CN102858332A - 含酮洛芬的水基贴剂 - Google Patents
含酮洛芬的水基贴剂 Download PDFInfo
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Abstract
提供了含有作为活性成分的酮洛芬的贴剂,其为具有酮洛芬的优异经皮吸收性和安全性、并且具有高保存稳定性的水性贴剂,特征在于含有酮洛芬、胺类和聚乙二醇,在膏体中酮洛芬的配合量为0.1~5重量%、胺类的配合量为0.5~10重量%、以及聚乙二醇的配合量为5~30重量%,特别地,应用二异丙醇胺作为胺类。
Description
技术领域
本发明涉及含有酮洛芬作为活性成分的水基贴剂,具体地,涉及酮洛芬的主药稳定性、以及经皮吸收性优异的水基贴剂。
背景技术
含有具有抗炎症活性的酮洛芬作为活性成分的水基贴剂是公知的。酮洛芬对水的溶解度低,因此,在配合于水基贴剂时,常常使用克罗米通、脂肪酸、脂肪酸酯、精油类、多元醇、表面活性剂等特定的溶解剂作为难溶性药物溶解剂(专利文献1和2)。但是,制备这些贴剂时,其制备方法中必须采用某些设计,具有制备中的生产效率差的基本缺点。
即,用于在溶解酮洛芬中使用的特定溶解剂一般为亲脂性溶剂,在制备水基贴剂时,在添加这些溶剂时,如果不注意,则可能对贴剂的性质产生不利影响,所述影响为水溶性高分子化合物的不溶解或亲脂性溶剂的分离等。
另外,通常的水基贴剂中常常以高浓度配合甘油等多元醇,在配合的药物是酮洛芬时,在具有羧酸基的酮洛芬与具有羟基的多元醇(例如甘油)、低级醇或甲醇等溶解剂之间,以作为水基贴剂的基质成分的有机酸、聚丙烯酸等弱酸为催化剂,在比较低的温度下进行酯化反应,产生保存稳定性低的问题。
为了解决该问题,提议将含有分子中具有羧酸基的酮洛芬的非甾体消炎镇痛剂分散在甘油和碳原子数3~30的二元醇中而使其稳定化(专利文献3)。
但是,即使在该专利文献中记载的贴剂中,作为水基贴剂的基质的甘油是必须成分,因此考虑到长期稳定性时,担心由于酯化反应而降低保存稳定性。另外,一般而言,如果药物在贴剂中以分散状态存在,保存稳定性增加但经皮吸收性降低,因此期望保存稳定性与经皮吸收性均好的水基贴剂。
一方面,在一般的油基贴剂中配合的贴剂基质中,酮洛芬的溶解性常常是优异的,另外,通常用作酮洛芬的溶解剂的脂肪酸酯、精油类或克罗米通等通常与酮洛芬的相容性良好。
因此,配合了酮洛芬的油基贴剂的经皮吸收性高,并且这些油基贴剂在不配合多元醇类时能够维持其性质,因此能够获得酮洛芬的高稳定性。
由于上述理由,一直以来进行了大量的涉及配合酮洛芬的油基贴剂的发明(专利文献4和5),在实际的药品市场中,涉及这些油基贴剂的制品大量流通。但是,油基贴剂存在对皮肤的刺激性的问题,提供安全性更高的制品成为课题。
现有技术文献
专利文献
专利文献1 特开昭58-083623号公报
专利文献2 特开昭61-275212号公报
专利文献3 特开2002-193793号公报
专利文献4 国际公开WO93/04677号
专利文献5 特开2004-43512号公报。
发明内容
发明要解决的课题
鉴于上述现状,本发明的课题是提供含有酮洛芬作为活性成分的贴剂,其具有酮洛芬的优异经皮吸收性和安全性,并且具有高保存稳定性。
本发明人为了解决相关课题进行了深入研究,结果发现,通过选择对酮洛芬显示出优异溶解性的溶剂即胺类作为主药溶解剂,进一步地,将酮洛芬溶解在配合了与酮洛芬相互作用小的聚乙二醇的水基基质中,获得显示出酮洛芬的优异经皮吸收性、安全性和高保存稳定性的水基贴剂,从而完成本发明。
解决课题的手段
因此,本发明的基本方案是以含有酮洛芬、胺类和聚乙二醇为特征的水基贴剂。
更具体地,本发明为膏体(paste)中酮洛芬的配合量为0.1~5重量%、胺类的配合量为0.5~10重量%、和聚乙二醇的配合量为5~30重量%的水基贴剂。
最具体地,本发明为应用二异丙醇胺作为胺类的水基贴剂。
发明效果
根据本发明,选择胺类作为酮洛芬的溶解剂,在配合了聚乙二醇的水基基质中溶解酮洛芬,从而提供能够使酮洛芬在水基基质中稳定溶解的水基贴剂。
特别地,在本发明中在含有水溶性低的酮洛芬作为活性成分的水基贴剂中,将胺类、特别是二异丙醇胺作为酮洛芬的溶解剂,并将酮洛芬溶解在配合了与酮洛芬相互作用小的聚乙二醇的水基贴剂基质中,可以提供皮肤渗透性高、且皮肤刺激性低、进一步地主药稳定性高的含酮洛芬水基贴剂。
