CN1342087A - 长期稳定的制剂 - Google Patents
长期稳定的制剂 Download PDFInfo
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- CN1342087A CN1342087A CN00804421A CN00804421A CN1342087A CN 1342087 A CN1342087 A CN 1342087A CN 00804421 A CN00804421 A CN 00804421A CN 00804421 A CN00804421 A CN 00804421A CN 1342087 A CN1342087 A CN 1342087A
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Abstract
一种稳定的G-CSF制剂,所述制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的G-CSF,且在50℃1个月或60℃2周的加速试验后甲硫氨酸-氧化的G-CSF为1%或更少。一种抑制含有甲硫氨酸残基的生理活性蛋白质产生甲硫氨酸残基被氧化的衍生物的方法,其特征在于将甲硫氨酸加到含有该蛋白质的组合物中。
Description
发明领域
本发明涉及G-CSF(粒性白细胞集落刺激因子)制剂,尤其涉及活性组分损失少及低甲硫氨酸-氧化的G-CSF含量的特别稳定的G-CSF制剂。
现有技术
G-CSF是一种分子量约为20,000的糖蛋白,它作用于嗜中性白细胞的前体细胞以促进它们增殖和分化而成熟。
通过培养患口腔基底癌病人的一种肿瘤细胞系,可提纯出高纯度的人G-CSF。目前,采用基因工程技术已成功地克隆了人G-CSF基因,可从微生物或动物细胞大量生产重组人G-CSF。我们也已将这种提纯的G-CSF转化为制剂产品,并作为抗感染药供应市场(日本专利2116515)。
G-CSF的用量极小,即含有0.1-1000μg(优选5-500μg)G-CSF的制剂通常可供一个成年人每周给药1-7次。但是,这种G-CSF易被安瓿、注射器等的壁吸附。G-CSF不稳定,对环境因素如温度、湿度、氧、UV射线等非常敏感,并可发生物理或化学变化包括缔合、聚合或氧化,这将导致活性大大丧失。
因此,设计了多种配方以向市场提供稳定的G-CSF制剂。例如,含有以下至少一种成分的制剂:(a)选自苏氨酸、色氨酸、赖氨酸、羟赖氨酸、组氨酸、精氨酸、半胱氨酸、胱氨酸和甲硫氨酸的至少一种氨基酸;(b)至少一种含硫的还原剂;或(c)至少一种抗氧剂(日本专利2577744)。也有含表面活性剂如聚山梨酯为稳定剂的G-CSF制剂(日本专利申请146826/88)。
也有报道含有麦芽糖、棉子糖、蔗糖、海藻糖或氨基糖的G-CSF冻干制剂,它可以限制G-CSF在容器中的沉积从而抑制其化学变化(日本专利公开504784/96)。
市场上的一些产品,通常含有蛋白质如人血清白蛋白或纯化的明胶作为稳定剂,用来抑制化学或物理变化。然而,添加这种蛋白质稳定剂也带来了一些问题,例如,必需的且非常复杂的除去病毒污染的过程。
然而,在没有这种蛋白质的情况下,又可能产生Met(甲硫氨酸)-氧化的G-CSF,这就带来了变质的问题。
发明内容
本发明的一个目的是提供一种G-CSF制剂,它可更稳定地长期贮存,并且Met-氧化的G-CSF的含量较低。
经过仔细的针对上述目的的研究,我们完成了本发明G-CSF制剂,通过加入特定氨基酸联用为稳定剂,可使该制剂在长期贮存后仍含高剩余率的G-CSF,并且其中Met-氧化的G-CSF的含量较低。
因此,本发明提供了一种稳定的G-CSF制剂,该制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的G-CSF,在50℃1个月或60℃2周的加速试验后Met-氧化的G-CSF为1%或更少。
本发明还提供含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苏氨酸和天冬酰胺的氨基酸;一种或多种选自疏水性氨基酸的氨基酸;和甲硫氨酸的所述G-CSF制剂。
本发明提供所述G-CSF制剂,其中的疏水性氨基酸选自苯丙氨酸、色氨酸和亮氨酸。
本发明还提供含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸和谷氨酸的氨基酸;一种或多种选自苯丙氨酸、色氨酸和亮氨酸的氨基酸;和甲硫氨酸的所述G-CSF制剂。
本发明还提供含有苯丙氨酸、精氨酸和甲硫氨酸的所述G-CSF制剂。
本发明还提供基本上不含蛋白质为稳定剂的所述G-CSF制剂。
本发明还提供冻干制剂形式的所述G-CSF制剂。
本发明还提供另外含有露醇的所述G-CSF制剂。
本发明还提供另外含有表面活性剂的所述G-CSF制剂。
本发明还提供其中表面活性剂为聚氧乙烯脱水山梨糖醇烷基酯的所述G-CSF制剂。
本发明还提供其中表面活性剂为吐温20和/或80的G-CSF制剂。
本发明还提供pH值为5-7的所述G-CSF制剂。
本发明还提供pH值为5.5-6.8的所述G-CSF制剂。
本发明还提供pH值为6.5的所述G-CSF制剂。
本发明还提供G-CSF产自CHO细胞的所述G-CSF制剂。
本发明还提供一种稳定的G-CSF制剂,所述制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的G-CSF,其特征在于含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苏氨酸和天冬酰胺的氨基酸;和一种或多种选自疏水性氨基酸的氨基酸;其中pH值为5-7。
