CN101754757A - 含5-甲基-1-苯基-2-(1h)-吡啶酮的粘贴剂 - Google Patents
含5-甲基-1-苯基-2-(1h)-吡啶酮的粘贴剂 Download PDFInfo
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- CN101754757A CN101754757A CN200880100095A CN200880100095A CN101754757A CN 101754757 A CN101754757 A CN 101754757A CN 200880100095 A CN200880100095 A CN 200880100095A CN 200880100095 A CN200880100095 A CN 200880100095A CN 101754757 A CN101754757 A CN 101754757A
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- quality
- transdermal absorption
- acid
- alite paste
- absorption formulation
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Abstract
本发明的课题是提供含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂。作为本发明的解决问题的方法是，提供包含透皮吸收制剂层的粘贴剂，其特征在于，该透皮吸收制剂层含有作为有效成分的5-甲基-1-苯基-2-(1H)-吡啶酮或其医学上可接受的盐类，并含有溶解剂和水性基剂(或橡胶系基剂)，且基于透皮吸收制剂层的总量，含有0.1～30质量％的该有效成分。
Description
技术领域
本发明涉及一种粘贴剂，该粘贴剂包含透皮吸收制剂层，并能够有效地预防和治疗皮肤病，例如，肥厚性瘢痕、瘢痕疙瘩、接触性皮炎、传染性疣(瘊)、掌足脓包症或纤维性皮肤病等。更详细地说，涉及一种粘贴剂，其特征在于，含有5-甲基-1-苯基-2-(1H)-吡啶酮(通用名：吡非尼酮(Pirfenidone))或其医学上可接受的盐类作为有效成分。
背景技术
已知5-甲基-1-苯基-2-(1H)-吡啶酮对预防和治疗纤维性疾病是有用的，所述纤维性疾病例如，肺纤维症、前列腺纤维化肥大、肾硬化症等。
并且，到目前为止，作为用于治疗肺纤维症的药剂，提出了含有5-甲基-1-苯基-2-(1H)-吡啶酮作为主药的片剂(参阅专利文献1)。另外，作为用于治疗纤维性皮肤病的其他剂型的药剂，还提出了溶液状药物组合物(参阅专利文献2)。
但是，对于使用5-甲基-1-苯基-2-(1H)-吡啶酮或其医学上可接受的盐类作为有效成分，且皮肤透过性、药效持续性等优异，粘着性、柔软性、凝集性等良好的皮肤病预防或治疗用粘贴剂，尚未为人们所知。
专利文献1：国际公开第2002/060446号小册子
专利文献2：特开2004-203795号公报
发明内容
发明要解决的问题
本发明是为了解决上述问题而做出的，其目的是提供一种有效成分(5-甲基-1-苯基-2-(1H)-吡啶酮或其医学上可接受的盐类)的皮肤透过性、药效持续性、粘着性、柔软性和/或凝集性良好的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂。
用于解决问题的方法
本发明者们为了实现上述目的进行了积极研究，结果发现：(1)通过在水性基剂中使用的数种溶解剂中，选择薄荷油、油醇、异丙醇、丙二醇、丁二醇、N-甲基吡咯烷酮、二甘醇单乙醚、甘油三乙酸酯、甘油、克罗米通(Crotamiton)、聚乙二醇、肉豆蔻酸异丙酯、三(乙基己酸)甘油酯、癸二酸二异丙酯、癸二酸二乙酯、己二酸二异丙酯、柠檬酸三乙酯、水杨酸乙二醇酯、碳酸亚丙酯和中链脂肪酸甘油三酯作为溶解剂，可以提高5-甲基-1-苯基-2-(1H)-吡啶酮相对于水性基剂的溶解性，从而在基剂中保持用于发挥药效的充分量的5-甲基-1-苯基-2-(1H)-吡啶酮；以及(2)通过在配合有该溶解剂的水性基剂中，将其组成特定为基于透皮吸收制剂层的总量，水溶性高分子1～20质量％、交联剂0.01～20质量％、多元醇10～80质量％、水5～80质量％，可以制造出具有作为粘贴剂良好的粘着性、柔软性和/或凝集性的水性型的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂。
