明は、下記一般式（１）で表されるキトサン、及び／又は、前記キトサンのアセチル化物であるキチンを、合計で０．５〜２０重量％含有する皮膚外用組成物である。An object of the present invention is to provide a composition for external use on the skin, which has an extremely excellent effect of improving skin dryness trouble. The present invention is an external composition for skin containing 0.5 to 20% by weight in total of chitosan represented by the following general formula (1) and / or chitin which is an acetylated product of the chitosan.

Description

本発明は、皮膚バリア機能改善効果、抗炎症効果及び止痒効果等の優れた皮膚乾燥トラブル改善効果を有するとともに、良好な使用感を示す皮膚外用組成物に関する。  The present invention relates to an external composition for skin having excellent skin dryness trouble improving effects such as a skin barrier function improving effect, an anti-inflammatory effect and an antipruritic effect, and exhibiting a good feeling of use.

従来から、皮膚の乾燥トラブルを防ぐための外用剤として、尿素、ヘパリン類似物質又はワセリンのような様々な医薬品が用いられている。しかし、これらは効果が充分ではなかったり、また、べたつき感、違和感又は刺激感といった不快な使用感がある。
一方、化粧品原料としては、キトサン及びその誘導体が使用されているが、これらに関する皮膚乾燥トラブル改善効果については報告されていない（例えば、特開平１０−１８２３３２号公報及び特開２０００−２１２２０３号公報参照）。
他方、使用感をよくするための試みとしては、乳液、クリーム等の乳化系製剤の開発が行われている。しかしながら、これらの乳化系製剤には、細胞膜の破壊やタンパク質変性等による細胞毒性を示すものが多いことが知られている界面活性剤や乳化剤が使われていることから、皮膚バリア機能を低下させ、かえって皮膚の乾燥を悪化させてしまうことがあるという問題があった。
発明の要約
本発明は、上記現状に鑑み、極めて優れた皮膚乾燥トラブル改善効果を有する皮膚外用組成物を提供することを目的とする。
本発明者らは、鋭意検討した結果、下記一般式（１）で表されるキトサン若しくは該キトサンがアミノ基において酸とともに塩を形成しているがそれ以外には修飾されていないもの、及び／又は、上記キトサンのアセチル化物であるキチンが、皮膚バリア機能改善効果及び抗炎症効果に優れることを新たな評価系を用いることで見出し、しかも極めて優れた止痒効果を有することも見出した。更に、従来の製剤化では、塗り心地等の商品性を向上するために必須とされてきた界面活性剤、両溶媒性基剤及びメイラード反応抑制効果を有する硫黄原子含有化合物の配合が、キトサン及び／又はキチンの経皮水分蒸散抑制効果を著しく損なうことを見出し、これらを製剤中に配合しないことによりキトサン及び／又はキチンの効果が著しく向上することを見出した。

