CN107073080A - 包含α‑型干扰素的稳定的不含苄醇的水溶液制剂 - Google Patents
包含α‑型干扰素的稳定的不含苄醇的水溶液制剂 Download PDFInfo
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- CN107073080A CN107073080A CN201580050780.3A CN201580050780A CN107073080A CN 107073080 A CN107073080 A CN 107073080A CN 201580050780 A CN201580050780 A CN 201580050780A CN 107073080 A CN107073080 A CN 107073080A
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Abstract
本发明提供了稳定的、等渗的水溶液制剂,其包含:(i)0.1‑0.5mg/mLα‑型干扰素,优选聚乙二醇化α‑型干扰素;(ii)维持pH为6.0±0.5的20mM乙酸盐缓冲剂系统;(iii)5‑20mM的L‑甲硫氨酸;(iv)120‑150mM的氯化钠;(v)有效稳定α‑型干扰素、优选聚乙二醇化α‑型干扰素以防止其活性损失的0.01‑0.07%重量的表面活性剂;和(vi)足以制备上述列出的成分的溶液的量的注射用水。
Description
公开了稳定的、不含苄醇的水溶液制剂,其包含α-型干扰素、优选聚乙二醇化α-型干扰素;维持pH为6.0±0.5的缓冲剂;作为表面活性剂的聚山梨酯20或泊洛沙姆188;作为稳定剂的L-甲硫氨酸;和张度剂,并且该水溶液制剂将聚乙二醇化α-型干扰素的高化学和物理学稳定性维持延长的储存时间期限(至少在2-8℃的目标储存温度18个月或在25℃的升高温度6个月)。
发明背景
本发明涉及稳定的水溶液制剂,其将干扰素α、优选聚乙二醇化干扰素α的高生物学活性以及高化学和高物理学稳定性维持延长的时间期限,即在作为商品生物药物产品通常所需的预期的储存温度(2-8℃)至少18个月,优选24个月或以上。物理学稳定性通过控制可溶性(寡聚化形式和更高可溶性聚集物,如例如通过尺寸排阻色谱法显示)和不溶性(可见和/或次可见颗粒)聚集种类形成、通过控制视觉外观如浊度和脱色以及活性成分的恒定总浓度(例如通过反相HPLC显示)来证实。通过控制典型地通过碎片化发生的活性成分降解(例如通过反相HPLC显示)、氧化(特别是甲硫氨酸侧链)、天冬酰胺残基的脱酰胺作用、天冬氨酸残基的异构化(后面三种情形例如通过肽作图、使用受控的限制性蛋白质水解后肽的质谱分析显示)来证实化学稳定性。
干扰素溶液的制备涉及因活性成分对物理学和化学影响的敏感性导致的许多问题。如同另外的蛋白质,水溶液中的干扰素易经历化学降解机制例如蛋白质水解、氧化、二硫化物交换、寡聚化、脱酰胺作用和β-消除,以及物理机制例如聚集、沉淀和吸附。因此,干扰素溶液包含添加物,其存在是为了抵抗这些效应。
美国专利No.4,496,537公开了生物学稳定的干扰素α水溶液制剂,其包含干扰素α、人血清白蛋白和丙氨酸或甘氨酸、水和维持pH在6.5-8.0的缓冲剂系统。人血清白蛋白(“HSA”)用作干扰素α的稳定剂并且通过将干扰素α涂布和/或吸附在混合容器、加工设备和储存容器的不锈钢和玻璃表面上防止干扰素α从溶液中损失。包含干扰素α和HSA的溶液制剂在将这类溶液储存在2-8℃延长期限即2年以上时,维持干扰素α的化学和生物学稳定性。然而,鉴于潜在的病毒污染和形成共价聚集物(通过二硫化物形成/二硫化物借助于其游离硫羟基移动),由此可能导致免疫原性,潜在地导致功效损失甚至过敏反应,所以HSA存在问题。
随后,已经提出了避免使用HSA和包含另外的助剂、特别是非离子洗涤剂的干扰素α溶液(参见,例如WO 89/04177)。由于干扰素α具有高度活性并且以最低浓度存在于药物制剂中,所以干扰素制剂的稳定性和确保活性成分的恒定浓度是特别重要的。已经发现,为了确保最佳应用特性,干扰素溶液的赋形剂必须从大量潜在适合的试剂中谨慎地选择并且彼此协调。例如,玻璃表面上干扰素-α2a的吸附在pH 5-6具有最大值,使得该pH在原则上似乎是不利的。另一方面,共价降解反应通过在该pH的最小值来进行。商品HSA-稳定的溶液具有pH 7。干扰素溶液的应用特性以不可预测的方式受到众多不相关因素影响。