另外，本发明者们发现：通过(1)在橡胶基剂中使用的数种溶解剂中，选择薄荷油、油醇、异丙醇、丙二醇、丁二醇、N-甲基吡咯烷酮、二甘醇单乙醚、甘油三乙酸酯、甘油、克罗米通、聚乙二醇、肉豆蔻酸异丙酯、三(乙基己酸)甘油酯、癸二酸二异丙酯、癸二酸二乙酯、己二酸二异丙酯、柠檬酸三乙酯、水杨酸乙二醇酯和碳酸亚丙酯作为溶解剂，以及(2)在配合有该溶解剂的橡胶系基剂中，将其组成特定为橡胶系高分子10～50质量％、增塑剂10～50质量％、增粘剂5～50质量％，可以制造出具有如上所述效果的油性型的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂，从而完成了本发明。
即，本发明的第一方案涉及一种粘贴剂，是包含透皮吸收制剂层的粘贴剂，其特征在于，该透皮吸收制剂层含有作为有效成分的5-甲基-1-苯基-2-(1H)-吡啶酮或其医学上可接受的盐类，并含有溶解剂和水性基剂，且基于透皮吸收制剂层的总量，含有0.1～30质量％的该有效成分。
本发明的第二方案涉及如第一方案所述的粘贴剂，其特征在于，所述溶解剂选自薄荷油、油醇、异丙醇、丙二醇、丁二醇、N-甲基吡咯烷酮、二甘醇单乙醚、甘油三乙酸酯、甘油、克罗米通、聚乙二醇、肉豆蔻酸异丙酯、三(乙基己酸)甘油酯、癸二酸二异丙酯、癸二酸二乙酯、己二酸二异丙酯、柠檬酸三乙酯、水杨酸乙二醇酯、碳酸亚丙酯和中链脂肪酸甘油三酯。
本发明的第三方案涉及如第一或第二方案所述的粘贴剂，其特征在于，基于透皮吸收制剂层的总量，所述水性基剂含有1～20质量％的水溶性高分子、0.01～20质量％的交联剂、10～80质量％的多元醇、5～80质量％的水。
本发明的第四方案涉及一种粘贴剂，是包含透皮吸收制剂层的粘贴剂，其特征在于，该透皮吸收制剂层含有作为有效成分的5-甲基-1-苯基-2-(1H)-吡啶酮或其医学上可接受的盐类，并含有溶解剂和橡胶系基剂，且基于透皮吸收制剂层的总量，含有0.1～30质量％的该有效成分。
本发明的第五方案涉及如第四方案所述的粘贴剂，其特征在于，所述溶解剂选自薄荷油、油醇、异丙醇、丙二醇、丁二醇、N-甲基吡咯烷酮、二甘醇单乙醚、甘油三乙酸酯、甘油、克罗米通、聚乙二醇、肉豆蔻酸异丙酯、三(乙基己酸)甘油酯、癸二酸二异丙酯、癸二酸二乙酯、己二酸二异丙酯、柠檬酸三乙酯、水杨酸乙二醇酯和碳酸亚丙酯。
本发明的第六方案涉及如第四或第五方案所述的粘贴剂，其特征在于，基于透皮吸收制剂层的总量，所述橡胶系基剂含有10～50质量％的橡胶系高分子、10～50质量％的增塑剂、5～50质量％增粘剂。
发明的效果
本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂通过根据所使用的基剂(水性基剂或橡胶系基剂)不同来选择使用适当的溶解剂，从而可以提高有效成分(5-甲基-1-苯基-2-(1H)-吡啶酮或其医学上可接受的盐类)相对于基剂的溶解能力，因此有效成分的皮肤透过性高，并能够在基剂中保持用于发挥药效的充分量的有效成分，从而其药效在长时间内持续。
进而，本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂通过根据基剂不同来选择适当的溶解剂，并将该溶解剂与特定的基剂成分组合，从而使粘贴剂具有良好的粘着性、柔软性和/或凝集性。
因此，通过使用本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂，能够有效地预防或治疗肥厚性瘢痕、瘢痕疙瘩、接触性皮炎、传染性疣(瘊)、掌足脓包症或纤维性皮肤病等皮肤病。
此外，本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂能够通过粘贴在患处来进行药效成分、即5-甲基-1-苯基-2-(1H)-吡啶酮的局部给药，并且该药效成分能够直接渗透到粘贴剂所粘贴的患处部位。
因此，由于本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂的药剂不会扩散到全身，因而不会产生光过敏症等副作用，并能够有效地预防或治疗皮肤病。
附图说明
图1是显示将实施例1的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂粘贴到大鼠的皮肤上之后，经过时间与5-甲基-1-苯基-2-(1H)-吡啶酮的累积透过量的关系的曲线图。
图2是显示将实施例1的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂粘贴到大鼠的皮肤上之后，经过时间与皮肤透过速度的关系的曲线图。
图3是显示试验例2的猪肥厚性瘢痕抑制试验的结果的曲线图。
具体实施方式
本发明的粘贴剂的有效成分是5-甲基-1-苯基-2-(1H)-吡啶酮。
另外，作为有效成分的5-甲基-1-苯基-2-(1H)-吡啶酮也可以是其医学上可接受的盐类。
