201114865 六、發明說明： 【發明所屬之技術領域】 本發明是關於一種經皮吸收型製劑，更詳而言之，是 關於一種經皮吸收型製劑，其在支撐體的單面上至少具備 含有黏著劑的黏著劑層，並貼附於皮膚而使用。 【先前技術】 通過皮膚面而將藥劑投予至生物體内的經皮吸收型製 劑’已提出各種將含有藥劑成分的黏著劑層形成於不織布 或塑膠膜的單面而成之帶狀或片狀製劑。對於此種貼附於 皮膚而應用之類型的經皮吸收型製劑，所要求的是長時間 持續一定血中濃度的特性，以及抑制其從所應用之皮膚面 脫落的特性。前者的特性，可藉由在黏著劑層中含有充分 量的藥劑成分而達成。 基於此種觀點’而探討了各種交聯型的黏著劑來作為 經皮吸收型製劑用的黏著劑。例如，在專利文獻1中，提 出了一種交聯型皮膚用黏著劑，其為將：將二丙酮丙烯醯 胺共聚合而成的樹脂、及含有一級胺基及/或羧醯肼基 (carboxyl hydrazide)的樹脂加以混合並使其交聯而成的類 型。 又，專利文獻2中，提出一種醫療用經皮吸收膠帶製 劑用的非水性黏著劑，其中作為黏著劑而使用：將分子内 具有乙醯乙醯基的（甲基）丙烯酸系單體與其他丙烯酸系 單體共聚合，而使存在於該共聚物之分子内的乙醯乙醯基 201114865 彼此交聯而成之物。 又，專利文獻3中，則提出一種醫療用膠帶劑，其中 為了改善凝聚力及黏貼力（黏著力），所使用的黏著劑是址 合下述而成：將曱基丙烯酸-2-乙醯乙醯氧基乙基醋及其他 乙烯基單體共聚合而獲得之能自行交聯的黏著性聚合物 A、 以及將烧基之碳原子數為4個〜1〇個的（甲基）丙缔 酸烷基酯及其他乙烯基單體共聚合而成的黏著性聚合物 B。 [先前技術文獻] (專利文獻） 專利文獻1 :曰本專利特開2005_325 101號公報 專利文獻2 ·國際公開W02004/112*760號公報 專利文獻3 :國際公開w〇2〇〇6/〇64747號公報 【發明内容】 [發明所欲解決之問題] 藉由使用專利文獻1及2所記載的交聯型黏著劑，而 能夠在黏著劑層中含有充分量的藥劑成分。但是，使用此 種黏著劑而成的經皮吸收型製劑，會有難以使黏貼性（黏 著1± )長時間持續的情形’例如’可能會有不適於持續數 日貼附於皮膚之用途上的情形。另一方面，如同專利文獻 3所記載般’ ϋ由將交聯型的黏著劑與非交聯型的黏著劑 加以』σ ’而能夠謀求改善黏貼性。&而，此黏著劑由於 黏著劑層中所含有的交聯型黏著劑的比例減少、能夠長時 201114865 間安定而含有於黏著劑層中之藥劑成 少， 分或塑化劑的量減BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a percutaneous absorption type preparation, and more particularly to a percutaneous absorption type preparation which has at least one side of a support body. The adhesive layer of the adhesive is applied to the skin. [Prior Art] A percutaneous absorption type preparation in which a pharmaceutical agent is administered to a living body through a skin surface has been proposed in various strips or sheets in which a pressure-sensitive adhesive layer containing a pharmaceutical ingredient is formed on one side of a nonwoven fabric or a plastic film. Formulation. For such a type of percutaneous absorption preparation to be applied to the skin, it is required to maintain a certain concentration of blood in a long period of time and to suppress the peeling property from the applied skin surface. The former characteristics can be achieved by containing a sufficient amount of the pharmaceutical ingredient in the adhesive layer. Based on this point of view, various cross-linking type adhesives have been discussed as adhesives for percutaneous absorption type preparations. For example, Patent Document 1 proposes a crosslinked skin adhesive which comprises a resin obtained by copolymerizing diacetone acrylamide and a primary amine group and/or a carboxyl group (carboxyl). The type of hydrazide resin is mixed and crosslinked. Further, Patent Document 2 proposes a non-aqueous adhesive for medical percutaneous absorption tape preparation, which is used as an adhesive: a (meth)acrylic monomer having an ethyl acetyl group in the molecule and others The acrylic monomer is copolymerized, and the ethyl acetoxime 201114865 present in the molecule of the copolymer is crosslinked with each other. Further, in Patent Document 3, there is proposed a medical tape agent in which an adhesive to be used is used to improve cohesive force and adhesive force (adhesion): the methacrylic acid -2-acetonitrile Adhesive polymer A which is self-crosslinking obtained by copolymerization of decyloxyethyl vinegar and other vinyl monomers, and (meth)c-butyl having a carbon number of 4 to 1 Å Adhesive polymer B obtained by copolymerizing an acid alkyl ester and other vinyl monomers. [Prior Art Document] (Patent Document) Patent Document 1: Japanese Patent Laid-Open Publication No. 2005-325 No. JP-A No. 2005-325 No. Patent Publication No. WO-2004-112*760 Patent Document 3: International Publication No. 2〇〇6/〇64747 [Problem to be Solved by the Invention] By using the crosslinked adhesive described in Patent Documents 1 and 2, a sufficient amount of the chemical component can be contained in the adhesive layer. However, the percutaneous absorption type preparation using such an adhesive may have a situation in which it is difficult to maintain the adhesiveness (adhesion 1±) for a long period of time. For example, there may be an unsuitable application for attachment to the skin for several days. The situation. On the other hand, as described in Patent Document 3, it is possible to improve the adhesiveness by adding a cross-linking type adhesive and a non-crosslinking type adhesive to "σ". & However, the amount of the cross-linking adhesive contained in the adhesive layer is reduced, and the amount of the agent contained in the adhesive layer can be reduced in the long-term stability of 201114865, and the amount of the plasticizer is reduced.
作為適用於長時間的經皮吸收型製劑，仍謀求更加改善的 間的 貼性 黏貼性。As a percutaneous absorption type preparation suitable for a long period of time, it is still desired to further improve the adhesiveness between the two.
經皮吸收型製劑，該經皮吸收型製劑在黏著劑層中使用能 夠含有充分量的藥劑及塑化劑之交聯型黏著劑，且能夠長 時間維持黏貼性。 [解決問題之技術手段] 本發明者專心進行研究’結果發現藉由在黏著劑層中 含有包含下述Acr-A及Acr-B之黏著劑，也就是含有2種 交聯型丙烯酸系黏著劑，則能夠解決上述課題，而完成了 本發明。Acr-A ’是以一定的比率含有下述成分的樹脂混合 物：以（曱基）丙稀酸院基酯為主要單體成分且含有3〜 45質量％之二丙酮丙烯醯胺作為必要單體成分的丙烯酸系 共聚物（X)、以及以（甲基）丙烯酸烷基酯為主要單體成 分且在側鍵含有一級胺基及/或叛酿肼基（carboxyl hydrazide)的丙稀酸系共聚物（Y)。Acr-B，則是由下述成 分所形成的共聚物：（曱基）丙烯酸乙醯乙醢氧基烷基酯、 以及能與該（曱基）丙烯酸乙醯乙醯氧基烷基酯共聚合之 1種或2種以上的乙烯基單體。 亦即，本發明是（1 ) 一種經皮吸收塑製劑’其在支撐 201114865 體的單面上至少具備含有黏著劑的黏著劑層’其特徵在 於：作為前述黏著劑，含有下述丙烯酸系樹脂Acr_A及 Acr-B 0 (Acr-A )In the percutaneous absorption type preparation, the percutaneous absorption type preparation uses a crosslinked type adhesive which can contain a sufficient amount of a drug and a plasticizer in the adhesive layer, and can maintain adhesiveness for a long period of time. [Technical means for solving the problem] The present inventors focused on the research. As a result, it was found that an adhesive containing the following Acr-A and Acr-B is contained in the adhesive layer, that is, two kinds of crosslinked acrylic adhesives are contained. The above problems can be solved and the present invention has been completed. Acr-A ' is a resin mixture containing a compound having the following composition as a main monomer component and containing 3 to 45% by mass of diacetone acrylamide as an essential monomer. The acrylic copolymer (X) of the component, and the acrylic copolymer having the alkyl (meth) acrylate as a main monomer component and containing a primary amine group and/or a carboxyl hydrazide at a side bond (Y). Acr-B is a copolymer formed from the following components: (mercapto) acetamethylene acrylate, and can be co-linked with the (indenyl) ethoxylated alkyl acrylate. One or two or more kinds of vinyl monomers are polymerized. That is, the present invention is (1) a transdermally absorbable plastic preparation which has at least an adhesive layer containing an adhesive on a single surface supporting the body of 201114865, characterized in that it contains the following acrylic resin as the above-mentioned adhesive. Acr_A and Acr-B 0 (Acr-A )