美国专利No.5,762,923公开了不含HSA的干扰素-α水溶液制剂,其包含干扰素α、非离子洗涤剂、用于调整pH 4.5-6.0的缓冲剂、苄醇和任选的等渗剂,该制剂表现出最佳应用特性,即储存稳定性和声称量的活性成分的生物利用度。更具体地,美国专利No.5,762,923公开了干扰素水溶液制剂,其包含式(I)的聚乙二醇化干扰素α-2a、
10mg/mL量的苄醇、作为缓冲剂调整至最终pH 6.0的乙酸钠/乙酸、作为张度剂的氯化钠和作为表面活性剂的聚山梨酯80。从美国专利No.5,762,923中所示的数据中显而易见的是实现了溶液的可接受的储存稳定性,条件是通过添加苄醇制备该溶液。
然而,在大量药物和生物技术应用中,如用于制备(聚乙二醇化)α-型干扰素的制备方法中,转移流体的过程中维持流体完整性(即定性和定量组成以及总体积)是非常重要的。流体或其组分的一种或几种例如通过迁移至管壁的损耗可以导致终产物结果中的不一致性。已知苄醇被多种管材料吸附并且特别是被硅橡胶制成的管吸附,而这些材料广泛应用于许多制药加工设施中。
因此,从制备工艺角度来看,期望避免使用苄醇。然而,不含苄醇的α-型干扰素、优选聚乙二醇化α-型干扰素制剂仍然应当提供至少相同的储存稳定性。因此,需要重新配制现存的α-型干扰素,优选聚乙二醇化α-型干扰素溶液产品,得到不含苄醇、同时将水溶液制剂中高化学、高物理学稳定性和高干扰素α、优选聚乙二醇化干扰素α活性维持延长储存期限的溶液制剂。
发明概述
本发明基于如下令人惊奇的发现:可以通过用L-甲硫氨酸取代避免预先用作α-型干扰素、优选聚乙二醇化α-型干扰素制剂中的稳定剂的苄醇,从而提供还包含聚山梨酯20或泊洛沙姆188作为表面活性剂的制剂。例如,仅用L-甲硫氨酸替换商品制剂(40kDa支链聚乙二醇化干扰素α2a)中的苄醇将导致商品制剂提供的延长储存期限的水溶液制剂中化学、物理学稳定性和聚乙二醇化干扰素α活性更低。然而,L-甲硫氨酸与聚山梨酯20或泊洛沙姆188的组合将导致形成相差无几的稳定性。
不预期受到任何理论约束,本发明制剂中的表面活性剂似乎是更稳定的,因为PS20比PS80倾向于降解更少,这可能导致得到的制剂的氧化性应激减少。由于L-甲硫氨酸不会形成过氧化物(与苄醇相反),所以本发明的制剂可以不储存在惰性气体(例如氮气)罩中,并且由此具有改善的储存稳定性。此外,药物产品的制备方法得到简化,因为L-甲硫氨酸(与苄醇相反)不易于被典型地用于制备方法中的塑料或合成橡胶(如,例如硅橡胶管道、PTFE管道、塑料接管)吸收或吸附其上,并且完全不会蒸发。因此,管线阻塞的关键性下降并且管线阻塞后应当被清除的药物产品部件的冲洗体积或数量得以减少。本发明的制剂还为药物产品组合物提供了更好的稳定性,因为L-甲硫氨酸不会蒸发或透过合成橡胶容器盖(如,例如橡胶塞)并且也不会被它们吸附或吸附其上。
本发明提供了稳定的、等渗水溶液制剂,其维持高生物学α-型干扰素活性并且不含苄醇,该制剂包含:
(i)0.1-0.5mg/mL,优选0.18、0.27或0.36mg/mL的α-型干扰素,优选聚乙二醇化α-型干扰素;
(ii)维持pH为6.0±0.5的20mM的乙酸盐、优选乙酸钠缓冲剂系统;
(iii)5-20mM,优选10mM的L-甲硫氨酸;
(iv)120-150mM,优选130-140mM或137mM的氯化钠;
(v)有效稳定α-型干扰素,优选聚乙二醇化α-型干扰素以防止其活性损失的0.01-0.07,优选0.02%重量的表面活性剂;和
(vi)足以制备上述列出的成分的溶液的量的注射用水。
在本发明的一个可选的实施方案中,所述表面活性剂是聚山梨酯20或泊洛沙姆188。在一个实施方案中,所述表面活性剂是聚山梨酯20。
在本发明的进一步的实施方案中,所述聚乙二醇化α-型干扰素是式(I)的生理学活性聚乙二醇化α-型干扰素结合物
