201028181 六、發明說明： _ 【發明所屬之技術領域】 本發明係關於吩坦尼之皮虜透過性優異，保存中製劑 安定性高，且對皮膚之剌激性低'之含吩坦尼（fentanyl ) 之外用貼附劑。 【先前技術】 φ 吩坦尼及檸檬酸吩坦尼係於動物實驗中，經確認具有 相對於嗎啡（morphine )約200倍之鎭痛效果之合成麻醉 藥性鎭痛藥。至今，市售以治療癌疼痛爲目的之含有吩坦 尼之藥池型經皮收型持續性製劑，該製劑可保持大約爲有 效血中濃度24〜72小時。 然而，藥池型經皮吸收型持續性製劑係投予後藥物吸 收相當緩慢，因初次投予後至12〜24小時未達到有效血 中濃度，所以有不能得到迅速的鎭痛效果之缺點，因係藥 # 池型製劑，所以有發生漏液之問題、及因含有乙醇而有於 投予部位之刺激性非常高之缺點。 作爲解決此等缺點之手段，曾嘗試基質型經皮吸收貼 附劑。例如雖揭示使用丙烯酸系黏著劑爲主要基劑之經皮 吸收製劑（專利文獻1及2)，但一般而言，丙烯酸系黏 著劑係有藥物釋出性低，必須提高製劑中之主藥含量，否 則不能得到所需之藥物釋出性之問題。另外，藉由提高製 劑中之主藥配合量，而有保存中主藥結晶化等之問題、及 製劑使用後製劑中吩坦尼殘留等之問題。另外，亦揭示使 -5- 201028181 用聚異丁烯爲主要基劑之製劑（專利文獻3及4)。 另一方面，雖亦揭示使用苯乙烯•異戊二烯·苯乙烯 嵌塊共聚物（以下簡稱爲SIS。）爲主要基劑之黏著劑層 之含吩坦尼之貼附劑（SIS系製劑）（專利文獻5及6 ) ，但仍未開發同時滿足使用時長期間安定的主藥釋出性、 長期間之保存安定性、及長期間貼附時對皮膚之安全性。 例如，含有N-甲基-2-吡咯烷酮作爲吸收促進劑之SIS系 製劑雖顯示藉由N-甲基-2-吡咯烷酮之吸收促進作用而縮 短經皮吸收延遲時間之效果，但因N-甲基-2-吡咯烷酮爲 揮發律，所以保存中或貼附中N-甲基-2-吡咯烷酮揮發， 有藥物之釋出能力改變之問題（專利文獻5)。揭示其他 用以投予吩坦尼或該類似物之經皮貼附劑（專利文獻7) 。此先行技術雖亦含單層聚合物而成之基質型製劑，但因 爲與上述市售之吩坦尼製劑於生物學上等價爲特徵，所以 關於投予後之吩坦尼血中濃度變化，與藥池型經皮吸收型 持續性製劑同樣地留有不能得到迅速的鎭痛效果之缺點。 [專利文獻1]特表2004-513890 [專利文獻2]特表2005-501111 [專利文獻 3]W02004/024155 [專利文獻4]特開2006·76994 [專科文獻5]特開2000-4 4476 [專利文獻 6]W02003-070228 [專利文獻7]特表2004-524336 201028181 【發明內容】 發明之揭示 發明所欲解決之課題 因此，本發明之目的係提供吩坦尼之皮虜透過性優異 ，保存中製劑安定性高，且對皮膚之刺激性低之含吩坦尼 外用貼附劑。 • 課題之解決手段 本發明者等爲解決上述課題，努力進行硏究的結果， 發現藉由使活性成分吩坦尼及松香系樹脂之配合比率、及 松香系樹脂及總賦予黏著樹脂之配合比率最適合化，可解 決上述課題。 亦即，於支持體上，層合以SIS爲基劑之黏著劑層之 外用貼附劑，發現藉由於該黏著劑層，配合由松香系樹脂 及其他至少1種賦予黏著樹脂而成之賦予黏著樹脂；聚丁 ® 烯及流動鏈烷烴而成之軟化劑；脂肪酸酯；及作爲活性成 分之吩坦尼而成之外用貼附劑，松香系樹脂對吩坦尼之配 .合比率係重量比爲1〜5倍量，而且，松香系樹脂對總賦 予黏著樹脂配合量之配合比率係重量比爲0.1〜0.6倍量 ’可得到吩坦尼之皮膚透過性優異，製劑安定性高，且對 皮膚之刺激性低之貼附劑，而完成本發明。 亦即，本發明係於支持體上，層合以SIS爲基劑之黏 著劑層之外用貼附劑，該黏著劑層係另外含有由松香系樹 脂及其他至少1種賦予黏著樹脂而成之賦予黏著樹脂，以 -7- 201028181 30〜60重量％爲宜，聚丁烯及流動鏈烷烴而成之軟化劑， 以5〜40重量％爲宜，脂肪酸酯以1〜20重量％爲宜，及 1〜10重量％之吩坦尼，而且，松香系樹脂對吩坦尼之配 合比率係重量比爲1〜5倍量，接著，松香系樹脂對總賦 予黏著樹脂配合量之配合比率係重量比爲0.1〜0.6倍量 爲特徵之含吩坦尼之外用貼附劑。 發明之功效 n 本發明之貼附劑係藉由採用如上述之特徵組成，達成 可提供吩坦尼之皮膚透過性優異，保存中製劑安定性高， 且對皮膚之刺激性低之貼附劑等之效果。 進而，賦予黏著樹脂係由松香系樹脂及石油系樹脂而 成時，吩坦尼對製劑中之溶解性、主藥釋出性及皮膚黏著 性之平衡良好。另外，藉由配合脂肪酸酯類，尤其肉豆蔻 酸異丙酯作爲吸收促進劑於黏著劑層，可提高吩坦尼之皮 膚透過性。另外，判定配合作爲軟化劑之流動鏈烷烴及聚 n 丁烯於黏著劑層時，對皮虜之黏著性及製劑中之主藥溶解 性之平衡良好，尤其流動鏈烷烴及聚丁烯之配合比於0.5 :1〜3 : 1之範圍係效果最高，可得到兼具可防止製劑中 主藥之結晶化，並且對皮膚刺激性低之貼附劑。 另外，亦判定藉由使賦予黏著樹脂之配合量對黏著劑 層整體之配合量爲3 0%以上，可得到於皮膚黏著性上更優 異之本發明之貼附劑。 201028181 _ 用以實施發明之最佳型態 . 本發明之黏著劑層中作爲主要基劑所使用之SIS對黏 著劑層整體之配合量係以5〜50重量％爲宜，以10〜30 重量％尤佳。 本發明之黏著劑層中所配合之賦予黏著樹脂係藉由混 合SIS’給予對皮膚之黏著性者，除了松香系樹脂之外， 可列舉石油系樹脂、聚萜樹脂、酚醛樹脂、萜烯酚樹脂、 φ 二甲苯系樹脂等。作爲松香系樹脂，可列舉松香酯、氫化 松香、松香甘油酯、氫化松香甘油酯、松香酸、聚合松香 等’但以氫化松香甘油酯尤佳。 作爲松香系樹脂以外之其他賦予黏著樹脂，以使用石 油系樹脂爲宜，石油系樹脂係可列舉脂肪族飽和烴樹脂、 脂環族飽和烴樹脂、芳香族烴樹脂等，但以脂環族飽和烴 樹脂爲宜。 賦予黏著樹脂係以對黏著劑層整體之重量爲30〜60 • 重量％之比率配合。未滿3 0重量％，作爲黏附劑之黏著物 性變差，超過60重量％時，黏著黏性變得過強，自皮膚 剝離時，因發生物理上皮膚刺激，所以不適宜。 另外，考慮吩坦尼於製劑中之溶解性及皮虜透過性之 平衡時，添加對吩坦尼之配合比率（重量比）爲1〜5倍 量，以2〜4倍量爲宜之松香系樹脂係有效的。松香系樹 脂之添加量若多於吩坦尼配合量之5倍量時，藥物之皮虜 透過性降低，少於1倍量時，藥物溶解性降低，對主藥成 分之結晶化等、製劑物性出現不良影響。 -9- 201028181 另外，松香系樹脂對總賦予黏著樹脂配合量之配合比 率（重量比）係以0.1〜0.6倍量爲宜，以0.2〜0.4倍量 尤佳。松香系樹脂之添加量若對總賦予黏著樹脂配合量多 於0.6倍量時，藥物之皮膺透過性降低’若少於0.1倍量 時，藥物溶解性降低，對主藥成分之結晶化等、製劑物性 出現不良影響。201028181 VI. Description of the invention: _ [Technical field to which the invention pertains] The present invention relates to a phenanthrene containing phenanthrene which is excellent in permeability, high in stability in storage, and low in irritability to the skin. Fentanyl ) Use a patching agent. [Prior Art] φ phenanthrene and citrate citrate are synthetic animal analgesic drugs which have been confirmed to have an analgesic effect about 200 times that of morphine in animal experiments. To date, a phenanthrene-containing drug-containing percutaneous sustained-type preparation for the purpose of treating cancer pain has been commercially available, and the preparation can maintain an effective blood concentration of about 24 to 72 hours. However, the drug-pool type percutaneous absorption type sustained preparation is quite slow after the administration of the drug, and the effective blood concentration is not reached after 12 to 24 hours after the initial administration, so there is a disadvantage that the rapid analgesic effect cannot be obtained. Medicine # Pool type preparation, there is a problem that leakage occurs, and there is a