在含酮洛芬水基贴剂中,胺类与聚乙二醇的组合是极度特异性的,因此,本发明提供的水基贴剂兼具以前的水基贴剂无法获得的酮洛芬的优异经皮吸收性、安全性和高保存稳定性,其效果是显著的。
附图说明
图1是显示试验例3中体外大鼠皮肤渗透性试验的结果的图。
具体实施方案
如上述,本发明的基本方案是以含有酮洛芬、胺类和聚乙二醇为特征的水基贴剂。
以下,对于本发明进一步详细说明。
本发明提供的水基贴剂中,制剂中酮洛芬的配合量没有特别限制,只要可以制备制剂即可,优选酮洛芬可以以相对于膏体总重量0.1~5重量%配合。更优选0.5~2重量%。
膏体中的酮洛芬含量不足0.1重量%时,酮洛芬的经皮吸收性不充分,另外,酮洛芬超过5重量%配合时,使用后不经皮吸收而在制剂中残留的主药成分增加,这是不优选的。
本发明中使用的胺类一般常常作为水基贴剂中基质成分的pH调节剂使用,本发明中其作为难溶性酮洛芬的溶解剂而配合。
使用的胺类例如可列举,单乙醇胺、二乙醇胺、三乙醇胺、二异丙醇胺、三异丙醇胺等,特别优选二异丙醇胺。
本发明提供的水基贴剂中胺类的配合量没有特别限制,只要可以制备制剂即可,优选胺类可以以相对于膏体总重量为0.5~10重量%、更优选1~5重量%的范围进行配合。
膏体中的胺含量不足0.5重量%时,制剂中的酮洛芬的溶解不充分,结果恐怕产生结晶析出或经皮吸收性降低等不利的影响。
一方面,胺超过10重量%配合时,制剂的pH过度上升,产生粘着力降低等对制剂的性质不利的影响。
本发明中,水基贴剂的基质中配合的聚乙二醇发挥酮洛芬的酯化抑制剂的作用。所述聚乙二醇的平均分子量优选为600以下,具体地为选自聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600的1种或2种以上的聚乙二醇。
平均分子量为600以上的聚乙二醇不是优选的,因为其熔点高于40℃,在与本发明的水基贴剂配合时水溶性高分子等基质成分不能充分分散,可能出现未溶解的基质成分。
使用的聚乙二醇的配合量没有特别限制,只要可以制备制剂即可,优选聚乙二醇可以以相对于膏体总重量为5~30重量%、更优选10~20重量%的范围进行配合。
膏体中的聚乙二醇含量不足5重量%时,制剂中的酮洛芬的稳定性降低,另外,聚乙二醇超过30重量%时,制剂的性质受到影响,例如贴附时产生滴流,这不是优选的。
本发明提供的水基贴剂中,可以使用用于通常的外用制剂中的各种基质成分,只要其不施加额外影响。
这样的基质成分没有特别限定,例如可列举,通常使用的聚丙烯酸钠、聚丙烯酸、羧乙烯基聚合物、羧甲纤维素钠、羟丙基纤维素、聚乙烯醇、明胶等水溶性高分子化合物;甘油、丙二醇、1,3-丁二醇等多元醇类;氢氧化铝、硫酸铝钾、甘氨酸铝等交联剂;高岭土、氧化钛等无机粉末;柠檬酸、依地酸钠、酒石酸等pH调节剂;聚氧乙烯去水山梨糖醇单油酸酯、去水山梨糖醇单油酸酯、聚氧乙烯单油酸酯、甘油脂肪酸酯、聚甘油脂肪酸酯、聚氧乙烯脂肪酸酯、去水山梨糖醇脂肪酸酯、聚氧乙烯去水山梨糖醇脂肪酸酯、聚氧乙烯山梨糖醇脂肪酸酯、聚氧乙烯氧化蓖麻油、聚氧乙烯烷基醚等表面活性剂;对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等防腐剂;和纯化水等。
进一步地,根据需要,可以适当地适量添加吸收促进剂、抗氧化剂、增香剂、着色剂等。
其中,优选将水溶性高分子化合物以1~30重量%、交联剂以0.01~5重量%、纯化水以10~90重量%、无机粉末以0~20重量%范围,各自配合在贴剂膏体成分中。另外,必须根据前述聚乙二醇配合量进一步增减多元醇类,优选多元醇类与聚乙二醇共同配合10~50重量%。
应用上述各成分制备的本发明的水基贴剂(膏体层)的厚度(排除下述背层和覆盖表面的膜的厚度)没有特别限定,涂覆量150~1000g/m2是足够的,更优选300~700g/m2。
本发明的水基贴剂的膏体通过利用常规方法将上述成分混合、搅拌、熟化等而制备,本发明的水基贴剂可以通过将得到的膏体在不织布、织布、片、膜等背层上铺展、支持后用保护膜覆盖而制备。
应用的背层的材料可以列举聚乙烯、聚丙烯、聚氯乙烯、聚酯、尼龙、聚氨基甲酸乙酯、人造纤维等,特别是在膏体层薄时,优选使用以它们作为材料的多孔体或发泡体与织布或不织布的层压体等。