其中R和R’是甲基,X是NH,n和n’的平均总和为850至1000,并且聚乙二醇单元的分子量为约40kDa。
在另一个实施方案中,上述聚乙二醇化α-型干扰素是α-2a干扰素。
本发明进一步提供了稳定的水溶液制剂,其包含:
(i)式(I)的聚乙二醇化α-型干扰素 0.18mg/mL
其中R和R’是甲基,X是NH,n和n’的平均总和为850至1000,聚乙二醇单元的分子量为约40kDa,并且IFNα是IFNα-2a
本发明还提供了稳定的水溶液制剂,其包含:
(i)式(I)的聚乙二醇化α-型干扰素 0.18mg/mL
其中R和R’是甲基,X是NH,n和n’的平均总和为850至1000,聚乙二醇单元的分子量为约40kDa,并且IFNα是IFNα-2a
本发明还提供了另一种稳定的水溶液制剂,其包含:
(i)式(I)的聚乙二醇化α-型干扰素 0.27mg/mL
其中R和R’是甲基,X是NH,n和n’的平均总和为850至1000,聚乙二醇单元的分子量为约40kDa,并且IFNα是IFNα-2a
本发明还提供了另一种稳定的水溶液制剂,其包含:
(i)式(I)的聚乙二醇化α-型干扰素 0.27mg/mL
其中R和R’是甲基,X是NH,n和n’的平均总和为850至1000,聚乙二醇单元的分子量为约40kDa,并且IFNα是IFNα-2a
本发明还提供了另一种稳定的水溶液制剂,其包含:
(i)式(I)的聚乙二醇化α-型干扰素 0.36mg/mL
其中R和R’是甲基,X是NH,n和n’的平均总和为850至1000,聚乙二醇单元的分子量为约40kDa,并且IFNα是IFNα-2a
本发明还提供了另一种稳定的水溶液制剂,其包含:
(i)式(I)的聚乙二醇化α-型干扰素 0.36mg/mL
其中R和R’是甲基,X是NH,n和n’的平均总和为850至1000,聚乙二醇单元的分子量为约40kDa,并且IFNα是IFNα-2a
详细描述
我们已经选择了特定量的特定组成分,使得我们研发了聚乙二醇化α-型干扰素水溶液制剂,其不含苄醇,而能够将聚乙二醇化α-型干扰素的高化学、生物学和物理学稳定性维持延长的时间期限。
本文在涉及本发明制剂时所用的术语“不含苄醇”或“无苄醇”是指在本发明的溶液制剂的制备过程中不使用苄醇。
适合于本发明制剂的缓冲剂系统是维持该水溶液制剂的pH在5.5至6.5、优选5.8至6.2并且最优选6.0的那些。乙酸钠/乙酸缓冲剂系统的应用是优选的。维持期望的5.5至6.5的pH范围的其它适合的缓冲剂系统包括柠檬酸钠/柠檬酸以及磷酸氢二钠和磷酸二氢钠。可用于本发明的张度剂是能够赋予本发明制剂与人体血清等渗的任意试剂。典型的适合的张度剂包括氯化钠、甘露醇、甘氨酸、葡萄糖和山梨醇。氯化钠作为张度剂的应用是优选的。
脱水山梨醇一-9-十八烯酸酯聚(氧基-1,2-乙二基)衍生物聚山梨酯20可用作防止聚乙二醇化α-型干扰素蛋白质例如40kDa支链聚乙二醇化α-2a干扰素吸附在用于制备包含聚乙二醇化α-型干扰素的指定制剂的设备的不锈钢和玻璃表面上的表面活性剂。对于包含0.1 0.5mg/mL聚乙二醇化α-型干扰素的制剂,聚山梨酯20的量范围为0.005-0.5%重量,优选0.02%重量。令人惊奇地,我们已经发现聚山梨酯20防止聚乙二醇化α-2a干扰素损耗并且能够全身递送聚乙二醇化α-2a干扰素,不会损失生物学活性。在研发本发明制剂的过程中,我们令人惊奇地发现,与其它脱水山梨醇一-9-十八烯酸酯聚(氧基-1,2-乙二基)衍生物表面活性剂,例如聚山梨酯80相比,聚山梨酯20在L-甲硫氨酸(替代苄醇)的存在下给聚乙二醇化α-2a干扰素提供了更优的化学和生物学稳定性。
当使用泊洛沙姆188以相同浓度替代聚山梨酯20时,实现了类似的化学和生物学稳定性。