Figure 2004085486
本発明は、上記一般式（１）で表されるキトサン、及び／又は、上記キトサンのアセチル化物であるキチン（以下、本明細書では、単に、キトサン及び／又はキチンと称す）を含有し、好ましくは界面活性剤、両溶媒基剤及びメイラード反応抑制効果を有する硫黄原子含有化合物を含有しないことを特徴とする皮膚外用組成物である。
発明の詳細な開示
以下に本発明を詳述する。
本発明で用いられるキトサンは、上記一般式（１）で表される化合物であり、キチンを濃アルカリ溶液等と加熱する等して、４０ｍｏｌ／ｍｏｌ％以上の脱アセチル化をすることにより得られるポリ−Ｎ−アセチル−Ｄ−グルコサミンである。本発明で用いられるキトサンには、上記一般式（１）で表されるキトサンがアミノ基において有機酸や無機酸とともに塩を形成しているものも含まれる。しかしながら、本発明で用いられるキトサンには、塩形成以外の修飾を受けたキトサン誘導体は含まれない。なお、本発明で用いられるキトサンを製造するための原料であるキチンの種類や、キトサンの製造方法については特に限定されない。
本発明の皮膚外用組成物は、キトサン及び／又はキチンを０．５〜２０重量％含有する。０．５重量％未満であると、充分な効果が得られないことがあり、２０重量％を越えても、それ以上効果が著しく高まることはなく、むしろ粘度が高まり、溶解しにくくなって、製剤化が困難となる。好ましい含有量は０．５〜１０重量％であり、より好ましくは０．５〜８重量％であり、更に好ましくは１〜６重量％であり、最も好ましくは１〜４重量％である。
上記キトサン及び／又はキチンは、平均重合度が５以上、１０００未満であるのが好ましい。５未満であると、充分に皮膚乾燥トラブル改善効果が得られないことがあり、１０００以上になると、物性が変わり、やはり充分に皮膚乾燥トラブル改善効果が得られなくなることがある。より好ましくは１０以上、８００未満であり、更に好ましくは５０以上、５００未満である。
また、上記キトサン及び／又はキチンは、平均重合度が５以上、１０００未満（低重合度キトサン及び／又はキチン）と平均重合度が１０００以上、５０００未満（高重合度キトサン及び／又はキチン）との混合物であることが好ましい。
高い皮膚乾燥トラブル改善効果を有する平均重合度が５以上、１０００未満のキトサン及び／又はキチンと、のびがよく軽い使用感（さっぱり感）と浸透性（なじみ易さ）を得ることができる平均重合度が１０００以上、５０００未満のキトサン及び／又はキチンとを混合して用いることにより両者の特徴を併せ持つ皮膚外用組成物が得られる。
上記低重合度キトサン及び／又はキチンと高重合度キトサン及び／又はキチンとの混合比としては、低重合度キトサン及び／又はキチン１００重量部に対して、高重合度キトサン及び／又はキチン３０〜３００重量部が好ましい。この範囲外であると、両者が分離し易くなり製剤化が困難となることがある。より好ましくは５０〜１５０重量部である。
なお、上記キトサン及び／又はキチンの平均重合度とは、キトサンのＣ６Ｈ１１ＮＯ４を１単位として（ｎ＝１）、極限粘度から求められた数値のことである。
更に、本発明の皮膚外用組成物をゲル濾過高速液体クロマトグラフィー（ＧＰＣ）で分子量分布を測定したとき、上記キトサン及び／又はキチンは、重量平均分子量の数平均分子量に対する比（重量平均分子量／数平均分子量）が１０以上であることが好ましい。本発明で用いられるキトサン及び／又はキチンが、低重合度キトサン及び／又はキチンと高重合度キトサン及び／又はキチンとの混合物であると、重量平均分子量の数平均分子量に対する比が１０以上となり易い。重量平均分子量の数平均分子量に対する比が１０未満の場合、充分な効果が得られなかったり、製剤化が困難となることがある。
本発明の皮膚外用組成物は、上記キトサンに塩を形成させ水溶化するために、酸が配合されていてもよい。
上記酸としては無機酸、有機酸のいずれも用いることができる。上記無機酸としては、例えば、塩酸、リン酸、硫酸、硝酸等が挙げられる。上記有機酸としては、例えば、酢酸、コハク酸、リンゴ酸、乳酸、酪酸、フマル酸、マロン酸、イタコン酸、グルコン酸、グリコール酸、酒石酸、クエン酸等が挙げられる。特に、カルボン酸にヒドロキシル基を有する化学構造を持つ脂肪酸であるヒドロキシ酸が好ましい。これらの酸は単独で用いられてもよいし、２種以上が併用されてもよい。
上記酸の含有量は、０．１〜２０重量％であることが好ましい。０．１重量％未満では充分に水溶化できないことがあり、２０重量％を越えると、適用部位によっては皮膚刺激性を示す可能性がある。より好ましくは、０．５〜１０重量％である。
本発明の皮膚外用組成物は、更に液体油類を含有することが好ましい。液体油類は化粧料等でよく用いられるものである。上記液体油類としては、例えば、スクワラン等の炭化水素類、トリグリセライド等のグリセライド油類等が挙げられる。なかでも、スクワランが特に好適である。
上記液体油類の含有量は、２〜２０重量％であることが好ましく、より好ましくは５〜１５重量％である。
本発明の皮膚外用組成物は、更に尿素を含有することが好ましい。上記キトサン及び／又はキチンは水溶液中において、熱によりメイラード反応を起こしやすく褐変化することがあるが、本発明者らは、尿素を添加することにより上記キトサン及び／又はキチンが安定化して、褐変化を防止できることを見出した。
上記尿素の含有量は、０．１〜３重量％であることが好ましい。０．１重量％未満であると、充分な効果が得られないことがあり、３重量％を越えると、効果がそれ以上高まらないだけでなく、キトサンが析出し、製剤化が困難となることがある。より好ましくは０．１〜１．５重量％である。
なお、本発明の皮膚外用組成物は、例えば亜硫酸塩等のメイラード反応防止効果を有する硫黄原子含有化合物は本発明の効果を消失させる恐れがあるので、含有しないことが好ましい。
本発明の皮膚外用組成物は、更に、界面活性剤及び両溶媒性基剤を含有しないことが好ましい。例えばドデシル硫酸ナトリウム等のイオン性界面活性剤や、例えばグリセリン等の両溶媒性基剤は、本発明の効果を消失させたり、製剤化が困難となる恐れがある。なお、本発明において、界面活性剤、両溶媒性基剤及びメイラード反応抑制効果を有する硫黄原子含有化合物を含有しないとは、これらの物質を全く含有しないことを意味するのみならず、これらの物質が通常乳化作用やメイラード反応抑制反応を起こさない範囲内で混入している場合をも含むこととする。例えば、本発明の皮膚外用組成物に、界面活性剤としてドデシル硫酸ナトリウムが０．１％未満混入している場合や、また両溶媒性基剤としてグリセリンが１％未満混入している場合は、本発明の皮膚外用組成物は、これらの化合物を含有していないものとする。
本発明の皮膚外用組成物の剤形としては特に限定されず、例えば、軟膏剤、クリーム剤、液剤等が挙げられ、上記液剤としては、ゲル剤、ゾル剤、水溶液剤、アルコール剤、油剤、懸濁型ローション剤、乳剤型ローション剤、ニス剤、湿布剤、噴霧剤等が挙げられる。
本発明の皮膚外用組成物の製造方法としては特に限定されず、従来公知の方法により製造することができる。
本発明の皮膚外用組成物の適用量は、有効成分の種類、濃度や塗布する部位の状態により適宜決定され、特に限定されないが、通常は１日に１〜数回、０．０１〜１０ｇ／１回程度で適用することが好ましい。また、本発明の皮膚外用組成物の適用方法としても特に限定されず、手指やへら等の器具を用いた通常の皮膚外用組成物の塗布方法の他、ポンプ式、スプレー式、チューブ式容器から直接塗布する方法等が挙げられる。
本発明の皮膚外用組成物は、本発明の目的を阻害しない範囲で、粉末、油分、増粘剤、有機溶剤、可塑剤、色素、顔料、香料、防腐剤、抗酸化剤等を適宜含有していても良い。Conventionally, various medicines such as urea, heparin-like substances, and petrolatum have been used as external preparations for preventing skin dryness problems. However, these are not effective enough and have an unpleasant feeling of use such as stickiness, discomfort or irritation.
On the other hand, chitosan and its derivatives have been used as cosmetic raw materials, but no reports have been made on the effect of improving skin dryness related to these (see, for example, JP-A-10-182332 and JP-A-2000-212203). ).
On the other hand, as an attempt to improve the feeling of use, development of emulsion preparations such as emulsions and creams has been performed. However, these emulsified preparations use surfactants and emulsifiers that are known to have many cytotoxic effects due to cell membrane destruction and protein denaturation, etc., so that the skin barrier function is lowered. On the contrary, there was a problem that the dryness of the skin may be worsened.
SUMMARY OF THE INVENTION An object of the present invention is to provide a composition for external use on the skin, which has an extremely excellent effect on improving skin dryness trouble in view of the above-mentioned present situation.