本发明还提供一种稳定的G-CSF制剂,所述制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的G-CSF,其特征在于含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸和谷氨酸的氨基酸;和一种或多种选自苯丙氨酸、色氨酸和亮氨酸的氨基酸;其中pH值为5-7。
本发明还提供pH值为6.5的上述两种制剂中的任何一种G-CSF制剂。
本发明还提供一种抑制含有甲硫氨酸残基的生理活性蛋白质在甲硫氨酸残基上氧化产生变体的方法,包括将甲硫氨酸加到含有所述蛋白质的组合物中。
本发明提供所述方法,其中生理活性蛋白质为细胞因子或生理活性肽。
本发明提供所述方法,其中生理活性蛋白质为集落刺激因子或PTH。
本发明提供所述方法,其中生理活性蛋白质为G-CSF、红细胞生成素或PTH。
本发明提供所述方法,其中不存在作为稳定剂的其它蛋白质。
本发明提供所述方法,所述组合物含有具有甲硫氨酸残基的生理活性蛋白质,其中所述组合物为冻干或溶液形式。
本发明还提供含有具有甲硫氨酸残基的生理活性蛋白质的稳定组合物,其中还含有甲硫氨酸和一种或多种其它氨基酸。
本发明提供含有具有甲硫氨酸残基的生理活性蛋白质的稳定组合物,其中所述一种或多种的氨基酸选自赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苯丙氨酸、色氨酸、亮氨酸、异亮氨酸、缬氨酸、丙氨酸、脯氨酸、甘氨酸、丝氨酸、苏氨酸、天冬酰胺、谷氨酰胺和酪氨酸。
本发明提供含有具有甲硫氨酸残基的生理活性蛋白质的稳定组合物,其特征在于它不含其他蛋白质为稳定剂。
附图简述
图1为60℃加速试验2周后,用下述方法2测定的试样34和36的色谱图。
图2为刚制备后及50℃加速试验1个月后,用下述方法2测定的试样34-36的色谱图。
图3为用实施例6中方法测定的甲状旁腺素溶液制剂的HPLC色谱图(50℃下贮存3天),这表明加入甲硫氨酸可抑制甲硫氨酸残基的氧化。其中,中央最高峰对应着未破坏PTH,而标为Met-8和Met-18的峰分别对应着在第8和18甲硫氨酸残基氧化的PTH。
本发明最优选实施方案
用于本发明制剂的G-CSF包括任何高纯度的人G-CSF。具体而言,它可衍生于天然来源或基因重组,只要它基本上具有与哺乳动物的G-CSF特别是人G-CSF一样的生物活性。基因重组的G-CSF可与天然G-CSF具有相同的氨基酸序列,或在所述氨基酸序列中含有中间缺失、取代或添加一个或多个氨基酸,只要它也具有所述的生物活性。本发明中的G-CSF可用任何方法制备,例如可用各种技术从人肿瘤细胞系的培养物中提取和纯化,或在大肠杆菌、酵母菌、中国仓鼠卵巢细胞(CHO)、C127等中采用基因工程技术生产,然后再用各种技术提取和纯化。优选G-CSF在大肠杆菌、酵母菌或CHO中采用基因重组技术生产,最优选在CHO中采用基因重组生产。
本发明G-CSF制剂优选基本上不含蛋白质,如人血清白蛋白或纯化明胶为稳定剂。
与已知的G-CSF制剂相比,本发明G-CSF制剂非常稳定,该制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的、优选95%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的、优选95%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的、优选95%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的、优选95%或更多的G-CSF,和或在50℃1个月或60℃2周的加速试验后含有1%或更少、优选低于检测限的Met-氧化的G-CSF。
本发明G-CSF制剂的一个实施例是一种G-CSF制剂,该制剂中含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苏氨酸和天冬酰胺,优选一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸和谷氨酸的氨基酸;一种或多种选自疏水性氨基酸,优选选自苯丙氨酸、色氨酸和亮氨酸的氨基酸;和甲硫氨酸。
本发明G-CSF制剂的另一实施例是一种稳定的G-CSF制剂,该稳定制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的G-CSF,并且在50℃1个月或60℃2周的加速试验后检测Met-氧化的G-CSF的含量为1%或更少,其特征在于含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苏氨酸和天冬酰胺的氨基酸,优选一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸和谷氨酸的氨基酸;一种或多种选自疏水性氨基酸,优选选自苯丙氨酸、色氨酸和亮氨酸的氨基酸;和甲硫氨酸其中PH值为5-7。
本发明所用氨基酸包括游离氨基酸及其盐如钠盐、钾盐和盐酸化物。本发明制剂可含有这些氨基酸的D-、L-和DL-变体,优选为L-变体及其盐。
根据所用氨基酸的类型,采用下述实验方法确定加入本发明制剂中的氨基酸的量的优选范围。通常,所加的最终剂量为0.001-50mg/ml。例如,优选加入0.1-25mg/ml、更优选1-20mg/ml的苯丙氨酸,优选加入0.1-25mg/ml、更优选1-20mg/ml的精氨酸,和优选加入0.001-5mg/ml、更优选0.01-4mg/ml的甲硫氨酸。