可用于本发明制剂中的聚乙二醇化α-型干扰素的量范围为0.1至0.5mg/mL。本文所用的术语“聚乙二醇化α-型干扰素”是指一个或多个聚乙二醇(PEG)分子和一个或多个α-型干扰素分子的共价结合物。用于本发明制剂的优选的结合物具有1至4个PEG分子/干扰素分子,并且更优选地,所述结合物为单一PEG分子与单一干扰素分子之间。聚乙二醇化干扰素可以包含单一位置异构体或结合物位置异构体混合物,例如PEG分子共价连接至各干扰素分子上的不同氨基酸残基。例如,美国专利No.5,951,974描述了PEG-干扰素α结合物位置异构体的混合物的制备,其中异构体的一些是PEG与干扰素分子的组氨酸残基之间的结合物,所述混合物中的另外的异构体是PEG与干扰素赖氨酸残基之间的结合物,并且还有另外的异构体是PEG与干扰素分子的氨基末端之间的结合物。
所述结合物中的PEG分子可以具有不同的分子量。优选地,所述PEG分子具有40,000的平均分子量。在特别优选的实施方案中,使用支链PEG40000制备所述结合物,即这意味着所述结合物中的PEG分子具有约40,000的平均分子量。
用于本发明的聚乙二醇化α-型干扰素结合物的干扰素部分可以是本领域技术人员公知的任意的天然存在的或重组干扰素α。可以用于本发明制剂中的天然和重组α-干扰素包括干扰素α-n1(例如 )、干扰素α-n3、干扰素α-2a(A,Hoffmann-LaRoche,Inc.)、干扰素α-2b(A,Schering-PloughCorp.)、干扰素α-2c(Boehringer Ingelheim,Inc.)和复合干扰素(InterMune,Inc.)。优选的干扰素是干扰素α-2a和干扰素α-2b。最优选地,干扰素α-2a用于制备本发明制剂的活性成分。
PEG和干扰素分子的结合可以通过本领域技术人员公知的任意结合反应来进行,例如在美国专利No.5,612,460、5,711,944和5,951,974中所述。优选地,PEG分子借助于氨基甲酸乙酯键共价连接至干扰素分子。
用于本发明制剂的最优选的聚乙二醇化α-型干扰素是支链PEG40000-干扰素α-2a。
用于制备本发明制剂的水优选是注射用水。
在本发明水溶液制剂的研发过程中,该水溶液制剂可以在不使用苄醇作为稳定剂的情况下历经延长的储存期限维持聚乙二醇化α-型干扰素的高生物学活性以及高化学和物理学稳定性,我们鉴定,当将聚山梨酯20或泊洛沙姆188用作表面活性剂时,L-甲硫氨酸可以唯一地成功替代苄醇作为稳定剂。
聚乙二醇化α-型干扰素制剂可用于治疗多种疾病状态,例如肾细胞癌、AIDS-相关卡波西氏肉瘤、慢性和急性乙型肝炎、慢性和急性非甲非乙/丙型肝炎。本发明的制剂可用于治疗这些疾病状态,优选为可注射水溶液。
实施例
下列非限制性实施例示例聚乙二醇化α-型干扰素水溶液的制备。
制剂制备和组成
在商品Pegasys药物物质(1-2mg/mL Peg干扰素α-2a、20mM乙酸/乙酸钠pH 6.0、50mM氯化钠)中掺入不同的浓缩赋形剂储备溶液,并且同时稀释以便得到最终药物产品制剂,其包含0.27mg/mL Peg干扰素α-2a、20mM乙酸/乙酸钠pH 6.0、137mM NaCl、如下所示水平的L-甲硫氨酸、0.2mg/mL聚山梨酯20或泊洛沙姆188。作为对照,按照相同方法混合目前的Pegasys药物产品销售制剂(0.27mg/mL Peg干扰素α-2a、20mM乙酸/乙酸钠pH 6.0、137mMNaCl、10mg/mL苄醇、0.05mg/mL聚山梨酯80)。在通过搅拌谨慎匀化后,使用0.22μm亲水性PVDF过滤器无菌过滤全部最终的总体溶液。对于稳定性评价,将所述溶液以无菌方式灌注入无菌预先硅化处理的玻璃注射器(灌注体积:1mL)并且用无菌橡胶塞密封。将样品分别储存在5℃和25℃,并且在如下所示的时间点使用针对商品药物产品建立的分析方法(尺寸排阻色谱法和反相HPLC)分析纯度。
稳定性数据
用于显示在不同温度储存过程中制剂的纯度的分析方法揭示出新制剂(F1和F2)与目前包含苄醇的制剂(F20)相比极为类似至几乎相同的稳定性性质。既不含L-甲硫氨酸也不含苄醇的F17显示出需要存在具有抗氧化剂特性的试剂来防止API氧化。
F1:包含聚山梨酯20的具有10mM L-甲硫氨酸的制剂;F2:包含泊洛沙姆188的具有10mM L-甲硫氨酸的制剂;F17:如F2,但不含L-甲硫氨酸;F20:目前的制剂(20mM乙酸/乙酸Na pH 6.0、137mM NaCl、10mg/mL苄醇、0.05mg/mL聚山梨酯80)