As a result of intensive studies, the present inventors have found that chitosan represented by the following general formula (1) or the chitosan that forms a salt with an acid at the amino group but is not otherwise modified, and / or Alternatively, it was found that chitin, which is an acetylated product of chitosan, is excellent in skin barrier function improving effect and anti-inflammatory effect by using a new evaluation system, and also has an extremely excellent antipruritic effect. Furthermore, in the conventional formulation, a combination of a surfactant, a solvating base, and a sulfur atom-containing compound having a Maillard reaction inhibitory effect, which have been indispensable for improving the merchantability such as coating comfort, It has been found that the effect of chitin on transdermal moisture transpiration is significantly impaired, and that the effects of chitosan and / or chitin are remarkably improved by not blending these in the preparation.
Figure 2004085486
The present invention contains chitosan represented by the general formula (1) and / or chitin which is an acetylated product of the chitosan (hereinafter simply referred to as chitosan and / or chitin in the present specification), Preferably, it is a composition for external use for skin, which does not contain a surfactant, both solvent bases, and a sulfur atom-containing compound having a Maillard reaction inhibitory effect.
Detailed Disclosure of the Invention The present invention is described in detail below.
The chitosan used in the present invention is a compound represented by the above general formula (1), and is obtained by deacetylating at least 40 mol / mol% by heating chitin with a concentrated alkaline solution or the like. Poly-N-acetyl-D-glucosamine. The chitosan used in the present invention includes those in which the chitosan represented by the general formula (1) forms a salt with an organic acid or an inorganic acid at the amino group. However, chitosan used in the present invention does not include chitosan derivatives subjected to modifications other than salt formation. In addition, it does not specifically limit about the kind of chitin which is a raw material for manufacturing chitosan used by this invention, and the manufacturing method of chitosan.
The external composition for skin of the present invention contains 0.5 to 20% by weight of chitosan and / or chitin. If the amount is less than 0.5% by weight, a sufficient effect may not be obtained. If the amount exceeds 20% by weight, the effect is not remarkably increased. Rather, the viscosity increases and it becomes difficult to dissolve. Formulation becomes difficult. The preferred content is 0.5 to 10% by weight, more preferably 0.5 to 8% by weight, still more preferably 1 to 6% by weight, and most preferably 1 to 4% by weight.
The chitosan and / or chitin preferably has an average degree of polymerization of 5 or more and less than 1000. If it is less than 5, the effect of improving skin dryness trouble may not be obtained sufficiently, and if it is 1000 or more, the physical properties may change, and the effect of improving skin dryness trouble may not be obtained sufficiently. More preferably, it is 10 or more and less than 800, More preferably, it is 50 or more and less than 500.
The chitosan and / or chitin has an average polymerization degree of 5 or more and less than 1000 (low polymerization degree chitosan and / or chitin) and an average polymerization degree of 1000 or more and less than 5000 (high polymerization degree chitosan and / or chitin). It is preferable that it is a mixture.
Achieving a high degree of skin dryness trouble with an average degree of polymerization of 5 or more and less than 1000 chitosan and / or chitin, an average polymerization that is easy to spread and light (feels refreshing) and penetrates (easy to fit) By using a mixture of chitosan and / or chitin having a degree of 1000 or more and less than 5000, a composition for external use having both characteristics can be obtained.
As a mixing ratio of the low polymerization degree chitosan and / or chitin and the high polymerization degree chitosan and / or chitin, the high polymerization degree chitosan and / or chitin 30 to 100 parts by weight of the low polymerization degree chitosan and / or chitin. 300 parts by weight is preferred. If it is out of this range, it may be easy to separate them, making formulation difficult. More preferably, it is 50-150 weight part.
The average degree of polymerization of chitosan and / or chitin is a numerical value obtained from the intrinsic viscosity with C 6 H 11 NO 4 of chitosan as one unit (n = 1).
Furthermore, when the molecular weight distribution of the external composition for skin of the present invention was measured by gel filtration high performance liquid chromatography (GPC), the chitosan and / or chitin was a ratio of the weight average molecular weight to the number average molecular weight (weight average molecular weight / number). The average molecular weight is preferably 10 or more. If the chitosan and / or chitin used in the present invention is a mixture of low-polymerization chitosan and / or chitin and high-polymerization chitosan and / or chitin, the ratio of the weight average molecular weight to the number average molecular weight tends to be 10 or more. . When the ratio of the weight average molecular weight to the number average molecular weight is less than 10, a sufficient effect may not be obtained or formulation may be difficult.