本发明制剂可含有等渗剂,例如,聚乙二醇;和糖类如右旋糖酐,甘露醇、山梨醇、肌醇、葡萄糖、果糖、乳糖、木糖、甘露醇、麦芽糖、蔗糖和棉子糖。优选甘露醇。制剂中所加甘露醇的量为1-100mg/ml、更优选5-60mg/ml。
本发明制剂还进一步含有表面活性剂。典型的表面活性剂包括:
非离子表面活性剂,例如,脱水山梨醇脂肪酸酯如脱水山梨醇单辛酸酯、脱水山梨醇单月桂酸酯、脱水山梨醇单棕榈酸酯;甘油脂肪酸酯如甘油一辛酸酯、甘油一豆蔻酸酯、甘油一硬脂酸酯;聚甘油脂肪酸酯如十甘油基一硬脂酸酯、十甘油基二硬脂酸酯、十甘油基一亚油酸酯;聚氧乙烯脱水山梨醇脂肪酸酯如聚氧乙烯脱水山梨醇单月桂酸酯、聚氧乙烯脱水山梨醇单油酸酯、聚氧乙烯脱水山梨醇单硬脂酸酯、聚氧乙烯脱水山梨醇单棕榈酸酯、聚氧乙烯脱水山梨醇三油酸酯、聚氧乙烯脱水山梨醇三硬脂酸酯;聚氧乙烯山梨醇脂肪酸酯如聚氧乙烯山梨醇四硬脂酸酯、聚氧乙烯山梨醇四油酸酯;聚氧乙烯甘油基脂肪酸酯如聚氧乙烯甘油基单硬脂酸酯;聚乙二醇脂肪酸酯如聚乙二醇二硬脂酸酯;聚氧乙烯烷基醚如聚氧乙烯十二烷基醚;聚氧乙烯-聚氧丙烯烷基醚如聚氧乙烯-聚氧丙烯乙二醇醚、聚氧乙烯-聚氧丙烯丙基醚、聚氧乙烯-聚氧丙烯十六基醚;聚氧乙烯烷基苯基醚如聚氧乙烯壬基苯基醚;聚氧乙烯硬化蓖麻油如聚氧乙烯蓖麻油、聚氧乙烯硬化蓖麻油(聚氧乙烯氢化蓖麻油);聚氧乙烯蜂蜡衍生物如聚氧乙烯山梨醇蜂蜡;聚氧乙烯羊毛脂衍生物如聚氧乙烯羊毛脂;聚氧乙烯脂肪酰胺如HLB值为6-18的聚氧乙烯硬脂酰胺。
阴离子表面活性剂,例如,具有C10-C18烷基的烷基硫酸盐如十六烷基硫酸钠、十二烷基硫酸钠、油基硫酸钠;平均具有2-4个环氧乙烷(EO)摩尔数单位和C10-C18烷基的聚氧乙烯烷基醚硫酸盐,如聚氧乙烯十二烷基硫酸钠;具有C8-C18烷基的烷基磺基琥珀酸酯盐如十二烷基磺基琥珀酸钠。
天然表面活性剂,例如,卵磷脂;甘油磷脂类;神经鞘磷脂类如神经鞘磷脂;含C12-18脂肪酸的蔗糖脂肪酸酯。一种或多种上述表面活性剂可联用加入本发明制剂中。
优选表面活性剂为聚氧乙烯脱水山梨醇脂肪酸酯,更优选为吐温20、21、40、60、65、80、81、85,最优选为吐温20和80。
典型地,加入本发明G-CSF制剂中的表面活性剂的量为0.0001-1重量份/每重量份G-CSF,优选为0.01-5重量份/每重量份G-CSF,最优选为0.2-2重量份/每重量份G-CSF。
本发明G-CSF制剂的pH值优选为5-7,更优选为5.5-6.8,更优选为6-6.7,最优选为6.5。
如有需要,本发明G-CSF制剂可进一步含有稀释剂、增溶剂、赋形剂、pH值调节剂、安抚剂、缓冲剂、含硫还原剂、抗氧剂等。例如,含硫还原剂包括N-乙酰半胱氨酸、N-乙酰高半胱氨酸、硫辛酸、硫二甘醇、硫代乙醇胺、硫代甘油、硫代山梨醇、巯基乙酸及其盐、硫代硫酸钠、谷胱甘肽、和含巯基的化合物如含1-7个碳原子的硫代链烷酸。抗氧剂包括异抗坏血酸、二丁基(对)甲酚、丁基羟基茴香醚、α-生育酚、醋酸生育酚、L-抗坏血酸及其盐、L-抗坏血酸基棕榈酸酯、L-抗坏血酸基硬脂酸酯、亚硫酸氢钠、亚硫酸钠、没食子酸三戊酯、没食子酸丙酯或螫合剂如乙二胺四乙酸二钠(EDTA)、焦磷酸钠、偏磷酸钠。也可加入其它常规组分,例如无机盐如氯化钠。氯化钾、氯化钙、磷酸钠、磷酸钾、碳酸氢钠;和有机盐如柠檬酸钠、柠檬酸钾、醋酸钠。
本发明G-CSF制剂包括溶液剂、冻干制剂、喷雾干燥剂等。最优选冻干制剂。
按已知溶液剂技术,将组分溶于含水缓冲剂如磷酸缓冲液(优选为磷酸氢二钠-磷酸二氢钠体系)和/或柠檬酸缓冲液(优选为柠檬酸钠缓冲液),可制得本发明溶液制剂,或按标准方法经冻干或喷雾-干燥制得溶液制剂。
本发明稳定的G-CSF制剂可采用非肠道途径给药如注射(皮下、静脉内或肌内注射)或经皮、粘膜、鼻腔、肺部给药,但也可经口服给药。
本发明G-CSF制剂可包装于密封的无菌塑料或玻璃容器中,使用前用纯水(注射用灭菌水)溶解。
本发明制剂中G-CSF的量可根据所治疾病的种类、疾病的严重性、患者年龄或其它因素而确定,但一般采用1-1000μg/ml,优选10-800μg/ml,更优选为50-500μg/ml。
本发明制剂在临床上非常有用,已发现它们可提高基于免疫应答如病人抵抗力的保护功能;或者,当他们与其它药物如抗生素、抗菌剂或抗癌剂联用于感染疾病或癌症的化学疗法时,可增强活性。因此,本发明制剂可与这些药物联合给药。
如下述实施例所证实的,本发明G-CSF制剂在25℃3个月的长期贮存试验后,或在40℃2个月的长期贮存试验后,或在50℃1个月的加速试验后,或在60℃2周的加速试验后仍显示出非常高的剩余率。而且,在50℃1个月或60℃2周的加速试验后只观察到有少量的甲硫氨酸-氧化的G-CSF。本发明的G-CSF制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的、优选95%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的、优选95%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的、优选95%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的、优选95%或更多的G-CSF,在50℃1个月或60℃2周的加速试验后含有1%或更少、优选低于检测限的Met-氧化的G-CSF。