图1显示通过尺寸排阻色谱法测定的纯度:在5℃储存时单体的含量:
图2显示通过尺寸排阻色谱法测定的纯度:在25℃储存时单体的含量:
图3显示通过反相HPLC测定的纯度:在5℃储存时未氧化的API的含量:
图4显示通过反相HPLC测定的纯度:在25℃储存时未氧化的API的含量:
Claims (9)
1.稳定的、等渗的水溶液制剂,其包含:(i)0.1-0.5mg/mL的α-型干扰素,优选聚乙二醇化α-型干扰素;(ii)维持pH为6.0±0.5的20mM的乙酸盐缓冲剂系统;(iii)5-20mM的L-甲硫氨酸;(iv)120-150mM的氯化钠;(v)有效稳定α-型干扰素、优选聚乙二醇化α-型干扰素以防止其活性损失的0.01-0.07%重量的表面活性剂;和(vi)足以制备上述列出的成分的溶液的量的注射用水。
2.权利要求1的组合物,其中所述表面活性剂是聚山梨酯20或泊洛沙姆188。
3.权利要求1的组合物,其中所述表面活性剂是聚山梨酯20。
4.权利要求1的组合物,其中所述聚乙二醇化α-型干扰素是式(I)的生理学活性聚乙二醇化α-型干扰素结合物:
其中R和R’是甲基,X是NH,n和n’的平均总和为850至1000,聚乙二醇单元的分子量为约40kDa,并且IFNα是IFNα-2a。
5.稳定的水溶液制剂,其包含:
(i)式(I)的聚乙二醇化α-型干扰素 0.36mg/mL
其中R和R’是甲基,X是NH,n和n’的平均总
和为850至1000,聚乙二醇单元的分子量为约
40kDa,并且IFNα是IFNα-2a
6.稳定的水溶液制剂,其包含:
(i)式(I)的聚乙二醇化α-型干扰素 0.36mg/mL
其中R和R’是甲基,X是NH,n和n’的平均
总和为850至1000,聚乙二醇单元的分子量为
约40kDa,并且IFNα是IFNα-2a
7.制品,其包含包装材料和任意上述权利要求的制剂,其中所述包装材料是玻璃小瓶。
8.制品,其包含包装材料和任意上述权利要求的制剂,其中所述包装材料是预装注射器。
9.制备稳定的、等渗的水溶液制剂的方法,所述水溶液制剂具有高生物学α-型干扰素、优选聚乙二醇化α-型干扰素活性,该方法包括混合如下成分:(i)0.1-0.5mg/mL的α-型干扰素,优选聚乙二醇化α-型干扰素;(ii)维持pH为6.0±0.5的20mM乙酸盐缓冲剂系统;(iii)10mM的L-甲硫氨酸;(iv)140mM的氯化钠;(v)有效稳定α-型干扰素、优选聚乙二醇化α-型干扰素以防止其活性损失的0.02%重量的表面活性剂;和(vi)制备水溶液的足量水。
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EP14186040 | 2014-09-23 | ||
EP14186040.3 | 2014-09-23 | ||
PCT/EP2015/071536 WO2016046101A1 (en) | 2014-09-23 | 2015-09-21 | Stable, benzyl alcohol-free aqueous solution formulations containing alpha-type interferon |
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US (1) | US20170360891A1 (zh) |
EP (1) | EP3200767A1 (zh) |
JP (1) | JP6445169B2 (zh) |
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CN1141808A (zh) * | 1995-04-06 | 1997-02-05 | 弗·哈夫曼-拉罗切有限公司 | 干扰素溶液 |
CN1544472A (zh) * | 2003-11-24 | 2004-11-10 | 中国药科大学 | 支链聚乙二醇-干扰素及其制法和用途 |
CN1816347A (zh) * | 2003-05-01 | 2006-08-09 | 阿雷斯贸易股份有限公司 | 不含人血清白蛋白的稳定化干扰素液体制剂 |