作为这样的盐类，可列举例如，与盐酸、硫酸、磷酸、对甲苯磺酸、甲磺酸等酸的酸加成盐，或者例如钠盐、钾盐等与碱形成的盐等。
在本发明的粘贴剂中，有效成分的配合量根据配方不同而不同，优选基于透皮吸收制剂层的总量，配合约0.1～30质量％，优选为约0.5～20质量％，特别优选为约0.5～10质量％。
本发明的粘贴剂中所使用的溶解剂，根据溶解或悬浮有效成分5-甲基-1-苯基-2-(1H)-吡啶酮的基剂(水性基剂或橡胶系基剂)不同而不同。
在使用水性基剂作为基剂的情况下，溶解剂可以选自薄荷油、油醇、异丙醇、丙二醇、丁二醇、N-甲基吡咯烷酮、二甘醇单乙醚、甘油三乙酸酯、甘油、克罗米通、聚乙二醇、肉豆蔻酸异丙酯、三(乙基己酸)甘油酯、癸二酸二异丙酯、癸二酸二乙酯、己二酸二异丙酯、柠檬酸三乙酯、水杨酸乙二醇酯、碳酸亚丙酯和中链脂肪酸甘油三酯中；另外，在使用橡胶系基剂作为基剂的情况下，溶解剂可以选自薄荷油、油醇、异丙醇、丙二醇、丁二醇、N-甲基吡咯烷酮、二甘醇单乙醚、甘油三乙酸酯、甘油、克罗米通、聚乙二醇、肉豆蔻酸异丙酯、三(乙基己酸)甘油酯、癸二酸二异丙酯、癸二酸二乙酯、己二酸二异丙酯、柠檬酸三乙酯、水杨酸乙二醇酯和碳酸亚丙酯。
根据基剂而使用的这些溶解剂，可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些溶解剂的配合量约为0.1～20质量％。
本发明的粘贴剂的基剂优选为水性基剂或橡胶系基剂。作为水性基剂，例如，可以使用成分(1)水溶性高分子、成分(2)交联剂、成分(3)多元醇和水混合而成的基剂；另外，作为橡胶系基剂，例如，可以使用成分(4)橡胶系高分子、成分(5)增塑剂、成分(6)增粘剂混合而成的基剂。
作为成分(1)水溶性高分子，可以使用例如，聚丙烯酸、聚丙烯酸盐、聚丙烯酸部分中和物、聚丙烯酰胺、聚乙烯亚胺、聚乙烯醇、聚乙烯基吡咯烷酮、羧基乙烯基聚合物、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、丙烯酸淀粉、乙基乙酸乙烯酯、明胶、淀粉、オイドラギツド(商品名)、藻酸、藻酸钠、黄蓍胶等，但不限于这些。另外，这些水溶性高分子可以仅使用1种，或者2种以上适当混合使用。
基于透皮吸收制剂层的总量，这些水溶性高分子的配合量约为1～20质量％，优选为约5～15质量％。
作为成分(2)交联剂，例如，可以使用在溶解于水等中时生成二价或三价的金属离子的盐类等。作为这样的交联剂的例子，可以列举氢氧化铝、氢氧化铝镁等氢氧化物，或者氯化铝、硫酸铝、二羟基氨基乙酸铝、高岭土、硬脂酸铝、氢氧化镁、氯化镁、硫酸镁等无机酸或有机酸的正盐或它们的碱性盐，明矾等复盐，以及铝酸钠等铝酸盐，无机性铝配盐和有机性铝螯合化合物、合成水滑石、偏硅酸铝酸镁、硅酸铝酸镁、硝酸铝、硫酸铝、EDTA-铝盐、尿囊素铝、乙酸铝、甘羟铝等，但不限于这些。另外，这些交联剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些交联剂的配合量为0.01～20质量％，优选为0.02～5质量％。
作为上述交联剂的产生二价或三价金属离子的盐类，可以是水溶性的、也可以是难溶于水的。当使用难溶于水的铝化合物作为上述交联剂时，可以在应进行凝胶化的反应体系中添加反应速度调节剂，特别是通过添加酸能够加快凝胶化反应速度。特别是通过添加含羟基的有机酸或其盐类作为酸，能够显著加快凝胶化反应。作为这些交联反应的速度调节剂，可以使用柠檬酸、乳酸、酒石酸、葡糖酸、乙醇酸、苹果酸、富马酸、甲磺酸、马来酸、乙酸、EDTA二钠盐、脲、三乙胺、氨水等相对于金属离子具有螯合物形成能力或配位能力的有机酸、有机酸盐、有机碱等，以及盐酸、磷酸、硫酸、硝酸、氢溴酸等无机酸等，但不限于这些。
作为成分(3)多元醇的例子，可列举乙二醇、1，3-丙二醇、1，3-丁二醇、乙二醇单丁醚、三乙二醇、1，4-丁二醇、甘油、三羟基异丁烷、赤藓醇、季戊四醇、木糖醇、阿东糖醇、阿洛糖醇、山梨糖醇、山梨糖醇液、甘露糖醇、聚乙二醇等，但不限于这些。另外，这些多元醇可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些多元醇的配合量约为10～80质量％，优选为约10～60质量％。
另外，水性基剂包含水，基于透皮吸收制剂层的总量，其配合量约为5～80质量％。
优选水性基剂基于其总量，含有5～15质量％的水溶性高分子、0.02～5质量％的交联剂、10～60质量％的多元醇、10～60质量％的水。
作为成分(4)橡胶系高分子的例子，可列举苯乙烯-异戊二烯-苯乙烯嵌段共聚物、苯乙烯-丁二烯嵌段共聚物、聚异丁烯、生橡胶、聚异戊二烯、聚丁烯等，但不限于这些。这些橡胶系高分子可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些橡胶系高分子的配合量约为10～50质量％。