Acr-A，是含有100質量份之下述丙烯酸系共聚物 (X)、與0.1〜30質量份之下述丙烯酸系共聚物（Y)之樹 脂混合物。 丙烯酸系共聚物（X )，是以（曱基）丙烯酸烷基酯作 為主要單體成分，且含有3〜45質量％之二丙酮丙烯醯胺 作為必要單體成分，並且不含游離羧基之丙烯酸系共聚物。 丙烯酸系共聚物（Y )，是以（曱基）丙烯酸烷基酯作 為主要單體成分，且在側鏈含有一級胺基及/或羧醯肼 基，並且不含游離羧基之丙烯酸系共聚物。 (Acr-B )Acr-A is a resin mixture containing 100 parts by mass of the following acrylic copolymer (X) and 0.1 to 30 parts by mass of the following acrylic copolymer (Y). The acrylic copolymer (X) is an acrylic acid having a (meth)acrylic acid alkyl ester as a main monomer component and containing 3 to 45% by mass of diacetone acrylamide as an essential monomer component and containing no free carboxyl group. Is a copolymer. Acrylic copolymer (Y), an acrylic copolymer containing an alkyl (meth) acrylate as a main monomer component and containing a primary amine group and/or a carboxy fluorenyl group in a side chain, and containing no free carboxyl group . (Acr-B)
Acr-B，是由（甲基）丙烯酸乙醯乙醯氧基烷基酯、以 及能與前述（甲基）丙烯酸乙醯乙醯氧基烷基酯共聚合之 1種或2種以上的乙烯基單體所形成’並且不含游離羧基 之共聚物。 又本發明疋（2)如第（1)項所述之經皮吸收型製 劑，其中前述黏著劑層，進而含有藥劑及/或塑化劑。 又，本發明是（3 )如第（2 )項所述之經皮吸收型製 劑，其中前述藥劑是吩坦尼（fentanyI)及/或其鹽。 又，本發明是⑷如第⑺項或第（3)項所述之經 皮吸收型製劑，其中前述塑化·肉豆M酸異丙自旨及/或 201114865 棕櫚酸異丙酯。 又’本發明是（5)如第（丨）項至第（4)項中任一項 所述之經皮吸收型製劑，其中前述黏著劑層中所含有的丙 稀酸系樹脂Acr-A及Acr-B的質量比，是9〇 : 10〜5〇 : 5〇。 [功效] 根據本發明，可提供一種經皮吸收型製劑，該經皮吸 收型製劑，在黏著劑層中使用能夠含有充分量的藥劑及塑 化劑之交聯型黏著劑，且能夠長時間維持黏貼性。 【實施方式】 以下’對於本發明的經皮吸收型製劑之一種實施形態 進行說明’本發明不受以下實施形態所限定。 本實施形態的經皮吸收型製劑’是設計為：在支撐體 上具有藥劑面’而且使藥劑面接觸皮膚而應用時，有效成 分會通過皮膚而被吸收至體内。作為此種製劑，可舉出： 設計為有效成分通過皮膚而輸送至全身循環血流中的製 劑、或是設計為有效成分通過皮膚而輸送至局部的製劑。 刖者在日本藥典（japanese Pharmac〇p〇eia)中被分類為「經 皮吸收型製劑」，後者在日本藥典中被分類為「貼劑」，但 本發明的經皮吸收型製劑可以是任一種類型的製劑。 本實施形態的經皮吸收型製劑，在支撐體的單面上至 少具備黏著劑層。此黏著劑層含有藥劑成分，其接觸於皮 膚的面則成為藥劑面。以下針對黏著劑層、支撐體及藥劑 201114865 成分進行說明。 <黏著劑層> 黏著劑層’是用以賦 卞黏貼後的層’用來使經皮吸收 型製劑黏接於皮膚上。點装办丨麻. 、 反價上黏者劑層中含有藥劑成分。此藥劑 成分會通過黏著劑層與皮膚接觸的藥劑面而被皮膚吸收。 黏著劑層t’含有黏著劑、塑化劑、藥劑成分、及其他成 分。這些當中’藥劑成分將於後述，此處先針對黏著劑、 塑化劑、及黏著劑層中所含有的其他成分進行說明。 [黏著劑] 作為黏著劑，至少含有以下所說明的Acr_A及Aw。 及AwB是丙稀酸系樹脂’可分別交聯而形成網目 結構，且會遍佈黏著劑層全體而形成能夠含有藥劑成分及 可塑劑的網目結構。因此，本實施形態的經皮吸收型製劑 能夠含有充分量的藥劑成分及可塑劑。從而，本實施形態 的經皮吸收型製劑能夠長時間持續將有效成分之血中濃度 保持於一定水準。Acr-B is an ethyl ethoxylated alkyl (meth) acrylate and one or more kinds of ethylene copolymerizable with the above-mentioned (meth) acrylate ethoxylated alkyl ester. The base monomer forms 'and does not contain a copolymer of free carboxyl groups. The percutaneous absorption type preparation according to the item (1), wherein the adhesive layer further contains a drug and/or a plasticizer. The present invention is the percutaneous absorption type preparation according to the item (2), wherein the pharmaceutical agent is fentany I and/or a salt thereof. The present invention is the percutaneous absorption type preparation according to the above item (7) or (3), wherein the plasticized, nutmeg M acid isopropyl and / or 201114865 isopropyl palmitate. The percutaneous absorption type preparation according to any one of the items (4), wherein the acrylic resin Acr-A is contained in the adhesive layer. And the mass ratio of Acr-B is 9〇: 10~5〇: 5〇. [Efficacy] According to the present invention, there is provided a transdermal absorption type preparation which uses a cross-linking type adhesive capable of containing a sufficient amount of a drug and a plasticizer in the adhesive layer, and which can be used for a long time Maintain adhesion. [Embodiment] Hereinafter, an embodiment of the percutaneous absorption type preparation of the present invention will be described. The present invention is not limited by the following embodiments. The percutaneous absorption type preparation 'is designed according to the present embodiment is designed such that when the drug surface is provided on the support and the drug surface is applied to the skin, the effective ingredient is absorbed into the body through the skin. As such a preparation, a preparation designed to deliver an active ingredient to the systemic circulating bloodstream through the skin, or a preparation designed to deliver the active ingredient to the skin through the skin may be mentioned. The latter is classified as a "percutaneous absorption type preparation" in the Japanese Pharmacopoeia (Japanese Pharmac〇p〇eia), and the latter is classified as a "patch" in the Japanese Pharmacopoeia, but the percutaneous absorption preparation of the present invention may be One type of formulation. The percutaneous absorption type preparation of the present embodiment has at least an adhesive layer on one side of the support. This adhesive layer contains a pharmaceutical ingredient, and the surface which contacts the skin becomes a pharmaceutical surface. The adhesive layer, the support, and the pharmaceutical agent 201114865 will be described below. <Adhesive Layer> The adhesive layer 'is used to bond the adhered layer' to adhere the percutaneous absorption type preparation to the skin. Point to install ramie. The anti-price upper adhesive layer contains pharmaceutical ingredients. This pharmaceutical ingredient is absorbed by the skin through the adhesive surface of the adhesive layer which is in contact with the skin. The adhesive layer t' contains an adhesive, a plasticizer, a pharmaceutical ingredient, and other components. In these, the pharmaceutical ingredients will be described later, and the adhesive, the plasticizer, and other components contained in the adhesive layer will be described first. [Adhesive] As the adhesive, at least Acr_A and Aw described below are contained. And AwB is an acrylic resin, which can be crosslinked to form a mesh structure, and spreads over the entire adhesive layer to form a mesh structure which can contain a pharmaceutical component and a plasticizer. Therefore, the percutaneous absorption type preparation of the present embodiment can contain a sufficient amount of the drug component and the plasticizer. Therefore, the percutaneous absorption type preparation of the present embodiment can maintain the blood concentration of the active ingredient at a constant level for a long period of time.
Acr-A及Acr-B是不含游離羧基之丙烯酸系樹脂。因 此’本實施形態的經皮吸收型製劑，除了對皮膚的刺激性 小以外，即便黏著劑層所含有的藥劑成分是會與酸反應或 相互作用的成分’也能夠防止藥劑成分的安定性受損、或 經皮吸收性降低。另外，所謂的「不含游離羧基」，是意謂 在設計上，全部的羧基均被轉換為酯鍵等取代基。因此， 即便Acr-A及Acr-B含有例如藉由酯鍵等之水解而產生的 叛基、或來自原料之雜質的叛基，也包含於本發明的範圍 201114865 内0 (Acr-A ) 首先，針對丙烯酸系樹脂Acr-A進行說明。Acr-A，是 含有100質量份之下述丙烯酸系共聚物（X)、與0.1〜3〇 質量份之丙烯酸系共聚物（Y)的樹脂混合物。丙烯酸系共 聚物（X)，是以（曱基）丙烯酸烷基酯作為主要單體成分， 且含有3〜45質量％之二丙酮丙烯醯胺作為必要單體成 分，並且不含游離羧基之共聚物。丙烯酸系共聚物（Y)， 是以（曱基）丙烯酸烷基酯作為主要單體成分，且在側鏈 含有一級胺基及/或羧醯肼基，並且不含游離羧基之共聚 物。此種樹脂混合物，在使用作為黏著劑時，能夠基於丙 烯酸系共聚物（X)所含有的來自二丙酮丙稀醯胺的叛基、 與丙烯酸系共聚物（Y)所含有的一級胺基或羧醯肼基的交 聯反應’而在黏著劑層全體中形成微細的網目結構，並且 能夠在該網目結構中保持藥劑成分等；基於上述觀點，此 樹脂混合物能夠適合使用於經皮吸收型製劑用途。 丙烤酸系共聚物（X)的製造’可例示有下述方法：以 (甲基）丙烯酸烧基醋作為主要單體成分，添加二丙酮丙 烯酿胺且使其相對於單體全體而為3〜45質量％，並使其 進行自由基聚合。這些單體成分，可使用過氧化物或偶氮 系化合物之類的聚合起始劑’並藉由一般方法來使其聚 合。在使這些單體聚合之際，較佳為適當地添加溶媒來調 整反應溶液的黏度。 作為（甲基）丙烯酸烷基酯，齡枯& m ^ 較佳為使用烷基碳數為 201114865 .1〜12的（曱基）丙稀酸烧基醋。具體而言，可舉出.（ 基）丙稀酸甲酯、（甲基）丙烯酸乙酯、（甲基）而 酯、（甲基）丙烯酸丁酯、（甲基）丙烯酸-2-乙基己、 g、（甲 基）丙烯酸辛酯、（甲基）丙烯酸十二烷基酯等。這此 二（甲 基）丙烯酸烷基酯，可單獨或組合2種以上來使用。 丙烯酸系共聚物（Y)的製造，可例示有下述方法，、 (甲基）丙烯酸烷基酯作為主要單體成分，並添加用以導 入—級胺基之單體成分及/或用以導入羧醯肼基之單體成 分且使其相對於單體全體而為質量％，並使其進行 自由基聚合，之後將來自用以導入羧醯肼基之單體成分的 側鏈，轉換為羧醯肼基。使單體成分進行自由基聚合時， 可使用過氧化物或偶氮系化合物之類的聚合起始劑，並藉 由一般方法來使其聚合。