disadvantage that the irritancy at the site of administration is very high due to the presence of ethanol. As a means of solving these disadvantages, a matrix type percutaneous absorption patch has been tried. For example, although a percutaneous absorption preparation using an acrylic adhesive as a main base is disclosed (Patent Documents 1 and 2), in general, an acrylic adhesive has low drug release property, and it is necessary to increase the main drug content in the preparation. Otherwise, the problem of the release of the desired drug cannot be obtained. Further, by increasing the amount of the main drug in the preparation, there is a problem that the main drug is crystallized during storage, and the phenanthrene residue in the preparation after use of the preparation. Further, a formulation in which polyisobutylene is used as a main base of -5 to 201028181 is also disclosed (Patent Documents 3 and 4). On the other hand, a phenanthin-containing patch (SIS-based preparation) using an adhesive layer of styrene-isoprene-styrene block copolymer (hereinafter abbreviated as SIS) as a main base is also disclosed. (Patent Documents 5 and 6), but the development of the main drug release property for a stable period of use, the long-term storage stability, and the safety to the skin during long-term attachment have not been developed. For example, a SIS-based preparation containing N-methyl-2-pyrrolidone as an absorption enhancer exhibits an effect of shortening the percutaneous absorption delay time by absorption promotion of N-methyl-2-pyrrolidone, but N-A Since quinol-2-pyrrolidone is a volatile law, the N-methyl-2-pyrrolidone is volatilized during storage or attachment, and there is a problem that the drug releasing ability is changed (Patent Document 5). Other transdermal patches for administration of fentanyl or the like are disclosed (Patent Document 7). Although this prior art also contains a single-layer polymer matrix preparation, it is characterized by biological equivalence with the above-mentioned commercially available phenanthrene preparations, so regarding the concentration change of the phenanthrene blood after administration, In the same manner as the drug-cell type percutaneous absorption type sustained preparation, there is a disadvantage that a rapid analgesic effect cannot be obtained. [Patent Document 1] Japanese Patent Application Publication No. 2004-513890 [Patent Document 2] Japanese Patent Application Publication No. 2005-501111 [Patent Document 3] WO2004/024155 [Patent Document 4] JP-A-2006-76994 [Specialist Literature 5] Special Opening 2000-4 4476 [ [Patent Document 6] WO2003-070228 [Patent Document 7] Japanese Patent Application Publication No. 2004-524336 201028181 SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION Accordingly, an object of the present invention is to provide an excellent permeability and preservation of phenanthrene. A phenanthrene-containing topical patch having high stability and low irritation to the skin. In the inventors of the present invention, in order to solve the above problems, the inventors of the present invention have found that the blending ratio of the active ingredient phenanthrene and the rosin-based resin, and the blending ratio of the rosin-based resin and the total adhesive resin are found. It is most suitable for solving the above problems. That is, on the support, the adhesion agent other than the SIS-based adhesive layer was laminated, and it was found that the adhesive layer was provided by the rosin-based resin and at least one other type of adhesive resin. Adhesive resin; softening agent made of polybutylene ene and flowing paraffin; fatty acid ester; and phenanthrene as an active ingredient, external affixing agent, rosin resin to phenanthrene The weight ratio is 1 to 5 times, and the blending ratio of the rosin-based resin to the total amount of the adhesive resin is 0.1 to 0.6 times by weight, and the skin permeability of the phenanthrene is excellent, and the stability