CN106687126A - 因子viii制剂 - Google Patents
因子viii制剂 Download PDFInfo
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- CN106687126A CN106687126A CN201580041973.2A CN201580041973A CN106687126A CN 106687126 A CN106687126 A CN 106687126A CN 201580041973 A CN201580041973 A CN 201580041973A CN 106687126 A CN106687126 A CN 106687126A
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- waterborne compositions
- fviii
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Abstract
本发明涉及因子VIII组合物及其用途。
Description
发明背景
因子VIII(FVIII)是在血浆中发现的蛋白质,其在导致血液凝固的反应级联中充当辅因子。血液中FVIII活性的量的缺乏导致被称为血友病A的凝血障碍,一种主要影响男性的遗传病症。血友病A目前用来源于人血浆或使用重组DNA技术制备的FVIII的治疗性制剂治疗。这样的制剂响应于出血事件施用(按需治疗)或以频繁、规律的间隔施用以防止不受控制的出血(预防)。
已知FVIII在治疗制剂中相对不稳定。在血浆中,FVIII通常与另一种血浆蛋白vonWillebrand因子(vWF)(其在血浆中以VWF亚基对FVIII的大量摩尔过量存在,并被认为保护FVIII免于过早降解)复合。另一种循环血浆蛋白(白蛋白)也可在体内稳定FVIII中起作用。因此,目前市售的FVIII制剂经常依赖于将白蛋白和/或vWF用于在制造过程中和储存期间稳定FVIII。
然而,目前市售的FVIII制剂中使用的白蛋白和vWF来源于人血浆,并且这样的材料的使用具有某些缺点。通常加入与FVIII相比大量摩尔过量的白蛋白以增加FVIII在这样的制剂中的稳定性,这使得在这些制剂中更难以表征FVIII蛋白本身。人来源的白蛋白至FVIII的添加也被认为是关于重组产生的FVIII制剂的缺点。这是因为,在这样添加的白蛋白不存在的情况下,重组来源的FVIII制剂中的传播病毒的理论风险将降低。
已经描述了几种制备没有白蛋白或vWF(或具有相对低水平的这些赋形剂)的FVIII的尝试。例如,美国专利5,565,427(EP 508 194)描述了除了赋形剂如氯化钠和蔗糖之外还含有洗涤剂和氨基酸特别是精氨酸和甘氨酸的特定组合的FVIII制剂。
美国专利US 5,763,401(EP 818 204)还描述了不含白蛋白的治疗性FVIII制剂,其包含15-60mM蔗糖、至多50mM NaCl、至多5mM氯化钙、65-400mM甘氨酸和至多50mM组氨酸。
Osterberg(转让给Pharmacia&Upjohn)的美国专利5,733,873(EP 627 924)公开了包含0.01-1mg/ml表面活性剂的制剂。
还描述了使用低或高浓度的氯化钠的其它尝试。美国专利4,877,608(EP 315968)公开了具有相对低浓度的氯化钠即0.5mM至15mM NaCl的制剂。
另一方面,美国专利5,605,884(EP 0 314 095)教导了具有相对高浓度的氯化钠的制剂的用途。
其它FVIII制剂公开于WO 2010/054238,EP 1 712 223,WO 2000/48635,WO 96/30041,WO 96/22107,WO 2011/027152,EP 2 361 613,EP 0 410 207,EP 0 511 234,US5565427,EP 0 638 091,EP 0 871 476,EP 0 819 010,US 5874408,US 2005/0256038,US2008/0064856,WO 2005/058283,WO 2012/037530和WO 2014/026954中。EP 1 712 223A1公开了包含组氨酸和CaCl2的FVIII组合物,但EP 1 712 223A1的组合物中的组氨酸和Ca2+的组合浓度太低,不能在水溶液中赋予所需的FVIII稳定性。
现有技术的其它治疗性FVIII制剂通常包含白蛋白和/或vWF用于稳定FVIII的目的,因此与本公开内容不相关。
制备FVIII组合物的一个问题是提供适合于冻干并在随后的重构后使用的溶液。在这方面的重要标准是FVIII溶液应当显示稳定的FVIII活性并且在冻干之前应该不显示浊度。如果FVIII水溶液在冻干之前是浑浊的,则这是溶液中的一种或多种物质(包括FVIII本身)已经聚集的清楚迹象。这是非常不希望的,因为这通常是变性蛋白(其导致活性降低)的指示。FVIII制剂的第二个主要问题是其在冻干后的稳定性。稳定性差的迹象包括冻干、储存和重构后FVIII的剩余活性降低以及FVIII的高分子量复合物的存在。
因此,存在对于不显示任何浊度或其它相关的品质损害(例如冻干前的活性显著丧失)并且同时在冻干后具有长期稳定性的包含FVIII的组合物的巨大需求。由于就组合物而言,冻干前的稳定溶液和稳定冻干物的要求可能显著不同,因此当开发这样的稳定制剂时必须考虑该两个条件。
现在已经令人惊讶地发现,这可以通过根据本发明的组合物实现,所述组合物包含在某一最小浓度下的组氨酸和钙。本发明人特别发现,关于FVIII稳定性,较低浓度的组氨酸可以通过较高的钙浓度平衡,反之亦然。这例如在EP 1 712 223 A1中没有被公开,因此,其中描述的组合物没有预见在本发明中要求保护的主题。具体地,EP 1 712 223 A1的组合物的组氨酸浓度低于本申请的权利要求1所要求的。本发明的组合物具有另外的优点,即它们在体积渗透摩尔浓度方面接近生理条件。这避免了可能由存在于因子VIII的许多现有技术制剂中的显著超体积渗透摩尔浓度的组合物引起的刺激或其它局部效应。
发明概述
本发明涉及FVIII的水性组合物,该组合物可用于治疗患有血友病A的受试者。
以下项目(1)至(93)描述了本发明的各个方面和实施方案:
(1)凝血因子VIII的水性组合物,其包含:
a.FVIII分子;
b.40至195mM的钠盐;
c.组氨酸;
d.至少1mM的钙盐;和
e.表面活性剂;
其中[His]≥180mM-20*[Ca2+],其中[Ca2+]是所述水性组合物中钙离子的浓度,以毫摩尔/升表示,并且[His]是所述水性组合物中组氨酸的浓度,以毫摩尔/升表示;并且其中所述组合物的体积渗透摩尔浓度为600mOsmol/L或更低。
(2)凝血因子VIII的水性组合物,其包含:
a.FVIII分子;
b.40至95mM的钠盐;
c.组氨酸
d.至少1mM的钙盐;和
e.表面活性剂;
其中[His]≥180mM-20*[Ca2+],其中[Ca2+]是水性组合物中钙离子的浓度,以毫摩尔/升表示,[His]是所述水性组合物中组氨酸的浓度,以毫摩尔/升表示,并且其中所述组合物的体积渗透摩尔浓度优选为600mOsmol/L或更低。
(3)凝血因子VIII的水性组合物,其包含:
a.FVIII分子;
b.至少40mM的钠盐;
c.组氨酸
d.蔗糖
e.至少1mM的钙盐;和
f.表面活性剂;
其中[His]≥180mM-20*[Ca2+],其中[Ca2+]是水性组合物中钙离子的浓度,以毫摩尔/升表示,[His]是所述水性组合物中组氨酸的浓度,以毫摩尔/升表示,并且其中所述组合物的体积渗透摩尔浓度优选为600mOsmol/L或更低。
(4)根据上述任一项所述的水性组合物,其中所述式子满足条件:[His]>0。
(5)根据项目(1)或(3)所述的水性组合物,其中,所述钠盐的浓度为50至150mM。
(6)根据上述任一项所述的水性组合物,其中所述钠盐的浓度为50至95mM。
(7)根据上述任一项所述的水性组合物,其中所述钠盐的浓度为50至75mM。
(8)根据上述任一项所述的水性组合物,其中所述钠盐的浓度为60至70mM。
(9)根据上述任一项所述的水性组合物,其中所述钠盐的浓度为约65mM。
(10)根据上述任一项所述的水性组合物,其中组氨酸的浓度为至少5mM。
(11)根据上述任一项所述的水性组合物,其中组氨酸的浓度为至少10mM。
(12)根据上述任一项所述的水性组合物,其中组氨酸的浓度为至少20mM。
(13)根据上述任一项所述的水性组合物,其中组氨酸的浓度为至少30mM。
(14)根据上述任一项所述的水性组合物,其中组氨酸的浓度为至少40mM。
(15)根据上述任一项所述的水性组合物,其中组氨酸的浓度为至少50mM。
(16)根据上述任一项所述的水性组合物,其中组氨酸的浓度为50至150mM。
(17)根据上述任一项所述的水性组合物,其中组氨酸的浓度为约100mM。
(18)根据上述任一项所述的水性组合物,其中所述组合物的pH为5至9。
(19)根据上述任一项所述的水性组合物,其中所述组合物的pH为6至8。
(20)根据上述任一项所述的水性组合物,其中所述组合物的pH为6.5至7.5。
(21)根据上述任一项所述的水性组合物,其中所述组合物的pH为6.8至7.2。
(22)根据上述任一项所述的水性组合物,其中所述组合物的pH为约7。
(23)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+25℃的温度和40%的相对湿度下储存6个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
(24)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+25℃的温度和40%的相对湿度下储存12个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
(25)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+25℃的温度和40%的相对湿度下储存18个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
(26)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+25℃的温度和40%的相对湿度下储存24个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
(27)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+25℃的温度和40%的相对湿度下储存36个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
(28)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+40℃的温度和60%的相对湿度下储存6个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
(29)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+40℃的温度和60%的相对湿度下储存12个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
(30)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+40℃的温度和60%的相对湿度下储存18个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
(31)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+40℃的温度和60%的相对湿度下储存24个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
(32)根据上述任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+25℃的温度和40%的相对湿度下储存12个月和(iii)随后在蒸馏水中重构冻干的组合物之后,其浊度为18NTU或更小。
(33)根据上述任一项所述的水性组合物,其中所述钙盐是氯化钙。
(34)根据上述任一项所述的水性组合物,其中所述钠盐是氯化钠。
(35)根据上述任一项所述的水性组合物,其中所述组合物还包含碳水化合物。
(36)根据上述(35)所述的水性组合物,其中所述碳水化合物选自蔗糖、海藻糖和棉子糖。
(37)根据上述(35)或(36)所述的水性组合物,其中所述碳水化合物是蔗糖。
(38)根据上述(35)至(37)中任一项所述的水性组合物,其中碳水化合物的浓度为1至20%w/w。
(39)根据上述(35)至(37)中任一项所述的水性组合物,其中碳水化合物的浓度为2至10%w/w。
(40)根据上述(35)至(37)中任一项所述的水性组合物,其中碳水化合物的浓度为3至8%w/w。
(41)根据上述(35)至(37)中任一项所述的水性组合物,其中碳水化合物的浓度为4至6%w/w。
(42)根据上述(35)至(37)中任一项所述的水性组合物,其中所述碳水化合物的浓度为约5%w/w。
(43)根据上述任一项所述的水性组合物,其中所述表面活性剂的浓度为至少0.001%v/v。
(44)根据上述任一项所述的水性组合物,其中所述表面活性剂的浓度为0.001至0.1%v/v。
(45)根据上述任一项所述的水性组合物,其中所述表面活性剂的浓度为0.002至0.2%v/v。
(46)根据上述任一项所述的水性组合物,其中所述表面活性剂的浓度为0.005%v/v。
(47)根据上述任一项所述的水性组合物,其中所述表面活性剂是非天然存在的表面活性剂。
(48)根据上述任一项所述的水性组合物,其中所述表面活性剂为聚山梨醇酯80。
(49)根据上述任一项所述的水性组合物,其中所述表面活性剂为聚山梨醇酯20。
(50)根据上述任一项所述的水性组合物,其中所述组合物还包含至少一种除组氨酸以外的氨基酸。
(51)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸选自精氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、甲硫氨酸、苯丙氨酸、亮氨酸、异亮氨酸及其组合。
(52)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸是精氨酸。
(53)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸是天冬酰胺。
(54)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸是天冬氨酸。
(55)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸是谷氨酸。
(56)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸是谷氨酰胺。
(57)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸是赖氨酸。
(58)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸是甲硫氨酸。
(59)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸是苯丙氨酸。
(60)根据上述(50)所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸是异亮氨酸。
(61)根据上述(50)至(60)中任一项所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸的浓度为至少0.1mM。