从下述实施例的结果可见,通过加入一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苏氨酸和天冬酰胺的氨基酸,和一种或多种选自疏水性氨基酸的氨基酸,可提高本发明制剂在常温长期贮存试验后G-CSF的剩余率;并且通过加入甲硫氨酸,可使Met-氧化的G-CSF的浓度低于检测限。期望不受任何特定理论的约束,我们推测:加入的甲硫氨酸代替了G-CSF的甲硫氨酸残基被氧化,这样就减少Met-氧化的G-CSF量。
含有甲硫氨酸残基的生理活性蛋白质易于在甲硫氨酸残基氧化产生生理活性较小的变体,当向这种生理活性蛋白质的组合物中加入甲硫氨酸时,即可防止所述生理活性蛋白在甲硫氨酸残基氧化产生变体。当所述生理活性蛋白质组合物中不含其它蛋白质为稳定剂或所述蛋白质组合物为冻干或溶液制剂时,最有可能在甲硫氨酸残基氧化产生变体,因此加入甲硫氨酸似乎特别有效。
将其它一种或多种氨基酸加入本发明组合物中,可制得稳定的含具有甲硫氨酸残基的生理活性蛋白质组合物,它可抑制所述生理活性蛋白质在甲硫氨酸残基氧化产生变体并抑制其分解、聚集等。
出于这种目的而加入的氨基酸包括赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苯丙氨酸、色氨酸、亮氨酸、异亮氨酸、缬氨酸、丙氨酸、脯氨酸、甘氨酸、丝氨酸、苏氨酸、天冬酰胺、谷氨酰胺和酪氨酸,优选为组氨酸、精氨酸和苯丙氨酸。
本发明的生理活性蛋白质包括,例如:
细胞因子如白介素(例如,IL-1至L-13)、集落刺激因子(例如,粒性白细胞集落刺激因子(G-CSF)、巨噬细胞集落刺激因子(M-CSF)、粒性白细胞/巨噬细胞集落刺激因子(GM-CSF)、红细胞生成素(EPO)干扰素(例如,IFN-α、β、γ)、肿瘤坏死因子(例如TNF-α、IFN-β)、转化生长因子(TGF)、血小板衍生的生长因子(PDGF)、LIF(白细胞抑制因子)、制瘤素M(OSM)、移动抑制因子(MGF)、趋化因子(例如,IL-8、LD78、MCP-1)。
生理活性的肽例如胰岛素、高血糖素、甲状旁腺素(PTH)、胃泌素、选择蛋白、缩胆囊素、肠抑胃肽、P物质、胃动素、脾多肽、神经降压肽、肠高血糖素、分泌胃泌素的肽、生长抑素-28、强啡肽、促生长激素神经肽、香草环己酮、胰抑制素(pancreostatin)和zeopsin;生物酶如在活性中心含有甲硫氨酸残基的酶(如苹果酸脱氢酶);及它们的变体。
本发明生理活性蛋白优选为细胞因子或生理活性肽,更优选为集落刺激因子如G-CSF或红细胞生成素或PTH,更优选为G-CSF、红细胞生成素或PTH。
下面的实施例用于说明本发明,但不作任何限制。在本发明描述的基础上,本领域技术人员可能加以变化和修饰,但是这些变化和修饰也包括在本发明中。
实施例
实验方法
制备溶液剂并无菌过滤,其中所含各种组分的含量如下列表1和2所示,然后精密取1mL无菌包装于小瓶中并冻干。冻干后,严密盖上瓶盖制备G-CSF冻干制剂。
表1
G-CSF | 苯丙氨酸 | 精氨酸 | 甲硫氨酸 | 甘霉醇 | 吐温20 | 缓冲液pH | |
试样1 | 250μg | 10mg | 10mg | 0 | 50mg | 0.1mg | 磷酸盐,pH7.4 |
试样2 | 250μg | 10mg | 10mg | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
G-CSF | 苯丙氨酸 | 精氨酸 | 甲硫氨酸 | 甘露醇 | 吐温20 | 缓冲液pH | |
试样3 | 100μg | 0mg | 0mg | 0 | 50mg | 0.1mg | 磷酸盐pH6.5 |
试样4 | 100μg | 10mg | 0mg | 0 | 50mg | 0.1mg | 磷酸盐pH6.5 |
试样5 | 100μg | 0mg | 10mg | 0 | 50mg | 0.1mg | 磷酸盐pH6.5 |
试样6 | 100μg | 10mg | 10mg | 0 | 50mg | 0.1mg | 磷酸盐pH6.5 |
G-CSF | 苯丙氨酸 | 精氨酸 | 甲硫氨酸 | 甘露醇 | 吐温20 | 缓冲液,pH | |
试样7 | 250μg | 0mg | 0mg | 0 | 50g | 0.1mg | 磷酸盐,pH6.5 |
试样8 | 250μg | 10mg | 0mg | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样9 | 250μg | 0mg | 10mg | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样10 | 250μg | 10mg | 10mg | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
G-CSF | 氨基酸1 | 氨基酸2 | 甲硫氨酸 | 甘露醇 | 吐温20 | 缓冲液pH | |
