CN102470178B - 托伐普坦固体分散体及其制备方法 - Google Patents
托伐普坦固体分散体及其制备方法 Download PDFInfo
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- CN102470178B CN102470178B CN2011800032986A CN201180003298A CN102470178B CN 102470178 B CN102470178 B CN 102470178B CN 2011800032986 A CN2011800032986 A CN 2011800032986A CN 201180003298 A CN201180003298 A CN 201180003298A CN 102470178 B CN102470178 B CN 102470178B
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- solid dispersion
- organic solvent
- crospolyvinylpyrrolidone
- water
- tolvaptan
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Abstract
一种托伐普坦固体分散体及其制备方法,所述固体分散体包含托伐普坦和交联聚乙烯吡咯烷酮,重量比为1∶0.05-20,优选为1∶0.1-10,更优选2∶1。该固体分散体还可含有水溶性聚合物,例如聚乙烯吡咯烷酮、羟丙基纤维素、羟乙基纤维素或甲基纤维素,其中托伐普坦∶交联聚乙烯吡咯烷酮∶水溶性聚合物的重量比优选为2∶1∶0.1。该固体分散体具有好的热力学稳定性和溶解性,其制成的药物组合物具有提高的释放速率和生物利用度。
Description
技术领域
本发明属化学制药领域,具体涉及一种包含交联聚乙烯吡咯烷酮的托伐普坦固体分散体。
背景技术
托伐普坦(tolvaptan)血管加压素受体拮抗剂,化学名称为7-氯-5-羟基-1-[2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基]-2,3,4,5-四氢吡喃-1H-苯并氮杂卓,结构式如下:
美国食品药品管理局批准日本大冢制药公司生产的托伐普坦(tolvaptan,血管加压素V2受体拮抗剂)的新药上市申请,在心衰模型中,托伐普坦只表现出排水利尿作用,显著降低心脏前负荷,而对后负荷和肾功能无影响。许多治疗心衰和低钠血症的临床试验,证明托伐普坦在容量负荷过度的心衰患者,能有效减少液体潴留,并纠正低钠。托伐普坦能有效缓解心功能衰竭患者的肺充血症状和体征,还能减轻体重,保护肾功能,没有严重的不良反应。已经证实托伐普坦相关化合物对治疗以下疾病是有用的:高容或等容性低钠血症伴心力衰竭、肝硬化、抗利尿激素分泌异常综合症。
托伐普坦为白色晶体或结晶粉末,在水中几乎不溶,因而,当水不溶性的托伐普坦经口给药时,它的生物利用度不可避免地是低的。
为了克服此问题,日本专利公布号JP11021241A公开了一种托伐普坦固体制剂组合物的制备方法,该方法包括以下步骤:将托伐普坦和羟丙基纤维素按照一定比例溶解于有机溶媒中,依照喷雾干燥方法将有机溶剂除去以获得托伐普坦固体分散体组合物,并添加其他药用辅料制成固体制剂。
发明内容
本发明人出乎意料的发现,通过将托伐普坦与包含交联聚乙烯吡咯烷酮(即交联聚维酮)的载体所制备的托伐普坦固体分散体,表现出了比现有技术包含羟丙基纤维素的托伐普坦制剂更高的活性成分的溶解性和稳定性;也更加方便制备成普通固体制剂,进一步研究还发现在交联聚乙烯吡咯烷酮的基础上添加其它水溶性聚合物可以使药物的溶出效率进一步提高。
本发明的一个目的是提供一种比常规托伐普坦制剂表现更高水溶性和生物利用度的托伐普坦固体分散体,以及其制备方法。
本发明的另一个目的是提供一种经口给药的,包含托伐普坦固体分散体的药物组合物。
根据本发明的一个方面,提供了一种包含有非晶型的活性成分托伐普坦或其盐、交联聚乙烯吡咯烷酮的固体分散体。较好的实施方式是使活性成分托伐普坦或其盐与交联聚乙烯吡咯烷酮的重量比控制在1∶0.05-20;优选重量比为1∶0.1-10,优选是2∶1。