(62)根据上述(50)至(60)中任一项所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸的浓度为至少1mM。
(63)如上述(50)至(60)中任一项所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸的浓度为5至300mM。
(64)根据上述(50)至(60)中任一项所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸的浓度为10至200mM。
(65)根据上述任一项所述的水性组合物,其中所述组合物还包含至少一种抗氧化剂。
(66)根据上述(65)所述的水性组合物,其中所述至少一种抗氧化剂选自还原型谷胱甘肽、甲硫氨酸、半胱氨酸、亚硫酸钠、维生素A、维生素E、抗坏血酸、抗坏血酸钠及其组合。
(67)根据上述(65)所述的水性组合物,其中所述至少一种抗氧化剂是还原型谷胱甘肽。
(68)根据上述(65)所述的水性组合物,其中所述至少一种抗氧化剂是甲硫氨酸。
(69)根据上述(65)所述的水性组合物,其中所述至少一种抗氧化剂是半胱氨酸。
(70)根据上述(65)所述的水性组合物,其中所述至少一种抗氧化剂是亚硫酸钠。
(71)根据上述(65)所述的水性组合物,其中所述至少一种抗氧化剂是维生素A。
(72)根据上述(65)所述的水性组合物,其中所述至少一种抗氧化剂是维生素E。
(73)根据上述(65)所述的水性组合物,其中所述至少一种抗氧化剂是抗坏血酸。
(74)根据上述(65)所述的水性组合物,其中所述至少一种抗氧化剂是抗坏血酸钠。
(75)根据上述(65)至(74)中任一项所述的水性组合物,其中所述至少一种抗氧化剂的浓度为至少0.05mM。
(76)根据上述(65)至(74)中任一项所述的水性组合物,其中所述至少一种抗氧化剂的浓度为0.05至100mM。
(77)根据上述(65)至(74)中任一项所述的水性组合物,其中所述至少一种抗氧化剂的浓度为0.1至20mM。
(78)根据上述(65)至(74)中任一项所述的水性组合物,其中所述至少一种抗氧化剂的浓度为0.25至5mM。
(79)根据上述任一项所述的水性组合物,其中所述因子VIII分子是非天然存在的FVIII分子。
(80)根据(79)所述的水性组合物,其中所述因子VIII分子已被重组产生。
(81)根据(79)或(80)所述的水性组合物,其中所述因子VIII分子具有不同于人血浆来源的FVIII的糖基化模式。
(82)根据上述(79)至(81)中任一项所述的水性组合物,其中所述FVIII分子具有不同于SEQ ID NO:1的氨基酸序列。
(83)根据上述(79)至(82)中任一项所述的水性组合物,其中所述FVIII分子选自(i)B结构域缺失或截短的FVIII分子,(ii)单链FVIII分子,(iii)具有保护基团或半衰期延长部分的FVIII分子,(iv)包含与异源氨基酸序列融合的FVIII氨基酸序列的融合蛋白,和(v)其组合。
(84)根据上述任一项所述的水性组合物,其中所述因子VIII分子具有如SEQ IDNO:2所示的氨基酸序列。
(85)根据上述任一项所述的水性组合物,其中所述组合物的浊度为18NTU或更小,优选为6NTU或更小,更优选为3NTU或更小。
(86)根据上述(85)所述的水性组合物,其中所述组合物在冻干之前具有18NTU或更小,优选6NTU或更小,更优选3NTU或更小的浊度。
(87)根据上述(85)所述的水性组合物,其中所述组合物在冻干和在蒸馏水中重构后的浊度为18NTU或更小,优选为6NTU或更小,更优选为3NTU或更小。
(88)一种可通过冻干根据上述任一项所述的水性组合物而获得的组合物。
(89)一种可通过用水溶液重构根据上述(88)所述的冻干的水性组合物而获得的水性组合物。
(90)(89)所述的水性组合物,其中所述水溶液选自蒸馏水、盐溶液和包含组氨酸的溶液。
(91)一种稳定FVIII分子的方法,包括混合上述(1)至(3)中任一项定义的组分以获得水性组合物,并冻干该水性组合物。
(92)(91)的方法,其中所得的水性组合物为根据上述(1)至(87)中任一项所述的组合物。
(93)一种治疗凝血障碍的方法,包括向受试者施用药学有效量的上述(89)或(90)所述的组合物。
附图概述
图1描述了本发明组合物中组氨酸和钙离子的浓度之间的关系。该图总结了使用不同组氨酸和氯化钙浓度的液体制剂研究(实施例7)的结果,其中其它赋形剂保持恒定(65mmol/L氯化钠,5%蔗糖,0.005%80)。点表示高于18NTU的阈值水平的浊度,菱形表示澄清的溶液(浊度小于或等于18NTU)。该图说明如果应用某些浓度的组氨酸和钙离子,则得到澄清的溶液。澄清溶液的要求由下文给出的式子表示。
发明详述
因子VIII分子
如本文所用,术语“因子VIII”或“FVIII”是指具有人天然因子VIII的至少一部分凝血活性的分子。人FVIII由2351个氨基酸(包括信号肽)和2332个氨基酸(不含信号肽)组成。“人天然FVIII”是具有如SEQ ID NO:1(氨基酸1-2332)所示的全长序列的人血浆来源的FVIII分子。详细的结构域结构A1-a1-A2-a2-B-a3-A3-C1-C2具有相应的氨基酸残基(参考SEQ ID NO 1):A1(1-336),a1(337-372),A2(373-710),a2(711-740),B(741-1648),a3(1649-1689),A3(1690-2020),C1(2021-2173)和C2(2174-2332)。
FVIII分子的凝血活性可以使用一步凝血测定法(例如,如Lee等人,ThrombosisResearch 30,511 519(1983)中所述的)或生色底物测定法(例如来自Chromogenix-Instrumentation Laboratory SpA V.le Monza 338-20128Milano,Italy的coamaticFVIII测试试剂盒)来测定。这些活性测定法的进一步细节描述于下文中。
优选地,根据本发明使用的FVIII分子具有人天然FVIII的至少10%的比摩尔活性。术语“比摩尔活性”是指每摩尔FVIII的凝血活性,并以“IU/摩尔FVIII”表示。
在优选的实施方案中,FVIII分子是非天然存在的FVIII分子。优选地,非天然存在的FVIII分子已被重组产生。在另一个实施方案中,FVIII分子已在细胞培养物中产生。在另一个优选的实施方案中,非天然存在的FVIII分子具有不同于血浆来源的FVIII的糖基化模式的糖基化模式。在另一个实施方案中,FVIII分子选自(i)B结构域缺失或截短的FVIII分子,(ii)单链FVIII分子,(iii)重组产生的双链FVIII分子,(iv)具有保护基团或半衰期延长部分的FVIII分子,(v)包含与异源氨基酸序列融合的FVIII氨基酸序列的融合蛋白,和(vi)其组合。
术语“因子VIII”和“FVIII”在本文中同义使用。在本发明意义上的“因子VIII组合物”包括包含FVIII和FVIIIa的组合物。FVIIIa通常可以相对组合物中FVIII蛋白的总量以少量存在,例如,约1至2%FVIIIa。“FVIII”包括可能存在和发生于一个个体至另一个个体的FVIII的天然等位基因变异。通过使用熟知的生产和纯化方法,FVIII可以是血浆来源的或重组产生的。糖基化、酪氨酸硫酸化和其它翻译后修饰的程度和位置可以取决于选择的宿主细胞及其生长条件而变化。
术语FVIII包括FVIII类似物。本文所用的术语“FVIII类似物”是指FVIII分子(全长或B结构域截短/缺失的),其中与SEQ ID NO1或者对于B结构域截短/缺失的FVII分子而言SEQ ID NO 1的相应部分相比,一个或多个氨基酸已经被取代或缺失。FVIII类似物不天然存在,而是通过人工操作获得。
包含在本发明的组合物中的因子VIII分子也可以是B结构域截短/缺失的FVIII分子,其中剩余的结构域对应于SEQ ID NO:1的氨基酸编号1-740和1649-2332中所示的序列。其它形式的B结构域缺失的FVIII分子在其a3结构域中另外具有部分缺失,其导致单链FVIII分子。
因此,这些FVIII分子是在转化的宿主细胞(优选哺乳动物来源的)中产生的重组分子。然而,B结构域缺失的FVIII中剩余的结构域(即三个A结构域,两个C结构域和a1、a2和a3区)可以与如SEQ ID NO 1所示的相应氨基酸序列(氨基酸1-740和1649-2332)稍微不同,例如约1%,2%,3%,4%或5%不同。
包含在本发明的组合物中的FVIII分子可以是双链FVIII分子或单链FVIII分子。包含在本发明的组合物中的FVIII分子也可以是FVIII的生物活性片段,即其中除了B结构域之外的结构域已经缺失或截短,但是其中缺失的/截短形式的FVIII分子保持其支持血块形成的能力的FVIII。可以使用本领域熟知的技术在体外评估FVIII活性。根据本发明的测定FVIII活性的优选测试是生色底物测定法或一步测定法(见下文)。可以在剩余的结构域中引入氨基酸修饰(取代,缺失等),例如,以改变因子VIII与各种其它组分(例如VonWillebrand因子(vWF),低密度脂蛋白受体相关蛋白(LPR),各种受体,其它凝血因子,细胞表面等)的结合能力,或以引入和/或消除糖基化位点等。不消除FVIII活性的其它突变也可以提供在用于本发明的组合物中的FVIII分子/类似物中。
FVIII类似物还包括FVIII分子,其中亲本多肽的一个或多个氨基酸残基已缺失或被其它氨基酸残基取代,和/或其中额外的氨基酸残基已被添加至亲本FVIII多肽。
此外,因子VIII分子/类似物可以包含例如分子的截短的B结构域中和/或一个或多个其它结构域中的其它修饰(“FVIII衍生物”)。这些其它修饰可以是与因子VIII分子缀合的各种分子的形式(例如,聚合化合物,肽化合物,脂肪酸来源的化合物等)。
术语FVIII包括糖基聚乙二醇化(glycopegylate)的FVIII。在本上下文中,术语“糖基聚乙二醇化的FVIII”旨在表示其中一个或多个PEG基团已通过多肽的多糖侧链(聚糖)连接于FVIII多肽的因子VIII分子(包括全长FVIII和B-结构域截短/缺失的FVIII)。
术语FVIII包括具有保护基团或半衰期延长部分的FVIII分子。术语“保护基团”/“半衰期延长部分”在本文中被理解为是指连接至一个或多个氨基酸位点链官能团例如-SH、-OH、-COOH、-CONH2、NH2或一个或多个N-和/或O-聚糖结构并且可增加许多治疗性蛋白质/肽的体内循环半衰期(当与这些蛋白质/肽缀合时)的一个或多个化学基团。保护基团/半衰期延长部分的实例包括:生物相容性脂肪酸及其衍生物,羟基烷基淀粉(HAS)例如羟基乙基淀粉(HES),聚(Glyx-Sery)n(高氨基酸聚合物(HAP)),透明质酸(HA),Heparosan聚合物(HEP),磷酰胆碱基聚合物(PC聚合物),聚合物(Mersana Therapeutics,MA,USA),葡聚糖,聚唾液酸(PSA),聚乙二醇(PEG),Fc结构域,转铁蛋白,白蛋白,弹性蛋白样肽,聚合物(Amunix,CA,USA),白蛋白结合肽,von Willebrand因子片段(vWF片段),羧基末端肽(CTP肽,Prolor Biotech,IL)及其任何组合(参见例如McCormick,C.L.,A.B.Lowe,and N.Ayres,Water-Soluble Polymers,in Encyclopedia of PolymerScience and Technology.2002,John Wiley&Sons,Inc.)。衍生化的方式不是关键的,并且可以根据上文进行阐明。
可根据本发明使用的FVIII分子包括融合蛋白,其包含与异源氨基酸序列(优选半衰期延长氨基酸序列)融合的FVIII氨基酸序列。优选的融合蛋白是Fc融合蛋白和白蛋白融合蛋白。术语“Fc融合蛋白”在本文中意在包括与可以源自任何抗体同种型的Fc结构域融合的FVIII。由于IgG抗体的相对长的循环半衰期,通常优选的将是IgG Fc结构域。此外,可以修饰Fc结构域以调节某些效应子功能,例如,补体结合和/或结合至某些Fc受体。FVIII与Fc结构域的融合(其具有结合FcRn受体的能力)通常将导致与wt FVIII的半衰期相比融合蛋白的延长的循环半衰期。因此,用于本发明的FVIII分子也可以是FVIII类似物的衍生物,例如FVIII类似物的融合蛋白,聚乙二醇化或糖基聚乙二醇化的FVIII类似物,或缀合至肝素前体(heparosan)聚合物的FVIII类似物。术语“白蛋白融合蛋白”在本文中意在包括与白蛋白氨基酸序列或其片段或衍生物融合的FVIII。异源氨基酸序列可以融合至FVIII的N-或C-末端,或者其可以内部插入FVIII氨基酸序列内。异源氨基酸序列可以是WO 2008/077616A1中描述的任何“半衰期延长多肽”,其公开内容通过引用并入本文。
用于本发明的组合物的FVIII分子的实例包括例如WO 2010/045568、WO 2009/062100、WO 2010/014708、WO 2008/082669、WO 2007/126808、US 2010/0173831、US 2010/0173830、US 2010/0168391、US 2010/0113365、US 2010/0113364、WO 2003/031464、WO2009/108806、WO 2010/102886、WO 2010/115866、WO 2011/101242、WO 2011/101284、WO2011/101277、WO 2011/131510、WO 2012/007324、WO 2011/101267、WO 2013/083858和WO2004/067566中描述的FVIII分子。
可用于本发明的组合物中的FVIII分子的实例包括 的活性成分以及WO 2008/135501、WO 2009/007451中所述的FVIII分子和WO 2004/067566的命名为“dBN(64-53)”的构建体。该构建体具有SEQ ID NO:2中所示的氨基酸序列。
本发明的组合物中因子VIII的浓度通常在10-10,000IU/mL的范围内。在不同的实施方案中,本发明的组合物中FVIII分子的浓度为10-8,000IU/mL,或10-5,000IU/mL,或20-3,000IU/mL,或50-1,500IU/mL,或3,000IU/mL,或2,500IU/mL,或2,000IU/mL,或1,500IU/mL,或1,200IU/mL,1,000IU/mL,或800IU/mL,或600IU/mL,或500IU/mL,或400IU/mL,或300IU/mL,或250IU/mL,或200IU/mL,或150IU/mL,或100IU/mL。
“国际单位”或“IU”是如通过FVIII活性测定法(例如使用针对以“IU”校准的国际标准制剂校准的标准品的一步凝血测定法或生色底物FVIII活性测定法)测量的FVIII的凝血活性(效力)的测量单位。一步凝血测定法是本领域已知的,例如在N Lee,Martin L,等人,An Effect of Predilution on Potency Assays of FVIII Concentrates,Thrombosis Research(Pergamon Press Ltd.)30,511 519(1983)中所述的。一步测定法的原理:该测试作为活化的部分凝血致活酶时间(aPTT)测定法的修改版本执行:血浆与磷脂和表面活化剂的孵育导致固有凝血系统的因子的激活。钙离子的添加触发凝血级联。确定形成可测量的纤维蛋白凝块的时间。该测定在因子VIII缺陷型血浆的存在下执行。通过包括在待测试样品中的凝血因子VIII恢复缺陷型血浆的凝血能力。凝血时间的缩短与样品中存在的因子VIII的量成比例。凝血因子VIII的活性通过与具有已知活性的因子VIII的标准制剂直接比较来以国际单位定量。