of the preparation is high. The present invention is completed by a patch which is less irritating to the skin. That is, the present invention is applied to a support by laminating an adhesive layer other than the SIS-based adhesive, and the adhesive layer additionally contains a rosin-based resin and at least one other adhesive resin. The adhesive resin is preferably -7-201028181 30~60% by weight, and the softener of polybutene and flowing paraffin is preferably 5~40% by weight, and the fatty acid ester is preferably 1~20% by weight. And 1 to 10% by weight of phenanthrene, and the mixing ratio of the rosin-based resin to the phenanthrene is 1 to 5 times, and then the mixing ratio of the rosin-based resin to the total amount of the adhesive resin is A patch containing phenanthrene which is characterized by a weight ratio of 0.1 to 0.6 times. Efficacy of the Invention n The patch of the present invention is obtained by using the above-mentioned characteristic composition, and is excellent in the skin permeability of phenanidone, high in stability in storage, and low in irritation to the skin. Etc. Further, when the adhesive resin is made of a rosin-based resin and a petroleum-based resin, the balance of solubility, main drug release property, and skin adhesiveness of the styrene is good. Further, by blending fatty acid esters, particularly isopropyl myristate as an absorption enhancer in the adhesive layer, the skin permeability of phenanthrene can be improved. In addition, when the flow alkane and poly n-butene as a softener are judged to be in the adhesive layer, the balance between the adhesion to the skin and the solubility of the main drug in the preparation is good, especially the combination of the flow alkane and the polybutene. The ratio of 0.5:1 to 3:1 is the highest, and a patch which can prevent crystallization of the main drug in the preparation and has low irritation to the skin can be obtained. In addition, it is also determined that the amount of the adhesive resin to be added to the entire adhesive layer is 30% or more, whereby the patch of the present invention which is more excellent in skin adhesiveness can be obtained. 201028181 _ The best form for carrying out the invention. The SIS used as the main base in the adhesive layer of the present invention is preferably used in an amount of 5 to 50% by weight, preferably 10 to 30% by weight. % is especially good. The adhesive resin to be applied to the adhesive layer of the present invention is adhered to the skin by mixing SIS'. In addition to the rosin-based resin, petroleum resin, polyfluorene resin, phenol resin, terpene phenol may be mentioned. Resin, φ xylene resin, etc. Examples of the rosin-based resin include rosin ester, hydrogenated rosin, rosin glyceride, hydrogenated rosin glyceride, rosin acid, and polymerized rosin. However, hydrogenated rosin glyceride is particularly preferable. A petroleum-based resin is preferably used as the adhesive resin other than the rosin-based resin, and examples of the petroleum-based resin include an aliphatic saturated hydrocarbon resin, an alicyclic saturated hydrocarbon resin, and an aromatic hydrocarbon resin, but are saturated with an alicyclic group. A hydrocarbon resin is preferred. The adhesive resin is applied in a ratio of 30 to 60% by weight based on the entire weight of the adhesive layer. When it is less than 30% by weight, the adhesiveness as an adhesive is deteriorated. When it exceeds 60% by weight, the adhesiveness becomes too strong, and when it peels from the skin, physical skin irritation occurs, which is not preferable. In addition, when considering the balance between the solubility of the phenanthrene in the preparation and the permeability of the skin, the ratio of the addition of phenanthrene (weight ratio) is 1 to 5 times, and the amount of rosin is preferably 2 to 4 times. The resin is effective. When the amount of the rosin-based resin added is more than 5 times the amount of the phenanthrene compound, the permeability