本发明的固体分散体可以只由活性成分和交联聚乙烯吡咯烷酮组成。进一步的,本发明的固体分散体也可进一步加入水溶性聚合物。本发明通过加入一种或多种的水溶性聚合物,以进一步改善固体分散体物理性质。该水溶性聚合物为固体分散体中常用的水溶性聚合物,可以选自但不限于下述聚合物:
烷基纤维素,例如甲基纤维素;
羟烷基纤维素,例如羟甲基纤维素、羟乙基纤维素、羟丙基纤维素和羟丁基纤维素;
羟烷基烷基纤维素,例如羟乙基甲基纤维素和羟丙基甲基纤维素;
羧烷基纤维素,例如羧甲基纤维素;
羧烷基纤维素的碱金属,例如羧甲基纤维素钠;
羧烷基烷基纤维素,例如羧甲基乙基纤维素;
羧烷基纤维素酯;
果胶,例如羧甲基支链淀粉钠;
甲壳质衍生物,例如脱乙酞壳多糖;
多糖,例如藻酸、它的碱金属和铵盐、角叉菜胶(caragenan)、半乳甘露聚糖、黄蓄胶、琼脂、阿拉伯树胶、瓜耳胶和黄原酸胶;
聚甲基丙烯酸及其盐;
聚甲基丙烯酸及其盐、甲基丙烯酸酯共聚物、氨烷基甲基丙烯酸酯共聚物;
聚乙烯醇缩乙醛和二乙基氨基醋酸酯;
糖型表面活性剂,例如蔗糖二硬脂酸酯、蔗糖单/二硬脂酸酯和蔗糖单棕搁酸酯;
聚乙烯醇;
聚乙烯吡咯烷酮和聚乙烯吡咯烷酮-醋酸乙烯酯共聚物;
聚环氧烷,例如聚环氧乙烷和聚环氧丙烷;
或环氧乙烷-环氧丙烷共聚物。
在以上提及的水溶性聚合物中,烷基纤维素、羟烷基纤维素、羧烷基烷基纤维素或它们的碱金属盐、聚乙烯吡咯烷酮是优选的,并且羟丙基甲基纤维素、聚乙烯吡咯烷酮是更优选的。其中较好的实施方式是将水溶性聚合物与交联聚乙烯吡咯烷酮的重量比在1∶5-20,优选1∶8-15,最优选1∶10。
通过研究发现,由于水溶性聚合物能进一步改善固体分散体的性质,因此其中进一步加入的水溶性聚合物的量没有特殊限定,本领域技术人员可以根据生产实际进行选择得到,实际研究中发现水溶性聚合物相对于交联聚乙烯吡咯烷酮的用量达到1∶5-20时表现出的提高效果具有数据上的统计意义,优选1∶8-15,最优选1∶10。
另外,在本发明的实施例中描述的组合物可以被参考为对本发明效果的优选例证。本发明比较好的固体分散体实施方式是含有以下成分和比例的固体分散体:
其中所述水溶性聚合物为聚乙烯吡咯烷酮、羟丙基纤维素、羟乙基纤维素或甲基纤维素,效果最好的是聚乙烯吡咯烷酮或羟丙基纤维素的实施方式。
对于含有水溶性聚合物的技术方案而言,固体分散体可不再含有其他成分,即仅有活性成分、交联聚乙烯吡咯烷酮和水溶性聚合物组成。
在本发明的非晶形的托伐普坦固体分散体的制备中,可单独采用交联聚乙烯吡咯烷酮,或水溶性聚合物与交联聚乙烯吡咯烷酮的组合作为载体。具体操作时,可按照以下步骤进行操作:
(1)将托伐普坦或其盐溶解在有机溶剂中;
(2)对于不含水溶性聚合物的固体分散体来说,将交联聚乙烯吡咯烷酮溶解或分散在有机溶剂中;
对于含水溶性聚合物的固体分散体来说,可直接将交联聚乙烯吡咯烷酮和水溶性聚合物同时溶解或分散在有机溶剂中形成一个溶液,也可分别将交联聚乙烯吡咯烷酮和水溶性聚合物溶解或分散在两种有机溶剂中形成两种溶液,根据药物或固体分散体载体的溶解或分散的需要,有机溶剂中可含有水;
(3)将上述药物和固体分散体载体的几种溶液混合,除去有机溶剂,得到固体分散体混合物。
将有机溶剂除去得到固体分散体的方法可根据本领域的常规操作方法操作,例如蒸发法、喷雾干燥法或流化床干燥法,对于本发明而言优选使用喷雾干燥法。
本发明中将药物或固体分散体载体溶解的有机溶剂可以使用可溶解上述物质或比较容易分散的溶剂,选自甲醇、乙醇、异丙醇等低级醇类;丙酮、丁酮等酮类;二氯甲烷、二氯乙烷、三氯甲烷、四氯化碳等卤化碳氢类及它们的混合溶媒等。同时,根据需要也可加水。例如甲醇、乙醇、异丙醇、丙酮、丁酮、二氯甲烷、二氯乙烷、三氯甲烷或四氯化碳。在这些有机溶媒中,低级醇类和卤化碳氢类的混合溶媒,从溶解性及蒸馏除去等方面来说比较理想,具体包括甲醇或乙醇和二氯甲烷的混合液。在具体实施时比较好的实施方式是:使用乙醇与二氯甲烷的混合物溶解托伐普坦或其盐;使用乙醇与二氯甲烷的混合物或乙醇溶解交联聚乙烯吡咯烷酮和水溶性聚合物。
本发明的非晶形的托伐普坦固体分散体粒径范围为0.01-400μm,优选0.1-300μm,更优选1-200μm。