作为成分(5)增塑剂的例子，可列举液体石蜡、植物油、动物油、聚丁烯、低分子聚异丁烯、凡士林、羊毛脂、高级脂肪族酯等，但不限于这些。另外，这些增塑剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些增塑剂的配合量约为10～50质量％。
作为成分(6)增粘剂的例子，可列举石油树脂、松香系树脂、氢化松香、酯胶、萜烯树脂、改性萜烯树脂、芳香烃树脂、脂肪烃树脂等，但不限于这些。这些增粘剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些增粘剂的配合量约为5～50质量％。
优选橡胶系基剂基于其总量，含有10～40质量％的橡胶系高分子、10～40质量％的增塑剂、5～40质量％的增粘剂。
在本发明的粘贴剂的透皮吸收制剂层中，除了作为有效成分的5-甲基-1-苯基-2-(1H)-吡啶酮或其医学上可接受的盐类、以及溶解剂和水性或橡胶系基剂之外，可以根据需要配合其他各种添加剂，例如，在现有的透皮吸收制剂中常用的透皮吸收促进剂、增粘剂、软化剂、抗氧化剂、抗老化剂、保存剂、着香剂、pH调节剂、乳化剂、分散剂、稳定剂、防腐剂、赋形剂等。
作为透皮吸收促进剂的例子，只要是在现有的透皮吸收制剂中常用的即可，不特别限制，可列举例如，醇、脂肪酸、脂肪酸酯、脂肪酸醚、乳酸酯、乙酸酯、萜烯系化合物、吡咯烷酮衍生物、有机酸、有机酸酯、精油、烃、碳酸亚丙酯、氮酮(azone)或其衍生物等。更具体地说，作为透皮吸收促进剂，可列举乙醇、月桂醇、肉豆蔻醇、鲸蜡醇、克罗米通、环糊精、硫代乙醇酸钙、N-甲基-2-吡咯烷酮、乳酸乙酯、乳酸鲸蜡酯、乳酸、脲、1-薄荷醇、d-苧烯、d，l-樟脑等。这些透皮吸收促进剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些透皮吸收促进剂的配合量约为0.1～20质量％。
作为增粘剂的例子，可列举硅氧烷橡胶、聚异丁烯橡胶、苯乙烯-嵌段共聚物橡胶、丙烯酸橡胶、天然橡胶系粘附性物质等，但不限于这些。这些增粘剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些增粘剂的配合量约为5～50质量％。
作为软化剂的例子，可列举液体石蜡、聚丁烯、蓖麻油、棉籽油、棕榈油、椰子油、加工用油等，但不限于这些。这些软化剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些软化剂的配合量约为1～50质量％。
作为抗氧化剂的例子，可列举抗坏血酸、棕榈酸抗坏血酸酯、亚硫酸氢钠、乙二胺四乙酸钠、乙二胺四乙酸4钠、干燥亚硫酸钠、柠檬酸、柠檬酸钠、乙酸生育酚、dl-α-生育酚、二氯异氰脲酸钾、二丁基羟基甲苯、丁基羟基苯甲醚、大豆卵磷脂、焦亚硫酸钠、苯并三唑、季戊四醇四[3-(3，5-二叔丁基-4-羟基苯基)丙酸酯]、没食子酸丙酯、2-巯基苯并咪唑等，但不限于这些。这些抗氧化剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些抗氧化剂的配合量约为0.005～20质量％。
作为抗老化剂的例子，可列举甘氨酸、脯氨酸、羟脯氨酸、亮氨酸、丙氨酸、γ-氨基丁酸、ε-氨基己酸等氨基酸类，视黄醇、硫胺素、核黄素、盐酸吡哆醇、泛酸等维生素类，乙醇酸、乳酸、水杨酸等羟基酸类，单宁、黄酮类化合物、皂苷、尿囊素以及来源于春黄菊、甘草、罗马春黄菊、胡萝卜、稻等植物的成分、提取物和精油等，但不限于这些。这些抗老化剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些抗老化剂的配合量约为0.005～20质量％。
作为保存剂的例子，可列举对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、氯丁醇、苯甲醇等，但不限于这些。这些保存剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些保存剂的配合量约为0.005～5质量％。
作为着香剂的例子，可列举偶苯酰、乙酸里那醇酯、乙酸戊酯、苯甲醛、肉桂醛、香茅醛、薄荷醇、柠檬醛、茉莉酮(cis-Jasmon)等香料物质和水杨酸甲酯、樟脑、甲酚等药效物质。这些着香剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些着香剂的配合量约为0.05～5质量％。