of the drug is reduced. When the amount is less than 1 time, the solubility of the drug is lowered, and the crystallization of the main drug component is prepared. Physical properties have an adverse effect. -9- 201028181 In addition, the blend ratio (weight ratio) of the rosin-based resin to the total amount of the adhesive resin is preferably 0.1 to 0.6 times, more preferably 0.2 to 0.4 times. When the amount of the rosin-based resin to be added is more than 0.6 times the total amount of the adhesive resin, the permeability of the drug is reduced. If the amount is less than 0.1 times, the solubility of the drug is lowered, and the main component is crystallized. The physical properties of the preparation have adverse effects.
本發明之黏著劑層所配合之脂肪酸酯係作爲吸收促進 劑作用者，並無特別定，可舉例如肉豆蔻酸異丙酯、己二 酸二異丙酯、癸二酸二乙酯等，其中以肉豆蔻酸異丙酯尤 佳。黏著劑層中作爲該配合量’以1〜20重量％爲宜’以 2〜10重量％尤佳。脂肪酸酯之配合量若爲1重量％以下 ，藥物之皮膚透過性不足，20重量％以上時’因發生黏著 層之凝聚力降低，殘留基劑於肌膚之問題’所以不適宜。 ❹ 本發明之黏著劑層所配合之流動鏈烷烴及聚丁烯而成 之軟化劑係用以藉由使黏著劑柔軟’提升對皮膚之追隨性 ，並且調整黏著力，減輕物理上皮膚刺激所配合’亦考慮 吩坦尼溶解性、及對製劑物性之效果所配合’該配合量係 以5〜40重量％爲宜，以1〇〜30重量％尤佳。因爲若少於 5重量％，對皮膚之追隨性差’變得容易剝落’若超過40 重量％時，黏著劑之凝集力降低，貼附部位發生殘留糊膠 ，所以不適宜。流動鏈烷烴及聚丁烯之吩坦尼溶解性係聚 丁烯大，亦可調節製劑中主藥之溶解性。作爲該配合比’ 以流動鏈烷烴：聚丁烯=·· 1〜3 : 1爲宜’以1 : 1〜2 :1尤佳。流動鏈烷烴之配合量若多於3: 1時’製劑中 -10- 201028181 _ 之吩坦尼溶解性降低，主藥之結晶化等之不良影響出現， 進而，製劑對皮膚之黏著性降低。另外，若少於0.5 : 1 時，黏著力變得過強，皮膚刺激變強。 作爲本發明所使用之黏著劑層之基劑成分，除了 SIS 以外，爲調整基劑之黏著性·安定性，因應需要，可適當 選擇、添加通常製造貼附劑之黏著劑層時所使用之成分。 具體上可使適當適量含有聚乙烯吡咯烷酮、聚乙烯吡咯烷 φ 酮/醋酸乙烯共聚物等之吸水性高分子、二氧化鈦、矽類 等之無機塡充劑、及二丁基羥基甲苯（BHT )等。 本發明之黏著層所配合之吩坦尼的量係以0.1〜10重 量％爲宜，以1〜8重量％尤佳，以3〜8重量％更好。 有關本發明之黏著劑層之厚度雖無特別限制，但過薄 時，黏著力降低，過厚時，膏體中不能利用的藥物增加， 成本變高，另外，並且因爲衣服摩擦等而變得容易剝離， 所以以20〜100//m爲宜。 # 一般顯示貼附劑中支持體之柔軟性、伸縮性影響對皮 庸之追隨性，對提升藥物之經皮吸收性有極大關係。因此 ，本發明之貼附劑中，使用柔軟性、伸縮性高之支持體， 作爲如此支持體，雖可列舉低密度高分子薄膜、不織布、 織布等，但就泛用性、經濟性等觀點，以聚對苯二甲酸乙 二醇酯爲宜。該薄膜的厚度係以0.1〜100 Am爲宜。貼附 於皮虜時，100 μηι以上之厚度，因聚對苯二甲酸乙二醇 酯薄膜之剛性而不能追隨皮膚的凹凸或動作，結果係藥物 之皮虜吸收性降低。 -11 - 201028181 本發明之貼附劑係於黏著劑層上面具有剝離膜。剝離 膜係可使用聚對苯二甲酸乙二醇酯、聚丙烯、紙等。爲使 剝離膜至最適合剝離力，因應需要，可經矽處理。 本發明之貼附劑係例如可由下述方法製造。 溶解含黏著賦予劑之基劑成分於甲苯等之有機溶劑後 ，與溶解於適當有機溶劑之其他成分攪拌混合。塗佈所得 溶液於經矽處理之剝離膜上，以9(TC乾燥10分鐘，形成 20〜lOOym之黏著層。層合支持體之聚對苯二甲酸乙二 醇酯面於所得之黏著層後，切成適當大小及形狀，可得本 發明之經皮吸收製劑。 【實施方式】 [實施例] 接著，列舉實施例更具體地說明本發明，但本發明並 非局限於以下實施例者。另外，實施例中「份」爲「重量 份」，除非例外。 實施例1〜7 依據表1記載之處方’製作各外用貼附劑。松香系樹 脂/吩坦尼（重量比）及松香系樹脂/總賦予黏著樹脂（重 量比）合記於表。 -12- 201028181 表 1 組成/ 實施例 實施例 實施例 實施例 實施例 實施例 實施例 實施例 1 2 3 4 5 6 7 苯乙烯•異戊二烯 η 苯乙烯嵌塊共聚物 16 16 16 16 16 16 16 _ 氫化松香甘油酯 15 5 9 24 10 15 —--. _ 脂環族飽和烴樹脂 35 45 41 26 40 _ —--— 35 J 聚丁烯 10 10 10 10 10 14 — 流動烴 11 15 11 11 15 7 is BHT 2 2 2 2 2 2 ----- ^__肉豆蔻酸異丙酯 5 5 5 5 5 — I 5 < -_ 吩坦尼 6 2 6 6 2 6 〜--- 松香系樹脂/吩坦尼 --— 2.5 2.5 1.5 4.0 5.0 2 5 〜_(重量比） 2.5 松香系樹脂/總賦予黏著樹脂 —--- -__(重量比） 0.30 0.10 0.18 0.48 0.20 0.30 〇.3〇 參考例1〜5 依據表2記載之處方，製作各外用貼附劑。松香系樹 _ S曰/吩坦尼（重量比）及松香系樹脂/總賦予黏著樹脂（重 量比）合記於表。 -13- ^_ 2 ^_ 2201028181 組赫考例 參考例1 參考例2 參考例3 參考例4 .'**----- 苯乙烯•異戊二烯 苯乙烯嵌塊共聚物 16 20 16 16 _^^例 5 16 氫化松香甘油酯 5 4 12 15 —-—. 〇c 脂環族飽和烴樹脂 20 3 11 35 聚丁烯 10 10 10 1 一丨 一 2〇 流動鏈院烴 40 54 38 20 1 BHT 2 2 2 2 2 肉丑蔑酸異丙酯 5 5 5 5 5 吩坦尼 2 2 6 6 6 松香系樹脂驅尼 (重量比） 2.5 2.0 2.0 2.5 2.5 松香系樹脂/總賦予黏著樹脂 (重量比） 0.20 0.57 0.52 0.30 0.30 比較例1〜9 依據表3_1及表3-2記載之處方，依據上述之製造方 法，製作比較例1〜6之外用貼附劑。比較例7係參考 W〇2〇〇4/〇24l55實施例1，製造貼附劑。比較例8係參考 特開2006-76994試驗例No.6，製造貼附劑。比較例9係 因凝聚力不足’所以不能製造貼附劑。 -14- 201028181 表3-1 組齡匕較例 比較例1 比較例2 比較例3 比較例4 比較例5 苯乙烯•異戊二烯 苯乙烯嵌塊共聚物 16 20 16 16 16 氫化松香甘油酯 3 8 6 35 3 脂環族飽和烴樹脂 47 3 44 15 47 聚丁烯 10 10 10 10 10 流動鏈院烴 11 42 16 11 16.5 BHT 2 2 2 2 2 肉豆蔻酸異丙酯 5 5 5 5 5 吩坦尼 6 10 1 6 0.5 松香系樹脂驅尼 (重量比） 0.5 0.8 6.0 5.8 6.0 松香系樹脂/總賦予黏著樹脂 (重量比） 0.06 0.73 0.12 0.7 0.06 表3-2 組成/比較例 比較例6 比較例7 比較例8 比較例9 苯乙烯•異戊二烯 苯乙烯嵌塊共聚物 16 8 3 氫化松香甘油酯 15 15 —脂環族飽和烴樹脂 35 44.5 29.2 35 聚丁烯 10 聚異丁烯（低分子量） 8 37.2 一聚異丁烯（高分子量） 13 8 26.6 _流動徑 36.7 24 BHT 2 2 肉豆蔻酸異丙酯 5 5 5 — 吩麵 6 2 2 6 _ 矽關 0.8 試驗例1: in vitro大鼠皮膚透過性試驗 -15- 201028181 爲檢討吩坦尼之藥物釋出性，對實施例1、3、4、5 、6、7、參考例1〜5、及比較例3〜8，進行大鼠之in vitro皮膚透過性試驗。 安裝除毛大鼠腹部摘出皮膚於Franz型擴散槽，於該 內側加滿碟酸緩衝生理食鹽水，於水套（water jacket ) 中回流37°C之溫水。將各製劑打孔成圓形（Φ 16mm)， 貼附於大鼠摘出皮膚，經時地採取接受液，由液相層析法 測定吩坦尼透過量，計算透過速度（4〜12hr)。該結果 係如表4-1、表4-2及表4-3表示。 