The external composition for skin of the present invention may contain an acid in order to form a salt on the chitosan to make it water-soluble.
As the acid, either an inorganic acid or an organic acid can be used. Examples of the inorganic acid include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Examples of the organic acid include acetic acid, succinic acid, malic acid, lactic acid, butyric acid, fumaric acid, malonic acid, itaconic acid, gluconic acid, glycolic acid, tartaric acid, and citric acid. In particular, a hydroxy acid which is a fatty acid having a chemical structure having a hydroxyl group in the carboxylic acid is preferred. These acids may be used independently and 2 or more types may be used together.
The acid content is preferably 0.1 to 20% by weight. If it is less than 0.1% by weight, it may not be sufficiently water-soluble, and if it exceeds 20% by weight, it may cause skin irritation depending on the application site. More preferably, it is 0.5 to 10% by weight.
It is preferable that the external composition for skin of this invention contains liquid oil further. Liquid oils are often used in cosmetics and the like. Examples of the liquid oil include hydrocarbons such as squalane and glyceride oils such as triglyceride. Of these, squalane is particularly suitable.
The content of the liquid oil is preferably 2 to 20% by weight, more preferably 5 to 15% by weight.
The external composition for skin of the present invention preferably further contains urea. In the aqueous solution, the chitosan and / or chitin is liable to undergo a Maillard reaction due to heat and may turn brown. However, the present inventors stabilize the chitosan and / or chitin by adding urea, and brown We found that change can be prevented.
The urea content is preferably 0.1 to 3% by weight. If it is less than 0.1% by weight, a sufficient effect may not be obtained. If it exceeds 3% by weight, not only the effect will not be further enhanced, but also chitosan will precipitate, making formulation difficult. There is. More preferably, it is 0.1 to 1.5% by weight.
In addition, since the sulfur atom containing compound which has the Maillard reaction prevention effect, such as a sulfite, for example, may lose | disappear the effect of this invention, it is preferable not to contain the composition for external use of this invention.
It is preferable that the composition for external use of the present invention does not contain a surfactant and a solvating base. For example, ionic surfactants such as sodium dodecyl sulfate and amphoteric bases such as glycerin may cause the effects of the present invention to be lost or make preparation difficult. In the present invention, not containing a surfactant, a both-solvent base and a sulfur atom-containing compound having a Maillard reaction inhibitory effect means not containing these substances at all, but also these substances. In general, it includes a case where it is mixed within a range not causing an emulsifying action or a Maillard reaction suppression reaction. For example, when the skin external composition of the present invention contains less than 0.1% sodium dodecyl sulfate as a surfactant, or when less than 1% glycerin is mixed as a solvating base, The external composition for skin according to the present invention does not contain these compounds.
The dosage form of the external composition for skin of the present invention is not particularly limited, and examples thereof include ointments, creams, liquids, etc. Examples of the liquids include gels, sols, aqueous solutions, alcohols, oils, Suspension lotions, emulsion lotions, varnishes, poultices, sprays and the like can be mentioned.
It does not specifically limit as a manufacturing method of the external composition for skin of this invention, It can manufacture by a conventionally well-known method.
The application amount of the external composition for skin of the present invention is appropriately determined depending on the type and concentration of the active ingredient and the state of the site to be applied, and is not particularly limited, but is usually 1 to several times a day, 0.01 to 10 g / It is preferable to apply it about once. Further, the application method of the external composition for skin of the present invention is not particularly limited, and it can be applied from a pump type, a spray type, a tube type container in addition to a normal application method for an external skin composition using a finger or a spatula. The method of apply | coating directly etc. are mentioned.
The composition for external use of the skin of the present invention appropriately contains powder, oil, thickener, organic solvent, plasticizer, dye, pigment, fragrance, preservative, antioxidant, etc., as long as the object of the present invention is not impaired. May be.