作为pH调节剂，只要是在现有的透皮吸收制剂中常用的即可，不特别限制，可列举例如，盐酸、硫酸、硝酸、氢溴酸、磷酸等无机酸或它们的盐，乙酸、琥珀酸、富马酸、苹果酸、草酸、乳酸、戊二酸、水杨酸、酒石酸等有机酸或它们的盐，棕榈酸、硬脂酸、油酸、亚油酸等脂肪酸或它们的盐，以及氢氧化钠、氢氧化钙等无机碱，氨、二异丙醇胺、二乙醇胺、三乙醇胺、三乙胺等有机碱。这些pH调节剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些pH调节剂的配合量约为0.05～10质量％。
作为乳化剂的例子，可列举失水山梨糖醇单油酸酯、聚丙烯酸、聚丙烯酰胺、聚N-乙烯基吡咯烷酮、甲壳质、脱乙酰壳多糖、纤维素等，但不限于这些。这些乳化剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些乳化剂的配合量约为0.05～10质量％。
作为分散剂的例子，只要能够提高透皮吸收制剂层中各种成分的分散性即可，不特别限制，可列举例如，合成硅酸铝、含水硅酸铝、氢氧化铝、硅酸镁、氧化锌、氧化钛、硬脂酸金属盐等脂肪酸金属盐等。这些分散剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些分散剂的配合量约为0.5～50质量％。
作为稳定剂，例如，可以使用上述作为pH调节剂所例示的稳定剂。另外，作为稳定剂，还可以使用亚硫酸氢钠、抗坏血酸、抗坏血酸钠、丁基羟基苯甲醚、二丁基羟基甲苯、没食子酸丙酯、乙酸生育酚、D-α-生育酚等。这些稳定剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些稳定剂的配合量约为0.005～20质量％。
作为防腐剂的例子，可列举对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、苯氧基乙醇等，但不限于这些。这些防腐剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些防腐剂的配合量约为0.005～5质量％。
作为赋形剂的例子，可列举葡萄糖、果糖、半乳糖、甘露糖、帕拉金糖、蔗糖、麦芽糖、乳糖、海藻糖、寡糖类、糊精等糖类，结晶纤维素、甲基纤维素、羧甲基纤维素或其盐、羟丙基纤维素、羟丙基甲基纤维素等纤维素类等，但不限于这些。这些赋形剂可以仅使用1种，或者2种以上适当混合使用。基于透皮吸收制剂层的总量，这些赋形剂的配合量约为0.1～40质量％。
根据用途不同，本发明的粘贴剂可以是例如巴布剂、硬膏药、胶带剂等各种粘贴剂形式。本发明的粘贴剂可以通过例如以下方法来制造：将规定量的5-甲基-1-苯基-2-(1H)-吡啶酮和溶解剂添加到水性基剂或橡胶系基剂中制成透皮吸收制剂，将该制剂以规定的厚度涂布在适当的支持体上形成透皮吸收制剂层，然后在它上面被覆规定的衬里，并将其剪裁成所需的尺寸。另外，本发明的粘贴剂根据其制造方法不同，也可以通过例如以下方法来形成：首先将含有5-甲基-1-苯基-2-(1H)-吡啶酮和溶解剂的基剂(透皮吸收制剂)涂布在衬里上形成透皮吸收制剂层，然后在其上被覆支持体，将该透皮吸收制剂层转印到该支持体上。
另外，因为本发明的粘贴剂与患处直接接触，所以在如上所述制造之后，优选进行灭菌处理。作为灭菌方法，只要是现有药剂的灭菌中常用的方法即可，不特别限制，例如，可使用γ射线灭菌法、电子束灭菌法、高压蒸气灭菌法、环氧乙烷气体灭菌法等。
对本发明的粘贴剂中所使用的支持体不特别限制，可以使用作为粘贴剂的支持体常用的材料。作为这些支持体，例如，可以使用天然或合成高分子的纺织布、无纺布、片、膜或它们的层叠体，优选为氯乙烯膜、聚乙烯系膜、乙烯共聚膜、聚丙烯系膜、聚氨酯、以及纺织布和无纺布以及它们与塑料的层叠体。
另外，可以适当选择这些支持体的尺寸、形状、厚度等。
对本发明的粘贴剂中所使用的衬里不特别限制，可以使用作为粘贴剂的衬里常用的材料。作为这些衬里，可列举例如，天然或合成高分子的片、膜或它们的层叠体，优选为进行了方便剥离的处理(例如，涂布合成高分子)的剥离纸、玻璃纸、聚乙烯、聚对苯二甲酸乙二酯、聚丙烯、聚酯、聚偏二氯乙烯等的片、膜或它们的层叠体。
下面，列举实施例和试验例对于本发明的有用性进行说明，但是本发明不限于这些实施例和试验例。另外，如果没有特别的记载，则份是基于质量的份。
实施例
实施例1
将5份聚丙烯酸钠、2.5份丙烯酸淀粉、1份羧甲基纤维素钠和30份浓甘油混合(A液)。将2份或3份作为有效成分的5-甲基-1-苯基-2-(1H)-吡啶酮和1份酒石酸与54.13份或53.16份水混合(B液)。将1份薄荷油(溶解剂)溶解在0.3份表面活性剂中(C液)。在A液中加入B液和C液，进一步加入3份聚丙烯酸共聚乳剂和0.04份氢氧化铝凝胶并混合均匀。将该混合物(透皮吸收制剂)在聚乙烯制膜(衬里)上延展形成透皮吸收制剂层，在它上面被覆聚酯制的无纺布(支持体)。将其剪裁成所需的尺寸，从而得到实施例1的含有2％或3％的5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂。