本发明的非晶形的托伐普坦固体分散体没有在它的DSC扫描中显示任何的吸热峰,也没有在它的粉末X-射线衍射谱中显示结晶折射峰,表明本发明分散体中所包含的托伐普坦是稳定的非晶形式。
另外,本发明提供了一种包含与药用载体、赋形剂和添加剂一起的固体分散体,用于经口给药的药物组合物。该药物组合物可以根据任何的常规方法而以散剂、颗粒、片剂、软或硬胶囊、丸剂或包衣制剂的形式来配制。例如,可以将以粉末或粒状形式的固体分散体与润滑剂或其它的药物添加剂一起填充进入到硬胶囊中,或者与压片用药物添加剂一起制成片剂形式,然后任选地根据任何的常规方法包衣,以获得包衣制剂。
本发明制剂可以以单独剂量或分开剂量经口给药。
在本发明中,在制备包含固体分散体的经口给药的组合物的过程中,可以任选地加入一种或更多种的药用赋形剂,以改善固体分散体的流动性和其它的物理性质。该药用赋形剂可以选乳糖、淀粉、羟基乙酸淀粉钠、聚乙烯聚吡咯烷酮、交联羧甲纤维素钠、麦芽糖糊精、微晶纤维素、磷酸钙、碳酸氢钙和微晶纤维素组成的组合。此外,在本发明中可以采用润滑剂,例如硬脂酸、硬脂酸镁和滑石粉。
附图说明
结合以下附图,本发明的以上和其他的目的和特征将会变得显而易见,该附图分别表示:
图1:实施例1粉末X-射线衍射的谱图;
图2:实施例1-10、比较例1-2的体外释放曲线;
图3:原料药、实施例4、比较例2的体内生物利用度曲线。
具体实施方式
给出以下实施例,但并不以任何方式限制本发明的范围。
实施例1
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将10g交联聚乙烯聚吡咯烷酮加入乙醇中,分散均匀,然后将托伐普坦溶液和交联聚维酮分散液混合,进行喷雾干燥得托伐普坦固体分散体,其粒径分布在1μm~400μm,平均粒径为52μm。
实施例2
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将2g交联聚乙烯聚吡咯烷酮加入乙醇中,分散均匀,然后将托伐普坦溶液和交联聚维酮分散液混合,进行喷雾干燥得托伐普坦固体分散体,其粒径分布在1μm~400μm,平均粒径为52μm。
实施例3
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将200g交联聚维酮加入乙醇中,分散均匀,然后将托伐普坦溶液和交联聚维酮分散液混合,进行喷雾干燥得托伐普坦固体分散体,其粒径分布在1μm~400μm,平均粒径为52μm。
实施例4
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将1g聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将10g交联聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的混合物中并且均匀分散,然后将托伐普坦溶液和其他添加剂分散液混合,进行喷雾干燥,得托伐普坦固体分散体,其粒径分布1μm~100μm,平均粒径25μm。
实施例5
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将1g羟丙基甲基纤维素加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将10g交联聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的混合物中并且均匀分散,然后将托伐普坦溶液和其他添加剂分散液混合,进行喷雾干燥,得托伐普坦固体分散体,其粒径分布1μm~100μm,平均粒径25μm。
实施例6
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将1g羟乙基纤维素加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将10g交联聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的混合物中并且均匀分散,然后将托伐普坦溶液和其他添加剂分散液混合,进行喷雾干燥,得托伐普坦固体分散体,其粒径分布1μm~100μm,平均粒径25μm。
实施例7