使單體成分進行自由基聚合之 際’較佳為適當地添加溶媒來調整反應溶液的黏度。另外， 製造共聚物（B)之際所使用的（甲基）丙烯酸烷基酯，可 使用與上述共聚物（A )中所例示者相同之物。 又，為了發揮與丙烯酸系共聚物（X )的適度的交聯性， 在丙烯酸系共聚物（Y)的1分子鏈中，丙烯酸系共聚物（γ) 中的一級胺基及/或羧醯肼基以存在2個以上為佳，較佳 為存在3個以上。 進而’用以導入一級胺基之單體成分及/或用以導入 緩酿肼基之單體成分、與（甲基）丙烯酸烷基酯單體，較 佳為混合使其莫耳比為1 : 5〜1 : I 〇〇而共聚合。 作為用以對於丙烯酸系共聚物（Y)導入一級胺基之單 10 201114865 體成刀 可舉出具有能與（甲基）丙稀酸炫基酯聚合之乙 嫌美且直七 土 /、有一級胺基的化合物。作為此種化合物，可例示 如乙烯胺等。 作為用以對丙烯酸系共聚物（Y)導入羧醯肼基之單體 成刀 可舉出具有能與（甲基）丙烯酸烷基酯聚合的乙婦 基且具有能與醯肼基反應之酮基的化合物。作為此種化合 物可例示如二丙酮丙烯醯胺、丙烯醛、甲基丙烯酸乙醯 乙酿氧基乙I旨等。 欲將來自用以導入羧醯肼基之單體成分的側鏈轉換為 羧醯肼基，只要將上述自由基聚合中所獲得的聚合物溶解 於極性溶媒，並在酸觸媒的存在下，使其與二羧酸二醯肼 反應即了。作為二缓酸二醢肼，可例示如：己二酸二醯肼、 戊二酸二醯肼、庚二酸二醯肼等。 另外，本說明書中所謂的「主要單體成分」，是意謂相 對於共聚物為50質量。/。以上而含有的單體成分、或是在複 數個單體成分中以最高比例而含有的單體成分。 (Acr-B ) 接著，針對丙烯酸系樹脂Acr_B進行說明。Acr_B，是 由（甲基）丙烯酸乙醯乙醯氧基烷基酯、以及能與該（曱 基）丙烯酸乙醯乙醯氧基烷基酯共聚合之丨種或2種以上 的乙烯基單體所形成，並且不含游離羧基之共聚物。此種 共聚物’在使用作為黏著劑時，&夠基於共聚物所含有的 乙醯乙醯氧基烷基彼此的交聯反應’而在黏著劑層全體中 形成微細的網目結構，並且能夠在該網目結構中保㈣劍 201114865 71备基於上述觀點，此種共聚物適合使用於經皮吸收 型製劑用途。 作為（曱基）丙烯酸乙醯乙醯氧基烷基酯，可舉出如： 、酿乙酿基使伸烧基二醇（alkylene glycol)類的一個經基 被酿化、以丙稀酸或甲基丙烯酸使另一個羥基被醯化而成 的化合物。作為此種化合物，例如可例示：以甲基丙烯酸 2乙醯乙醯氧基乙酯、丙烯酸2_乙醯乙醯氧基乙酯為佳， 較佳為甲基丙烯酸2-乙醯乙醯氧基乙酯。又，當將共聚物 總質量設為100時’在共聚物中的（曱基）丙烯酸乙醯乙 醯氧基烷基酯的含量以5〜5〇質量％左右為佳，較佳為1〇 〜45質量％左右。 作為能夠與（甲基）丙烯酸乙醯乙醯氧基烷基酯共聚 σ的乙稀基单體，可舉出在分子内具有乙醯基的化合物。 作為此種化合物，可例示如：烷基碳數為丨〜12的（曱基） 丙烯酸烷基酯類；在分子内具有羥基、醯胺基、烷氧基烷 基等官能基的官能性單體類；及聚伸烷基二醇二（甲基） 丙烯酸酯類等。這些乙醯基單體，可組合丨種或2種以上 來使用。 作為烷基碳數為1〜12的（甲基）丙烯酸烷基酯類， 具體而言可舉出如：（甲基）丙烯酸甲酯、（甲基）丙烯酸 乙酯、（曱基）丙烯酸丙酯、（甲基）丙烯酸丁酯、（甲基） 丙烯酸-2-乙基己酯、（甲基）丙烯酸辛酯、（甲基）丙烯酸 十二烷基酯等。又，作為在分子内具有官能基的官能性單 體類，具體而言可舉出如：（甲基）丙烯酸2_甲氧基乙酯、 12 201114865 二丙酮丙烯醯胺、（甲基）丙烯酸2-羥乙酯等。又，作為聚 伸烷基二醇二（甲基）丙烯酸酯類，具體而言可舉出如： 二乙二醇^ (甲基）丙歸酸醋、三乙二醇二（甲基）丙稀 酸酯、四乙二醇二（甲基）丙烯酸酯等。 (甲基）㈣酸乙醯乙醯氧基院基醋與其他乙酿基單 體的共聚物，可使用過氧化物或偶氮系化合物之類的聚合 起始劑’並藉由一般方法來製造。 如同先前所說明 聯型的樹脂也就是上 ’本實施形態的黏著劑，至少含有交 述Acr-A、及同樣為交聯型的樹脂也 就是Acr-B。一般而言，若將此種交聯型的樹脂使用作為 黏著劑，則黏著劑層的黏著力會有降低的趨勢。但是，本 發明人等意外地發現，併用上述八…八與Acr_B而成的黏 著劑，會顯示比單獨使用這些樹脂時更為良好的黏貼性， 而完成了本發明。單獨使用Aer_A或Aer_B作為黏著劑的 情形中，經皮吸收型製劑的黏貼性在應用於皮膚起1曰後 就已幾乎喪失。相對於此’併用Acr_A與八㈣而使用作 為黏著劑的情形中，經皮吸收型製劑的黏貼性在應用於皮 膚起可保持3日以上。進而，在本發明中，亦可不需為了 賦予黏貼性而併用非交聯型的樹脂來作為黏著劑，所以可 以對於黏著劑層添加多量的藥劑成分。另外，亦可視需要 而在含有上述Acr_A與Acr_B的黏著劑中，添加非交聯型 的樹脂。 黏著劑中所含有的Acr-A與Acr-B的質量比，以9〇 10〜49 : 51為佳，較佳為90 ·· 1〇〜5〇 : 5〇，更佳為85 13 201114865 15〜50. 50。藉由黏著劑中所含有的AcrB為ι〇質量％以 上，在添加有藥劑成分等的黏著劑層中，經時所致之凝膠 分率上升會受到抑制，所以可使經皮吸收型製劑的品質較 為安定。又，藉由黏著劑中所含有的Acr-B & 51質量％以 下，可使黏著劑的凝膠分率較為充分，並且可抑制因經皮 吸收型製劑對皮膚之貼附時間增加而伴隨產生的黏著劑層 之垂流或凝聚力之降低。 此處，所謂的凝膠分率’是表示在黏著劑層所含有的 樹脂成分（黏著劑）中，相對於樹脂成分全體之不溶於溶 劑的樹脂成分的比率。作為此時的溶劑，可例示如乙酸乙 δ曰。此處’隨著Aer_A < Ae卜B進行交聯，凝膠分率會變 大，所以凝膠分率也是表示Acr-A或Acr-B所得之交聯程 度的拓杌如同先前已說明，Acr-A或Acr-B可以分別單 獨交聯而形成網目結構，但凝膠分㈣程度會如上述般依Acr-A and Acr-B are acrylic resins which do not contain a free carboxyl group. Therefore, the percutaneous absorption type preparation of the present embodiment can prevent the stability of the pharmaceutical ingredient from being affected even if the pharmaceutical ingredient contained in the adhesive layer is a component that reacts or interacts with the acid, in addition to being less irritating to the skin. Loss, or transdermal absorbability is reduced. Further, the phrase "free of a free carboxyl group" means that all of the carboxyl groups are converted into a substituent such as an ester bond by design. Therefore, even if Acr-A and Acr-B contain a rebel group derived from hydrolysis of an ester bond or the like, or a rebel group derived from a raw material, it is included in the range of 201114865 of the present invention (Acr-A) first. The acrylic resin Acr-A will be described. Acr-A is a resin mixture containing 100 parts by mass of the following acrylic copolymer (X) and 0.1 to 3 parts by mass of the acrylic copolymer (Y). The acrylic copolymer (X) is a (meth)acrylic acid alkyl ester as a main monomer component, and contains 3 to 45% by mass of diacetone acrylamide as an essential monomer component, and does not contain a copolymer of a free carboxyl group. Things. The acrylic copolymer (Y) is a copolymer of a (meth)acrylic acid alkyl ester as a main monomer component and a primary amine group and/or a carboxyl group in a side chain, and which does not contain a free carboxyl group. When the resin mixture is used as an adhesive, it can be based on a thiol derived from diacetone acrylamide contained in the acrylic copolymer (X) and a primary amine group contained in the acrylic copolymer (Y) or The cross-linking reaction of the carboxymethyl group forms a fine mesh structure in the entire adhesive layer, and can maintain a pharmaceutical component or the like in the mesh structure; based on the above viewpoint, the resin mixture can be suitably used for a percutaneous absorption preparation. use. The production of the acrylic acid-based copolymer (X) can be exemplified by adding (meth)acrylic acid-based vinegar as a main monomer component, adding diacetone acrylamide and making it relative to the entire monomer. 3 to 45 mass% and subject it to radical polymerization. These monomer components can be polymerized by a usual method using a polymerization initiator such as a peroxide or an azo compound. When these monomers are polymerized, it is preferred to appropriately add a solvent to adjust the viscosity of the reaction solution. As the alkyl (meth)acrylate, it is preferred to use a (mercapto)acrylic acid vinegar having an alkyl carbon number of 201114865.1~12. Specific examples thereof include (meth)methyl acrylate, ethyl (meth)acrylate, (meth) ester, butyl (meth)acrylate, and 2-ethyl (meth)acrylate. Hex, g, octyl (meth)acrylate, dodecyl (meth)acrylate, and the like. These bis(meth)acrylic acid alkyl esters may be used singly or in combination of two or more. The production of the acrylic copolymer (Y) may, for example, be a method in which a (meth)acrylic acid alkyl ester is used as a main monomer component, and a monomer component for introducing an amine group is added and/or The monomer component of the carboxymethyl group is introduced and made to have a mass % relative to the entire monomer, and subjected to radical polymerization, and then the side chain derived from the monomer component for introducing the carboxymethyl group is converted into a carboxy group.