另一种标准测定法是生色底物测定法。生色底物测定可以商购,例如coamaticFVIII测试试剂盒(Chromogenix-Instrumentation Laboratory SpA V.le Monza 338-20128Milano,Italy)。生色测定法的原理:在钙和磷脂的存在下,因子X被因子IXa活化为因子Xa。该反应由作为辅因子的因子VIIIa刺激。FVIIIa通过反应混合物中的少量凝血酶由待测量样品中的FVIII形成。当使用Ca2+、磷脂和因子IXa的最佳浓度和过量的因子X时,因子X的活化与因子VIII的效力成比例。活化的因子X从生色底物S-2765释放生色团pNA。因此,在405nm下测量的pNA的释放与所形成的FXa的量成比例,并因此也与样品的因子VIII活性成比例。
除非在其出现的上下文中另有说明,冷冻干燥或冻干应用于表示干燥过程,其中将材料(即活性药物成分和各种制剂添加剂或“赋形剂”)的溶液转化为固体。典型的冷冻干燥过程由“冷冻”、“初级干燥”和“次级干燥”三个阶段组成。在冷冻阶段,几乎所有含有的水都转化成冰,并且溶质转化为固体(结晶或无定形)。在初级干燥阶段中,通过直接升华(其通过在水分子(冰)和周围大气之间保持有利的压力梯度来实现)从产物中除去冰。在次级干燥阶段,通过解吸作用从产物中除去残余水分。
如果对冷冻干燥的组合物给定浓度(w/v),它们指的是正好在冷冻干燥前的体积。
除非另有说明,百分数表示重量/重量百分比,并且温度以摄氏度表示。
体积渗透摩尔浓度
本发明的因子VIII组合物通常具有小于0.6Osm/L的体积渗透摩尔浓度。这比包含高浓度氯化钠的许多现有技术制剂中的体积渗透摩尔浓度更接近生理条件。在本发明的不同实施方案中,制剂具有低于0.55Osm/L,低于0.5Osm/L,低于0.45Osm/L或低于0.4Osm/L的体积渗透摩尔浓度。术语“体积渗透摩尔浓度”和“渗透浓度”在本文中可互换使用。
体积渗透摩尔浓度或渗透浓度是溶质浓度的量度,定义为每升(L)溶液的溶质的渗透摩尔(Osm)的数量(osmol/L或Osm/L)。而摩尔浓度测量每单位体积溶液的溶质的摩尔数,体积渗透摩尔浓度测量每单位体积溶液的溶质颗粒的渗透摩尔数。
体积渗透摩尔浓度的理论计算是本领域技术人员公知的。简而言之,对溶液的每种组分计算渗透系数f、分子在水中解离成的颗粒数n和摩尔浓度的乘积,并将所有组分的结果相加。溶液的体积渗透摩尔浓度可以从以下表达式计算:Osm/L=∑i fi ni Ci,其中指数i表示特定组分的身份;f是特定组分的渗透系数;n是分子在水中解离成的颗粒数;C是组分的摩尔浓度。摩尔浓度具有一定的温度依赖性;对于本目的,其指在25℃的浓度。
评估溶液在注射后可能施加的渗透压的替代方法是通过评估重量渗透摩尔浓度,其中相对于溶剂质量评估组分的含量。如果溶液的密度和溶解组分的干质量已知,重量渗透摩尔浓度(osmolality)和体积渗透摩尔浓度(osmolarity)可以容易地相互转化。重量渗透摩尔浓度可以通过多种方法(最常见的是冰点降低)测量。
例如,对于水,1Osmol的溶质加入到1kg的水中使冰点降低1.86℃。例如,在欧洲药典2.2.35和美国药典第785章中描述了通过冰点抑制测量溶液的重量渗透摩尔浓度的方法。
下表列出了一些重要赋形剂的渗透系数和颗粒数n。对于其它组分,f=1的值为实际目的提供了足够好的近似值,并且n的值对于与用于肠胃外使用的药物制剂相关的基本上所有化合物是公知的。
赋形剂 | f | n |
NaCl | 0.93 | 2 |
CaCl2 | 0.86 | 3 |
蔗糖 | 1.02 | 1 |
组氨酸 | 1.0 | 1 |
L-甲硫氨酸 | 1.0 | 1 |
泊洛沙姆-188 | 1.0 | 1 |
聚山梨醇酯20 | 1.0 | 1 |
聚山梨醇酯80 | 1.0 | 1 |
盐
根据本发明的组合物包含钠盐。
在一个实施方案中,本发明的组合物含有至少40mM的钠盐(例如NaCl)。在一系列实施方案中,组合物包含40至195mM的钠盐(例如NaCl)或45至180mM,或45至150mM,或50至125mM或50至100mM,或60至95mM,或60至75mM,例如约65mM。在另一个实施方案中,钠盐(例如NaCl)的浓度为40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94或95mM。
优选地,钠盐是氯化钠;在另一个实施方案中,盐是乙酸钠。在第三个实施方案中,本发明的组合物含有氯化钠和乙酸钠的混合物。
根据本发明的组合物还包含钙盐。根据本发明使用的钙盐通常可溶于水,使得其在溶解于水溶液中时分解成一种或多种钙离子和抗衡阴离子。术语“Ca2+”与术语“钙离子”同义。
在一个实施方案中,钙浓度由下式定义,其中[Ca2+]是以毫摩尔/升计的钙离子浓度,[His]是以毫摩尔/升计的组氨酸浓度:
[Ca2+]≥9mM-0.05*[His]
在另一个实施方案中,钙浓度通过下式定义,其中[Ca2+]是以毫摩尔/升计的钙离子浓度,[His]是以毫摩尔/升计的组氨酸浓度:
[Ca2+]≥9.5mM-0.05*[His]
在另一个实施方案中,钙浓度通过下式定义,其中[Ca2+]是以毫摩尔/升计的钙离子浓度,[His]是以毫摩尔/升计的组氨酸浓度:
[Ca2+]≥10mM-0.05*[His]
在另一个实施方案中,钙浓度通过下式定义,其中[Ca2+]是以毫摩尔/升计的钙离子浓度,[His]是以毫摩尔/升计的组氨酸浓度:
[Ca2+]≥10.5mM-0.05*[His]
上述式子的条件为[Ca2+]>0。通常,组合物含有至少1mM,优选至少2mM,更优选至少4mM,最优选至少5mM的钙盐。在另一个实施方案中,组合物含有高达100mM的钙盐。在另一个实施方案中,组合物包含1-50mM的钙盐,或2-40mM,或3-30mM,或4-20mM。在一个具体实施方案中,组合物含有约10mM的钙盐。
钙盐可以例如选自氯化钙、乙酸钙、葡萄糖酸钙、乳酸钙、苯甲酸钙及其混合物、以及本领域技术人员熟知的其它可溶性钙盐。在优选的实施方案中,钙盐是氯化钙。
组氨酸
根据本发明的组合物包含组氨酸,优选L-组氨酸。
在一个实施方案中,组氨酸浓度由下式定义,其中[Ca2+]是以毫摩尔/升计的钙离子浓度,[His]是以毫摩尔/升计的组氨酸浓度:
[His]≥180mM-20*[Ca2+]
在另一个实施方案中,组氨酸浓度由下式定义,其中[Ca2+]是以毫摩尔/升计的钙离子浓度,[His]是以毫摩尔/升计的组氨酸浓度:
[His]≥190mM-20*[Ca2+]
在另一个实施方案中,组氨酸浓度由下式定义,其中[Ca2+]是以毫摩尔/升计的钙离子浓度,[His]是以毫摩尔/升计的组氨酸浓度:
[His]≥200mM-20*[Ca2+]
在另一个实施方案中,组氨酸浓度由下式定义,其中[Ca2+]是以毫摩尔/升计的钙离子浓度,[His]是以毫摩尔/升计的组氨酸浓度:
[His]≥210mM-20*[Ca2+]
上述式子的条件是[His]>0。通常,组氨酸的浓度为至少5mM,优选至少10mM,优选至少20mM,优选20-400mM,优选至少25mM,优选25-200mM,优选至少50mM,优选50-300mM,优选55-170mM,优选60-150mM,优选65-120mM,更优选50-100mM,例如约100mM。在另一个实施方案中,组氨酸的浓度为10,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,105,110,115,120,130,140,150,160,170,180,190,200,300或400mM。
表面活性剂
根据本发明的组合物包含表面活性剂。如本文所用,“表面活性剂”是指保护活性物质避免空气与溶液界面或溶液与表面界面诱导的应激或损伤的试剂。优选地,表面活性剂是非天然存在的表面活性剂。
典型的非天然存在的表面活性剂(括号[]中给出商品名称的实例)是聚氧乙烯山梨糖醇酐脂肪酸酯,例如聚氧乙烯(20)山梨糖醇酐单月桂酸酯20],聚氧乙烯(20)山梨糖醇酐单棕榈酸酯[40]或聚氧乙烯(20)山梨糖醇酐单油酸酯[80],泊洛沙姆如聚氧丙烯-聚氧乙烯嵌段共聚物F68/泊洛沙姆188],聚乙二醇辛基苯基醚[X-100]或聚氧乙二醇十二烷基醚[35]。表面活性剂在水性组合物中的使用是本领域技术人员公知的。为了方便起见,参考Remington:TheScience and Practice of Pharmacy,19th edition,1995。在本发明的一个实施方案中,组合物包含山梨糖醇酐单油酸酯[80]。在某些实施方案中,本发明的组合物包含对氧化不敏感的表面活性剂,例如烷基糖。在另一个实施方案中,表面活性剂是植物来源的表面活性剂,和/或其不含石油化学品,和/或其已经在不使用石化产品的情况下生产。
在一个实施方案中,表面活性剂的浓度为至少0.001%v/v,优选0.001-0.1%v/v,优选0.002-0.3%v/v,更优选0.003-0.1%v/v,最优选约0.005%v/v。在另一个实施方案中,表面活性剂的浓度为0.001,0.002,0.003,0.004,0.005,0.006,0.007,0.008,0.009,0.01,0.02,0.03,0.04,0.05,0.06,0.07,0.08,0.09,0.1,0.2,0.5,0.7,0.8,0.9或1.0%v/v。在一个实施方案中,聚氧乙烯(20)山梨糖醇酐单油酸酯[80]的浓度为至少0.001%v/v,优选0.001-0.1%v/v,优选0.002-0.3%v/v,更优选0.003-0.1%v/v,最优选约0.005%v/v。
缓冲剂
根据本发明的组合物可以包含缓冲试剂。如本文所用,“缓冲试剂”或“缓冲剂”是指将制剂的pH维持在其中制剂的施用(例如静脉内或皮下)通常良好耐受的范围内(例如pH5至9)并且还避免pH变化并保护活性物质避免冻干过程中的pH诱导的应激或损伤的试剂。用作缓冲物质的物质的典型实例是例如碳酸盐,磷酸盐,柠檬酸盐,硼酸盐,2-氨基-2-羟甲基-1,3-丙二醇[=TRIS],组氨酸,甘氨酸。
缓冲剂(或缓冲试剂)可以选自乙酸盐,苯甲酸盐,碳酸盐,柠檬酸盐,甘氨酰甘氨酸,Hepes,组氨酸,甘氨酸,和TRIS,n,n-二(羟乙基)甘氨酸(bicine),三(羟甲基)甲基甘氨酸(tricine),琥珀酸盐,天冬氨酸,谷氨酸或其混合物。在本发明的一个实施方案中,缓冲物质的浓度为1至200mM,例如1至150mM或1至50mM或1至25mM或5至20mM或5至15mM。
本发明的组合物通常具有4至10的pH。在另一个实施方案中,组合物具有5.0至9.0或6.0至8.0或6.5至7.5或6.8至7.2或约7的pH。在其它实施方案中,组合物的pH为5.5±0.2,5.6±0.2,5.7±0.2,5.8±0.2,5.9±0.2,6.0±0.2,6.1±0.2,6.2±0.2,6.3±0.2,6.4±0.2,6.5±0.2,6.6±0.2,6.7±0.2,6.8±0.2,6.9±0.2,7.0±0.2,7.1±0.2,7.2±0.2,7.3±0.2,7.4±0.2,或7.5±0.2。在其它实施方案中,组合物的pH为5.5±0.1,5.6±0.1,5.7±0.1,5.8±0.1,5.9±0.1,6.0±0.1,6.1±0.1,6.2±0.1,6.3±0.1,6.4±0.1,6.5±0.1,6.6±0.1,6.7±0.1,6.8±0.1,6.9±0.1,7.0±0.1,7.1±0.1,7.2±0.1,7.3±0.1,7.4±0.1,或7.5±0.1。在其它实施方案中,稳定制剂的pH为5.5,5.6,5.7,5.8,5.9,6.0,6.1,6.2,6.3,6.4,6.5,6.6,6.7,6.8,06.9,7.0,7.1,7.2,7.3,7.4,7.5,7.6,7.7,7.8,7.9,或8.0。
碳水化合物
本发明的组合物还可以包含碳水化合物。如本文所用,“碳水化合物”是指糖,例如单糖、二糖或多糖或水溶性葡聚糖,包括例如果糖,葡萄糖,甘露糖,甘露醇,山梨糖,山梨醇,木糖,麦芽糖,乳糖,蔗糖,半乳糖,葡聚糖,海藻糖,支链淀粉,糊精,环糊精,可溶性淀粉,羟乙基淀粉和羧甲基纤维素。
碳水化合物可以例如选自单糖,二糖或多糖(包括例如单糖果糖、葡萄糖、甘露糖、半乳糖,二糖乳糖、蔗糖、海藻糖、麦芽糖和多糖葡聚糖、棉子糖、水苏糖)。
在本发明的一个实施方案中,FVIII组合物包含选自以下的一种或多种碳水化合物:蔗糖,棉子糖,海藻糖或其混合物。在一个实施方案中,FVIII组合物包含浓度为2至10%w/w,优选3至8%w/w,优选4至6%w/w,最优选5%w/w的碳水化合物。在另一个实施方案中,碳水化合物的浓度为2、3、4、5、6、7、8、9或10%w/w。
在具体实施方案中,碳水化合物是蔗糖。在一个实施方案中,FVIII组合物包含浓度为2-10%w/w,优选3-8%w/w,优选4-6%w/w,最优选5%w/w的蔗糖。在另一个实施方案中,蔗糖的浓度为2、3、4、5、6、7、8、9或10%w/w。
在具体实施方案中,碳水化合物是海藻糖。在一个实施方案中,FVIII组合物包含浓度为2至10%w/w,优选3至8%w/w,优选4至6%w/w,最优选5%w/w的海藻糖。在另一个实施方案中,海藻糖的浓度为2、3、4、5、6、7、8、9或10%w/w。
在具体实施方案中,碳水化合物是棉子糖。在一个实施方案中,FVIII组合物包含浓度为2至10%w/w,优选3至8%w/w,优选4至6%w/w,最优选5%w/w的棉子糖。在另一个实施方案中,棉子糖的浓度为2、3、4、5、6、7、8、9或10%w/w。
氨基酸
在一个实施方案中,本发明的组合物还包含除组氨酸以外的一种或多种氨基酸。如本文所用,“氨基酸”是指任何天然或非天然的药学上可接受的氨基酸。氨基酸的非限制性实例包括异亮氨酸,丙氨酸,亮氨酸,天冬酰胺,赖氨酸,天冬氨酸,甲硫氨酸,半胱氨酸,苯丙氨酸,谷氨酸,苏氨酸,谷氨酰胺,色氨酸,甘氨酸,缬氨酸,脯氨酸,硒代半胱氨酸,丝氨酸,酪氨酸,精氨酸,组氨酸,鸟氨酸,牛磺酸等。除组氨酸以外的氨基酸优选选自精氨酸,天冬酰胺,天冬氨酸,谷氨酸,谷氨酰胺,赖氨酸,甲硫氨酸,苯丙氨酸,异亮氨酸,亮氨酸及其组合。
在一个实施方案中,水性组合物包含精氨酸和异亮氨酸。
在一个实施方案中,水性组合物包含精氨酸、谷氨酸和苯丙氨酸。
在一个实施方案中,水性组合物包含精氨酸、谷氨酸、苯丙氨酸和甲硫氨酸。
在一个实施方案中,水性组合物包含精氨酸、异亮氨酸和甲硫氨酸。
在一个实施方案中,水性组合物包含谷氨酰胺、谷氨酸、异亮氨酸和甲硫氨酸。
在一个实施方案中,除组氨酸以外的氨基酸的浓度为至少0.2mM,优选1至300mM,优选5至300mM,优选10至200mM,优选55至150mM,优选25至100mM,优选40至180mM,优选50至90mM。在另一个实施方案中,除组氨酸以外的氨基酸的浓度为0.2,0.5,1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,105,110,115,120,125,130,135,140,145,150,155,160,165,170,175,180,185,190,195或200mM。
在一个实施方案中,精氨酸的浓度为至少1mM,优选5至300mM,优选10至200mM,优选55至150mM,优选25至100mM,优选40至180mM,优选50至90mM。在另一个实施方案中,精氨酸的浓度为1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,105,110,115,120,125,130,135,140,145,150,155,160,165,170,175,180,185,190,195或200mM。
在一个实施方案中,异亮氨酸的浓度为至少1mM,优选5至300mM,优选10至200mM,优选55至150mM,优选25至100mM,优选40至180mM,优选50至90mM。在另一个实施方案中,异亮氨酸的浓度为1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,105,110,115,120,125,130,135,140,145,150,155,160,165,170,175,180,185,190,195或200mM。