覆盖膏体表面的塑料膜可以使用单独的聚乙烯、聚丙烯、聚酯、聚氯乙烯、剥离纸或其层压体,可以对其进行硅酮处理、电晕放电处理、浮雕处理、等离子体处理等而使用。
实施例
以下,通过具体的实施例和比较例、以及各种试验例更详细地说明本发明,但本发明不限于这些实施例。
实施例1:
将甘油142.5g、聚乙二醇(400)150g、聚丙烯酸7.5g、聚丙烯酸钠40g、羧甲纤维素钠40g、羟丙基纤维素5g、依地酸钠0.6g、二羟铝氨乙酸盐(dihydroxyaluminum aminoacetate)0.9g、对羟基苯甲酸甲酯1g、对羟基苯甲酸丙酯0.5g、酒石酸15g、20%聚丙烯酸水溶液200g、纯化水适量均一地混合,制备含水凝胶。
随后,将二异丙醇胺10g与在适量水中溶解的酮洛芬20g在预先制备的凝胶中均一混合,得到贴剂用膏体。
将得到的膏体涂覆在层压不织布上,使膏体重量为500g/m2,粘着面用聚酯膜覆盖,得到期望的水基贴剂。
实施例2~4:
根据下述表1中示出的配方,与上述实施例1同样地得到实施例2~4的水基贴剂。
另外,表中也示出如实施例1的配方,其配合量以重量%表示,但在各实施例的制备中,以其10倍量单位(g换算)进行制备。
表1
比较例1:
比较例1使用市售含酮洛芬2重量%的膏剂(膏体厚:143g/m2)。
比较例2:
将甘油350g、聚丙烯酸50g、聚丙烯酸钠40g、羧甲纤维素钠40g、羟丙基纤维素5g、依地酸钠0.6g、二羟铝氨乙酸盐0.9g、丙二醇30g、对羟基苯甲酸甲酯1g、对羟基苯甲酸丙酯0.5g、酒石酸15g、20%聚丙烯酸水溶液200g、33%聚乙烯醇水溶液20g、纯化水适量均一混合,制备含水凝胶。
随后,将克罗米通20g和在聚乙二醇(400)40g中溶解的酮洛芬20g在预先制备的凝胶中均一混合,得到贴剂用膏体。
将得到的膏体涂覆在层压不织布上,使膏体重量为500g/m2,粘着面用聚酯膜覆盖,得到比较例2的水基贴剂。
比较例3~4:
根据下述表2示出的配方,与上述比较例2同样地得到比较例3~4的水基贴剂。
另外,表中也示出比较例2的配方,其配合量以重量%表示,但在各比较例的制备中,以其10倍量单位(g换算)进行制备。
表2
试验例:
试验例1:稳定性试验1
上述得到的实施例1和比较例2~4的各贴剂在铝袋中密封包装后,在4℃保存条件下保存1个月,目视观察各制剂中酮洛芬的结晶析出的有无。其结果在下述表3中示出。
表中的○表示不结晶析出的样品,×表示结晶析出的样品。
表3
实施例1 | 比较例2 | 比较例3 | 比较例4 | |
1个月保存后 | ○ | ○ | ○ | × |
试验例2:稳定性试验2
上述得到的实施例1和比较例2~4的各贴剂在铝袋中密封包装后,在40℃/75%RH的保存条件下保存3个月,通过高效液相色谱法测定这些各制剂中的酮洛芬含量。
其结果在下述表4中示出。
对于结果,以初始配合量作为100%,保存后的酮洛芬含量以%表示。
表4
实施例1 | 比较例2 | 比较例3 | 比较例4 | |
初始 | 100.0 | 100.0 | 100.0 | 100.0 |
3个月保存后 | 96.8 | 83.1 | 91.6 | 90.9 |
另外,对于实施例1和比较例3的贴剂,通过高效液相色谱法测定同样的保存条件下制剂中的类似物(酮洛芬的甘油酯)生成量。
其结果在下述表5中示出。另外,对于类似物的生成量,以类似物的生成重量相对于配合的酮洛芬重量的比率(%)表示。
表5
实施例1 | 比较例3 | |
初始 | 0.02 | 0.02 |
3个月保存后 | 0.71 | 1.84 |
如通过上述各稳定性试验的结果判定的,与比较例的各制剂比较时,本发明的贴剂的酮洛芬的稳定性高得多。特别是对于不配合聚乙二醇的比较例3,其酮洛芬稳定性低并且酮洛芬类似物的生成量也多。
另外,对于不配合胺类的比较例2和比较例4的水基贴剂,酮洛芬稳定性低,特别是其中比较例4在4℃保存条件下结晶析出,对于各比较例的制剂,酮洛芬在制剂中以非常不稳定的状态存在。
试验例3:体外的皮肤渗透试验
对实施例1中得到的水基贴剂、和作为市售品的比较例1的含酮洛芬2重量%的膏剂,应用大鼠皮肤进行体外皮肤渗透试验。
将脱毛雄性大鼠(Wistar系,7周龄)的背部取出皮肤在于37℃保温的纵型渗透试验用扩散池中固定,将作为试验对象的制剂贴附在取出皮肤的角质层侧,在内侧(真皮层侧)加入作为接收液的磷酸缓冲盐水(PBS)10mL。其后,随时间收集0.2 mL接收液,通过液相色谱法测定酮洛芬渗透量,根据其值计算皮肤渗透速度(flux)。