表4-1 試驗製劑 實施例1 實施例3 實施例4 實施例5 實施例6 實施例7 吩坦尼濃度(％) 6 6 6 2 6 6 釋出速度(Pg/cm2/hr) 8.7 8.3 9.3 4.3 9.0 11.7 表4-2 試驗製劑 參考例1 參考例2 參考例3 參考例4 例 5 吩坦尼濃度(％) 2 2 6 6 6 釋出速度(Pg/cm2/hr) 3.5 5.2 11.9 9.5 一· _ 8.7 表4-3 試驗製劑 比較例3 比較例4 比較例5 比較例ό 比較例7 吩坦尼濃度(％) 1 6 0.5 6 2 釋出速度Wcm2/hr) 1.7 4.8 0.5 7.1 2.6The fatty acid ester to which the pressure-sensitive adhesive layer of the present invention is incorporated is not particularly limited as an absorption enhancer, and examples thereof include isopropyl myristate, diisopropyl adipate, and diethyl sebacate. Among them, isopropyl myristate is especially preferred. The amount of the compounding agent in the adhesive layer is preferably from 1 to 20% by weight, more preferably from 2 to 10% by weight. When the blending amount of the fatty acid ester is 1% by weight or less, the skin permeability of the drug is insufficient, and when it is 20% by weight or more, the "cohesive force of the adhesive layer is lowered and the residual agent is applied to the skin" is not preferable.流动 The soft paraffin and polybutene softener combined with the adhesive layer of the present invention are used to improve the adhesion to the skin by softening the adhesive, and to adjust the adhesion to reduce physical skin irritation. The blending is also considered to be in accordance with the solubility of the phenanthrene and the effect on the physical properties of the preparation. The blending amount is preferably 5 to 40% by weight, particularly preferably 1 to 30% by weight. If it is less than 5% by weight, the skin's followability is poor, and it becomes easy to peel off. If it exceeds 40% by weight, the cohesive force of the adhesive is lowered, and residual paste is generated at the attached portion, which is not preferable. The phenanthrene solubility of the flow alkane and polybutene is large, and the solubility of the main drug in the preparation can also be adjusted. The mixing ratio 'is preferably a flow paraffin: polybutene = 1·3: 1 is preferable to 1:1 to 2:1. When the compounding amount of the flow paraffin is more than 3:1, the solubility of the phenantini is lowered in the preparation -10- 201028181 _, and the adverse effects such as crystallization of the main drug occur, and further, the adhesion of the preparation to the skin is lowered. In addition, if it is less than 0.5:1, the adhesive force becomes too strong and the skin irritation becomes strong. In addition to the SIS, the base component of the adhesive layer used in the present invention is used to adjust the adhesion and stability of the base, and if necessary, the adhesive layer which is usually used for the production of the adhesive can be appropriately selected and used. ingredient. Specifically, an appropriate amount of a water-absorbent polymer such as polyvinylpyrrolidone or polyvinylpyrrolidine φ ketone/vinyl acetate copolymer, an inorganic chelating agent such as titanium oxide or ruthenium, and a dibutyl hydroxytoluene (BHT) may be contained. . The amount of phenanthrene to be adhered to the adhesive layer of the present invention is preferably 0.1 to 10% by weight, more preferably 1 to 8% by weight, still more preferably 3 to 8% by weight. The thickness of the adhesive layer of the present invention is not particularly limited, but when the thickness is too thin, the adhesive force is lowered. When the thickness is too thick, the amount of the drug which cannot be used in the paste is increased, the cost is increased, and the clothing becomes rubbed or the like. It is easy to peel off, so it is preferably 20~100//m. # Generally, it shows that the softness and flexibility of the support in the patch have a great influence on the percutaneous absorption of the drug. Therefore, in the patch of the present invention, a support having a high flexibility and a high stretchability is used. Examples of such a support include a low-density polymer film, a nonwoven fabric, a woven fabric, and the like, but they are general-purpose, economical, and the like. From the viewpoint, polyethylene terephthalate is preferred. The thickness of the film is preferably from 