醯肼基. When the monomer component is subjected to radical polymerization, a polymerization initiator such as a peroxide or an azo compound can be used and polymerized by a usual method. When the monomer component is subjected to radical polymerization, it is preferred to appropriately add a solvent to adjust the viscosity of the reaction solution. Further, the alkyl (meth)acrylate used in the production of the copolymer (B) can be the same as those exemplified in the above copolymer (A). Further, in order to exhibit appropriate crosslinkability with the acrylic copolymer (X), the primary amine group and/or the carboxy group in the acrylic copolymer (γ) in one molecular chain of the acrylic copolymer (Y) The thiol group is preferably two or more, and more preferably three or more. Further, 'the monomer component for introducing the primary amine group and/or the monomer component for introducing the slow-melting base group, and the alkyl (meth)acrylate monomer are preferably mixed to have a molar ratio of 1 : 5~1 : I 共 and co-aggregate. As a single 10 201114865 body for introducing a primary amine group to the acrylic copolymer (Y), it can be exemplified by a compound which can be polymerized with (meth)acrylic acid leuco ester and which is straight and seven soils/ A primary amine based compound. As such a compound, for example, vinylamine or the like can be exemplified. The monomer used for introducing the carboxymethyl group to the acrylic copolymer (Y) can be exemplified by a ketone having an ethyl group which can be polymerized with an alkyl (meth) acrylate and having a reaction with a thiol group. Base compound. As such a compound, for example, diacetone acrylamide, acrolein, methacrylic acid ethoxylate, and the like can be exemplified. To convert a side chain derived from a monomer component for introducing a carboxymethyl group into a carboxy fluorenyl group, the polymer obtained by the above radical polymerization is dissolved in a polar solvent and, in the presence of an acid catalyst, It reacts with diquinone dicarboxylate. Examples of the dibasic acid diterpene include dioxane adipate, diammonium glutarate, and diammonium pimelate. In addition, the "main monomer component" as used herein means 50 mass with respect to a copolymer. /. The monomer component contained above or the monomer component contained in the highest proportion among the plurality of monomer components. (Acr-B) Next, the acrylic resin Acr_B will be described. Acr_B is an ethylene(meth)acrylate ethoxylated alkyl ester and a kind of two or more vinyl monomers copolymerizable with the (indenyl) ethoxylated alkyl acrylate. The body is formed and does not contain a copolymer of free carboxyl groups. When such a copolymer is used as an adhesive, a fine mesh structure is formed in the entire adhesive layer based on the crosslinking reaction between the ethyl ethoxylated alkyl groups contained in the copolymer. In the mesh structure, (4) Sword 201114865 71 is based on the above viewpoint, and such a copolymer is suitable for use in a percutaneous absorption type preparation. Examples of the (indenyl) acetoacetoxy acrylate include, for example, a brewing base such that one of the alkylene glycols is brewed, and acrylic acid or A compound in which methacrylic acid causes another hydroxyl group to be deuterated. As such a compound, for example, 2-ethinylethyl methacrylate or 2-ethyl acetoxyethyl acrylate may be exemplified, and 2-ethyl oxime methacrylate is preferred. Base ethyl ester. Further, when the total mass of the copolymer is 100, the content of (mercapto) acetamethylene acrylate in the copolymer is preferably from 5 to 5 % by mass, preferably 1 Torr. ~45% by mass or so. The ethylenic monomer which can copolymerize σ with the ethoxylated alkyl (meth) acrylate may, for example, be a compound having an ethoxy group in the molecule. Examples of such a compound include alkyl (meth) acrylates having an alkyl group having a carbon number of 丨 12 and a functional group having a functional group such as a hydroxyl group, a guanamine group or an alkoxyalkyl group in the molecule. Body; and polyalkylene glycol di(meth) acrylates. These ethyl thiol monomers may be used in combination or in combination of two or more. Specific examples of the alkyl (meth)acrylate having an alkyl group having 1 to 12 carbon atoms include methyl (meth)acrylate, ethyl (meth)acrylate, and ethyl (meth)acrylate. Ester, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, octyl (meth)acrylate, dodecyl (meth)acrylate, and the like. Further, examples of the functional monomer having a functional group in the molecule include, for example, 2-methoxyethyl (meth)acrylate, 12 201114865 diacetone acrylamide, and (meth)acrylic acid. 2-hydroxyethyl ester and the like. Further, specific examples of the polyalkylene glycol di(meth)acrylates include diethylene glycol (meth) propionate vinegar and triethylene glycol di(meth) propyl group. Dilute ester, tetraethylene glycol di(meth)acrylate, and the like. (meth) (tetra) a copolymer of acetamethylene ethoxylate ketone with other ethylenic monomers, a polymerization initiator such as a peroxide or an azo compound can be used' and by a general method Manufacturing. The resin which is linked as described above, that is, the adhesive of the above embodiment, contains at least Acr-A and a resin which is also a crosslinked type, that is, Acr-B. In general, when such a crosslinked type resin is used as an adhesive, the adhesive strength of the adhesive layer tends to decrease. However, the inventors have unexpectedly found that the use of the above-mentioned eight-eighth and Acr-B adhesives exhibits better adhesion than when these resins are used alone, and completed the present invention. In the case where Aer_A or Aer_B is used alone as an adhesive, the adhesiveness of the percutaneous absorption type preparation is almost lost after being applied to the skin. In contrast, in the case where Acr_A and octa (A) are used together as an adhesive, the adhesiveness of the percutaneous absorption type preparation can be maintained for more than 3 days when applied to the skin. Further, in the present invention, it is not necessary to use a non-crosslinking type resin as an adhesive in order to impart adhesiveness, so that a large amount of a chemical component can be added to the adhesive layer. Further, a non-crosslinking type resin may be added to the adhesive containing the above Acr_A and Acr_B as needed. The mass ratio of Acr-A to Acr-B contained in the adhesive is preferably 9〇10~49:51, preferably 90··1〇~5〇: 5〇, more preferably 85 13 201114865 15 ~50. 50. When the amount of AcrB contained in the adhesive is 3% by mass or more, in the adhesive layer to which the chemical component or the like is added, the increase in the gel fraction due to the passage of time is suppressed, so that the percutaneous absorption preparation can be obtained. The quality is more stable. Moreover, the gel fraction of the adhesive can be sufficiently made by the Acr-B & 51 mass% or less contained in the adhesive, and the increase in the adhesion time of the skin by the percutaneous absorption type preparation can be suppressed. A decrease in the sag or cohesion of the resulting adhesive layer. Here, the gel fraction ' is a ratio of the resin component (adhesive) contained in the adhesive layer to the resin component insoluble in the solvent. As the solvent at this time, for example, ethyl acetate δ is exemplified. Here, 'Aer_A < Ae B B cross-links, the gel fraction becomes larger, so the gel fraction is also a degree of cross-linking indicating the degree of cross-linking obtained by Acr-A or Acr-B as previously explained. Acr-A or Acr-B can be crosslinked separately to form a mesh structure, but the degree of gelation (4) will be as above.