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将1g羧甲基纤维素钠加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将10g交联聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的混合物中并且均匀分散,然后将托伐普坦溶液和其他添加剂分散液混合,进行喷雾干燥,得托伐普坦固体分散体,其粒径分布1μm~100μm,平均粒径25μm。
实施例8
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将1g甲基纤维素加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将10g交联聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的混合物中并且均匀分散,然后将托伐普坦溶液和其他添加剂分散液混合,进行喷雾干燥,得托伐普坦固体分散体,其粒径分布1μm~100μm,平均粒径25μm。
实施例9
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将2g蔗糖酯加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将10g交联聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的混合物中并且均匀分散,然后将托伐普坦溶液和其他添加剂分散液混合,进行喷雾干燥,得托伐普坦固体分散体,其粒径分布1μm~100μm,平均粒径25μm。
实施例10
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将0.5g聚乙烯醇加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,将10g交联聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的混合物中并且均匀分散,然后将托伐普坦溶液和其他添加剂分散液混合,进行喷雾干燥,得托伐普坦固体分散体,其粒径分布1μm~100μm,平均粒径25μm。
比较例1
将10g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,直接进行喷雾干燥,得托伐普坦无定型粉末,其粒径分布0.01μm~200μm,平均粒径28μm。
比较例2
将20g托伐普坦加入到二氯甲烷和乙醇的混合物中,并且搅拌直至该溶液变为澄清,然后,往里加入10g的羟丙基纤维素并且均匀分散,并且进行喷雾干燥得托伐普坦固体分散体,其粒径分布1~400μm,平均粒径56μm。
溶出试验
将实施例1~10、比较例、对照样品(结晶原料粒径分布为1~400μm,平均粒径83μm)的各粉末,分别称取适量(相当于托伐普坦100mg),加入溶出仪中,0.2%(W/V)十二烷基硫酸钠水溶液900ml为溶剂,桨板法,转速:100转/分钟,进行溶出试验。分别于5分钟、10分钟、15分钟、20分钟、30分钟、45分钟取样作为供试溶液,测定,计算溶出度。
溶出度(%)的计算方式为,将一定量托伐普坦溶解于甲醇后,移取5ml至100ml量瓶中,以0.2%(W/V)十二烷基硫酸钠水溶液稀释制成浓度为20μg/ml的溶液作为标准溶液,在波长269mm和330mm波长处测定标准溶液和供试溶液中的吸光度。通过得到的吸光度差的比得到溶出率。结果如下表1所示:
表1
根据上述实验结果可以看出:
(1)使用交联聚乙烯吡咯烷酮作为托伐普坦固体分散体的载体可以显著提高药物的释放特性,对于现有技术中使用羟丙基纤维素作为固体分散体载体来说,效果提高显著。药物和交联聚乙烯吡咯烷酮之间的比例可以在很大范围内进行选择,在1∶0.1-10的范围内都具有较好的释放特性,在约1∶0.5时效果最好。