实施例2
将10份聚异丁烯、25份苯乙烯-异戊二烯-苯乙烯嵌段共聚物、0.5份二丁基羟基甲苯、39.5份液体石蜡、17份石油系树脂在140℃下混合(A液)。将3份作为有效成分的5-甲基-1-苯基-2-(1H)-吡啶酮均匀混合在5份丙二醇(溶解剂)中。将A液加热至120℃，然后在A液中加入B液进行混合。将该混合物(透皮吸收制剂)在聚酯制无纺布(支持体)上延展形成透皮吸收制剂层，在它上面被覆聚酯制膜(衬里)，冷却至室温，然后将其剪裁成所需的尺寸，得到实施例2的含有3％的5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂。
试验例1：体外(in vitro)皮肤透过性试验
1)试验方法
在戊巴比妥钠麻醉下，将Wistar系雄性大鼠(7周龄)的腹部剃毛，切取皮肤，非常小心地除去皮肤真皮侧的脂肪。在预先循环了37℃的水的纵型扩散池中贴合皮肤使真皮侧向下，然后在其中央部分粘贴冲裁成直径1cm的实施例1所制造的2％粘贴剂，然后使用圆顶型池夹持固定。接着，在真皮侧加入用37℃的恒温槽保温的接收液，在取样口上安装、固定L字管，然后进一步加入一定量的接收溶液。用磁力搅拌器搅拌接收溶液，然后，经时地采样一定量的接收溶液，并补充相同量的接收溶液。通过使用以下所示条件的高速液相色谱(HPLC)，对所采样的样品中的有效成分(5-甲基-1-苯基-2-(1H)-吡啶酮)的量进行定量，计算出5-甲基-1-苯基-2-(1H)-吡啶酮的累积皮肤透过量和皮肤透过速度。其结果分别示于图1和图2。
<HPLC条件>
柱：CAPCELL PAK C18 5μm 4.6×150mm
柱温：40℃
流速：1mL/分钟
检测波长：318nm
进样量：10μL
流动相：乙腈∶甲醇∶50mM磷酸缓冲液(pH2.7)＝225∶100∶675(9∶4∶27)
2)结果
(1)5-甲基-1-苯基-2-(1H)-吡啶酮的累积皮肤透过量
如图1所示，自粘贴到皮肤上起12小时之后，在实施例1的本发明的粘贴剂中，有效成分(5-甲基-1-苯基-2-(1H)-吡啶酮)仅残存约20％左右。换而言之，即实施例1的本发明的粘贴剂在24小时内有累计约90％的有效成分被释放到皮肤中(透过皮肤)。
由此可判断，本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂的有效成分的皮肤透过性及其药效持续性优异。
(2)5-甲基-1-苯基-2-(1H)-吡啶酮的皮肤透过速度
如图2所示，实施例1的粘贴剂自粘贴到皮肤上起3小时的期间，有效成分(5-甲基-1-苯基-2-(1H)-吡啶酮)的皮肤透过速度为0.1mg/cm2/小时以上，速度非常快。
由此可判断，本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂的速效性优异。
试验例2：肥厚性瘢痕治疗试验
1)试验方法
将在养猪场内通过割伤而产生肥厚性瘢痕的猪(18周龄/Duroc种系/雌性)分成对照组、基剂组和3％粘贴剂组的3组。在3％粘贴剂组和基剂组的各只猪的肥厚性瘢痕部位，自形成割伤之后25天起，以每天1次、每次24小时的方式，分别贴合实施例1的本发明的粘贴剂、以及除了从透皮吸收制剂层除去5-甲基-1-苯基-2-(1H)-吡啶酮之外与实施例1相同的粘贴剂。
在9周之后，使用数显尺测定各组猪的肥厚性瘢痕部位的摘取皮肤(瘢痕皮肤)的厚度和正常的摘取皮肤的厚度。
通过杜奈特(Dunnett)多重比较检验对于得到的3组猪的瘢痕皮肤和正常的皮肤的厚度进行统计分析。结果示于图3。
在图3中，**表示p＜0.01(相对于对照组)。
2)结果
如图3所示，在使用了透皮吸收制剂层中含有5-甲基-1-苯基-2-(1H)-吡啶酮与溶解剂的组合的本发明的粘贴剂的粘贴剂组中，瘢痕皮肤的厚度几乎减少(恢复)到正常皮肤的厚度，与此相对，在透皮吸收制剂层中不含该组合的基剂组中，瘢痕皮肤的厚度几乎未减少。
由上述结果可判断，本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂在以猪为模型的肥厚性瘢痕的预防和治疗中是有效的。
由于在被认为与人类皮肤结构类似的猪皮肤中得到了这样的结果，因而也可以说本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂在人的肥厚性瘢痕的预防和治疗中也同样是有效的。