照Acr-A與Acr_B的比率而變化。因此，藉由混合使用心卜A 與Acr-B ’这些成分之間可能會產生某種相互作用。從而， 藉由混合Acr-A肖Acr_B而如上述般能獲得充分的黏貼 性，可能也是這些成分之間產生某種相互㈣的結果。 另外’黏著劑的凝膠分率，以30〜70%為佳。藉由黏 著劑的凝膠分率為鳩以上，可抑制因經皮吸收型製劑對 皮膚之貼附時間增加而伴隨產生的黏著劑層之垂流或凝聚 力降低。藉由黏著劑的凝膠分率$ 7()%以下，可獲得充分 的皮膚黏貼性。 [塑化劑] 14 201114865 & 2黏著劑層中’可含有塑化劑。作為此種塑化劑… 般而D可使用具有高沸點的油狀物 g ^ 舉出：肉豆蔻 —曰 '癸二酸二乙醋' 己二酸二異…油酸乙醋、 =異=、月桂酸乙醋、肉豆蔑酸辛醋、肉豆缝酸異 十-自曰、中鏈脂肪酸三酸甘油酯等脂肪酸酯衍生物；己基 癸醇、辛基十二醇等高級烷醇衍生物；聚乙二醇、聚丙二 醇等聚稀烴二醇類；橄禮油、藥麻油等油脂類等。這二 中’肉豆謹酸異丙醋 '標摘酸異丙醋等，會作為黏著劑的 塑化劑而作用’且具有促進經皮吸收型製劑中之藥劑成分 擴散的效果、與促進藥劑成分之皮膚穿透的效果，、因此較 佳。這些可單獨或併用2種以上來使用。塑化劑的調配量， 以相對於黏著劑層的全體質量為卜⑽質量％為佳，較佳 為二〜35質量％，最佳為6〜3〇質量％。藉由塑化劑的調配 量是相對於黏著劑層的全體質量$ !質量％以上，可充分 地獲得上述效果。#由塑化劑的調配量是相對於黏著劑二 的全體質量為40質量％以下’而可抑制油狀物從黏著劑層 漏出之滲漏（bleeding)的發生。 [黏著劑層所含有的其他成分] 黏著劑層中，可為了賦予必要的功能而添加各種添加 劑。作為此種添加劑，可例示如：用以溶解藥劑成分的溶 劑、各種黏著劑、防腐劑、pH調整劑、螯合劑、經皮吸收 促進劑、抗氧化劑、賦形劑、香料 '著色劑等。 用以使藥劑成分溶解的溶劑，只要是會溶解藥劑的溶 劑，則無特別限定，以無皮膚刺激性的溶媒為佳。作為此 201114865 種溶劑，可舉出如 醇、辛醇等中級醇 類，脂肪酸醋類、 這些可單獨或併用 :乙醇、丙醇、異 類；甘油、乙二醇 聚乙稀醇、N-甲基 2種以上來使用。 丙醇專低級醇類；己 、二乙二醇等多元醇 °比B各啶酮、乳酸等。 ，在本實施形態的經皮吸收型製劑中，為了使黏著劑層 形成，作為一例，可舉出下述方法：將上述Acr_A、^_Ba、 藥劑成分、塑化劑等黏著劑層所應含有的成分，溶解於溶 劑而製作溶液，將該溶液塗佈於支撐體後，使溶劑藉由公 知的方法而加熱蒸散。作為此種方法所使用的溶劑，只要 是會在經皮吸收型製劑之製造步料的加熱乾燥步驟：散 的有機溶媒，則無特別限定，例如可舉出：丙_、甲基乙 基酮等酮類；6酸甲醋、乙酸乙醋、乙酸丙酯、乙酸；醋 等乙酸酯自；己烷、庚烷、辛烷、環己烷等脂肪族烴類； 苯、曱苯、二曱苯等芳香族烴類；異丙基醚、四氫呋喃、 二氧陸園（di〇xane)等醚類等有機溶劑。這些可單獨或併用 2種以上來使用。 <支撐體> 作為支撐體，以對於藥劑成分為不穿透或難以穿透並 且柔軟者為佳。具體而言，可舉出如：聚乙烯、聚丙稀、 乙稀/乙酸乙烯酯共聚物、乙烯/乙酸乙烯酯/一氧化碳 共聚物、乙烯/丙烯酸丁酯/一氧化碳共聚物、尼龍、聚 酉9 (聚對苯二曱酸乙二酯）、聚對笨二曱酸丁二酯等樹脂膜 或銘片等。可將此等加以積層而形成為片狀，亦可與織布 或不織布一起進行積層。又，為了提高與黏著劑層的黏接 201114865 性’亦可施加電暈處理、電漿放電處理等表面處理，或藉 由猫固劑來施加錯塗（anch〇r coat)處理。 <藥劑成分> 藥劑成分’是含有於黏著劑層，會通過藥劑面也就是 黏著劑層的表面而被皮膚吸收。本實施形態的經皮吸收型 製劑中’是使用吩坦尼作為藥劑成分。吩坦尼，是被稱為 1-苯乙基”4_N-丙醯基苯胺基哌啶 propionyl-anilinopiperidine)的化合物。本實施形態的經皮 吸收型製劑中所使用的吩坦尼，是吩坦尼（自由態）及/ 或其鹽。具體而言，可舉出如：吩坦尼（自由態）、擰檬酸 吩坦尼、鹽酸吩坦尼、硫酸吩坦尼等，亦可組合吩坦尼（自 由態）及其鹽而使用。所使用的吩坦尼，以吩坦尼（自由 態）及/或擰檬酸吩坦尼為佳，較佳為吩坦尼（自由態）。 黏著劑層中之吩坦尼的含量，可視使用目的等而適當 地決定’但因為若過少則藥理活性將變得不充分’若過多 則血中農度會急遽地上升或黏著性降低，因此以相對於黏 著劑層的全體質量而為〇.〇丨〜“質量％為佳，較佳為0.5 〜20質量％。在黏著劑層中’吩坦尼以溶解狀態、過飽和 狀態 '或結晶狀態存在即可。又，為了使吩坦尼持續具有 經皮吸枚性’亦可使吩坦尼的一部分為溶解狀態、一部分 為結晶狀態。 以上’對於本發明的經皮吸收型製劑，顯示了實施形 態而具體地說明’但本發明並不限定於上述實施形態，可 在本發明的構成範圍内加以適當變更而實施。 17 201114865 例如，在上述實施形態中’是使用吩坦尼作為藥劑成 分’但亦可使用其他藥劑成分。 [實施例] 以下，顯示實施例以進而具體地說明本發明的經皮吸 收型製劑，但本發明並不受下述實施例所限制。 [製作例1 ;丙烯酸系樹脂Acr-A] 將藉由以下所示之合成方法而獲得的丙烯酸系共聚物 (X )的溶液、與丙烯酸系共聚物（γ )的溶液加以混合， 且使溶液中所含有的丙烯酸系共聚物（X)與丙烯酸系共聚 物（Y)的質量比成為100 : 5 ’而獲得丙烯酸系樹脂Acr-A 的溶液。 •丙烯酸系共聚物（X ) 添加200質量份之丙烯酸_2_乙基己酯、1〇〇質量份之 丙烯酸丁酯、50質量份之二丙酮丙烯醯胺、及3〇〇質量份 之乙酸乙酯，並進行混合。將此混合物移至具備攪拌裝置 及循環冷卻裝置的可拆式燒瓶（separabie fiask)中，一邊進 行攪拌及氮氣取代’一邊升溫至75〇c。將在20質量份之 乙酸乙醋中溶解2質量份之過氧化苯曱醯而成的溶液分為 5份’將其中1份添加至可拆式燒瓶中，並開始進行聚合 反應。將剩餘的4份’從聚合反應開始後2小時起，每隔 1小時添加1份，添加結束後，進而使其反應2小時。另 外’為了進行黏度調整，反應開始後，每隔2小時添加5〇 質直伤之乙酸乙酯，共計添加4次。反應結束後，將其冷 18 201114865 卻，接著添加乙酸乙酯，藉此獲得固形分濃度為3〇質量％ 的丙稀酸系共聚物（X )的溶液。 •丙烯酸系共聚物（γ) 添加660質量份之丙烯酸乙酯、70質量份之二丙_丙 烯醯胺、40質量份之作為分子量調節劑的十二基硫醇、及 400質量份之乙酸乙酯，並進行混合。將此混合物移至具 備攪拌裝置及循環冷卻裝置的可拆式燒瓶中，一邊進行攪 拌及氮氣取代，一邊升溫至70。(：。將在1〇〇質量份之乙酸 乙酯中溶解5質量份之偶氮雙異丁腈而成的溶液分為5 份’將其中1份添加至可拆式燒瓶中，並開始進行聚合反 應。將剩餘的4份’從聚合反應開始後2小時起，每隔1 小時添加1份，添加結束後，進而使其反應2小時。另外， 為了進行黏度調整’反應開始後’每隔2小時添加5 0質量 份之乙酸乙酯’共計添加4次。之後，添加將40質量份之 己二酸二醯肼溶解於具有40質量份之純化水、1 600質量 份之甲醇、260質量份之乙酸乙酯的混合液而成的溶液， 並進而添加5質量份之濃鹽酸後，升溫至70〇C。反應結束 後’將其冷卻，以純化水清洗3次後，使生成物溶解於具 有700質量份之乙酸乙酯、1400質量份之丙酮、及400質 量份之曱醇的混合溶媒中，藉此獲得固形分濃度為30質量 %的丙烯酸系共聚物（γ )的溶液。 [製作例2 ;丙烯酸系樹脂Acr-B] 將158質量份之丙烯酸2-乙基己酯、35.1質量份之甲 19 201114865 基丙烯酸2-乙醯乙醯氧基乙酯、76.2質量份之曱基丙烯酸 甲酯、80.3質量份之二丙酮丙烯醯胺、及1〇質量份之四 乙二醇二甲基丙烯酸酯加以均勻地溶解，而製備單體溶 液。將1〇0質量份之此單體溶液，充填於具備：戴氏冷凝 器（Dimroth condenser)、溫度計、氮氣注入管及攪拌翼而成 之2公升的四口燒瓶，並添加350質量份之乙酸乙酯作為 溶劑。一邊以100 mL/分鐘的流量注入氮氣、一邊升溫至 75 C，在75 C維持30分鐘後，添加將〇 35質量份之過氧 化苯曱醯溶解於5質量份之乙酸乙酯而成者作為起始劑， 並將外溫没定為8 5 C。確認了溶劑之循環後，將剩餘的單 體溶液歷時3小時連續投入^在單體溶液開始連續投入之 1小時後起，歷時3小時投入500質量份之乙酸乙酯。投 入乙酸乙酯後持續攪拌12小時’之後投入〇 _ 5質量份之過 氧化笨曱醯作為追加觸媒，並持續加熱12小時後，加以冷 卻而獲得丙烯酸系樹脂Acr-B的溶液。 [比較製作例1 ;共聚物Z] 使用市售的丙稀酸系共聚物溶液（Nippon CarbideIt varies according to the ratio of Acr-A to Acr_B. Therefore, some interaction may occur between these components by mixing the use of A and Acr-B'. Thus, sufficient adhesion can be obtained by mixing Acr-A Shore Acr_B as described above, and it is also possible that some mutual (IV) results are produced between these components. Further, the gel fraction of the adhesive is preferably from 30 to 70%. When the gel fraction of the adhesive is 鸠 or more, it is possible to suppress a decrease in the sag or cohesive force of the adhesive layer which is caused by an increase in the adhesion time of the percutaneous absorption preparation to the skin. A sufficient skin adhesiveness can be obtained by the gel fraction of the adhesive of $7 (% or less). [Plasticizer] 14 201114865 & 2 The adhesive layer may contain a plasticizer. As such a plasticizer... As usual, D can be used as an oil having a high boiling point g ^ exemplified: nutmeg - 曰 'sebacic acid diacetic acid ' adipic acid diiso... oleic acid ethyl vinegar, = iso = , fatty acid esters such as lauric acid vinegar, myristic acid vinegar, soy sulphate, sulphuric acid, medium chain fatty acid triglyceride, etc.; higher alkanol derivatives such as hexyl decyl alcohol and octyldodecanol Polystyrene glycols such as polyethylene glycol and polypropylene glycol; oils such as olive oil and sesame oil. In the second two, 'myristic acid isopropyl vinegar' is labeled with acid isopropyl vinegar, etc., and acts as a plasticizer for the adhesive', and has an effect of promoting the diffusion of the pharmaceutical ingredient in the percutaneous absorption preparation, and a promoting agent. The effect of skin penetration of the ingredients is therefore preferred. These can be used individually or in combination of 2 or more types. The compounding amount of the plasticizer is preferably 10% by mass based on the total mass of the adhesive layer, preferably 2 to 35% by mass, most preferably 6 to 3% by mass. The above effect can be sufficiently obtained by the compounding amount of the plasticizer being more than or equal to the mass of the entire mass of the pressure-sensitive adhesive layer. # The amount of the plasticizer to be added is 40% by mass or less based on the total mass of the adhesive 2, and the occurrence of bleeding of the oily substance from the adhesive layer can be suppressed. [Other components contained in the adhesive layer] In the adhesive layer, various additives may be added in order to impart a necessary function. As such an additive, for example, a solvent for dissolving a drug component, various adhesives, a preservative, a pH adjuster, a chelating agent, a transdermal absorption enhancer, an antioxidant, an excipient, a perfume, a coloring agent, and the like can be exemplified. The solvent for dissolving the drug component is not particularly limited as long as it is a solvent which dissolves the drug, and a solvent having no skin irritation is preferred. Examples of the 201114865 solvent include intermediate alcohols such as alcohol and octanol, and fatty acid vinegars, which may be used singly or in combination: ethanol, propanol, heterogeneous; glycerin, ethylene glycol, polyethylene glycol, N-methyl Two or more types are used. Propyl alcohol-specific lower alcohols; polyols such as hexanes and diethylene glycols; In the percutaneous absorption type preparation of the present embodiment, in order to form the adhesive layer, an adhesive layer such as Acr_A, ^_Ba, a pharmaceutical component, or a plasticizer is contained as an example. The component is dissolved in a solvent to prepare a solution, and after the solution is applied to a support, the solvent is heated and evaporated by a known method. The solvent to be used in the method is not particularly limited as long as it is a heat drying step in the production of a percutaneous absorption type preparation, and examples thereof include, for example, propylene and methyl ethyl ketone. Ketones; 