在一个实施方案中,谷氨酸的浓度为至少1mM,优选5至300mM,优选10至200mM,优选55至150mM,优选25至100mM,优选40至180mM,优选50至90mM。在另一个实施方案中,谷氨酸的浓度为1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,105,110,115,120,125,130,135,140,145,150,155,160,165,170,175,180,185,190,195或200mM。
在一个实施方案中,苯丙氨酸的浓度为至少1mM,优选5至200mM,优选10至160mM,优选55至150mM,优选25至100mM,优选40至180mM,优选50至90mM。在另一个实施方案中,苯丙氨酸的浓度为1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,105,110,115,120,125,130,135,140,145,150,155,160,165,170,175,180,185,190,195或200mM。
抗氧化剂
本发明的组合物还可以含有一种或多种抗氧化剂。本发明含义内的“抗氧化剂”是减缓、抑制、中断和/或停止氧化过程的药学上相容的化合物或组合物。抗氧化剂特别包括以下物质:生育酚及其酯,还原型谷胱甘肽,甲硫氨酸,一硫代甘油,半胱氨酸,高半胱氨酸,胱硫醚,维生素A,芝麻油的芝麻酚,苯偶姻树脂的苯甲酸松柏酯,去甲二氢愈创木酸树脂和去甲二氢愈创木酸(NDGA),没食子酸酯(尤其是甲基、乙基、丙基、戊基、丁基、十二烷基没食子酸酯),丁基化羟基苯甲醚(BHAIBHT,也称为丁基对甲酚);抗坏血酸及其盐和酯(例如抗坏血酸棕榈酸酯(acorbyl palmitate)),异抗坏血酸(erythorbinic acid)(阿拉伯糖型抗坏血酸(isoascorbinic acid))及其盐和酯,单硫代甘油,甲醛次硫酸钠,偏亚硫酸氢钠,亚硫酸氢钠,亚硫酸钠,偏亚硫酸氢钾,丁基化羟基苯甲醚,丁基化羟基甲苯BHT),丙酸。典型的抗氧化剂是生育酚,例如α-生育酚及其酯,丁基化羟基甲苯和丁基化羟基苯甲醚。术语“生育酚”还包括生育酚的酯。已知的生育酚是α-生育酚。术语“α-生育酚”包括α-生育酚的酯(例如,α-生育酚乙酸酯)。在本发明的一个实施方案中,抗氧化剂是甲硫氨酸,例如L-甲硫氨酸。
在一个实施方案中,抗氧化剂的浓度为至少0.05mM,优选0.05至100mM,优选0.1至80mM,优选0.2至50mM,优选0.5至70mM,优选1至25mM,优选0.1至20mM,优选0.25至1mM。在另一个实施方案中,抗氧化剂的浓度为0.05,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,1.5,2.0,2.5,3.0,3.5,4.0,4.5,5.0,6.0,7.0,8.0,9.0,10.0,11.0,12.0,13.0,14.0,15.0,16.0,17.0,18.0,19.0,20.0,25.0,30.0,35.0,40.0,45.0,50.0,55.0,60.0,65.0,70.0,75.0,80.0,85.0,90.0,95.0或100.0mM。
在一个实施方案中,甲硫氨酸的浓度为至少0.05mM,优选0.05至100mM,优选0.1至80mM,优选0.2至50mM,优选0.5至70mM,优选1至25mM,优选0.1至20mM,优选0.25至5mM。在另一个实施方案中,甲硫氨酸的浓度为0.05,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,1.5,2.0,2.5,3.0,3.5,4.0,4.5,5.0,6.0,7.0,8.0,9.0,10.0,11.0,12.0,13.0,14.0,15.0,16.0,17.0,18.0,19.0,20.0,25.0,30.0,35.0,40.0,45.0,50.0,55.0,60.0,65.0,70.0,75.0,80.0,85.0,90.0,95.0或100.0mM。
在一个实施方案中,谷胱甘肽的浓度为至少0.05mM,优选0.05至100mM,优选0.1至80mM,优选0.2至50mM,优选0.5至70mM,优选1至25mM,优选0.1至20mM,优选0.25至1mM。在另一个实施方案中,谷胱甘肽的浓度为0.05,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,1.5,2.0,2.5,3.0,3.5,4.0,4.5,5.0,6.0,7.0,8.0,9.0,10.0,11.0,12.0,13.0,14.0,15.0,16.0,17.0,18.0,19.0,20.0,25.0,30.0,35.0,40.0,45.0,50.0,55.0,60.0,65.0,70.0,75.0,80.0,85.0,90.0,95.0或100.0mM。
稳定剂
本发明的组合物可以包含稳定剂。如本文所用,“稳定剂”是指有助于稳定处于溶液状态或在冻融以及冷冻干燥和脱水冻干物的随后储存期间的水性制剂中的不稳定治疗剂的化学品(其它同义词为例如“共溶剂”,“共溶质”,“化学添加剂”;“赋形剂”)。用于本文提供的制剂和方法的合适稳定剂的实例包括但不限于缓冲试剂(例如TRIS,HEPES,氨基酸等),渗透物(例如糖,糖醇等),冷冻保护剂/冻干保护剂(例如醇,诸如丙三醇,甲醇,异丙醇;糖,例如蔗糖,木糖醇,右旋糖,海藻糖;羧酸和羧酸盐,例如乳酸和乳酸盐,苹果酸和马来酸盐;PEG,例如乙二醇,PEG 200,PEG 2000,PEG 20 000;聚合物如聚乙烯吡咯烷酮,PVP12,PVP 17,PVP 30;填充剂(例如氨基酸,多元醇如甘露醇等),盐,聚合物,表面活性剂,抗氧化剂等。
稳定剂的浓度取决于试剂的化学性质,并且可以根据上文的公开内容进行选择。
稳定性
在上文提供的组合物的具体实施方案中,组合物是稳定的。本文所用的术语“稳定的”是指在储存一段时间后如通过FVIII活性测定法测量的组合物的效力是储存前的效力的至少80%。除非本文另有说明,稳定性测试如来自欧洲药品管理局的自2003年8月起的标题为“NOTE FOR GUIDANCE ON STABILITY TESTING:STABILITY TESTING OF NEW DRUGSUBSTANCES AND PRODUCTS”的文件CPMP/ICH/2736/99中所述进行。
在一系列实施方案中,本文提供的组合物在冻干后将稳定至少1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48或更多个月(25℃;40%相对湿度[RH])。在优选的实施方案中,冻干的组合物将稳定至少6个月(25℃;40%RH)。在更优选的实施方案中,冻干的组合物将稳定至少12个月(25℃;40%RH)。在另一个优选的实施方案中,冻干的组合物将稳定至少18个月(25℃;40%RH)。在另一个优选的实施方案中,冻干的组合物将稳定至少24个月(25℃;40%RH)。在另一个优选的实施方案中,冻干的组合物将稳定至少36个月(25℃;40%RH)。
在上文提供的组合物的具体实施方案中,当在25℃/40%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在30℃/40%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在40℃/40%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月。
在上文提供的组合物的另一个实施方案中,当在25℃/60%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在30℃/60%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在40℃/60%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月。
在上文提供的组合物的另一个实施方案中,当在25℃/65%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在30℃/65%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在40℃/65%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月。
在上文提供的组合物的另一个实施方案中,当在25℃/75%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在30℃/75%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在40℃/75%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月。
在上文提供的组合物的另一个实施方案中,当在25℃/25%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在30℃/25%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月,甚至更优选至少36个月。
在上文提供的组合物的另一个实施方案中,当在40℃/25%RH下储存时,冻干的组合物稳定至少6个月,优选至少12个月,更优选至少24个月。
优选地,在冻干的组合物在上述条件之一下储存后如通过SE-HPLC测定的高分子量组分的量为3%或更少。通过本申请实施例中所述的SE-HPLC测定高分子量组分的量。
在一个实施方案中,当在4℃以液体状态储存时,组合物稳定至少48小时,优选至少72小时,更优选至少96小时,最优选至少一周。当在2至8℃以液体状态储存时,水性组合物通常保持至少80%的其因子VIII活性至少48小时,优选至少72小时,更优选至少96小时,最优选至少一周。这适用于在冻干之前的水性组合物和/或在冻干和在水溶液例如在蒸馏水中重构后的水性组合物。
在上文提供的组合物的具体实施方案中,当在4℃下以液态储存时,组合物保持至少85%的其因子VIII活性至少48小时,优选至少72小时,更优选至少96小时,最优选至少一周。这适用于在冻干之前的水性组合物和/或在冻干和在水溶液例如在蒸馏水中重构后的水性组合物。
在上文提供的组合物的具体实施方案中,当在4℃下以液态储存时,组合物保持至少90%的其因子VIII活性至少48小时,优选至少72小时,更优选至少96小时,最优选至少一周。这适用于在冻干之前的水性组合物和/或在冻干和在水溶液例如在蒸馏水中重构后的水性组合物。
在本发明的具体实施方案中,组合物显示很少或没有浊度,例如。在冻干之前或在冻干和在水中重构后。如本文所用,术语“浊度”是指溶液的乳光。浊度可以目测或仪器测定,如Pharm.Eur.8.0第2.2.1节“Clarity and degree of opalescence of liquids”中所述的。本申请中对浊度的任何提及是指在Pharm.Eur.8.0第2.2.1节“Clarity and degreeof opalescence of liquids”中所述的方法。
在一个实施方案中,本发明的组合物具有18NTU或更小的浊度。在另一个实施方案中,本发明的组合物具有6NTU或更小的浊度。在另一个实施方案中,本发明的组合物具有3NTU或更小的浊度。在冻干前和在冻干和在蒸馏水中重构后满足这些浊度值。
在另一个实施方案中,本发明的组合物是澄清的。在本申请中,当组合物或溶液的乳光不比在Pharm.Eur.8.0第2.2.1节“Clarity and degree of opalescence ofliquids”中所述的“参考悬浮液III”的乳光更显著时,认为它是“澄清的”。当本文提及“不具有浊度”或“无浊度”的组合物时,应当理解,组合物根据此定义是“澄清的”。
优选的是以下组合物(表1),包括:
进一步优选的是以下组合物(表2),包括:
进一步优选的是以下组合物(表3),包括:
进一步优选的是以下组合物(表4),包括:
进一步优选的是以下组合物(表5),包括:
进一步优选的是以下组合物(表6),包括:
进一步优选的是以下组合物(表7),包括:
进一步优选的是以下组合物(表9),包括:
进一步优选的是以下组合物(表10),包括:
进一步优选的是以下组合物(表11),包括:
进一步优选的是以下组合物(表12),包括:
进一步优选的是以下组合物(表13),包括:
进一步优选的是以下组合物(表14),包括:
进一步优选的是以下组合物(表15),包括:
在另一个实施方案中,组合物170-233还包含表面活性剂,例如聚氧乙烯(20)山梨糖醇酐单油酸酯[例如80],优选浓度为至少0.001%w/w。
在另一个实施方案中,组合物170-233还包含除组氨酸以外的一种或多种氨基酸。所述另一种氨基酸选自精氨酸,天冬酰胺,天冬氨酸,谷氨酸,谷氨酰胺,赖氨酸,甲硫氨酸,苯丙氨酸,异亮氨酸或其混合物,优选浓度为至少1mM。
在另一个实施方案中,组合物170-233还包含抗氧化剂,优选浓度为至少0.05mM。抗氧化剂的实例包括但不限于还原型谷胱甘肽、甲硫氨酸、半胱氨酸、亚硫酸钠、维生素A、维生素E、抗坏血酸、抗坏血酸钠及其混合物。在本发明的一个实施方案中,抗氧化剂是甲硫氨酸,例如L-甲硫氨酸。
在另一个实施方案中,组合物170-233具有6.0-8.0或6.5-7.5或6.8-7.2或7的pH。
在另一个实施方案中,组合物170-233还包含:
a.聚氧乙烯(20)山梨糖醇酐单油酸酯[例如80]作为表面活性剂,优选浓度为至少0.001%w/w,
b.除了组氨酸之外的一种或多种氨基酸,其选自精氨酸,天冬酰胺,天冬氨酸,谷氨酸,谷氨酰胺,赖氨酸,甲硫氨酸,苯丙氨酸,异亮氨酸或其混合物,优选浓度为至少1mM,
c.选自还原型谷胱甘肽、甲硫氨酸、半胱氨酸、亚硫酸钠、维生素A、维生素E、抗坏血酸、抗坏血酸钠及其混合物的抗氧化剂,优选浓度为至少0.05mM,和
d.组合物具有6.0-8.0或6.5-7.5或6.8-7.2或7的pH。
优选的是以下组合物(表16),包括:
在另一个实施方案中,组合物234-297还包含表面活性剂,例如聚氧乙烯(20)山梨糖醇酐单油酸酯[例如80],优选浓度为至少0.001%w/w。
在另一个实施方案中,组合物234-297还包含除组氨酸以外的一种或多种氨基酸。所述另一种氨基酸选自精氨酸,天冬酰胺,天冬氨酸,谷氨酸,谷氨酰胺,赖氨酸,甲硫氨酸,苯丙氨酸,异亮氨酸或其混合物,优选浓度至少为1mM。
在另一个实施方案中,组合物234-297还包含抗氧化剂,优选浓度为至少0.05mM。抗氧化剂的实例包括但不限于还原型谷胱甘肽、甲硫氨酸、半胱氨酸、亚硫酸钠、维生素A、维生素E、抗坏血酸、抗坏血酸钠及其混合物。在本发明的一个实施方案中,抗氧化剂是甲硫氨酸,例如L-甲硫氨酸。
在另一个实施方案中,组合物234-297具有6.0-8.0或6.5-7.5或6.8-7.2或7的pH。
在另一个实施方案中,组合物234-297还包含:
e.聚氧乙烯(20)山梨糖醇酐单油酸酯[例如80]作为表面活性剂,优选浓度为至少0.001%w/w,
f.选自精氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、甲硫氨酸、苯丙氨酸、异亮氨酸或其混合物的除组氨酸以外的一种或多种氨基酸,优选浓度为至少1mM,
g.选自还原型谷胱甘肽、甲硫氨酸、半胱氨酸、亚硫酸钠、维生素A、维生素E、抗坏血酸、抗坏血酸钠及其混合物的抗氧化剂,优选浓度为至少0.05mM,和
h.组合物具有6.0-8.0或6.5-7.5或6.8-7.2或7的pH。
优选的是以下组合物(表17),其包括:
在另一个实施方案中,组合物298-361还包含表面活性剂,例如聚氧乙烯(20)山梨糖醇酐单油酸酯[例如80],优选浓度为至少0.001%w/w。
在另一个实施方案中,组合物298-361进一步包含除组氨酸以外的一种或多种氨基酸。所述另一种氨基酸选自精氨酸,天冬酰胺,天冬氨酸,谷氨酸,谷氨酰胺,赖氨酸,甲硫氨酸,苯丙氨酸,异亮氨酸或其混合物,优选浓度至少为1mM。