0.1 to 100 Am. When attached to the skin, the thickness of 100 μηι or more is not able to follow the unevenness or movement of the skin due to the rigidity of the polyethylene terephthalate film, and as a result, the absorbability of the skin of the drug is lowered. -11 - 201028181 The patch of the present invention has a release film on the adhesive layer. As the release film system, polyethylene terephthalate, polypropylene, paper, or the like can be used. In order to make the release film most suitable for peeling force, it can be treated by hydrazine as needed. The patch of the present invention can be produced, for example, by the following method. The base component containing the adhesion-imparting agent is dissolved in an organic solvent such as toluene, and then stirred and mixed with other components dissolved in a suitable organic solvent. The resulting solution was coated on a ruthenium-treated release film, and dried at 9 (TC for 10 minutes to form an adhesive layer of 20 to 100 μm. The polyethylene terephthalate of the laminate support was applied to the obtained adhesive layer. The percutaneous absorption preparation of the present invention can be obtained by cutting into an appropriate size and shape. [Embodiment] [Examples] Next, the present invention will be specifically described by way of examples, but the present invention is not limited to the following examples. In the examples, "parts" are "parts by weight" unless otherwise specified. Examples 1 to 7 Each external patch is prepared according to the contents shown in Table 1. Rosin resin / phenanthrene (weight ratio) and rosin resin / Total adhesion resin (weight ratio) is shown in the table. -12- 201028181 Table 1 Composition / Examples Examples Examples Examples Examples Examples Examples 1 2 3 4 5 6 7 Styrene • Isoprene Diene η styrene block copolymer 16 16 16 16 16 16 16 _ Hydrogenated rosin glyceride 15 5 9 24 10 15 —-. _ alicyclic saturated hydrocarbon resin 35 45 41 26 40 _ —-- — 35 J Polybutene 10 10 10 10 10 14 — flow 11 15 11 11 15 7 is BHT 2 2 2 2 2 2 ----- ^__ Isopropyl myristate 5 5 5 5 5 — I 5 < -_ phenanthrene 6 2 6 6 2 6 ~ --- Rosin resin / phenanthrene --- 2.5 2.5 1.5 4.0 5.0 2 5 ~ _ (weight ratio) 2.5 rosin resin / total adhesion resin ----- -__ (weight ratio) 0.30 0.10 0.18 0.48 0.20 0.30 〇.3〇 Reference Examples 1 to 5 Each external patch was prepared according to the conditions described in Table 2. Rosin tree _ S曰/Bentani (weight ratio) and rosin resin / total adhesive resin (weight ratio) ) Recorded in the table. -13- ^_ 2 ^_ 2201028181 Group Her test case Reference example 1 Reference example 2 Reference example 3 Reference example 4. '**----- Styrene • Isoprene styrene embedded Block copolymer 16 20 16 16 _^^ Example 5 16 Hydrogenated rosin glyceride 5 4 12 15 —- —. 〇c alicyclic saturated hydrocarbon resin 20 3 11 35 polybutene 10 10 10 1 丨 〇 〇 flow Chain hydrocarbon 40 54 38 20 1 BHT 2 2 2 2 2 ugly isopropyl citrate 5 5 5 5 5 phenanthrene 2 2 6 6 6 rosin resin flooding (weight ratio) 2.5 2.0 2.0 2.5 2.5 rosin Resin / total adhesion resin (Weight ratio) 0.20 0.57 0.52 0.30 0.30 Comparative Examples 1 to 9 According to the above-described production methods, the adhesives for Comparative Examples 1 to 6 were prepared in accordance with the conditions described in Tables 3_1 and 3-2. Comparative Example 7 was made by referring to Example 1 of W〇2〇〇4/〇24l55 to prepare a patch. Comparative Example 8 was prepared by referring to Test Example No. 6 of JP-A-2006-76994. In Comparative Example 9, the cohesive force was insufficient, so that the patch could not be produced. -14- 201028181 Table 3-1 Group age 匕 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Styrene • Isoprene Styrene Block Copolymer 16 20 16 16 16 Hydrogenated rosin glyceride 3 8 6 35 3 alicyclic saturated hydrocarbon resin 47 3 44 15 47 polybutene 10 10 10 10 10 flowing chain hydrocarbon 11 42 16 11 16.5 BHT 2 2 2 2 2 isopropyl myristate 5 5 5 5 5 Tenny 6 10 1 6 0.5 Rosin resin flooding (weight