试样11 | 100μg | 苯丙氨酸 | 赖氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样12 | 100μg | 苯丙氨酸 | 组氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样13 | 100μg | 苯丙氨酸 | 精氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样14 | 100μg | 苯丙氨酸 | 天冬氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样15 | 100μg | 苯丙氨酸 | 谷氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样16 | 100μg | 苯丙氨酸 | 丝氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样17 | 100μg | 苯丙氨酸 | 苏氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样18 | 100μg | 苯丙氨酸 | 酪氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样19 | 100μg | 苯丙氨酸 | 天冬酰胺 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样20 | 100μg | 苯丙氨酸 | 谷氨酰胺 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
每种情况中,均加入10mg苯丙氨酸(相当于60mM)。氨基酸2的加入量等于60mM(与氨基酸1等摩尔)。
G-CSF | 氨基酸1 | 氨基酸2 | 甲硫氨酸 | 甘露醇 | 吐温20 | 缓冲液pH | |
试样21 | 100μg | 精氨酸 | 丙氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样22 | 100μg | 箱氨酸 | 缬氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样23 | 100μg | 精氨酸 | 亮氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样24 | 100μg | 精氨酸 | 异亮氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样25 | 100μg | 精氨酸 | 甲硫氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样26 | 100μg | 精氨酸 | 色氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样27 | 100μg | 精氨酸 | 苯丙氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样28 | 100μg | 精氨酸 | 脯氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样29 | 100μg | 精氨酸 | 甘氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样30 | 100μg | 精氨酸 | 丝氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样31 | 100μg | 精氨酸 | 苏氨酸 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样32 | 100μg | 精氨酸 | 天冬酰胺 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
试样33 | 100μg | 精氨酸 | 谷氨酰胺 | 0 | 50mg | 0.1mg | 磷酸盐,pH6.5 |
每种情况中,均加入10mg精氨酸(相当于60mM)。氨基酸2的加入量等于60mM(与氨基酸1等摩尔)。
表2
G-CSF | Phe | Arg | Met | 甘露醇 | 吐温20 | 缓冲液pH | |
试样34 | 100μg | 10mg | 10mg | 0mg | 25mg | 0.1mg | 磷酸盐,pH6.5 |
试样35 | 100μg | 10mg | 10mg | 0.1mg | 25mg | 0.1mg | 磷酸盐,pH6.5 |
试样36 | 100μg | 10mg | 10mg | 1mg | 25mg | 0.1mg | 磷酸盐,pH6.5 |
将含有无菌制备的G-CSF的冻干制剂置于恒温箱中:60℃2周和1个月;50℃1、2和3个月;40℃2、4和6个月;和25℃3和6个月。
将加速和未加速试验的制剂用精密量取的1mL纯水溶解,配制试样供下面分析用。
用下列方法1测定每只小瓶中G-CSF的剩余率(%剩余)。同时用下列方法2测定Met-氧化的G-CSF的量。
方法1
用C4反相柱(4.6mm×250mm,300埃)经反相高效液相色谱测定每只小瓶中G-CSF的量,流动相由纯水、乙腈和三氟乙酸组成。进样量为5μgG-CSF,并用乙腈梯度洗脱,在215nm分光测定。
60℃2周和50℃1个月加速试验后,和60℃2周和1个月;50℃1、2和3个月;40℃2、4和6个月;和25℃3和6个月贮存后,用该法测定G-CSF的含量,并按下面的方程式计算G-CSF的%剩余。
方法2
用C4反相柱(4.6mm×250mm,300埃)经反相高效液相色谱测定每个试样中未破坏的G-CSF和Met-氧化的G-CSF的量,流动相由纯水、乙腈和三氟乙酸组成。用乙腈梯度洗脱G-CSF,在215nm分光测定。
实施例1
pH值对G-CSF剩余率的影响
按方法1中的方程式计算60℃2周和50℃1个月加速试验后按表1中不同pH值制备的试样1和2中G-CSF的剩余率。结果见表3。
表3
试样1,pH7.4 | 试样2,pH6.5 | |
50℃,1个月 | 97.7 | 99.7 |