発明の効果The invention's effect

本発明の皮膚外用組成物は、皮膚からの水分蒸散を抑制する効果に優れ、抗炎症効果と止痒効果とを有し、使用感がよいことにより、優れた皮膚乾燥トラブル改善効果を有する。即ち、種々の原因による皮膚の乾燥トラブル、例えば、環境の湿度低下、栄養障害、高齢化、皮膚疾患等に対する皮膚乾燥トラブル改善剤として用いることができる。
また、本発明の皮膚外用組成物は、アトピー性皮膚炎による皮膚乾燥、接触皮膚炎による皮膚乾燥、老人性乾皮症、腎透析後の皮膚乾燥、ひび、あかぎれ、進行性指掌角皮症等の皮膚乾燥トラブルにも有効である。The external composition for skin of the present invention is excellent in the effect of suppressing moisture transpiration from the skin, has an anti-inflammatory effect and an antipruritic effect, and has an excellent skin dryness trouble improving effect due to its good feeling of use. That is, it can be used as a skin dryness trouble improving agent for skin dryness troubles caused by various causes, for example, environmental humidity reduction, nutritional disorders, aging, skin diseases and the like.
In addition, the composition for external use of the skin of the present invention is skin dryness due to atopic dermatitis, skin dryness due to contact dermatitis, senile xeroderma, skin dryness after renal dialysis, cracks, scratches, progressive palmokeratoderma It is also effective for skin dryness troubles.

以下に実施例を掲げて本発明を更に詳しく説明するが、本発明はこれら実施例のみに限定されるものではない。
（実施例１〜１４、２６〜２８）
平均重合度が３０若しくは３００のアミノ基が修飾されていないキトサン（和光純薬工業社製）及び乳酸、酒石酸若しくは酢酸を、又は、平均重合度３０若しくは３００に調整した水溶性キチンを、それぞれ表１に示す配合量（重量％）となるように蒸留水に添加し、マグネチックスターラーを用いて攪拌して溶解し、実施例１〜１４、２６〜２８の組成物を得た。
（比較例１）
乳酸を２重量％となるように蒸留水に添加し、マグネチックスターラーを用いて攪拌して溶解し、比較例１の組成物を得た。
（比較例２、３）
比較例２としては白色ワセリン（日本薬局方品、丸石製薬社製）を用い、比較例３としては保湿剤としてよく用いられている尿素（和光純薬工業社製）をマクロゴール軟膏基剤（日本薬局方品、丸石製薬社製）に２０重量％となるように混合してなる２０％尿素含有マクロゴール軟膏を作製した。
（比較例４〜６）
キトサン誘導体として、サクシニルキトサン（片倉チッカリン社製）、サクシニルカルボキシメチルキトサン（川研ファインケミカル社製）又はキトサン−ピロリドンカルボン酸塩（片倉チッカリン社製）、及び、乳酸を、表１に示す配合量となるように用い、実施例１〜１４と同様の操作により、比較例４〜６の組成物を得た。
（評価）
実施例１〜１４、２６〜２８及び比較例１〜６で得られた組成物について、以下の方法により評価を行った。結果を表１に示した。
（１）モルモット角質剥離皮膚による乾燥肌モデルに対するバリア機能改善効果
５週齢ハートレー系雄性モルモットの背部を剃毛し、次に２．５ｃｍ幅粘着テープ（積水化学工業社製、セロハンテープ）を用い、モルモット背部上の２．５ｃｍ角部分に対して貼付・剥離を４回繰り返し、一定量の角質層を剥離し、乾燥肌モデルとした。角質層剥離部位に、各組成物０．１ｍＬを塗布した。塗布してから１時間後及び２４時間後に経表皮水分蒸散量（以下、ＴＥＷＬ）を、エバポリメーターＥＰ−１（ＳＥＲＶＯＭＥＤ社製）を用いて測定した。試験は、各組成物について３匹のモルモットを用い、ＴＥＷＬは３匹についての結果の平均値を示した。なお、ＴＥＷＬの数値が低いほどバリア機能改善効果が高いことを示す。
（２）モルモットストリッピング皮膚紅斑に対する評価
４週齢ハートレー系雄性モルモットの背部を剃毛し、セロハンテープを用いて、予め決めた背部正中寄り２．５ｃｍ角を３回ストリッピングし、上記で得られた外用組成物０．１ｇをストリッピング部位全体に行き渡るように塗布した。なお、背部正中反対側はストリッピングのみを行ない、コントロール部位とした。塗布４時間後に上記外用組成物を塗布した各部位の紅斑強度を色彩色差計（ミノルタ社製、ＣＲ２００）で測定（ａ＊）し、皮膚外用組成物の効果を以下の基準で評価した。評価はそれぞれ３匹のモルモットを用いて、平均値により判定した。結果を表１に示した。なお、紅斑強度が低い方が効果が高く、コントロール部位の紅斑強度は５．６であった。
評価基準 ○：紅斑強度が２．０未満、×：紅斑強度が２．０以上