在另一个实施方案中,组合物298-361还包含抗氧化剂,优选浓度为至少0.05mM。抗氧化剂的实例包括但不限于还原型谷胱甘肽、甲硫氨酸、半胱氨酸、亚硫酸钠、维生素A、维生素E、抗坏血酸、抗坏血酸钠及其混合物。在本发明的一个实施方案中,抗氧化剂是甲硫氨酸,例如L-甲硫氨酸。
在另一个实施方案中,组合物298-361具有6.0-8.0或6.5-7.5或6.8-7.2或7的pH。
在另一个实施方案中,组合物298-361进一步包含:
i.聚氧乙烯(20)山梨糖醇酐单油酸酯[例如80]作为表面活性剂,优选浓度为至少0.001%w/w,
j.选自精氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、甲硫氨酸、苯丙氨酸、异亮氨酸或其混合物的除组氨酸以外的一种或多种氨基酸,优选浓度为至少1mM,
k.选自还原型谷胱甘肽、甲硫氨酸、半胱氨酸、亚硫酸钠、维生素A、维生素E、抗坏血酸、抗坏血酸钠及其混合物的抗氧化剂,优选浓度为至少0.05mM,
l.组合物具有6.0-8.0或6.5-7.5或6.8-7.2或7的pH。
在具体的实施方案中,本发明涉及可通过冻干上述水性组合物获得的组合物。在另一个实施方案中,本发明涉及通过冻干上述水性组合物获得的组合物。
在具体的实施方案中,本发明涉及可通过用合适的溶剂重构上述冻干的水性组合物而获得的组合物。
在具体实施方案中,组合物可通过用合适的溶剂重构如上所述的冻干的水性组合物而获得,其中合适的溶剂是水溶液。
在具体的实施方案中,组合物可通过用水溶液重构如上所述的冻干的水性组合物而获得,其中所述水溶液选自林格氏溶液、林格氏乳酸盐溶液和用于肠胃外施用的任何其它合适的溶液。
在具体的实施方案中,组合物可通过用水溶液重构如上所述的冻干的水性组合物而获得,其中水溶液是水,优选“注射用水”。
在具体实施方案中,组合物可通过用水溶液重构如上所述的冻干的水性组合物而获得,其中水溶液是氯化钠溶液。
在具体实施方案中,组合物可通过用水溶液重构如上所述的冻干的水性组合物而获得,其中水溶液是组氨酸溶液。
本发明的另一方面是本文所述的组合物在治疗血液凝固障碍(例如血友病A)中的用途。
在上文提供的组合物的一个具体实施方案中,组合物被配制用于皮下和/或肌内施用。
组合物经口、局部、经皮、肠胃外、通过吸入喷雾、阴道、直肠或通过颅内注射施用,优选肠胃外施用。本文所用的术语肠胃外包括皮下注射、静脉内、肌内、脑池内注射或输注技术。还考虑了通过静脉内、皮内、肌内、乳房内、腹膜内、鞘内、眼球后、肺内注射和/或在特定部位的手术植入。通常,组合物基本上不含热原(参见例如Ph.Eur.7.0/2.06.08.00)和可能对接受者有害的其它杂质。
实施例
使用FVIII分子(SEQ ID NO:2;WO 2004/067566中描述的构建体dBN(64-53))进行以下实施例。该FVIII分子在下文中将被称为“CSL627”。
生色FVIII:C测定
使用Coamatic FVIII测试试剂盒(Chromogenix-Instrumentation LaboratorySpA V.le Monza 338-20128Milano,Italy)进行生色FVIII:C测定。
测定原理:在钙和磷脂的存在下,因子X被因子IXa活化为因子Xa。该反应由作为辅因子的因子VIIIa刺激。F VIIIa通过反应混合物中的少量凝血酶由待测量样品中的F VIII形成。当使用Ca2+、磷脂和因子IXa的最佳浓度和过量的因子X时,因子X的活化与因子VIII的效力成比例。活化的因子X从生色底物S-2765释放生色团pNA。因此,在405nm下测量的pNA的释放与所形成的FXa的量成比例,并因此也与样品的因子VIII活性成比例。该测定被适应于在来自Siemens Healthcare Diagnostics GmbH,Ludwig-Erhard-Straβe 12,65760Eschborn,Germany的自动凝血分析仪Behring Coagulation Timer(BCT)或BehringCoagulation System(BCS)上进行。
一步凝血测定
使用来自Siemens Healthcare Diagnostics products GmbH,Emil-von-Behring–Str.76,35041Marburg,Germany的Pathromtin SL试剂和FVIII缺陷型血浆进行FVIII:C一步凝血测定。
测定原理:该测试作为活化的部分凝血致活酶时间(aPTT)测定法的修改版本执行:血浆与磷脂和表面活化剂的孵育导致固有凝血系统的因子的激活。钙离子的添加触发凝血级联。测量形成可测量的纤维蛋白凝块的时间。该测定在因子VIII缺陷型血浆的存在下执行。通过包括在待测试样品中的凝血因子VIII恢复缺陷型血浆的凝血能力。凝血时间的缩短与样品中存在的因子VIII的量成比例。凝血因子VIII的活性通过与具有已知活性的因子VIII的标准制剂直接比较来以国际单位定量。
该测定被适应于在来自Siemens Healthcare Diagnostics GmbH,Ludwig-Erhard-Straβe 12,65760Eschborn,Germany的自动凝血分析仪Behring CoagulationTimer(BCT)或Behring Coagulation System(BCS)上进行。
通过尺寸排阻HPLC的高分子量组分(HMWC)
使用COSMOSIL Diol-300-II 7.5x 600mm柱(Nacalai Tesque,Kyoto,Japan)进行尺寸排阻HPLC,并且在激发波长280nm和发射波长340nm下进行荧光检测。流动相的组成为300mM NaCl,20mM HEPES,10mM CaCl2*2H2O,0,005%80,10%异丙醇,pH7.0。在环境室温下在75分钟内以0.5mL/min的流速等度洗脱。
实施例1:
在经由脱盐柱的缓冲液交换后,制备FVIII制剂并评价溶液性质
根据供应商的说明书,通过经由NAP-25脱盐柱(GE Healthcare SephadexTMG 25;目录号17-0852-01)的缓冲液交换将FVIII:C活性(生色底物法)为9500IU/ml的纯化的CSL627配制成所需组合物。该缓冲液交换导致1.4的稀释因子。
然后研究不同组合物在FVIII:C活性上的产率和其外观(浊度)。
FVIII:C的产率计算为在缓冲液交换后获得的组合物中FVIII:C的量除以在缓冲液交换前的溶液中的FVIII:C的量的百分比,通过缓冲液交换(稀释因子1.4)适当调整稀释度。
表18
*在经由脱盐柱的缓冲液交换后通过生色底物活性测定法测定的FVIII:C活性产率
实施例2:
在经由脱盐柱的缓冲液交换后,制备FVIII制剂并评价溶液性质
如实施例1所述通过缓冲液交换获得不同的组合物(起始材料中的FVIII:C活性为9733IU/mL)。评价组合物在缓冲液交换后的其外观。此外,随后将组合物无菌过滤(0.22μm),并在过滤(时间0)后直接测定它们的FVIII:C活性,并在+2-+8℃下储存1、2、3、15、30和60天和在+25℃和+40℃下储存1、2和3天后测定它们的FVIII:C活性。
将恢复(稳定性)计算为储存后的FVIII:C(生色底物FVIII活性测定)除以时间0时的FVIII:C活性的百分比。定义时间0(0.22μm过滤后)时的FVIII:C活性为100%。
表19
*FVIII:C恢复基于在不同温度条件下(液态下的稳定性测试)的储存后的FVIII:C活性测量(生色底物活性测定)
表20
*FVIII:C恢复基于在不同温度条件下(液态下的稳定性测试)的储存后的FVIII:C活性测量(生色底物活性测定)
表21
*FVIII:C恢复基于在不同温度条件下(液态下的稳定性测试)的储存后的FVIII:C活性测量(生色底物活性测定)
实施例3:
经由脱盐柱的缓冲液交换后溶液的外观
如实施例1所述通过缓冲液交换获得不同的组合物(起始材料中通过生色底物FVIII活性测定的FVIII:C活性为8317IU/mL)。评价组合物在缓冲液交换后的其外观。
表22
实施例4:
在经由脱盐柱的缓冲液交换后在FVIII:C活性上的产率和溶液的外观和在储存后FVIII:C活性的恢复。
如实施例1所述通过缓冲液交换获得不同的组合物(起始材料中的FVIII:C活性为4780IU/mL)。
评价组合物在缓冲液交换后的其外观。此外,随后将组合物无菌过滤(0.22μm),并在过滤(时间0)后直接测定它们的FVIII:C活性(生色底物测定),并在2-8℃下储存1、2和3天和在25℃和40℃下储存3天后测定它们的FVIII:C活性。
配制过程的在FVIII:C活性上的产率计算为在缓冲液交换后获得的组合物中的FVIII:C除以在缓冲液交换前的溶液中的FVIII:C的百分比,其中适当调整稀释度。将储存后的恢复(稳定性)计算为储存后的FVIII:C除以时间0时的FVIII:C活性的百分比。定义时间0(0.22μm过滤后)时的FVIII:C活性为100%。
表23
*经由脱盐柱的缓冲液交换后的FVIII:C恢复(基于使用生色底物FVIII活性测定的FVIII活性测量)
**在不同温度条件下(液态下的稳定性测试)的储存后的FVIII:C恢复(基于使用生色底物FVIII活性测定的FVIII活性测量)
实施例5:
在升高的温度下储存后在冷冻干燥的制剂中的HMWC形成(SE-HPLC)。
通过用合适的缓冲溶液稀释FVIII浓缩物来调节本实施例的制剂的FVIII:C活性和赋形剂的浓度。获得的制剂显示FVIII:C浓度为430-480IU/mL。然后将溶液分配(2.5mL)并冷冻干燥。将获得的冻干物储存在+40℃,并在1、3、6和12个月后取样。在冻干物储存之前和之后从重构的溶液中取样并在-70℃冷冻。在水浴(+37℃)中解冻后通过SE-HPLC测定样品中的HMWC。
表24
实施例6
在升高的温度下储存后在冷冻干燥的制剂中的FVIII:C生色底物活性测定和HMWC形成(SE-HPLC)
通过用合适的缓冲溶液稀释FVIII浓缩物来调节FVIII:C活性和赋形剂的浓度。然后将溶液分配(2.5mL)并冷冻干燥。将获得的冻干物储存在+40℃,并在1、3、6、12、18和24个月后取样。在冻干物储存之前和之后从重构的溶液中取样并在-70℃冷冻。在水浴(+37℃)中解冻后测定冷冻储存的样品中的HMWC。
测定冷冻干燥前的新鲜溶液中和直接在冷冻干燥后或储存后的新鲜重构冻干物中的FVIII:C活性(生色底物FVIII活性测定)。将恢复(稳定性)计算为储存后的FVIII:C除以时间0时的FVIII:C活性的百分比。定义时间0(冷冻干燥后)时的FVIII:C活性为100%。
表25
实施例7:
在经由脱盐柱的缓冲液交换后,制备FVIII制剂和评价溶液性质。
根据供应商的说明书并如实施例1中所述,通过经由NAP-25脱盐柱(GEHealthcare SephadexTMG 25;目录号17-0852-01)的缓冲液交换将纯化的CSL627配制成所需的组合物。随后,基于生色活性测定稀释不同的组合物以获得使用生色底物FVIII活性测定的约7000IU/mL的FVIII:C活性(效力)。然后研究不同的组合物的外观(浊度)。
表27
结果在图1中图示。点表示高于18NTU的阈值水平的浊度,菱形表示澄清的溶液(浊度小于或等于18NTU)。
实施例8
在升高的温度下储存后在冷冻干燥的制剂中的HMWC形成(SE-HPLC)。
通过用合适的缓冲溶液稀释FVIII浓缩物(CSL627)来调节本实施例的制剂的FVIII:C活性和赋形剂的浓度。获得的制剂显示约390-435IU/mL的FVIII:C浓度。然后将溶液分配(2.5mL)并冷冻干燥。将获得的冻干物储存在+40℃,并在1、3、6、9和12个月后取样。在冻干物储存之前和之后从重构的溶液中取样并在-70℃冷冻。在水浴(+37℃)中解冻后通过SE-HPLC测定样品中的HMWC。
表28
实施例9
在升高的温度下储存后在冷冻干燥的制剂中的FVIII:C生色底物活性测定和HMWC形成(SE-HPLC)
通过用合适的缓冲溶液稀释FVIII浓缩物(CSL627)来调节FVIII:C活性和赋形剂的浓度。然后将溶液分配(2.5mL)并冷冻干燥。将获得的冻干物储存在+40℃,并在1、3、6、9和12个月后取样。在冻干物储存之前和之后从重构的溶液中取样并在-70℃冷冻。在水浴(+37℃)中解冻后测定冷冻储存的样品中的HMWC。
测定冷冻干燥前的新鲜溶液中和直接在冷冻干燥后或储存后的新鲜重构冻干物中的FVIII:C活性(生色底物FVIII活性测定)。将恢复(稳定性)计算为储存后的FVIII:C除以时间0时的FVIII:C活性的百分比。定义时间0(冷冻干燥后)时的FVIII:C活性为100%。
表29
表30
实施例10
在升高的温度下储存后在冷冻干燥的制剂中的FVIII:C生色底物活性测定和HMWC形成(SE-HPLC)
通过用合适的缓冲溶液稀释FVIII浓缩物(CSL627)来调节FVIII:C活性和赋形剂的浓度。然后将溶液分配(2.5mL)并冷冻干燥。将获得的冻干物储存在+40℃,并在3、6和9个月后取样。在冻干物储存之前和之后从重构的溶液中取样并在-70℃冷冻。在水浴(+37℃)中解冻后测定冷冻储存的样品中的HMWC。
测定冷冻干燥前的新鲜溶液中和直接在冷冻干燥后或储存后的新鲜重构冻干物中的FVIII:C活性(生色底物FVIII活性测定)。将恢复(稳定性)计算为储存后的FVIII:C除以时间0时的FVIII:C活性的百分比。定义时间0(冷冻干燥后)时的FVIII:C活性为100%。
表31
表32
表33
表34
序列表
<110> CSL Behring GmbH
CSL Behring GmbH
<120> 因子VIII制剂
<130> A213
<150> EP 14179732.4
<151> 2014-08-04
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 2332
<212> PRT
<213> 智人
<400> 1
Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr
1 5 10 15
Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro
20 25 30
Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys
35 40 45
Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro
50 55 60
Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val
65 70 75 80
Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val
85 90 95
Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala
100 105 110
Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val
115 120 125
Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn
130 135 140
Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser
145 150 155 160
His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu
165 170 175
Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu
180 185 190
His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp
195 200 205