ratio) 0.5 0.8 6.0 5.8 6.0 Rosin resin / total adhesion resin (weight ratio) 0.06 0.73 0.12 0.7 0.06 Table 3-2 Composition / Comparative Example Comparative Example 6 Comparison Example 7 Comparative Example 8 Comparative Example 9 Styrene • Isoprene Styrene Block Copolymer 16 8 3 Hydrogenated Rosin Glycerate 15 15 — Cycloaliphatic Saturated Hydrocarbon Resin 35 44.5 29.2 35 Polybutene 10 Polyisobutylene (Low Molecular Weight) 8 37.2 polyisobutylene (high molecular weight) 13 8 26.6 _ flow path 36.7 24 BHT 2 2 isopropyl myristate 5 5 5 — phenotype 6 2 2 6 _ 矽关 0.8 test example 1: in vitro rat skin Transmittance test -15- 201028181 to review the release of phenanthrene The in vitro skin permeability test of rats was carried out for Examples 1, 3, 4, 5, 6, and 7, Reference Examples 1 to 5, and Comparative Examples 3 to 8. The abdomen of the hair removal rat was attached to the Franz-type diffusion tank, and the inside of the hair was filled with the acid buffered saline, and the warm water was refluxed at 37 ° C in a water jacket. Each preparation was perforated into a circular shape (Φ 16 mm), attached to the skin of the rat, and the receiving solution was taken over time, and the amount of phenanodane permeation was measured by liquid chromatography to calculate the permeation rate (4 to 12 hr). The results are shown in Table 4-1, Table 4-2, and Table 4-3. Table 4-1 Test Formulation Example 1 Example 3 Example 4 Example 5 Example 6 Example 7 Phentanitan concentration (%) 6 6 6 2 6 6 Release rate (Pg/cm2/hr) 8.7 8.3 9.3 4.3 9.0 11.7 Table 4-2 Test preparation Reference example 1 Reference example 2 Reference example 3 Reference example 4 Example 5 Phentane concentration (%) 2 2 6 6 6 Release rate (Pg/cm2/hr) 3.5 5.2 11.9 9.5 · _ 8.7 Table 4-3 Test preparation Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example ό Comparative Example 7 Benthanib concentration (%) 1 6 0.5 6 2 Release rate Wcm2/hr) 1.7 4.8 0.5 7.1 2.6
試驗例2:安定性試驗 關於實施例I、2、3、4及比較例1〜8，以目測觀察 -16- 201028181 經過室溫保存3個月後製劑之外觀之結果如表5所示。析 出結晶之製劑以X表示，未析出結晶之製劑以〇表示。 表 5Test Example 2: Stability test About Examples I, 2, 3, and 4 and Comparative Examples 1 to 8, visual observation was carried out. -16 - 201028181 The results of the appearance of the preparation after storage for 3 months at room temperature are shown in Table 5. The formulation in which crystals are precipitated is represented by X, and the preparation in which no crystals are precipitated is represented by 〇. table 5
試驗製劑 實施例 1 實施例 2 實施例 3 實施例 4 觀察結果 〇 〇 〇 〇 試驗製劑 比較例 1 比較例 2 比較例 3 比較例 4 比較例 5 比較例 6 比較例 7 比較例 8 觀察結果 X X 〇 〇 〇 X 〇 X 試驗例3 :黏著力試驗 關於實施例1、2、3、4、5、6、7、參考例1〜5及 比較例 1〜8，使用拉伸試驗器（流變計（rheometer ) CR500DX Sun科學公司製），藉由進行180°剝離試驗而 評估黏著力。結果係如表6-1、表6-2及表6-3表示。 表6-1 試驗製劑 實施例1 實施例2 實施例3 實施例4 實施例5 實施例6 實施例7 黏著力(g) 305.3 256.8 522.1 420.0 346.3 688.3 220.1 表6-2 試驗製劑 參考例1 參考例2 參考例3 參考例4 參考例5 黏著力(g) 8.0 4.7 17.9 144.8 1072.6 表6-3 試驗製劑 比較例 1 比較例 2 比較例 3 比較例 4 比較例 5 比較例 6 比較例 7 比較例 8 黏著力(g) 349.9 7.5 225.3 395.8 276.6 481.1 207.6 831.2 -17- 201028181 試驗例4:兔子皮膚短暫刺激性試驗 關於實施例1、實施例2及比較例8，進行兔子皮膚 短暫刺激性試驗。貼附各貼附劑於除毛之兔子背部72小 時，自剝離後第1小時、第24小時及第48小時之皮膚症 狀求出刺激指數（P.I.I.)。該評估基準及結果，分別如 表7-1、表7-2表示。Test Formulation Example 1 Example 2 Example 3 Example 4 Observation Results 〇〇〇〇 Test Formulation Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Observation Results XX 〇 〇〇X 〇X Test Example 3: Adhesion Test For Examples 1, 2, 3, 4, 5, 6, 7, Reference Examples 1 to 5 and Comparative Examples 1 to 8, a tensile tester (rheometer) was used. (Rheometer) CR500DX Sun Scientific Co., Ltd.) The adhesion was evaluated by performing a 180° peel test. The results are shown in Table 6-1, Table 6-2 and Table 6-3. Table 6-1 Test Formulation Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Adhesion (g) 305.3 256.8 522.1 420.0 346.3 688.3 220.1 Table 6-2 Test Formulation Reference Example 1 Reference Example 2 Reference Example 3 Reference Example 4 Reference Example 5 Adhesion (g) 8.0 4.7 17.9 144.8 1072.6 Table 6-3 Test preparation Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Adhesion (g) 349.9 7.5 225.3 395.8 276.6 481.1 207.6 831.2 -17- 201028181 Test Example 4: Rabbit skin transient irritation test With respect to Example 1, Example 2 and Comparative Example 8, a rabbit skin transient irritation test was carried out. The adhesion index (P.I.I.) was determined from the skin symptoms at the 1st hour, the 24th hour, and the 48th hour after peeling by attaching each patch to the back of the rabbit for hair removal for 72 hours. The evaluation criteria and results are shown in Table 7-1 and Table 7-2, respectively.