其结果在图1中示出。
试验例4:兔皮肤初步刺激性试验
对实施例1中得到的水基贴剂、和作为市售品的比较例1的含酮洛芬2重量%的膏剂,进行兔皮肤初步刺激性试验。
将各个制剂贴附于脱毛兔背部24小时,由剥离后1小时、24小时和48小时的皮肤症状求得刺激指数(P.I.I.)。
刺激指数(P.I.I.)的评价标准在下述表6中示出。
表6
P.I.I | 稳定性分类 |
P.I.I=0 | 无刺激物 |
0< P.I.I <2 | 弱刺激物 |
2 ≦P.I.I< 5 | 中等程度刺激物 |
5 ≦P.I.I | 强刺激物 |
其结果在下述表7中示出。
表7
试验制剂 | 实施例1 | 比较例1 |
刺激指数(P.I.I) | 0.04 | 0.08 |
根据图1和表7所示结果判定,本发明的水基贴剂与比较例1的膏剂比较时,本发明的水基贴剂的经皮吸收性、皮肤刺激性均优异。
根据以上结果可以得出结论,本发明提供的水基贴剂是兼具优异的酮洛芬经皮吸收性、安全性和高保存稳定性的制剂。
产业实用性
如上述,根据本发明,通过以水溶解性低的酮洛芬作为活性成分、将胺类用作溶解剂、进一步将酮洛芬在配合了聚乙二醇的贴剂基质中溶解,能够提供皮肤渗透性高、皮肤刺激性低和主药稳定性高的含酮洛芬水基贴剂。
本发明提供的水基贴剂与以往的含酮洛芬贴剂相比兼具高的酮洛芬的优异经皮吸收性、安全性和高保存稳定性,其医疗实用性很高。
Claims (3)
1.水基贴剂,其特征在于含有酮洛芬、胺类和聚乙二醇。
2.权利要求1记载的水基贴剂,其中膏体中酮洛芬的配合量是0.1~5重量%,胺类的配合量是0.5~10重量%,以及聚乙二醇的配合量是5~30重量%。
3.权利要求1或2记载的水基贴剂,其中胺类是二异丙醇胺。
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US (2) | US9271944B2 (zh) |
EP (1) | EP2545912B1 (zh) |
JP (1) | JP5622410B2 (zh) |
KR (1) | KR101819249B1 (zh) |
CN (2) | CN102858332A (zh) |
AU (1) | AU2011225100B2 (zh) |
CA (1) | CA2791498C (zh) |
ES (1) | ES2523126T3 (zh) |
HK (1) | HK1177690A1 (zh) |
TW (1) | TWI498131B (zh) |
WO (1) | WO2011111809A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109843282A (zh) * | 2016-10-12 | 2019-06-04 | 帝国制药株式会社 | 水性贴剂 |
CN113423394A (zh) * | 2019-02-14 | 2021-09-21 | 久光制药株式会社 | 泥罨剂 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6444305B2 (ja) * | 2013-08-09 | 2018-12-26 | 帝國製薬株式会社 | ベラプロスト含有貼付剤 |
BR112017013255B1 (pt) * | 2014-12-22 | 2022-08-09 | Hisamitsu Pharmaceutical Co., Inc | Cataplasma |
JP2020066592A (ja) * | 2018-10-24 | 2020-04-30 | 帝國製薬株式会社 | 水性貼付剤 |
CN109432061B (zh) * | 2018-11-09 | 2020-10-30 | 北京德默高科医药技术有限公司 | 含有布洛芬或其结构类似物的多层经皮给药*** |
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JP2002193793A (ja) * | 2000-12-26 | 2002-07-10 | Teikoku Seiyaku Co Ltd | 非ステロイド系消炎鎮痛貼付剤 |