进而，由上述肥厚性瘢痕试验的结果可认为，本发明的含5-甲基-1-苯基-2-(1H)-吡啶酮的粘贴剂对于以5-甲基-1-苯基-2(1H)-吡啶酮为治疗药有效的瘢痕疙瘩、接触性皮炎、传染性疣(瘊)、掌足脓包症或纤维性皮肤病等其他皮肤病的预防和治疗也同样是有效的。
Claims (6)
1.一种粘贴剂，是包含透皮吸收制剂层的粘贴剂，其特征在于，该透皮吸收制剂层含有作为有效成分的5-甲基-1-苯基-2-(1H)-吡啶酮或其医学上可接受的盐类，并含有溶解剂和水性基剂，且基于透皮吸收制剂层的总量，含有0.1～30质量％的该有效成分。
2.如权利要求1所述的粘贴剂，其特征在于，所述溶解剂选自薄荷油、油醇、异丙醇、丙二醇、丁二醇、N-甲基吡咯烷酮、二甘醇单乙醚、甘油三乙酸酯、甘油、克罗米通、聚乙二醇、肉豆蔻酸异丙酯、三(乙基己酸)甘油酯、癸二酸二异丙酯、癸二酸二乙酯、己二酸二异丙酯、柠檬酸三乙酯、水杨酸乙二醇酯、碳酸亚丙酯和中链脂肪酸甘油三酯。
3.如权利要求1或2所述的粘贴剂，其特征在于，基于透皮吸收制剂层的总量，所述水性基剂含有1～20质量％的水溶性高分子、0.01～20质量％的交联剂、10～80质量％的多元醇、5～80质量％的水。
4.一种粘贴剂，是包含透皮吸收制剂层的粘贴剂，其特征在于，该透皮吸收制剂层含有作为有效成分的5-甲基-1-苯基-2-(1H)-吡啶酮或其医学上可接受的盐类，并含有溶解剂和橡胶系基剂，且基于透皮吸收制剂层的总量，含有0.1～30质量％的该有效成分。
5.如权利要求4所述的粘贴剂，其特征在于，所述溶解剂选自薄荷油、油醇、异丙醇、丙二醇、丁二醇、N-甲基吡咯烷酮、二甘醇单乙醚、甘油三乙酸酯、甘油、克罗米通以及聚乙二醇、肉豆蔻酸异丙酯、三(乙基己酸)甘油酯、癸二酸二异丙酯、癸二酸二乙酯、己二酸二异丙酯、柠檬酸三乙酯、水杨酸乙二醇酯和碳酸亚丙酯。
6.如权利要求4或5所述的粘贴剂，其特征在于，基于透皮吸收制剂层的总量，所述橡胶系基剂含有10～50质量％的橡胶系高分子、10～50质量％的增塑剂、5～50质量％增粘剂。
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| JP2007139653A JP5248040B2 (ja) | 2007-05-25 | 2007-05-25 | ５−メチル−１−フェニル−２−（１ｈ）−ピリドン含有貼付剤 |
| JP139653/2007 | 2007-05-25 | ||
| PCT/JP2008/059672 WO2008146796A1 (ja) | 2007-05-25 | 2008-05-26 | ５－メチル－１－フェニル－２－（１ｈ）－ピリドン含有貼付剤 |
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| CN105213351A (zh) * | 2013-09-25 | 2016-01-06 | 南阳市汇博生物技术有限公司 | 用于增生性疤痕修复的贴膜 |
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| US20080210265A1 (en) | 2007-03-01 | 2008-09-04 | Crawford Charles A | Coating removal composition |
| JP5192296B2 (ja) * | 2007-07-05 | 2013-05-08 | 日東電工株式会社 | 貼付剤および貼付製剤 |
| JP2010120912A (ja) * | 2008-11-21 | 2010-06-03 | Lead Chemical Co Ltd | ５−メチル−１−フェニル−２−（１ｈ）−ピリドン含有貼付剤 |
| JP6014813B2 (ja) * | 2010-09-03 | 2016-10-26 | 株式会社 ケイ・エム トランスダーム | 経皮吸収製剤および皮膚貼付用粘着シート |
| JP5698018B2 (ja) * | 2011-02-02 | 2015-04-08 | 日東電工株式会社 | 貼付剤および貼付製剤 |
| CA2826218C (en) | 2011-02-02 | 2019-06-25 | Nitto Denko Corporation | A patch and patch preparation comprising a support and an adhesive layer |
| JP5934437B2 (ja) | 2012-05-28 | 2016-06-15 | アベックス アクティエボラーグ | 疣贅処置用組成物 |
| US10335389B2 (en) | 2013-08-09 | 2019-07-02 | Teikoku Seiyaku Co., Ltd. | Beraprost-containing patch |