(2)在以交联聚乙烯吡咯烷酮作为托伐普坦固体分散体的载体的基础上,可以添加其他水溶性聚合物与交联聚乙烯吡咯烷酮同时作为固体分散体载体。经过比较发现,由于水溶性聚合物能进一步改善固体分散体的性质,因此其中进一步加入的水溶性聚合物的量没有特殊限定,水溶性聚合物相对于交联聚乙烯吡咯烷酮的用量达到1∶5-20时表现出的提高效果具有数据上的统计意义,1∶10效果最好。这些水溶性聚合物中,效果最好的是羟丙基纤维素和聚乙烯吡咯烷酮,羟乙基纤维素和甲基纤维素次之。
实施例11
将固体分散体原料过40目筛、辅料过80目筛后,按处方量称取原辅料,混合均匀,用5%羟丙纤维素溶液适量制粒,于50℃左右通风干燥,干颗粒用20目筛整粒,外加交联聚维酮、硬脂酸镁混合均匀,填装胶囊。
实施例12
将固体分散体原料过40目筛、辅料过80目筛后,按处方量称取原辅料,混合均匀,用5%羟丙纤维素溶液适量制粒,于50℃左右通风干燥,干颗粒用20目筛整粒,外加交联羧甲基纤维素、硬脂酸镁混合均匀,压片,包衣即得。
实施例13
将固体分散体原料过40目筛、辅料过80目筛后,按处方量称取原辅料,混合均匀,用5%聚维酮溶液适量制粒,于50℃左右通风干燥,干颗粒用20目筛整粒,外加低取代羟丙纤维素、硬脂酸镁混合均匀,压片,即得。
Claims (23)
1.一种固体分散体,其特征在于:包含有非晶型的活性成分托伐普坦或其盐和交联聚乙烯吡咯烷酮,其中所述活性成分与交联聚乙烯吡咯烷酮的重量比为1:0.1-10。
2.根据权利要求1所述的固体分散体,其中所述活性成分与交联聚乙烯吡咯烷酮的重量比为2:1。
3.根据权利要求1或2所述的固体分散体,其中所述固体分散体由活性成分与交联聚乙烯吡咯烷酮组成。
4.根据权利要求1或2任意一项所述的固体分散体,其中所述固体分散体中还含有水溶性聚合物。
5.根据权利要求4所述的固体分散体,其中所述固体分散体由活性成分与交联聚乙烯吡咯烷酮和水溶性聚合物组成。
6.根据权利要求4所述的固体分散体,其中所述水溶性聚合物选自一种或多种:烷基纤维素、羟烷基纤维素或它们的碱金属盐、羟烷基烷基纤维素、羧烷基纤维素、羧烷基烷基纤维素、羧烷基纤维素酯、淀粉、果胶、蔗糖酯、聚乙烯吡咯烷酮。
7.根据权利要求4所述的固体分散体,其中所述水溶性聚合物选自一种或多种:羟丙基纤维素或聚乙烯吡咯烷酮。
8.根据权利要求5-7任意一项所述的固体分散体,其中所述水溶性聚合物与交联聚乙烯吡咯烷酮的重量比在1:5-20。
9.根据权利要求8所述的固体分散体,其中所述水溶性聚合物与交联聚乙烯吡咯烷酮的重量为1:8-15。
10.根据树种要求8所述的固体分散体,其中所述水溶性聚合物与交联聚乙烯吡咯烷酮的重量为1:10。
11.根据权利要求4所述的固体分散体,该固体分散体含有的托伐普坦:交联聚乙烯吡咯烷酮:水溶性聚合物的重量比为2:1:0.1,其中所述水溶性聚合物为聚乙烯吡咯烷酮、羟丙基纤维素、羟乙基纤维素或甲基纤维素。
12.根据权利要求11所述的固体分散体,该固体分散体由托伐普坦、交联聚乙烯吡咯烷酮和水溶性聚合物组成。
13.一种制备如权利要求1-3任意一项所述固体分散体的方法,其特征在于包括以下步骤:
1)将托伐普坦或其盐溶解在有机溶剂中;
2)将交联聚乙烯吡咯烷酮溶解或分散在有机溶剂中,根据溶解或分散的需要,所述有机溶剂中任选含有水;
3)将上述几种溶液混合,除去有机溶剂,得到固体分散体混合物。
14.一种制备如权利要求4-12任意一项所述固体分散体的方法,其特征在于包括以下步骤:
1)将托伐普坦或其盐溶解在有机溶剂中;
2)将交联聚乙烯吡咯烷酮和水溶性聚合物溶解或分散在有机溶剂中,或将交联聚乙烯吡咯烷酮和水溶性聚合物分别溶解或分散在有机溶剂中,根据溶解或分散的需要,所述有机溶剂中任选含有水;
3)将上述几种溶液混合,除去有机溶剂,得到固体分散体混合物。
15.根据权利要求13所述的方法,其中所述除去有机溶剂的方法选自蒸发法、喷雾干燥法或流化床干燥法。
16.根据权利要求13所述的方法,其中所述除去有机溶剂的方法为喷雾干燥法。
17.根据权利要求13所述的方法,其中步骤1)或2)中所述的有机溶剂选自甲醇、乙醇、异丙醇、丙酮、丁酮、二氯甲烷、二氯乙烷、三氯甲烷或四氯化碳。
18.根据权利要求17所述的方法,其中步骤1)中所述的有机溶剂是乙醇与二氯甲烷的混合物;和/或步骤2)中所述的有机溶剂是乙醇与二氯甲烷的混合物或乙醇。
19.根据权利要求14所述的方法,其中所述除去有机溶剂的方法选自蒸发法、喷雾干燥法或流化床干燥法。