JP2004131495A (ja) * | 2002-09-17 | 2004-04-30 | Nippon Boehringer Ingelheim Co Ltd | 非ステロイド系抗炎症剤の局所送達用医薬組成物 |
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GB2075837B (en) * | 1980-05-14 | 1984-03-14 | Hisamitsu Pharmaceutical Co | Topical pharmaceutical gel containing anti-inflammatory analgesic agents |
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JPS60155111A (ja) * | 1983-10-20 | 1985-08-15 | Hisamitsu Pharmaceut Co Inc | 安定なケトプロフェン含有外用経皮製剤 |
JPH0662401B2 (ja) | 1985-04-25 | 1994-08-17 | 久光製薬株式会社 | ケトプロフエン含有パツプ剤 |
JP2623580B2 (ja) * | 1987-07-20 | 1997-06-25 | 日産化学工業株式会社 | 消炎鎮痛クリーム剤 |
US5478567A (en) | 1991-08-30 | 1995-12-26 | Hisamitsu Pharmaceutical Co., Inc. | Antiphlogistic analgesic plaster |
JP3670211B2 (ja) * | 2000-12-25 | 2005-07-13 | ポーラ化成工業株式会社 | 粉体を含有するローション製剤 |
TW200418487A (en) | 2002-09-17 | 2004-10-01 | Nippon Boehringer Ingelheim Co | Pharmaceutical composition for topical delivery of meloxicam comprising an amine or amine as penetration enhancer. |
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KR20060004399A (ko) * | 2004-07-09 | 2006-01-12 | 에스케이케미칼주식회사 | 자기발열체를 이용한 케토프로펜의 경피투여 시스템 |
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JP4879928B2 (ja) | 2008-03-25 | 2012-02-22 | 帝國製薬株式会社 | ケトプロフェンリジン塩を含有する水性貼付剤 |
-
2010
- 2010-03-12 JP JP2010056098A patent/JP5622410B2/ja not_active Expired - Fee Related
-
2011
- 2011-03-11 US US13/583,940 patent/US9271944B2/en active Active
- 2011-03-11 EP EP11753467.7A patent/EP2545912B1/en active Active
- 2011-03-11 WO PCT/JP2011/055728 patent/WO2011111809A1/ja active Application Filing
- 2011-03-11 CA CA2791498A patent/CA2791498C/en active Active
- 2011-03-11 CN CN2011800130279A patent/CN102858332A/zh active Pending
- 2011-03-11 AU AU2011225100A patent/AU2011225100B2/en active Active