(評估基準） P.I.I 安定性區分 Ρ·Ι·Ι=0 無刺激物 0<Ρ.Ι.Ι<2 弱刺激物 2^Ρ.Ι.Ι<5 中程度的刺激物 P.I.I 強刺激物 表7-2 (結果) 試驗製劑 實施例1 實施例2 參考例5 比較例8 刺激指數(P.I.I) 1.8 1.6 2.2 3.0(Evaluation Criteria) PII Stability classification Ρ·Ι·Ι=0 No irritant 0 lt;Ρ.Ι.Ι<2 Weak irritant 2^Ρ.Ι.Ι<5 Moderate stimulant PII Strong stimulator Table 7 -2 (Results) Test Formulation Example 1 Example 2 Reference Example 5 Comparative Example 8 Stimulation Index (PII) 1.8 1.6 2.2 3.0
檢討 (1)由表4-1〜表4-3表示之結果，本發明之實施例 之貼附劑係顯示優異的藥物釋出性。尤其藥物含量與相同 濃度之比較例相比較，判定藥物釋出性優異。比較例3〜 5、7及8係於藥物釋出性上，比本發明之實施例之貼附 劑差許多。 (2 )由表5及表7-2顯示，本發明之實施例之貼附 劑係於安定性及安全性亦優異。比較例1、2、6、及8觀 -18- 201028181 察到結晶析出。 (3 )由其他、表4-1〜表7-1表示之結果，判定比較 例1、2及6係有製劑中主藥之結晶化之問題，比較例3 、4及5係主藥釋出性低，並且比較例7係主藥釋出性低 ，且黏著性亦低。另外，判定比較例8雖然黏著性高，但 主藥釋出性低，製劑中主藥結晶化，皮膚刺激性亦高。 試驗例5 :兔子血漿中濃度測定試驗 關於實施例1及市售品（溶解吩坦尼於乙醇之藥池型 貼附劑），進行兔子血漿中吩坦尼濃度之測定試驗（投予 量分別爲5mg )。貼附各貼附劑於經除毛之兔子背部72 小時，經時地採血，由液相層析法測定血漿中之吩坦尼濃 度。該結果如圖1所示。本實施例之貼附劑與市售品相比 較，關於持續性雖大致相等，但判定係血中藥物濃度開始 運作快之製劑。 產業上利用性 有關本發明之含吩坦尼之外用貼附劑係吩坦尼之皮膚 透過性優異，保存中製劑安定性高，且對皮膚之刺激性低 ，可使用於癌症等之疼痛治療。 【圖式簡單說明】 [圖1]表示試驗例4之兔子血漿中濃度測定試驗之結 果圖 -19 -Review (1) The results of Tables 4-1 to 4-3 show that the patch of the embodiment of the present invention exhibits excellent drug release properties. In particular, the drug content was judged to be excellent in drug release property as compared with the comparative example of the same concentration. Comparative Examples 3 to 5, 7 and 8 were in terms of drug release properties and were much inferior to the adhesives of the examples of the present invention. (2) As shown in Table 5 and Table 7-2, the patch of the embodiment of the present invention is excellent in stability and safety. Comparative Examples 1, 2, 6, and 8 Views -18- 201028181 Crystallization was observed. (3) From the results of other Tables 4-1 to 7-1, it was judged that Comparative Examples 1, 2 and 6 had the problem of crystallization of the main drug in the preparation, and Comparative Examples 3, 4 and 5 were the main drug release. The yield was low, and Comparative Example 7 was low in release rate of the main drug and low in adhesion. Further, although Comparative Example 8 was judged to have high adhesiveness, the main drug release property was low, and the main drug was crystallized in the preparation, and the skin irritation was also high. Test Example 5: Rabbit plasma concentration measurement test With respect to Example 1 and a commercial product (solvent-dissolving agent for dissolving phenanthrene in ethanol), a test for the concentration of phenanthrene in rabbit plasma was carried out (the amount of administration was respectively It is 5mg). Each patch was attached to the back of the depilated rabbit for 72 hours, blood was collected over time, and the concentration of phenanthrene in the plasma was determined by liquid chromatography. The result is shown in Figure 1. In the case of the patch of the present embodiment, compared with the commercially available product, although the persistence was substantially equal, it was determined that the drug concentration in the blood began to work fast. Industrial Applicability The phenanthrene-containing external patch of the present invention is excellent in skin permeability, high in stability during storage, and low in irritation to the skin, and can be used for pain treatment of cancer and the like. . [Simplified illustration of the drawing] [Fig. 1] shows the results of the concentration measurement test in rabbit plasma of Test Example 4 - 19