Figure 2004085486
Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.
(Examples 1-14, 26-28)
A chitosan (manufactured by Wako Pure Chemical Industries, Ltd.) with an average degree of polymerization of 30 or 300 and a lactic acid, tartaric acid or acetic acid, or water-soluble chitin adjusted to an average degree of polymerization of 30 or 300, respectively. It added to distilled water so that it might become the compounding quantity (weight%) shown in 1, and it stirred and melt | dissolved using the magnetic stirrer, and obtained the composition of Examples 1-14 and 26-28.
(Comparative Example 1)
Lactic acid was added to distilled water so that it might become 2 weight%, and it stirred and melt | dissolved using the magnetic stirrer, and obtained the composition of the comparative example 1.
(Comparative Examples 2 and 3)
As Comparative Example 2, white petrolatum (Japanese Pharmacopoeia, manufactured by Maruishi Pharmaceutical Co., Ltd.) is used. As Comparative Example 3, urea (manufactured by Wako Pure Chemical Industries, Ltd.) is used as a macrogol ointment base ( A 20% urea-containing macrogol ointment was prepared by mixing with Japanese Pharmacopoeia (manufactured by Maruishi Pharmaceutical Co., Ltd.) so as to be 20% by weight.
(Comparative Examples 4-6)
As chitosan derivatives, succinyl chitosan (manufactured by Katakura Chikkarin Co., Ltd.), succinyl carboxymethyl chitosan (manufactured by Kawaken Fine Chemical Co., Ltd.) or chitosan-pyrrolidone carboxylate (manufactured by Katakura Chikkarin Co., Ltd.), and lactic acid, The compositions of Comparative Examples 4 to 6 were obtained in the same manner as in Examples 1 to 14.
(Evaluation)
About the composition obtained in Examples 1-14, 26-28, and Comparative Examples 1-6, it evaluated by the following method. The results are shown in Table 1.
(1) Barrier function improvement effect on dry skin model by guinea pig exfoliated skin Shaved back of 5-week old Hartley male guinea pig, then using 2.5cm width adhesive tape (Sekisui Chemical Co., Ltd. cellophane tape) Then, the pasting and peeling were repeated 4 times on the 2.5 cm square part on the back of the guinea pig, and a certain amount of the stratum corneum was peeled off to obtain a dry skin model. Each composition 0.1mL was apply | coated to the stratum corneum peeling site | part. One hour and 24 hours after application, transepidermal water transpiration (hereinafter referred to as TEWL) was measured using an Evapolymeter EP-1 (manufactured by SERVOMED). The test used 3 guinea pigs for each composition, and TEWL showed the average of the results for 3 animals. In addition, it shows that the barrier function improvement effect is so high that the numerical value of TEWL is low.
(2) Evaluation of guinea pig stripping skin erythema The back of a 4-week-old Hartley male guinea pig is shaved, and a cellophane tape is used to strip a 2.5 cm square of a predetermined midline of the back, which is obtained above. 0.1 g of the obtained external composition was applied so as to spread over the entire stripping site. In addition, only the stripping was performed on the opposite side of the back midline as a control part. Four hours after application, the erythema intensity of each part where the above-mentioned composition for external application was applied was measured (a * ) with a color difference meter (CR200, manufactured by Minolta Co., Ltd.), and the effect of the external composition for skin was evaluated according to the following criteria. The evaluation was made based on an average value using three guinea pigs. The results are shown in Table 1. The lower the erythema intensity, the higher the effect, and the erythema intensity at the control site was 5.6.
Evaluation criteria ○: Erythema intensity is less than 2.0, x: Erythema intensity is 2.0 or more
Figure 2004085486

 実施例１５〜２５Examples 15-25

製剤組成の例として、平均重合度が３００及び３０００のアミノ基が修飾されていない各キトサン（和光純薬工業社製）、乳酸（エビス製薬社製）、スクワラン（マルハ社製）及び尿素（小堺製薬社製）を表２に示した配合量（重量％）となるように注射用水（大塚製薬社製）に添加し、攪拌、懸濁して、実施例１５〜２５の組成物を得た。
（比較例７、８）
使用感を比較するために市販品を用いた。比較例７としてはワセリン（丸石製薬社製）を、比較例８としてはヘパリノイド軟膏（マルホ製薬社製）を使用した。
（参考例１〜７）
使用感向上のために通常用いられる界面活性剤及び両溶媒性基剤を、平均重合度３０００のキトサンの代わりに配合して比較例の組成物を作製した。平均重合度３０００のキトサン以外は実施例１５〜２５におけると同様の原料に、ドデシル硫酸ナトリウム、グリセリン、ブチレングリコール、塩化ベンザルコニウム又はポリオキシエチレン硬化ヒマシ油（以上、和光純薬工業社製）を表２に示す配合量となるように加え、実施例１５〜２５と同様の操作により、参考例１〜７の組成物を得た。
（評価）
実施例１５〜２５、比較例７及び８、並びに、参考例１〜７の組成物について、以下の方法により評価を行った。結果を表２に示した。
（１）健常人による官能性評価
健常人１０名（男性５名、女性５名）により、外観及び使用感について、官能性評価を行った。上記項目について、５：非常に良好、４：良好、３：どちらともいえない、２：やや悪い、１：悪いの５段階評価をしてもらい、各数値の１０名の平均値を求めた。この数値が高いほど、製品性及び使用感がよいことを表す。
（２）モルモット角質層剥離皮膚による乾燥肌モデルに対するバリア機能改善効果
５週齢ハートレー系雄性モルモットの背部を剃毛し、次いで２．５ｃｍ幅のセロハンテープを用いて、モルモット背部上の２．５ｃｍ角の部分を４回貼付・剥離を繰り返し、一定の量の角質層を剥離し、乾燥肌モデルとした。角質層剥離部位に、各組成物０．１ｍＬを全体に行き渡るよう塗布した。塗布１時間及び２４時間後に、経表皮水分蒸散量（ＴＥＷＬ）を、エバポリメーターＥＰ−１（ＳＥＲＶＯＭＥＤ社製）を用いて測定した。試験は各例について３匹で行い、ＴＥＷＬはその平均値で示した。ＴＥＷＬは数値が低いほど、バリア機能改善効果が高いことを示す。