6-acid methyl vinegar, ethyl acetate, propyl acetate, acetic acid; acetates such as vinegar; aliphatic hydrocarbons such as hexane, heptane, octane, cyclohexane; benzene, toluene, and An aromatic hydrocarbon such as toluene; an organic solvent such as an ether such as isopropyl ether, tetrahydrofuran or dioxane. These can be used individually or in combination of 2 or more types. <Support> As the support, it is preferred that the drug component is not penetrating or difficult to penetrate and is soft. Specific examples thereof include polyethylene, polypropylene, ethylene/vinyl acetate copolymer, ethylene/vinyl acetate/carbon monoxide copolymer, ethylene/butyl acrylate/carbon monoxide copolymer, nylon, and polyfluorene 9 ( A resin film such as poly(ethylene terephthalate) or polybutylene phthalate or a monolith. These may be laminated to form a sheet, or may be laminated together with a woven fabric or a non-woven fabric. Further, in order to improve the adhesion to the adhesive layer, surface treatment such as corona treatment or plasma discharge treatment may be applied, or an anch〇r coat treatment may be applied by a cat solid. <Pharmaceutical component> The drug component is contained in the adhesive layer and is absorbed by the skin through the surface of the drug surface, that is, the adhesive layer. In the percutaneous absorption type preparation of the present embodiment, phenanthrene is used as a pharmaceutical ingredient. "Bentani, a compound called 1-phenylethyl" 4_N-propionyl-anilinopiperidine. The phenanthrene used in the percutaneous absorption preparation of the present embodiment is phenanthrene. Ni (free state) and / or a salt thereof, and specific examples thereof include: phenanthrene (free state), phenoxy citrate, phenentrene hydrochloride, phenidene sulfate, etc. Tenny (free state) and its salt are used. The phenanthrene used is preferably phenanthrene (free state) and/or phenoxy citrate, preferably phenanthrene (free state). The content of phenanthrene in the adhesive layer can be appropriately determined depending on the purpose of use, etc. However, if the amount is too small, the pharmacological activity will be insufficient. If too much, the agronomic degree of blood will rise sharply or the adhesiveness will decrease. The mass % is preferably 5% by mass based on the total mass of the adhesive layer, preferably 0.5 to 20% by mass. In the adhesive layer, "Bentene may be in a dissolved state, a supersaturated state" or a crystalline state. Further, in order to continue the percutaneous aspiration of phenanthrene, a part of the phenanthrene may be in a dissolved state and a part may be in a crystalline state. In the above, the percutaneous absorption type preparation of the present invention has been described as being specifically described. However, the present invention is not limited to the above embodiment, and can be appropriately modified and implemented within the scope of the invention. 17 201114865 For example, in the above embodiment, 'the use of phenanthrene as a drug component' is used, but other drug components may be used. [Examples] Hereinafter, the examples of the transdermally absorbable preparation of the present invention will be specifically described, but the present invention is not limited by the following examples. [Production Example 1; Acrylic Resin Acr-A] A solution of the acrylic copolymer (X) obtained by the synthesis method shown below and a solution of an acrylic copolymer (γ) were mixed and a solution was obtained. The mass ratio of the acrylic copolymer (X) and the acrylic copolymer (Y) contained in the mixture was 100 : 5 ', and a solution of the acrylic resin Acr-A was obtained. • Acrylic copolymer (X) 200 parts by mass of 2-ethylhexyl acrylate, 1 part by mass of butyl acrylate, 50 parts by mass of diacetone acrylamide, and 3 parts by mass of acetic acid Ethyl ester and mix. This mixture was transferred to a separable flask (separabie fiask) equipped with a stirring device and a circulating cooling device, and the temperature was raised to 75 〇c while stirring and nitrogen substitution. A solution obtained by dissolving 2 parts by mass of benzoquinone in 20 parts by mass of ethyl acetate was divided into 5 parts. One of them was added to a separable flask, and polymerization was started. The remaining 4 parts were added 1 part every hour from 2 hours after the start of the polymerization reaction, and after the addition was completed, the reaction was further carried out for 2 hours. Further, in order to adjust the viscosity, ethyl acetate of 5 ruthenium was added every 2 hours after the start of the reaction, and the total amount was added 4 times. After completion of the reaction, it was cooled to 18 201114865, and then ethyl acetate was added thereto to obtain a solution of the acrylic acid copolymer (X) having a solid content concentration of 3% by mass. • Acrylic copolymer (γ) 660 parts by mass of ethyl acrylate, 70 parts by mass of dipropyl acrylamide, 40 parts by mass of dodecyl mercaptan as a molecular weight regulator, and 400 parts by mass of acetic acid B Ester and mix. The mixture was transferred to a separable flask equipped with a stirring apparatus and a circulating cooling apparatus, and the temperature was raised to 70 while stirring and nitrogen substitution. (: A solution obtained by dissolving 5 parts by mass of azobisisobutyronitrile in 1 part by mass of ethyl acetate was divided into 5 parts', 1 part of which was added to a separable flask, and started The polymerization reaction was carried out, and the remaining 4 parts were added 1 part every 2 hours from the start of the polymerization reaction, and after the completion of the addition, the reaction was further carried out for 2 hours. In addition, in order to adjust the viscosity, the reaction was started. After adding 50 parts by mass of ethyl acetate in 2 hours, a total of 4 times was added. Thereafter, 40 parts by mass of dioxonium adipate was added to 40 parts by mass of purified water, 1 600 parts by mass of methanol, and 260 mass. A solution of a mixture of ethyl acetate and 5 parts by mass of concentrated hydrochloric acid was added thereto, and the temperature was raised to 70 ° C. After the completion of the reaction, the mixture was cooled, washed with purified water for 3 times, and then the product was dissolved. A solution of an acrylic copolymer (γ) having a solid content concentration of 30% by mass was obtained in a mixed solvent having 700 parts by mass of ethyl acetate, 1400 parts by mass of acetone, and 400 parts by mass of decyl alcohol. Production Example 2; Acrylic resin Acr-B] Will be 158 2 parts by weight of 2-ethylhexyl acrylate, 35.1 parts by mass of methyl 19 201114865 2-ethyl acetoxyethyl acrylate, 76.2 parts by mass of methyl methacrylate, 80.3 parts by mass of diacetone acrylamide And uniformly dissolving 1 part by mass of tetraethylene glycol dimethacrylate to prepare a monomer solution. 1 〇 part by mass of the monomer solution is filled in with a Dimroth condenser a two-liter four-necked flask made of a thermometer, a nitrogen gas injection tube, and a stirring blade, and 350 parts by mass of ethyl acetate was added as a solvent. While injecting nitrogen gas at a flow rate of 100 mL/min, the temperature was raised to 75 C. After 75 C was maintained for 30 minutes, 35 parts by mass of hydrazine benzoate was dissolved in 5 parts by mass of ethyl acetate as an initiator, and the external temperature was not determined to be 85 C. The solvent was confirmed. After the cycle, the remaining monomer solution was continuously supplied over 3 hours. After 1 hour from the start of the continuous start of the monomer solution, 500 parts by mass of ethyl acetate was charged over 3 hours. After stirring for 12 hours, the mixture was continuously stirred for 12 hours. 'After investing 〇 _ 5 quality The oxidized alum was used as an additional catalyst, and heating was continued for 12 hours, and then cooled to obtain a solution of the acrylic resin Acr-B. [Comparative Production Example 1; Copolymer Z] A commercially available acrylic acid system was used. Copolymer solution (Nippon Carbide