60℃,2周 | 95.8 | 97.1 |
如表所示,pH值为6.5的制剂比pH值为7.4更稳定。
实施例2
各种氨基酸对G-CSF剩余率的影响(1)
按表1所列氨基酸制备试样3-6(含G-CSF 100μg)和试样7-10(含G-CSF 250μg),按方法1中的方程式计算60℃2周和50℃1个月加速试验后上述制剂中G-CSF的剩余率。结果见表4和5。
表4 含100μg G-CSF的制剂
试样3 | 试样4 | 试样5 | 试样6 | |
苯丙氨酸 | 无 | 1mg | 无 | 10mg |
精氨酸 | 无 | 无 | 10mg | 10mg |
50℃,1个月 | 72.9% | 84.8% | 82.4% | 98.3% |
60℃,2周 | 67.2% | 77.9% | 68.8% | 95.0% |
表5 含250μg G-CSF的制剂
试样7 | 试样8 | 试样9 | 试样10 | |
苯丙氨酸 | 无 | 10mg | 无 | 10mg |
精氨酸 | 无 | 无 | 10mg | 10mg |
50℃,1个月 | 76.6% | 88.1% | 96.3% | 99.7% |
60℃,2周 | 74.0% | 78.1% | 90.7% | 97.1% |
与不含氨基酸所制剂相比,单独加入苯丙氨酸或精氨酸的制剂在任意G-CSF含量时均可改善稳定性,但不够显著。同时加入苯丙氨酸和精氨酸,可显著提高制剂的稳定性。
实施例3
各种氨基酸对G-CSF剩余率的影响(2)
按表1所列氨基酸,制备试样11-20(含苯丙氨酸作为氨基酸1,和赖氨酸、细氨酸、精氨酸、天门冬氨酸、谷氨酸、丝氨酸、苏氨酸、酪氨酸、天冬酰胺和谷氨酰胺之一作为氨基酸2),和试样21-33(含精氨酸作为氨基酸1,和丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸、色氨酸、苯丙氨酸、脯氨酸、甘氨酸、丝氨酸、苏氨酸、天冬酰胺和谷氨酰胺之一作为氨基酸2),按方法1中的方程式计算60℃2周和50℃1个月加速试验后上述制剂中G-CSF的剩余率。结果见表6和7。
表6
50℃,1月 | 60℃,2周 | |
试样11 | 92.8% | 91.2% |
试样12 | 98.8% | 97.5% |
试样13 | 98.0% | 96.0% |
试样14 | 95.7% | 96.7% |
试样15 | 95.6% | 94.0% |
试样16 | 88.4% | 87.8% |
试样17 | 96.4% | 90.7% |
试样18 | 84.6% | 81.7% |
试样19 | 95.0% | 95.3% |
试样20 | 89.8% | 87.2% |
表7
50℃,1月 | 60℃,2周 | |
试样21 | 89.0% | 84.4% |
试样22 | 88.9% | 86.5% |
试样23 | 96.3% | 96.2% |
试样24 | 88.5% | 89.3% |
试样25 | 95.5% | 88.5% |
试样26 | 101.4% | 98.6% |
试样27 | 97.0% | 95.7% |
试样28 | 89.4% | 82.5% |
试样29 | 90.9% | 71.2% |
试样30 | 89.2% | 85.2% |
试样31 | 90.6% | 87.3% |
试样32 | 94.0% | 88.6% |
试样33 | 90.1% | 84.6% |
可以观察到,苯丙氨酸与赖氨酸、苯丙氨酸与组氨酸、苯丙氨酸与精氨酸、苯丙氨酸与天门冬氨酸、苯丙氨酸与谷氨酸、苯丙氨酸与苏氨酸、或苯丙氨酸与天冬酰胺、或精氨酸与亮氨酸、精氨酸与色氨酸、或精氨酸与苯丙氨酸联用,可显著提高长期贮存的稳定性。
实施例4
长期贮存试验
制备含100μg或250μg G-CSF和10mg苯丙氨酸、10mg精氨酸和1mg甲硫氨酸的试样。按方法1中的方程式计算60℃2周和1个月;50℃1、2和3个月;40℃2、4和6个月;和25℃3或和6个月贮存后上述二制剂中G-CSF的剩余率。结果见表8。
表8
G-CSF(μg) | 60℃ | 50℃ | 40℃ | 25℃ | ||||||
2W1 | 1M2 | 1M | 2M | 3M | 2M | 4M | 6M | 3M | 6M | |
100 | 98.3 | 96.2 | 99.9 | 100.1 | 95.9 | 101.0 | 100.0 | 98.8 | 97.0 | 98.0 |
250 | 97.2 | 94.5 | 98.7 | 98.0 | 96.7 | 99.4 | 99.3 | 98.1 | 98.5 | 100.6 |
1:周
2:月
两种制剂均显示优良的G-CSF的剩余率。
实施例5
所加氨基酸对Met-氧化的G-CSF量的影响
按表2制备含不同量甲硫氨酸的色谱用试样34-36(含固定量的苯丙氨酸和精氨酸,及0mg、0.1mg或1mg甲硫氨酸),60℃2周加速试验后按方法2分析,结果见图1;取一个色谱用试样,分别于制备后和50℃一个月加速试验后立即按方法2分析,结果见图2。
不含甲硫氨酸的试样34在制备后和50℃一个月加速试验后立即可观察到Met-氧化的G-CSF的含量,而加入0.1mg或更多甲硫氨酸的试样在长期贮存后Met-氧化的G-CSF的含量被完全抑制。
按方法2中的方程式计算的Met-氧化的G-CSF的含量的结果见表9。
表9
试样340mg Met | 试样350.1mg Met | 试样361mg Met | |
50℃,1月 | 1.2% | N.D. | N.D. |
60℃,2周 | 1.7% | N.D. | N.D. |