Figure 2004085486
（比較例９、１０）
比較例９としては止痒外用剤として用いられている抗ヒスタミン軟膏（興和社製、「レスタミンコーワ」）を、比較例１０としては尿素軟膏（興和社製）を用いた。
（評価）
実施例１、２、３、６、１３、１５、１６、１９及び２５、並びに、比較例２、９及び１０の各組成物について、以下の方法により評価を行った。結果を表３に示した。
（１）止痒性評価１
風呂上がりに、肘窩及び膝窩に乾燥性の痒みを有する２９歳女性を被験者とし、各組成物を患部に塗布し、塗布直後から６時間後までの患部の痒みを評価した。「著効」の場合を◎、「有効」の場合を○、「やや有効」の場合を△、「無効」の場合を×として評価した。
（２）止痒性評価２
就寝時に背部に乾燥性の痒みを有する５７歳男性を被験者とし、各組成物を患部に塗布し、塗布直後から６時間後までの患部の痒みを評価した。「著効」の場合を◎、「有効」の場合を○、「やや有効」の場合を△、「無効」の場合を×として評価した。
（３）止痒性評価３
風呂上がりに、四肢に乾燥性の痒みを有する４３歳女性を被験者とし、各組成物を患部に塗布し、塗布直後から６時間後までの患部の痒みを評価した。「著効」の場合を◎、「有効」の場合を○、「やや有効」の場合を△、「無効」の場合を×として評価した。
Figure 2004085486
Examples of the pharmaceutical composition include chitosan (manufactured by Wako Pure Chemical Industries, Ltd.), lactic acid (manufactured by Ebisu Pharmaceutical Co., Ltd.), squalane (manufactured by Maruha Co., Ltd.), and urea (manufactured by Kominato). Pharmaceuticals) were added to water for injection (made by Otsuka Pharmaceutical Co., Ltd.) so as to have the blending amount (% by weight) shown in Table 2, and stirred and suspended to obtain compositions of Examples 15 to 25.
(Comparative Examples 7 and 8)
A commercial product was used to compare the feeling of use. As Comparative Example 7, Vaseline (manufactured by Maruishi Pharmaceutical) was used, and as Comparative Example 8, heparinoid ointment (manufactured by Maruho Pharmaceutical) was used.
(Reference Examples 1-7)
A comparative example composition was prepared by blending a surfactant and both solvating bases commonly used to improve the feeling of use in place of chitosan having an average polymerization degree of 3000. Except for chitosan having an average degree of polymerization of 3000, the same raw materials as in Examples 15 to 25 were used. Sodium dodecyl sulfate, glycerin, butylene glycol, benzalkonium chloride or polyoxyethylene hydrogenated castor oil (manufactured by Wako Pure Chemical Industries, Ltd.) Were added so as to have the blending amounts shown in Table 2, and the compositions of Reference Examples 1 to 7 were obtained in the same manner as in Examples 15 to 25.
(Evaluation)
The compositions of Examples 15 to 25, Comparative Examples 7 and 8, and Reference Examples 1 to 7 were evaluated by the following methods. The results are shown in Table 2.
(1) Sensory evaluation by healthy persons Sensory evaluation was performed on the appearance and feeling of use by 10 healthy persons (5 men and 5 women). Regarding the above items, 5 grades were evaluated: 5: very good, 4: good, 3: not good, 2: somewhat bad, 1: bad, and the average value of 10 people of each numerical value was obtained. The higher the value, the better the product quality and the feeling of use.
(2) Effect of improving barrier function on dry skin model with exfoliated skin of guinea pig stratum corneum Shaved back of 5-week-old Hartley male guinea pig, and then 2.5cm on back of guinea pig using 2.5cm wide cellophane tape The corner portion was affixed and peeled off four times, and a certain amount of stratum corneum was peeled off to obtain a dry skin model. 0.1 mL of each composition was applied over the entire stratum corneum peeling site. One hour and 24 hours after application, transepidermal water transpiration (TEWL) was measured using an Evapolymeter EP-1 (manufactured by Servomemed). The test was performed with 3 animals for each example, and TEWL was shown as the average value. TEWL indicates that the lower the value, the higher the barrier function improving effect.
Figure 2004085486
(Comparative Examples 9 and 10)
As comparative example 9, an antihistamine ointment (manufactured by Kowa Co., “Restamin Kowa”) used as an antipruritic external preparation was used, and as a comparative example 10, urea ointment (manufactured by Kowa Co., Ltd.) was used.
(Evaluation)
The compositions of Examples 1, 2, 3, 6, 13, 15, 16, 19, and 25 and Comparative Examples 2, 9, and 10 were evaluated by the following methods. The results are shown in Table 3.
(1) Fastening evaluation 1
After the bath, a 29-year-old woman with dry itch in the elbow and popliteal flotation was used as a test subject. Each composition was applied to the affected area, and the itch of the affected area was evaluated immediately after application until 6 hours later. The case of “significant” was evaluated as ◎, the case of “valid” as ◯, the case of “somewhat valid” as Δ, and the case of “invalid” as x.
(2) Fastness evaluation 2
A 57-year-old male with dry itch on the back at bedtime was used as a test subject, each composition was applied to the affected area, and the itch of the affected area was evaluated from immediately after application to 6 hours later. The case of “significant” was evaluated as ◎, the case of “valid” as ◯, the case of “somewhat valid” as Δ, and the case of “invalid” as x.
(3) Fastening evaluation 3
After the bath, a 43-year-old woman with dry itch on the limbs was used as a test subject. Each composition was applied to the affected area, and the itch of the affected area was evaluated immediately after application until 6 hours later. The case of “significant” was evaluated as ◎, the case of “valid” as ◯, the case of “somewhat valid” as Δ, and the case of “invalid” as x.
Figure 2004085486