20.根据权利要求14所述的方法,其中所述除去有机溶剂的方法为喷雾干燥法。
21.根据权利要求14所述的方法,其中步骤1)或2)中所述的有机溶剂选自甲醇、乙醇、异丙醇、丙酮、丁酮、二氯甲烷、二氯乙烷、三氯甲烷或四氯化碳。
22.根据权利要求21所述的方法,其中步骤1)中所述的有机溶剂是乙醇与二氯甲烷的混合物;和/或步骤2)中所述的有机溶剂是乙醇与二氯甲烷的混合物或乙醇。
23.一种包含根据权利要求1-12任意一项所述的固体分散体的药物组合物。
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CA2702904A1 (en) * | 2007-10-19 | 2009-04-23 | Otsuka Pharmaceutical Co., Ltd. | Matrix-type pharmaceutical solid preparation |
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2010
- 2010-06-25 CN CN2010102248840A patent/CN102293734A/zh active Pending
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2011
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- 2011-06-02 EP EP11797572.2A patent/EP2586464B1/en not_active Not-in-force
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- 2011-06-02 US US13/806,173 patent/US9408915B2/en not_active Expired - Fee Related
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CN101686941A (zh) * | 2007-06-21 | 2010-03-31 | 大塚制药株式会社 | 包含苯并氮杂的药物固体制剂及其生产方法 |
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HK1166005A1 (en) | 2012-10-19 |
EP2586464A1 (en) | 2013-05-01 |
RU2579745C2 (ru) | 2016-04-10 |
MX2012014251A (es) | 2013-01-18 |
CN102470178A (zh) | 2012-05-23 |
JP2013530189A (ja) | 2013-07-25 |
WO2011160541A1 (zh) | 2011-12-29 |
US9408915B2 (en) | 2016-08-09 |
EP2586464A4 (en) | 2014-11-26 |
CA2801098A1 (en) | 2011-12-29 |
JP5991968B2 (ja) | 2016-09-14 |
EP2586464B1 (en) | 2018-07-25 |
CN102293734A (zh) | 2011-12-28 |
KR20130094281A (ko) | 2013-08-23 |
AU2011269506A1 (en) | 2013-01-10 |
US20130102588A1 (en) | 2013-04-25 |
RU2012157685A (ru) | 2014-07-27 |
AU2011269506B2 (en) | 2015-04-09 |
BR112012031882A2 (pt) | 2016-11-08 |
KR101815722B1 (ko) | 2018-01-30 |
CA2801098C (en) | 2018-10-30 |
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