N.D.:低于检测限。
因此,加入0.1mg或更多甲硫氨酸可完全抑制Met-氧化的G-CSF的形成。
实施例6
含甲状旁腺素的溶液制剂中
加入甲硫氨酸抑制甲硫氨酸残基的氧化
制备含200μg/mL具有1-84个残基甲状旁腺素(缩写为PTH)(按WO9014415所述方法制备)的试样37-39溶液,其它组分如下面表10,无菌过滤后精密取1mL无菌包装于小瓶中,严密盖上瓶盖制备PTH溶液剂。
表10
甲状旁腺素 | 甲硫氨酸 | 吐温20 | 枸橼酸/磷酸缓冲液 | |
试样37 | 200μg/mL | No | 0.01% | 6.5 |
试样38 | 200μg/mL | 0.01% | 0.01% | 6.5 |
试样39 | 200μg/mL | 0.1% | 0.01% | 6.5 |
将无菌制备的PTH溶液剂置于50℃恒温箱中3天。
用C18反相柱(4.6mm×250mm,300埃)经反相高效液相色谱测定每个试样中PTH的量,流动相由纯水、乙腈和三氟乙酸组成。进样量为相当于10μgPTH的量,用乙腈梯度洗脱PTH,在215nm分光测定。
在这一试验系列中,在未破坏的PTH之前,检测到了在8位和18位甲硫氨酸残基被氧化的PTH,结果见图3。色谱图显示,制剂中加入甲硫氨酸可抑制PTH在8位和18位甲硫氨酸残基的氧化。同时还分发现。制剂中加入甲硫氨酸对甲硫氨酸残基以外的其它化学分解反应没有影响。这表明,试剂中加入甲硫氨酸仅特异地抑制蛋白质在甲硫氨酸残基的氧化,而不影响其它化学分解反应。
实用性
本发明G-CSF试剂是稳定的制剂,在长期贮存后具有非常高的G-CSF剩余率,并且可完全抑制G-CSF在甲硫氨酸残基的氧化。
Claims (30)
1.一种稳定的G-CSF制剂,所述制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的G-CSF,在50℃1个月的加速试验后或在60℃2周的加速试验后甲硫氨酸-氧化的G-CSF为1%或更少。
2.如权利要求1的G-CSF制剂,其中含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苏氨酸和天冬酰胺的氨基酸;一种或多种选自疏水性氨基酸的氨基酸;和甲硫氨酸。
3.如权利要求2的G-CSF制剂,其中所述疏水性氨基酸选自苯丙氨酸、色氨酸和亮氨酸。
4.如权利要求1的G-CSF制剂,其中含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸和谷氨酸的氨基酸;一种或多种选自苯丙氨酸、色氨酸和亮氨酸的氨基酸;和甲硫氨酸。
5.如权利要求1的G-CSF制剂,其中含有苯丙氨酸、精氨酸和甲硫氨酸。
6.如权利要求1-5之一的G-CSF制剂,其中基本上不含蛋白质为稳定剂。
7.如权利要求1-6之一的G-CSF制剂,为冻干制剂。
8.如权利要求1-7之一的G-CSF制剂,其中还含有甘露醇。
9.如权利要求1-8之一的G-CSF制剂,其中还含有表面活性剂。
10.如权利要求9的G-CSF制剂,所述表面活性剂为聚氧乙烯脱水山梨糖醇烷基酯。
11.如权利要求10的G-CSF制剂,所述表面活性剂为吐温20和/或80。
12.如权利要求1-11之一的G-CSF制剂,其中pH值为5-7。
13.如权利要求12的G-CSF制剂,其中pH值为5.5-6.8。
14.如权利要求13的G-CSF制剂,其中pH值为6.5。
15.如权利要求1-14之一的G-CSF制剂,其中G-CSF产自CHO细胞。
16.一种稳定的G-CSF制剂,所述制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的G-CSF,其特征在于含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苏氨酸和天冬酰胺的氨基酸;一种或多种选自疏水性氨基酸的氨基酸;其中pH值为5-7。
17.一种稳定的G-CSF制剂,所述制剂在25℃3个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在40℃2个月的长期贮存试验后仍剩余90%或更多的G-CSF,或在50℃1个月的加速试验后仍剩余90%或更多的G-CSF,或在60℃2周的加速试验后仍剩余90%或更多的G-CSF,其特征在于含有一种或多种选自赖氨酸、组氨酸、精氨酸、天门冬氨酸和谷氨酸的氨基酸;和一种或多种选自苯丙氨酸、色氨酸和亮氨酸的氨基酸;其中pH值为5-7。
18.如权利要求15或16的G-CSF制剂,其中pH值为6.5。
19.一种稳定的G-CSF制剂,其中基本上不产生甲硫氨酸氧化的变体。
20.一种稳定的G-CSF制剂,其中含有甲硫氨酸和其它一种或多种氨基酸,并且基本上不产生甲硫氨酸氧化的变体。
21.如权利更求19或20的G-CSF制剂,其中基本上不含蛋白质为稳定剂。
22.一种抑制含有甲硫氨酸残基的生理活性蛋白质在甲硫氨酸残基上氧化产生变体的方法,包括将甲硫氨酸加到含有所述蛋白质的组合物中。
23.如权利要求22的方法,所述生理活性蛋白质为细胞因子或生理活性肽。
24.如权利要求22的方法,其中所述生理活性蛋白质为集落刺激因子或PTH。
25.如权利要求22的方法,其中所述生理活性蛋白质为G-CSF、红细胞生成素或PTH。
26.如权利要求22-25之一的方法,其中不存在作为稳定剂的其它蛋白质。
27.如权利要求22-26之一的方法,所述组合物含有具有甲硫氨酸残基的生理活性蛋白质,其中所述组合物为冻干或溶液形式。
28.一种含有具有甲硫氨酸残基的生理活性蛋白质的稳定组合物,其中还含有甲硫氨酸和一种或多种其它氨基酸。