本発明は、上述の構成からなるので、優れた皮膚バリア機能改善効果、抗炎症効果及び止痒効果を有し、更に、良好な使用感を示す皮膚外用組成物を提供することができる。  Since this invention consists of the above-mentioned structure, it has the outstanding skin barrier function improvement effect, the anti-inflammatory effect, and the antipruritic effect, Furthermore, the composition for external use which shows a favorable usability | use_condition can be provided.

Claims (8)

下記一般式（１）で表されるキトサン、及び／又は、前記キトサンのアセチル化物であるキチンを、合計で０．５〜２０重量％含有することを特徴とする皮膚外用組成物。
Figure 2004085486
A skin external composition comprising 0.5 to 20% by weight in total of chitosan represented by the following general formula (1) and / or chitin which is an acetylated product of the chitosan.
Figure 2004085486
 キトサン及び／又はキチンは、平均重合度が５以上、１０００未満であることを特徴とする請求の範囲第１項記載の皮膚外用組成物。Chitosan and / or chitin have an average degree of polymerization of 5 or more and less than 1000. 平均重合度が５以上、１０００未満のキトサン及び／又はキチンと、平均重合度が１０００以上、５０００未満のキトサン及び／又はキチンとを含有することを特徴とする請求の範囲第１項記載の皮膚外用組成物。The skin according to claim 1, comprising chitosan and / or chitin having an average degree of polymerization of 5 or more and less than 1000 and chitosan and / or chitin having an average degree of polymerization of 1000 or more and less than 5000. Composition for external use. キトサン及び／又はキチンは、重量平均分子量の数平均分子量に対する比（重量平均分子量／数平均分子量）が１０以上であることを特徴とする請求の範囲第１、２又は３項記載の皮膚外用組成物。4. The composition for external use on the skin according to claim 1, 2 or 3, wherein chitosan and / or chitin has a ratio of weight average molecular weight to number average molecular weight (weight average molecular weight / number average molecular weight) of 10 or more. object. 更に液体油類を含有することを特徴とする請求の範囲第１、２、３又は４項記載の皮膚外用組成物。Furthermore, liquid oil is contained, The composition for external use of the skin of Claim 1, 2, 3 or 4 characterized by the above-mentioned. 液体油類は、スクワランであることを特徴とする請求の範囲第５項記載の皮膚外用組成物。The composition for external use on the skin according to claim 5, wherein the liquid oil is squalane. 更に尿素を含有し、かつ、メイラード反応抑制効果を有する硫黄原子含有化合物を含有しないことを特徴とする請求の範囲第１、２、３、４、５又は６項記載の皮膚外用組成物。The composition for external use according to claim 1, 2, 3, 4, 5 or 6, further comprising urea and not containing a sulfur atom-containing compound having a Maillard reaction inhibitory effect. 界面活性剤及び両溶媒性基剤を含有しないことを特徴とする請求の範囲第１、２、３、４、５、６又は７項記載の皮膚外用組成物。The composition for external use on the skin according to claim 1, 2, 3, 4, 5, 6 or 7, characterized by not containing a surfactant and a solvating base.
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JPH02101008A (en) * 1988-10-04 1990-04-12 Kanebo Ltd Skin cosmetic
JPH0399004A (en) * 1989-09-11 1991-04-24 Ajinomoto Co Inc Skin cosmetic
JP2001064149A (en) * 1999-08-30 2001-03-13 Pias Arise Kk Antiaging skin cosmetic
JP2001072565A (en) * 1998-06-13 2001-03-21 Beiersdorf Ag Preparation which contain chitosan and phospholipid contents and is used for makeup and dermatology
JP2002053428A (en) * 2000-08-12 2002-02-19 Tadashi Fukiya Skin care preparation
JP2002121128A (en) * 2000-10-12 2002-04-23 Lion Corp External skin preparation

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JPH02101008A (en) * 1988-10-04 1990-04-12 Kanebo Ltd Skin cosmetic
JPH0399004A (en) * 1989-09-11 1991-04-24 Ajinomoto Co Inc Skin cosmetic
JP2001072565A (en) * 1998-06-13 2001-03-21 Beiersdorf Ag Preparation which contain chitosan and phospholipid contents and is used for makeup and dermatology
JP2001064149A (en) * 1999-08-30 2001-03-13 Pias Arise Kk Antiaging skin cosmetic
JP2002053428A (en) * 2000-08-12 2002-02-19 Tadashi Fukiya Skin care preparation
JP2002121128A (en) * 2000-10-12 2002-04-23 Lion Corp External skin preparation

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