His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser
210 215 220
Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg
225 230 235 240
Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His
245 250 255
Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu
260 265 270
Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile
275 280 285
Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly
290 295 300
Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met
305 310 315 320
Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg
325 330 335
Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp
340 345 350
Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe
355 360 365
Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His
370 375 380
Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu
385 390 395 400
Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro
405 410 415
Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr
420 425 430
Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile
435 440 445
Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile
450 455 460
Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile
465 470 475 480
Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys
485 490 495
His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys
500 505 510
Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys
515 520 525
Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala
530 535 540
Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp
545 550 555 560
Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe
565 570 575
Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln
580 585 590
Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe
595 600 605
Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser
610 615 620
Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu
625 630 635 640
Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr
645 650 655
Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro
660 665 670
Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp
675 680 685
Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala
690 695 700
Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu
705 710 715 720
Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala
725 730 735
Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Arg Ser Thr Arg
740 745 750
Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp Ile Glu Lys
755 760 765
Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys Ile Gln Asn
770 775 780
Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser Pro Thr Pro
785 790 795 800
His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr Glu Thr Phe
805 810 815
Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn Ser Leu Ser
820 825 830
Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly Asp Met Val
835 840 845
Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu Lys Leu Gly
850 855 860
Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys Val Ser Ser
865 870 875 880
Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn Leu Ala Ala
885 890 895
Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met Pro Val His
900 905 910
Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe Gly Lys Lys Ser Ser Pro
915 920 925
Leu Thr Glu Ser Gly Gly Pro Leu Ser Leu Ser Glu Glu Asn Asn Asp
930 935 940
Ser Lys Leu Leu Glu Ser Gly Leu Met Asn Ser Gln Glu Ser Ser Trp
945 950 955 960
Gly Lys Asn Val Ser Ser Thr Glu Ser Gly Arg Leu Phe Lys Gly Lys
965 970 975
Arg Ala His Gly Pro Ala Leu Leu Thr Lys Asp Asn Ala Leu Phe Lys
980 985 990
Val Ser Ile Ser Leu Leu Lys Thr Asn Lys Thr Ser Asn Asn Ser Ala
995 1000 1005
Thr Asn Arg Lys Thr His Ile Asp Gly Pro Ser Leu Leu Ile Glu
1010 1015 1020
Asn Ser Pro Ser Val Trp Gln Asn Ile Leu Glu Ser Asp Thr Glu
1025 1030 1035
Phe Lys Lys Val Thr Pro Leu Ile His Asp Arg Met Leu Met Asp
1040 1045 1050
Lys Asn Ala Thr Ala Leu Arg Leu Asn His Met Ser Asn Lys Thr
1055 1060 1065
Thr Ser Ser Lys Asn Met Glu Met Val Gln Gln Lys Lys Glu Gly
1070 1075 1080
Pro Ile Pro Pro Asp Ala Gln Asn Pro Asp Met Ser Phe Phe Lys
1085 1090 1095
Met Leu Phe Leu Pro Glu Ser Ala Arg Trp Ile Gln Arg Thr His
1100 1105 1110
Gly Lys Asn Ser Leu Asn Ser Gly Gln Gly Pro Ser Pro Lys Gln
1115 1120 1125
Leu Val Ser Leu Gly Pro Glu Lys Ser Val Glu Gly Gln Asn Phe
1130 1135 1140
Leu Ser Glu Lys Asn Lys Val Val Val Gly Lys Gly Glu Phe Thr
1145 1150 1155
Lys Asp Val Gly Leu Lys Glu Met Val Phe Pro Ser Ser Arg Asn
1160 1165 1170
Leu Phe Leu Thr Asn Leu Asp Asn Leu His Glu Asn Asn Thr His
1175 1180 1185
Asn Gln Glu Lys Lys Ile Gln Glu Glu Ile Glu Lys Lys Glu Thr
1190 1195 1200
Leu Ile Gln Glu Asn Val Val Leu Pro Gln Ile His Thr Val Thr
1205 1210 1215
Gly Thr Lys Asn Phe Met Lys Asn Leu Phe Leu Leu Ser Thr Arg
1220 1225 1230
Gln Asn Val Glu Gly Ser Tyr Asp Gly Ala Tyr Ala Pro Val Leu
1235 1240 1245
Gln Asp Phe Arg Ser Leu Asn Asp Ser Thr Asn Arg Thr Lys Lys
1250 1255 1260
His Thr Ala His Phe Ser Lys Lys Gly Glu Glu Glu Asn Leu Glu
1265 1270 1275
Gly Leu Gly Asn Gln Thr Lys Gln Ile Val Glu Lys Tyr Ala Cys
1280 1285 1290
Thr Thr Arg Ile Ser Pro Asn Thr Ser Gln Gln Asn Phe Val Thr
1295 1300 1305
Gln Arg Ser Lys Arg Ala Leu Lys Gln Phe Arg Leu Pro Leu Glu
1310 1315 1320
Glu Thr Glu Leu Glu Lys Arg Ile Ile Val Asp Asp Thr Ser Thr
1325 1330 1335
Gln Trp Ser Lys Asn Met Lys His Leu Thr Pro Ser Thr Leu Thr
1340 1345 1350
Gln Ile Asp Tyr Asn Glu Lys Glu Lys Gly Ala Ile Thr Gln Ser
1355 1360 1365
Pro Leu Ser Asp Cys Leu Thr Arg Ser His Ser Ile Pro Gln Ala
1370 1375 1380
Asn Arg Ser Pro Leu Pro Ile Ala Lys Val Ser Ser Phe Pro Ser
1385 1390 1395
Ile Arg Pro Ile Tyr Leu Thr Arg Val Leu Phe Gln Asp Asn Ser
1400 1405 1410
Ser His Leu Pro Ala Ala Ser Tyr Arg Lys Lys Asp Ser Gly Val
1415 1420 1425
Gln Glu Ser Ser His Phe Leu Gln Gly Ala Lys Lys Asn Asn Leu
1430 1435 1440
Ser Leu Ala Ile Leu Thr Leu Glu Met Thr Gly Asp Gln Arg Glu
1445 1450 1455
Val Gly Ser Leu Gly Thr Ser Ala Thr Asn Ser Val Thr Tyr Lys
1460 1465 1470
Lys Val Glu Asn Thr Val Leu Pro Lys Pro Asp Leu Pro Lys Thr
1475 1480 1485
Ser Gly Lys Val Glu Leu Leu Pro Lys Val His Ile Tyr Gln Lys
1490 1495 1500
Asp Leu Phe Pro Thr Glu Thr Ser Asn Gly Ser Pro Gly His Leu
1505 1510 1515
Asp Leu Val Glu Gly Ser Leu Leu Gln Gly Thr Glu Gly Ala Ile
1520 1525 1530
Lys Trp Asn Glu Ala Asn Arg Pro Gly Lys Val Pro Phe Leu Arg
1535 1540 1545
Val Ala Thr Glu Ser Ser Ala Lys Thr Pro Ser Lys Leu Leu Asp
1550 1555 1560
Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln Ile Pro Lys Glu
1565 1570 1575
Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys Thr Ala Phe Lys
1580 1585 1590
Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys Glu Ser Asn His
1595 1600 1605
Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys Pro Glu Ile Glu
1610 1615 1620
Val Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg Leu Cys Ser Gln
1625 1630 1635
Asn Pro Pro Val Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr
1640 1645 1650
Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile
1655 1660 1665
Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp
1670 1675 1680
Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg His Tyr
1685 1690 1695
Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser
1700 1705 1710
Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro
1715 1720 1725
Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe
1730 1735 1740
Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu
1745 1750 1755
Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val
1760 1765 1770
Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser
1775 1780 1785
Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg
1790 1795 1800
Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys
1805 1810 1815
Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys
1820 1825 1830
Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His
1835 1840 1845
Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu
1850 1855 1860
Asn Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu
1865 1870 1875
Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu
1880 1885 1890
Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu
1895 1900 1905
Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly
1910 1915 1920
Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln
1925 1930 1935
Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile
1940 1945 1950
His Ser Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys
1955 1960 1965
Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe
1970 1975 1980
Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val
1985 1990 1995
Glu Cys Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu
2000 2005 2010
Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala
2015 2020 2025
Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr
2030 2035 2040
Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser
2045 2050 2055
Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val
2060 2065 2070
Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly
2075 2080 2085
Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile
2090 2095 2100
Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn
2105 2110 2115
Ser Thr Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser
2120 2125 2130
Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr
2135 2140 2145
Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg
2150 2155 2160
Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu
2165 2170 2175
Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser
2180 2185 2190
Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala
2195 2200 2205
Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val
2210 2215 2220
Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met
2225 2230 2235
Lys Val Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr
2240 2245 2250
Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly
2255 2260 2265
His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe
2270 2275 2280
Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp
2285 2290 2295
Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp
2300 2305 2310
Val His Gln Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala
2315 2320 2325
Gln Asp Leu Tyr
2330
<210> 2
<211> 1444
<212> PRT
<213> 人工序列
<220>
<223> 单链FVIII dBN(64-53)
<400> 2
Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser Trp Asp Tyr
1 5 10 15
Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg Phe Pro Pro
20 25 30
Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val Tyr Lys Lys
35 40 45
Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile Ala Lys Pro
50 55 60
Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln Ala Glu Val
65 70 75 80
Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser His Pro Val
85 90 95
Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser Glu Gly Ala
100 105 110
Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp Asp Lys Val
115 120 125
Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu Lys Glu Asn
130 135 140
Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser Tyr Leu Ser
145 150 155 160
His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile Gly Ala Leu
165 170 175
Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr Gln Thr Leu
180 185 190
His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly Lys Ser Trp
195 200 205
His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp Ala Ala Ser
210 215 220
Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr Val Asn Arg
225 230 235 240
Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val Tyr Trp His
245 250 255
Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile Phe Leu Glu
260 265 270
Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser Leu Glu Ile
275 280 285
Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met Asp Leu Gly
290 295 300
Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His Asp Gly Met
305 310 315 320
Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro Gln Leu Arg
325 330 335
Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp Leu Thr Asp
340 345 350
Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser Pro Ser Phe
355 360 365
Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr Trp Val His
370 375 380
Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro Leu Val Leu
385 390 395 400
Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn Asn Gly Pro
405 410 415
Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met Ala Tyr Thr
420 425 430
Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu Ser Gly Ile
435 440 445
Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu Leu Ile Ile
450 455 460
Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro His Gly Ile
465 470 475 480
Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys Gly Val Lys
485 490 495
His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe Lys Tyr Lys
500 505 510
Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp Pro Arg Cys
515 520 525
Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg Asp Leu Ala
530 535 540
Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu Ser Val Asp
545 550 555 560
Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val Ile Leu Phe
565 570 575
Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu Asn Ile Gln
580 585 590
Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp Pro Glu Phe
595 600 605
Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val Phe Asp Ser
610 615 620
Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp Tyr Ile Leu
625 630 635 640
Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe Ser Gly Tyr
645 650 655
Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr Leu Phe Pro
660 665 670
Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro Gly Leu Trp
675 680 685
Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly Met Thr Ala
690 695 700
Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp Tyr Tyr Glu