| WO2018204523A1 (en) * | 2017-05-03 | 2018-11-08 | Kuefner George C | Systems and methods for treating skin conditions with magnesium ion compositions |
| MX2021013944A (es) * | 2019-05-13 | 2022-04-01 | Bio Medical Sciences Inc | Productos para el tratamiento de heridas y cicatrices con ingredientes activos, procedimiento de fabricacion y articulos utiles. |
| WO2021022033A1 (en) | 2019-07-30 | 2021-02-04 | Leung Kai P | Layered composite for scar treatment and prevention |
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| CN1694699A (zh) * | 2002-11-05 | 2005-11-09 | 立德化学株式会社 | 含有3－甲基－1－苯基－2－吡唑啉－5－酮的透皮吸收制剂 |
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| CA1248450A (en) * | 1984-04-05 | 1989-01-10 | Kazuo Kigasawa | Soft patch |
| US5167649A (en) * | 1988-08-22 | 1992-12-01 | Zook Gerald P | Drug delivery system for the removal of dermal lesions |
| JP2002526447A (ja) * | 1998-09-18 | 2002-08-20 | メファ・アクチェンゲゼルシャフト | アルキルフェニルピリドンの局所製剤 |
| WO2002060446A1 (fr) | 2001-01-29 | 2002-08-08 | Shionogi & Co., Ltd. | Preparation medicamenteuse contenant du 5-methyle-1-phenyle-2-(1h)-pyridone en tant que principe actif |
| JP4542743B2 (ja) * | 2002-12-26 | 2010-09-15 | Ｋｄｌ株式会社 | ピリドン誘導体の溶液状医薬組成物 |
| WO2004073680A1 (ja) * | 2003-02-21 | 2004-09-02 | Shionogi & Co., Ltd. | 液滴分散型軟膏剤 |
| TW200501952A (en) * | 2003-02-21 | 2005-01-16 | Shionogi & Co | Pirfenidone gel formulations |
| JP2006298774A (ja) * | 2005-04-15 | 2006-11-02 | Lead Chemical Co Ltd | 経皮吸収型フリーラジカル抑制製剤 |
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| CN105213351A (zh) * | 2013-09-25 | 2016-01-06 | 南阳市汇博生物技术有限公司 | 用于增生性疤痕修复的贴膜 |
| CN105213351B (zh) * | 2013-09-25 | 2018-03-13 | 南阳市汇博生物技术有限公司 | 用于增生性疤痕修复的贴膜 |
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| BRPI0810957A2 (pt) | 2019-01-08 |
| US20100119584A1 (en) | 2010-05-13 |
| JP5248040B2 (ja) | 2013-07-31 |
| US8287900B2 (en) | 2012-10-16 |
| KR20100027139A (ko) | 2010-03-10 |
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