29.如权利要求28的组合物,其中所述一种或多种的氨基酸为选自赖氨酸、组氨酸、精氨酸、天门冬氨酸、谷氨酸、苯丙氨酸、色氨酸、亮氨酸、异亮氨酸、缬氨酸、丙氨酸、脯氨酸、甘氨酸、丝氨酸、苏氨酸、天冬酰胺、谷氨酰胺和酪氨酸。
30.如权利要求28或29的组合物,其中基本上不含作为稳定剂的其他蛋白质。
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- 2000-02-29 CN CN00804421A patent/CN1342087A/zh active Pending
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- 2000-02-29 KR KR1020057017282A patent/KR100731559B1/ko active IP Right Grant
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- 2000-02-29 DK DK00905397T patent/DK1197221T3/da active
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103599541A (zh) * | 2008-09-10 | 2014-02-26 | 弗·哈夫曼-拉罗切有限公司 | 用于防止蛋白质氧化降解的组合物和方法 |
CN102821787A (zh) * | 2010-01-15 | 2012-12-12 | 麒麟-安姆根有限公司 | 抗体制剂和治疗方案 |
CN102821787B (zh) * | 2010-01-15 | 2015-07-29 | 麒麟-安姆根有限公司 | 抗体制剂和治疗方案 |
WO2016090701A1 (zh) * | 2014-12-12 | 2016-06-16 | 薛传校 | 一种长效促排卵注射液 |
WO2021195877A1 (en) * | 2020-03-30 | 2021-10-07 | Sichuan Luzhou Buchang Bio-Pharmaceutical Co., Ltd. | Formulations of human parathyroid hormone (pth) and methods for producing same |
RU2820316C1 (ru) * | 2020-03-30 | 2024-06-03 | Сычуань Лучжоу Бучан Био-Фармасьютикал Ко., Лтд. | Составы на основе паратиреоидного гормона (pth) человека и способы их получения |
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EP1700605A3 (en) | 2007-06-13 |
HK1098963A1 (en) | 2007-08-03 |
DE60028037T2 (de) | 2006-12-21 |
AU772604B2 (en) | 2004-05-06 |
DK1197221T3 (da) | 2006-11-13 |
DE60028037D1 (de) | 2006-06-22 |
CN1879875B (zh) | 2010-08-25 |
TWI232749B (en) | 2005-05-21 |
JP2000247903A (ja) | 2000-09-12 |
HK1046239B (zh) | 2006-08-18 |
ES2263450T3 (es) | 2006-12-16 |
KR20050099637A (ko) | 2005-10-14 |
WO2000051629A1 (fr) | 2000-09-08 |
EP1700605A2 (en) | 2006-09-13 |
CN1879875A (zh) | 2006-12-20 |
KR100731559B1 (ko) | 2007-06-22 |
AU2695400A (en) | 2000-09-21 |
JP4607336B2 (ja) | 2011-01-05 |
HK1046239A1 (en) | 2003-01-03 |
KR20010102469A (ko) | 2001-11-15 |
PT1197221E (pt) | 2006-08-31 |
CA2381229A1 (en) | 2000-09-08 |
EP1197221B1 (en) | 2006-05-17 |
CA2381229C (en) | 2010-10-26 |
EP1700605B1 (en) | 2014-04-30 |
KR100656125B1 (ko) | 2006-12-12 |
EP1197221A1 (en) | 2002-04-17 |
ATE326233T1 (de) | 2006-06-15 |
US6908610B1 (en) | 2005-06-21 |
HK1045652A1 (zh) | 2002-12-06 |
CY1105528T1 (el) | 2010-07-28 |
EP1197221A4 (en) | 2003-01-29 |
CN101537173A (zh) | 2009-09-23 |
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