- 2011-03-11 ES ES11753467.7T patent/ES2523126T3/es active Active
- 2011-03-11 CN CN201610867783.2A patent/CN106913560A/zh active Pending
- 2011-03-11 TW TW100108261A patent/TWI498131B/zh active
- 2011-03-11 KR KR1020127025946A patent/KR101819249B1/ko active IP Right Grant
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2013
- 2013-04-22 HK HK13104827.6A patent/HK1177690A1/zh not_active IP Right Cessation
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2016
- 2016-01-21 US US15/003,398 patent/US20160136277A1/en not_active Abandoned
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JP2002193793A (ja) * | 2000-12-26 | 2002-07-10 | Teikoku Seiyaku Co Ltd | 非ステロイド系消炎鎮痛貼付剤 |
JP2004131495A (ja) * | 2002-09-17 | 2004-04-30 | Nippon Boehringer Ingelheim Co Ltd | 非ステロイド系抗炎症剤の局所送達用医薬組成物 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109843282A (zh) * | 2016-10-12 | 2019-06-04 | 帝国制药株式会社 | 水性贴剂 |
CN113423394A (zh) * | 2019-02-14 | 2021-09-21 | 久光制药株式会社 | 泥罨剂 |
US11903915B2 (en) | 2019-02-14 | 2024-02-20 | Hisamitsu Pharmaceutical Co., Inc. | Poultice |
Also Published As
Publication number | Publication date |
---|---|
CA2791498C (en) | 2017-04-18 |
AU2011225100B2 (en) | 2013-08-15 |
JP2011190194A (ja) | 2011-09-29 |
KR101819249B1 (ko) | 2018-01-16 |
AU2011225100A1 (en) | 2012-10-04 |
CN106913560A (zh) | 2017-07-04 |
HK1177690A1 (zh) | 2013-08-30 |
EP2545912A4 (en) | 2013-10-16 |
US20160136277A1 (en) | 2016-05-19 |
EP2545912B1 (en) | 2014-09-03 |
TWI498131B (zh) | 2015-09-01 |
TW201138864A (en) | 2011-11-16 |
ES2523126T3 (es) | 2014-11-21 |
EP2545912A1 (en) | 2013-01-16 |
JP5622410B2 (ja) | 2014-11-12 |
US20130005817A1 (en) | 2013-01-03 |
US9271944B2 (en) | 2016-03-01 |
KR20130059322A (ko) | 2013-06-05 |
WO2011111809A1 (ja) | 2011-09-15 |
CA2791498A1 (en) | 2011-09-15 |
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