Industries股份有限公司製，製品名：Nissetsu PE300 )作 為比較試驗用的共聚物Z。此丙烯酸系共聚物Z，是使85 質量份之丙烯酸-2-乙基己酯單體、10質量份之丙烯酸-2- 經乙、及5質量份之乙酸乙烯酯進行自由基共聚合所製 作而成。 [實施例1〜8] 20 201114865 將製作例1所獲得的丙烯酸系樹脂Acr-A溶液、及製 作例2所獲得的丙烯酸系樹脂Acr_B溶液加以混合，在此 混合溶液中’添加：作為塑化劑之肉豆蔻酸異丙酯（IpM ) 及棕櫚酸異丙酯（IPP )、以及作為添加劑之二丁基羥基甲 苯（BHT ) ’將溶液全體均勻地攪拌，藉此獲得混合液。在 塗刷面是經電暈處理而成且厚度為25 " m之pET (聚對苯 二甲酸乙二酯）製膜的支撐體上，塗刷此混合液且使其乾 燥後之黏著劑層的厚度成為5〇em，再使其乾燥，藉此形 成黏著劑層，而製作出實施例丨〜8的經皮吸收型製劑用貼 片。各成分的調配，是使其乾燥後的質量％成為如同表i 所不之值而進行。另外，表1所示的各數值，是意謂質量 % » [比較例1及2] 除了未調配部分的成分以外，以與上述實施例丨〜8同 樣的程序，來製作比較例1及2的經皮吸收型製劑用貼片。 各成分的調配，是使其乾燥後的質量％成為如同表1所示 之值而進行。 [比較例3 ] 除了取代丙烯酸系樹脂Acr-A而使用比較製作例i所 獲得的丙_系共聚物z，且未調配掠摘酸異丙自旨（Bp) 以外，以與上述實施例卜8同樣的程序，來製作比較例3 的經皮吸收型製劑用貼片。各成分的調配，是使 的質量％成為如同表1所示之值而進行。 '、'、 21 201114865 [表1] ------ 實施例 比較例 1 2 3 4 5 6 7 8 1 2 3 Acr-A i>6 43 45 50 50 59 34 58 89 Acr-B T3 ~~~ 25 29 34 34 34 35 11 一 69 71 共眾物Λ 1—---- 一 — — 一 _ 一 — _ _ 18 1PM 20 15 5 10 3 20 20 5 20 10 lPr 10 10 1 Λ 10 BHT - 1U 5 3 10 ιυ 5 — fr~ 1 1 1 1 1 1 1 1 1 [實施例9〜1 81 將氣作例1所獲得的丙稀酸系樹脂Acr_A溶液、及製 作例2所獲得的丙烯酸系樹脂Acr-B溶液加以混合，在此 混σ /谷液中，添加：作為藥劑成分之吩坦尼、作為塑化劑 之肉丑蔻酸異丙酯（ΙΡΜ )及棕櫚酸異丙酯（ΙΡΡ )、以及作 為添加劑之二丁基羥基甲苯（ΒΗΤ)，將溶液全體均勻地攪 拌，藉此獲得混合液。在塗刷面是經電暈處理而成且厚度 為25 y m之pet(聚對苯二甲酸乙二酯）製膜的支樓體上， 塗席丨此/昆s液且使其乾燥後之黏著劑層中的吩坦尼濃度成 為0.42 mg/cm2’再使其乾燥，藉此形成黏著劑層，而製 作出實施例9〜18的經皮吸收型製劑。各成分的調配，是 使其乾燥後的質量％成為如同表2所示之值而進行。另外， 表2所示的各數值，是意謂質量0/〇。 [比較例4] 除了取代丙晞酸系樹脂Acr_A而使用比較製作例1所 獲得的丙烯酸系共聚物Z，且未調配棕櫚酸異丙醋（ιρρ) 以外’以與上述實施例9〜18同樣的程序，來製作比較例 4的經皮吸收型製劑。各成分的調配，是使其乾燥後的質 22 201114865 量0/〇成為如同表2所示之值而進行。 [表2] 實施例 比較例 9 10 11 12 13 14 1S 16 17 18 4 Acr-A 52 39 42 46 46 55 30 54 51 54 — Acr-B 29 22 25 30 30 30 30 6 30 24 56 共聚物z — —— — — — _ — — 25 吩坦尼 8 8 7 8 8 8 9 9 5 10 8 IPM 5 20 15 5 10 3 20 20 6 5 10 IPP 5 10 10 10 5 3 10 10 6 5 _ BHT 1 1 1 1 1 1 1 1 2 2 1 [皮膚點貼性之評價] 將實施例1〜8及比較例1〜3之經皮吸收型製劑用貼 片（3.2 cmx 3·2 cm ; 10 cm2 )貼附於10位受測者的右上 臂，在貼附起經過72小時後，以目視觀察各受測者的皮膚 貼附狀態（剝離狀況）。將經皮吸收型製劑用貼片的全面均 貼附於皮膚上者設作「無剝離」，以下述基準來評價各受測 者的皮膚貼附狀態，並調查該當於各評價基準之受測者的 人數。其結果顯示於表3。 ◎:無剝離 〇：可辨認到極輕微的剝離 △:可辨認到四角有稍廣的剝離 X :可辨認到廣範圍的剝離、或是貼附部位 有大幅度的位移 23 201114865 [表3] 該當於 各評價基準之受測者的人數Γ人、 ◎ 〇 Δ X 實施例1 10 0 0 0 實施例2 10 0 0 0 實施例3 10 0 0 0 實施例4 10 0 0 0 實施例5 10 0 0 0 實施例6 10 0 0 0 實施例7 10 0 0 0 實施例8 10 0 0 0 比較例1 7 0 2 1 比較例2 3 4 2 1 比較例3 7 3 0 0 [豬之經皮吸收試驗 將豬（藍瑞斯&大約克夏’ U月齡，雌性，體重約25 kg )的背部進行除毛，清洗表面後，將經皮吸收型製劑於 無受傷的部位貼附72小時，進行藥劑成分（吩坦尼）的經 皮吸收試驗。貼附後，蓋上不浸透性油紙以覆蓋貼附部位， 以不織布黏性繃帶固定後，將全體以紗布覆蓋，並進而被 覆以黏著性布伸縮繃帶，再於其上以伸縮性網來覆蓋身體 全體。貼附經皮吸收型製劑起經過72小時後，以目視觀察 各製劑的皮膚貼附狀態（剝離狀況），並以與上述對於人類 之皮膚黏貼性試驗同樣的評價基準，來評價豬之皮膚黏貼 性。又，在72小時的貼附試驗之後，將試驗中所使用的經 皮吸收型製劑加以回收，在超音波照射下以甲醇萃取來調 查製劑中之藥劑成分的殘留量，並根據此殘留量來計算被 經皮吸收之藥劑的量。 上述試驗是對於實施例9〜丨8及比較例4的經皮吸收 24 201114865 型製劑（吩坦尼含量為2.1 mg/ 5 cm2)而進行。其結果顯 示於表4。 [緒之經皮吸收試驗2 ] 將豬（藍瑞斯&大約克夏，11月齡，雌性，體重約25 kg )的背部進行除毛’清洗表面後，將經皮吸收型製劑於 無文傷的部位貼附72小時，進行藥劑成分（吩坦尼）的經 皮吸收試驗。貼附後’蓋上不浸透性油紙以覆蓋貼附部位， 以不織布黏性繃帶固定後，將全體以紗布覆蓋，並進而被 覆以黏著性布伸縮繃帶，再於其上以伸縮性網來覆蓋身體 全體。在實施經皮吸收試驗期間，藉由自頸部插入並留置 於中心靜脈的插管（cannula)，於貼附後每隔一定時間即採 取血液’以測定血漿中之藥劑成分的濃度。 上述試驗是對於實施例9及比較例4的經皮吸收型製 劑（吩坦尼含量為16.8 mg/40 cm2)而進行。其結果顯示 於表5。另外，表5中，所謂的AUC，是指血液濃度—時 間曲線下面積（ngxhr/ ml )，所謂的Cmax，則是意謂最大 血中濃度（ng/ml)。 25 201114865 [表4] 藥劑的經虔吸收量（mg) 豬之皮膚黏貼性（72小時後） 實施例9 0.60 ◎ 實施例10 0.60 ◎ 實施例11 0.58 ◎ 實施例12 0.60 ◎ 實施例13 0.61 ◎ 實施例14 0.50 ◎ 實施例15 0.63 ◎ 實施例16 0.63 ◎ 實施例17 0.50 ◎ 實施例18 0.65 ◎ 比較例4 0.29 △ ◎:無剝離 〇：可辨認到極輕微的剝離 △:可辨認到四角有稍廣的剝離 X .可辨認到廣範圍的剝離、或是貼附部位有大幅度的位移 [表5] AUC (ngxhr/ml) Cmax (ng/ml) 藥劑之經皮吸收·§Γ7ΐί^ΤΊ 實施例9 39.1 0.70 --' 八·’八1人里 ι m ρ 1 4.2 ~ 比較例4 15.2 0.60 ... 2^8~~' 如同表3所示，可知相較於比較例 1〜3的經皮吸收型 製劑用貼片，實施例i〜8的經皮吸收型製劑用貼片中，貼 附於反贗起經過 ..， 阳〜1埋月 ’相較於單獨使用Acr_A及Acr-B這兩種交聯型黏著劑 县罝猫蚀田 Δ A ™ Λ 〇 ^ 到 〜V丨王人唧型黏著齊丨 或是單獨使用Acr-A及Acr-B且併用其他黏著劑的情形 併用Acr-A及ACr-B時，黏著力能夠長時間持續，因而 理解到本發明的有效性。另外’併用Acr_B與非交聯型; 著劑的比較例3,其初期的黏貼性（初期膠黏）雖然充分· 但會有黏著力隨著時間經過而降低的趨勢， ^ 卉72小時後丨 26 201114865 皮膚黏貼性呈現劣於實施例1〜8的結果。此種趨勢，在實 際上含有藥劑成分的經皮吸收型製劑中也同樣可觀察到 (實施例9〜1 8及比較例4，如表4 )。 又，如同表4所示，相較於比較例4的經皮吸收型製 劑，實施例9〜1 8的經皮吸收型製劑之藥劑的經皮吸收量 較多。進而，如同表5所示’可理解到，實施例9的經皮 吸收型製劑顯示出高於比較例4的經皮吸收型製劑的 AUC ’從維持血中濃度的觀點而言，以實施例9為佳。 由以上結果可理解到’若根據本發明的經皮吸收型製 I月b夠在黏著劑層中使用交聯型的黏著劑且長時間維 持黏貼性，而2，能夠長時間維持藥劑成分之血中濃度。 【圖式簡單說明】 無 【主要元件符號說明】 無 27Made by Industries Co., Ltd., product name: Nissetsu PE300) as a copolymer Z for comparative testing. The acrylic copolymer Z is produced by radical copolymerizing 85 parts by mass of 2-ethylhexyl acrylate monomer, 10 parts by mass of acrylic acid-2-B, and 5 parts by mass of vinyl acetate. Made. [Examples 1 to 8] 20 201114865 The acrylic resin Acr-A solution obtained in Production Example 1 and the acrylic resin Acr_B solution obtained in Production Example 2 were mixed, and in the mixed solution, 'addition: as plasticization The solution of isopropyl myristate (IpM) and isopropyl palmitate (IPP), and dibutylhydroxytoluene (BHT) as an additive uniformly stirred the entire solution, thereby obtaining a mixed solution. On the support surface of the pET (polyethylene terephthalate) film which is corona-treated and has a thickness of 25 " m, the adhesive is applied after the mixture is dried and dried The thickness of the layer was 5 〇em, and it was dried to form an adhesive layer, and a patch for a percutaneous absorption type preparation of Examples 丨8 was produced. The blending of the respective components is carried out so that the mass % after drying becomes a value which is not as shown in Table i. In addition, each numerical value shown in Table 1 means mass % » [Comparative Examples 1 and 2] Comparative Examples 1 and 2 were produced in the same manner as in the above Examples 丨 8 except for the components of the unmixed portions. A patch for a percutaneous absorption preparation. The blending of the respective components was carried out by setting the mass % after drying to the values shown in Table 1. [Comparative Example 3] The c-type copolymer z obtained in Comparative Preparation Example i was used instead of the acrylic resin Acr-A, and the above-mentioned Example was used in addition to the unmixed isopropylidene pick-up (Bp). In the same procedure, a patch for a percutaneous absorption type preparation of Comparative Example 3 was prepared. The blending of the components was carried out by setting the mass % as shown in Table 1. ', ', 21 201114865 [Table 1] ------ Example Comparative Example 1 2 3 4 5 6 7 8 1 2 3 Acr-A i>6 43 45 50 50 59 34 58 89 Acr-B T3 ~ ~~ 25 29 34 34 34 35 11 a 69 71 Total objects 1——————— 一———一_一— _ _ 18 1PM 20 15 5 10 3 20 20 5 20 10 lPr 10 10 1 Λ 10 BHT - 1U 5 3 10 ιυ 5 - fr~ 1 1 1 1 1 1 1 1 1 [Examples 9 to 1 81 The acrylic acid resin Acr_A solution obtained in Example 1 and the acrylic acid obtained in Production Example 2 The resin Acr-B solution is mixed, and in this mixed sigma / gluten solution, phenanthrene as a pharmaceutical ingredient, isopropyl ugly oxalate (ΙΡΜ) and isopropyl palmitate (as a plasticizer) are added. And the dibutyl hydroxytoluene (ΒΗΤ) as an additive, and the whole solution was uniformly stirred, thereby obtaining a mixed liquid. On the slab of the pet (polyethylene terephthalate) film which is corona-treated and has a thickness of 25 μm, the sputum is dried and dried. The phenanthrene concentration in the adhesive layer was changed to 0.42 mg/cm2' and dried to form an adhesive layer, and the percutaneous absorption type preparations of Examples 9 to 18 were produced. The blending of the respective components was carried out by