WO2008145323A1 (en) * | 2007-05-31 | 2008-12-04 | F. Hoffmann-La Roche Ag | Pharmaceutical formulation for interferons |
Family Cites Families (1)
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US5766582A (en) * | 1994-10-11 | 1998-06-16 | Schering Corporation | Stable, aqueous alfa interferon solution formulations |
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2015
- 2015-09-21 CN CN201580050780.3A patent/CN107073080A/zh active Pending
- 2015-09-21 WO PCT/EP2015/071536 patent/WO2016046101A1/en active Application Filing
- 2015-09-21 EP EP15766159.6A patent/EP3200767A1/en not_active Withdrawn
- 2015-09-21 JP JP2017535132A patent/JP6445169B2/ja not_active Expired - Fee Related
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2017
- 2017-03-23 US US15/467,884 patent/US20170360891A1/en not_active Abandoned
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CN1141808A (zh) * | 1995-04-06 | 1997-02-05 | 弗·哈夫曼-拉罗切有限公司 | 干扰素溶液 |
CN1816347A (zh) * | 2003-05-01 | 2006-08-09 | 阿雷斯贸易股份有限公司 | 不含人血清白蛋白的稳定化干扰素液体制剂 |
CN1544472A (zh) * | 2003-11-24 | 2004-11-10 | 中国药科大学 | 支链聚乙二醇-干扰素及其制法和用途 |
WO2008145323A1 (en) * | 2007-05-31 | 2008-12-04 | F. Hoffmann-La Roche Ag | Pharmaceutical formulation for interferons |
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CHOU DANNY K等: "Effects of solution conditions on methionine oxidation in albinterferon alfa-2b and the role of oxidation in its conformation and aggregation", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
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WO2016046101A1 (en) | 2016-03-31 |
JP6445169B2 (ja) | 2018-12-26 |
US20170360891A1 (en) | 2017-12-21 |
EP3200767A1 (en) | 2017-08-09 |
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