705 710 715 720
Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys Asn Asn Ala
725 730 735
Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro Ser Thr Arg
740 745 750
Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Thr Thr Leu Gln
755 760 765
Ser Asp Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met
770 775 780
Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro
785 790 795 800
Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu
805 810 815
Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn
820 825 830
Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln
835 840 845
Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu
850 855 860
Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu
865 870 875 880
Asp Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser
885 890 895
Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala
900 905 910
Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe
915 920 925
Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys
930 935 940
Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His
945 950 955 960
Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn
965 970 975
Pro Ala His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe
980 985 990
Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu
995 1000 1005
Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1010 1015 1020
Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met
1025 1030 1035
Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg
1040 1045 1050
Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile
1055 1060 1065
His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr
1070 1075 1080
Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val
1085 1090 1095
Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu
1100 1105 1110
Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val
1115 1120 1125
Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His
1130 1135 1140
Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp
1145 1150 1155
Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala
1160 1165 1170
Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu
1175 1180 1185
Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln
1190 1195 1200
Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser
1205 1210 1215
Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly
1220 1225 1230
Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys
1235 1240 1245
His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu
1250 1255 1260
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu
1265 1270 1275
Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu
1280 1285 1290
Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe
1295 1300 1305
Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His
1310 1315 1320
Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro
1325 1330 1335
Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr
1340 1345 1350
Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr
1355 1360 1365
Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp
1370 1375 1380
Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn
1385 1390 1395
Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu
1400 1405 1410
Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln
1415 1420 1425
Ile Ala Leu Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu
1430 1435 1440
Tyr
Claims (23)
1.凝血因子VIII的水性组合物,其包含:
a.FVIII分子;
b.40至195mM的钠盐;
c.组氨酸;
d.至少1mM的钙盐;和
e.表面活性剂;
其中[His]≥180mM-20*[Ca2+],其中[Ca2+]是所述水性组合物中钙离子的浓度,以毫摩尔/升表示,并且[His]是所述水性组合物中组氨酸的浓度,以毫摩尔/升表示,条件是[His]>0;并且其中所述组合物的体积渗透摩尔浓度为600mOsmol/L或更低。
2.根据权利要求1所述的水性组合物,其中所述水性组合物中的钠盐的浓度为45至95mM。
3.根据权利要求1或2所述的水性组合物,其中[His]为5至200mM。
4.根据前述权利要求中任一项所述的水性组合物,其中[Ca2+]为5至100mM。
5.根据前述权利要求中任一项所述的水性组合物,其中所述水性组合物的pH为5至9。
6.根据前述权利要求中任一项所述的水性组合物,其中所述组合物在(i)冻干、(ii)将冻干的组合物在+25℃的温度和40%的相对湿度下储存12个月和(iii)随后在蒸馏水中重构冻干的组合物之后,相对于在(i)冻干和不储存冻干的组合物、(ii)随后立即在蒸馏水中重构之后的相同组合物,显示至少80%的FVIII:C活性恢复。
7.根据前述权利要求中任一项所述的水性组合物,其中当在4℃以液态储存时,所述水性组合物保持至少80%的因子VIII活性持续至少48小时。
8.根据前述权利要求中任一项所述的水性组合物,其中所述钙盐是氯化钙。
9.根据前述权利要求中任一项所述的水性组合物,其中所述钠盐是氯化钠。
10.根据前述权利要求中任一项所述的水性组合物,其中所述组合物还包含碳水化合物。
11.根据权利要求10所述的水性组合物,其中所述碳水化合物是蔗糖。
12.根据权利要求10或11所述的水性组合物,其中所述碳水化合物的浓度为1至20%(w/w)。
13.根据前述权利要求中任一项所述的水性组合物,其中所述表面活性剂的浓度为0.001至0.2%(v/v)。
14.根据前述权利要求中任一项所述的水性组合物,其中所述表面活性剂是非天然存在的表面活性剂。
15.根据前述权利要求中任一项所述的水性组合物,其中所述组合物还包含除组氨酸以外的至少一种氨基酸。
16.根据权利要求15所述的水性组合物,其中所述除组氨酸以外的至少一种氨基酸选自精氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、甲硫氨酸、苯丙氨酸、亮氨酸、异亮氨酸及其组合。
17.根据前述权利要求中任一项所述的水性组合物,其中所述组合物还包含至少一种抗氧化剂。
18.根据权利要求17所述的水性组合物,其中所述至少一种抗氧化剂选自还原型谷胱甘肽、甲硫氨酸、半胱氨酸、亚硫酸钠、维生素A、维生素E、抗坏血酸、抗坏血酸钠及其组合。
19.根据权利要求17或18所述的水性组合物,其中所述至少一种抗氧化剂的浓度为0.05-100mM。
20.根据前述权利要求中任一项所述的水性组合物,其中所述FVIII分子是非天然存在的FVIII分子,优选重组产生的FVIII分子,例如(i)B结构域缺失或截短的FVIII分子,(ii)重组产生的双链FVIII分子,或(iii)单链FVIII分子。
21.通过冻干根据前述权利要求中任一项所述的水性组合物可获得的组合物。
22.凝血因子VIII的水性组合物,其可通过用水溶液重构根据权利要求21的冻干的组合物而获得。
23.一种稳定FVIII分子的方法,包括混合权利要求1中定义的组分以获得水性组合物,并冻干所述水性组合物。
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PCT/EP2015/066999 WO2016020210A1 (en) | 2014-08-04 | 2015-07-24 | Csl behring gmbh |
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EP (1) | EP3177317B1 (zh) |
JP (1) | JP6516829B2 (zh) |
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CA (1) | CA2956412A1 (zh) |
DK (1) | DK3177317T3 (zh) |
ES (1) | ES2788870T3 (zh) |
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MX (1) | MX2017000862A (zh) |
NZ (1) | NZ729629A (zh) |
PL (1) | PL3177317T3 (zh) |
RU (1) | RU2689338C2 (zh) |
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CN110950964B (zh) * | 2018-09-26 | 2021-06-18 | 安源医药科技(上海)有限公司 | 突变型单链人凝血因子viii融合蛋白及其制备方法与用途 |
CN113105562A (zh) * | 2018-09-26 | 2021-07-13 | 安源医药科技(上海)有限公司 | 突变型单链人凝血因子viii在制备融合蛋白中的应用 |
CN113105562B (zh) * | 2018-09-26 | 2023-12-01 | 安源医药科技(上海)有限公司 | 突变型单链人凝血因子viii在制备融合蛋白中的应用 |
CN112138149A (zh) * | 2019-06-28 | 2020-12-29 | 北京基科晟斯医药科技有限公司 | 重组凝血因子viii制剂 |
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BR112017002090A2 (pt) | 2018-01-30 |
AU2015299224A1 (en) | 2017-03-23 |
US20170252412A1 (en) | 2017-09-07 |
CN106687126B (zh) | 2020-07-28 |
RU2689338C2 (ru) | 2019-05-27 |
MX2017000862A (es) | 2017-05-01 |
IL250343B (en) | 2020-10-29 |
SG10201900598TA (en) | 2019-02-27 |
KR102192494B1 (ko) | 2020-12-18 |
CA2956412A1 (en) | 2016-02-11 |
JP2017528440A (ja) | 2017-09-28 |
EP3177317B1 (en) | 2020-03-18 |
DK3177317T3 (en) | 2020-06-15 |
SG11201700550YA (en) | 2017-02-27 |
RU2017106159A (ru) | 2018-09-06 |
PL3177317T3 (pl) | 2020-07-27 |
US10238718B2 (en) | 2019-03-26 |
WO2016020210A1 (en) | 2016-02-11 |
JP6516829B2 (ja) | 2019-05-22 |
RU2017106159A3 (zh) | 2018-11-28 |
BR112017002090B1 (pt) | 2021-06-01 |
NZ729629A (en) | 2021-12-24 |
IL250343A0 (en) | 2017-03-30 |
KR20170040327A (ko) | 2017-04-12 |
ES2788870T3 (es) | 2020-10-23 |
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AU2015299224B2 (en) | 2019-06-20 |
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