setting the mass % after drying to the values shown in Table 2. In addition, each numerical value shown in Table 2 means mass 0 / 〇. [Comparative Example 4] The acrylic copolymer Z obtained in Comparative Preparation Example 1 was used instead of the acrylic acid-based resin Acr_A, and the same as the above-mentioned Examples 9 to 18 except that the palmitic acid isopropyl vinegar (ιρρ) was not blended. The procedure of the percutaneous absorption type preparation of Comparative Example 4 was prepared. The blending of the components was carried out by making the amount of the dried material 22 201114865 0/〇 as shown in Table 2. [Table 2] Example Comparative Example 9 10 11 12 13 14 1S 16 17 18 4 Acr-A 52 39 42 46 46 55 30 54 51 54 — Acr-B 29 22 25 30 30 30 30 6 30 24 56 Copolymer z — —— — — — _ — — 25 Bentani 8 8 7 8 8 8 9 9 5 10 8 IPM 5 20 15 5 10 3 20 20 6 5 10 IPP 5 10 10 10 5 3 10 10 6 5 _ BHT 1 1 1 1 1 1 1 1 2 2 1 [Evaluation of skin sticking property] Patches of the percutaneous absorption type preparations of Examples 1 to 8 and Comparative Examples 1 to 3 (3.2 cm x 3·2 cm; 10 cm2) The right upper arm of the ten subjects was attached, and after 72 hours from the attachment, the skin attachment state (peeling condition) of each subject was visually observed. The skin patch of the percutaneous absorption type patch was attached to the skin as "no peeling", and the skin adherence state of each subject was evaluated on the basis of the following criteria, and the test was performed on each evaluation standard. The number of people. The results are shown in Table 3. ◎: No peeling 〇: A very slight peeling can be recognized △: It can be recognized that the four corners have a slightly wide peeling X: a wide range of peeling can be recognized, or a large displacement is applied to the attached portion 23 201114865 [Table 3] The number of subjects to be evaluated on each evaluation basis is ◎ 〇 Δ X Example 1 10 0 0 0 Embodiment 2 10 0 0 0 Embodiment 3 10 0 0 0 Embodiment 4 10 0 0 0 Example 5 10 0 0 0 Example 6 10 0 0 0 Example 7 10 0 0 0 Example 8 10 0 0 0 Comparative Example 1 7 0 2 1 Comparative Example 2 3 4 2 1 Comparative Example 3 7 3 0 0 [Pig of the pig In the absorption test, the back of the pig (Blue Rees & kexia 'U months old, female, weight about 25 kg) was depilated, and after washing the surface, the percutaneous absorption preparation was attached to the non-injured area for 72 hours. A transdermal absorption test of the pharmaceutical ingredient (Bentani) was performed. After attaching, cover the non-permeability oil paper to cover the attached part, and fix it with a non-woven adhesive bandage, cover the whole with gauze, and then cover the adhesive stretchable bandage, and then cover it with a stretchable net. The whole body. After 72 hours from the attachment of the percutaneous absorption type preparation, the skin attachment state (peeling condition) of each preparation was visually observed, and the skin adhesion of the pig was evaluated in the same evaluation criteria as the above-mentioned skin adhesion test for humans. Sex. Further, after the 72-hour adhesion test, the percutaneous absorption type preparation used in the test was collected, and the residual amount of the drug component in the preparation was investigated by ultrasonic extraction under ultrasonic irradiation, and based on the residual amount. The amount of the agent absorbed by the skin is calculated. The above test was carried out for the percutaneous absorption 24 201114865 type preparations (the phenanthrene content was 2.1 mg / 5 cm 2 ) of Examples 9 to 8 and Comparative Example 4. The results are shown in Table 4. [Essential Percutaneous Absorption Test 2] The hair of the pig (Blue Rees & about shire, 11 months old, female, weighing about 25 kg) was depilated to clean the surface, and the percutaneous absorption preparation was The wounded part was attached for 72 hours, and the percutaneous absorption test of the pharmaceutical ingredient (Bentani) was performed. After attaching, 'cover the non-permeable oil-proof paper to cover the attached parts. After fixing with the non-woven adhesive bandage, cover the whole with gauze, and then cover the adhesive stretchable bandage, and then cover it with a stretchable net. The whole body. During the percutaneous absorption test, blood was taken at a predetermined time after attachment by a cannula inserted from the neck and left in the central vein to determine the concentration of the drug component in the plasma. The above test was carried out on the percutaneous absorption type preparations (the phenanthrene content of 16.8 mg / 40 cm 2 ) of Example 9 and Comparative Example 4. The results are shown in Table 5. In addition, in Table 5, the so-called AUC refers to the area under the blood concentration-time curve (ngxhr/ml), and the so-called Cmax means the maximum blood concentration (ng/ml). 25 201114865 [Table 4] Radon absorbed amount of the drug (mg) Pig skin adhesion (after 72 hours) Example 9 0.60 ◎ Example 10 0.60 ◎ Example 11 0.58 ◎ Example 12 0.60 ◎ Example 13 0.61 ◎ Example 14 0.50 ◎ Example 15 0.63 ◎ Example 16 0.63 ◎ Example 17 0.50 ◎ Example 18 0.65 ◎ Comparative Example 4 0.29 △ ◎: No peeling 〇: Very slight peeling was recognized Δ: Four corners were recognized Slightly wide stripping X. A wide range of peeling or a large displacement of the attached part can be recognized [Table 5] AUC (ngxhr/ml) Cmax (ng/ml) Transdermal absorption of the drug ·§Γ7ΐί^ΤΊ Example 9 39.1 0.70 --' 八·'8 1 person ι m ρ 1 4.2 ~ Comparative Example 4 15.2 0.60 ... 2^8~~' As shown in Table 3, it can be seen that compared with Comparative Examples 1 to 3 A patch for a percutaneous absorption type preparation, a patch for a percutaneous absorption type preparation of Examples i to 8, attached to a sputum, and a cation of ~1 burial month compared to Acr_A and Acr alone -B These two kinds of cross-linking adhesives are 罝A TM Λ ^ to ~V丨王唧唧-type or separate With Acr-A and Acr-B in combination with an adhesive and the other case when using Acr-A and ACr-B, the adhesive force can be long lasting, and therefore to be understood that the effectiveness of the present invention. In addition, 'Acr_B is used in combination with non-crosslinked type; in Comparative Example 3, the initial adhesion (initial adhesion) is sufficient, but there is a tendency that the adhesion decreases with time. ^ After 72 hours, 26 201114865 Skin adhesiveness is inferior to the results of Examples 1-8. This tendency was also observed in the percutaneous absorption type preparation containing the pharmaceutical ingredient (Examples 9 to 18 and Comparative Example 4, as shown in Table 4). Further, as shown in Table 4, the transdermal absorption of the agents of the percutaneous absorption type preparations of Examples 9 to 18 was higher than that of the percutaneous absorption type preparation of Comparative Example 4. Further, as shown in Table 5, it is understood that the percutaneous absorption type preparation of Example 9 showed higher AUC' than the percutaneous absorption type preparation of Comparative Example 4 from the viewpoint of maintaining blood concentration, by way of Examples 9 is better. From the above results, it can be understood that 'the percutaneous absorption type I month b according to the present invention is sufficient to use a cross-linking type adhesive in the adhesive layer and maintain the adhesiveness for a long time, and 2, it is possible to maintain the pharmaceutical ingredient for a long period of time. Blood concentration. [Simple description of the diagram] None [Key component symbol description] None 27