CN1310673C - 含多肽的多分散混合物的组合物及其药物组合物 - Google Patents

含多肽的多分散混合物的组合物及其药物组合物 Download PDF

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CN1310673C
CN1310673C CNB200410064296XA CN200410064296A CN1310673C CN 1310673 C CN1310673 C CN 1310673C CN B200410064296X A CNB200410064296X A CN B200410064296XA CN 200410064296 A CN200410064296 A CN 200410064296A CN 1310673 C CN1310673 C CN 1310673C
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E·康菲诺
M·塞拉
D·泰特包姆
R·阿农
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Abstract

本发明提供了一种组合物，该组合物包含多肽的一种多分散混合物，所述多肽由谷氨酸、赖氨酸、丙胺酸和酪氨酸组成，其中所述混合物具有的平均分子量为约4-9千道尔顿。本发明还提供了一种用于治疗多发性硬化症的药物组合物，其包含治疗有效剂量的上述组合物。

Description

含多肽的多分散混合物的组合物及其药物组合物
本申请是申请日为1995年5月23日、发明创造名称为“共聚物组成改进的共聚物-1”的中国专利申请(国家申请号为95194101.1，国际申请号为PCT/US95/06551)的分案申请。
本申请是1994年11月23日递交的U.S.S.N.08/344248的部分后续申请，该申请是1994年5月24日递交的U.S.S.N.08/248037的后续。
发明背景
共聚物-1是髓鞘碱性蛋白(MBP)的合成多肽类似物，髓鞘碱性蛋白是髓鞘的天然成分。已表明其是多发性硬化症的有效的治疗剂(欧洲免疫学杂志[1971]1：242；神经科学杂志[1977]31：433)。本文所引用的所有参考文献都引入本文以供参考。早在50年代，在多发性硬化症的免疫疗法中对共聚物-1的观察表明髓鞘碱性蛋白成分，如MBP可阻止或控制实验性自身免疫脑脊髓炎(EAE)。EAE是一种诱发于敏感动物的类似于多发性硬化症的疾病。
共聚物-1是由Drs.Sela、Arnon及其合作者在Weizmann研究所(Rehovot，以色列)研究的。据示它可抑制EAE(欧洲免疫学杂志[1971]1：242；美国专利3,849,550)。最近表明共聚物-1有利于缓解多发性硬化症的恶化(新英格兰医学杂志[1987]317：406)。采用每日注射共聚物-1治疗的患者与对照组患者相比几乎没有恶化并且他们的残疾加剧较轻微。
共聚物-1是多肽的混合物，由丙氨酸、谷氨酸、赖氨酸和酪氨酸组成，摩尔比约为6∶2∶5∶1。它是通过化学聚合四种氨基酸形成的产物(平均分子量为23000道尔顿)而合成的(美国专利3849550)。
本发明的目的是提供一种改进组成的共聚物-1。
发明概述
本发明涉及一种共聚物-1组合物，该组合物基本上不含分子量大于40千道尔顿(KDa)的共聚物-1种类。
本发明另外涉及一种在分子量约为2KDa至20KDa范围内摩尔分级超过75％的共聚物-1。
另外，本发明涉及一种平均分子量约为4至8.6KDa的共聚物-1。
此外，本发明涉及一种药物组合物的以及用上述共聚物-1治疗多发性硬化症的方法。
附图简述
图1表示三批共聚物-1的分子量分布，显示出分子量大于40KDa种类的比例。图2表示与摩尔分级有关的相似数据。
发明详述
本发明涉及一种共聚物-1组合物，该组合物基本上不含分子量大于40千道尔顿(KDa)的共聚物-1种类。优选地，该组合物含有少于5％的分子量为40KDa或更高的共聚物-1种类。更优选该组合物含有少于2.5％的分子量为40KDa或更高的共聚物-1种类。
本发明另外涉及一种在分子量约为2KDa至20KDa范围内摩尔分级超过75％的共聚物-1。
此外，本发明涉及一种平均分子量约为4至8.6KDa的共聚物-1。更具体地说，本发明涉及一种平均分子量约为4至8KDa的共聚物-1以及平均分子量约为6.25至8.4KDa的共聚物-1。
本发明的共聚物-1可以通过本领域已知的方法制备，例如美国专利3849550中公开的方法，其中于环境温度将酪氨酸、丙氨酸、γ-谷氨酸苄酯以及E-N-三氟乙酰赖氨酸的N-羧酸酐在无水二烷中聚合，二乙胺作为引发剂。用溴化氢的冰醋酸溶液脱去谷氨酸的γ-羧基，然后用1M哌啶从赖氨酸残基上除去三氟乙酰基。对于本发明的目的而言，术语“环境温度”和“室温”应理解成从约20至约26℃的温度。
具有所需范围分子量的共聚物-1可以通过已知方法获得。该类方法包括将含有高分子量种类的共聚物-1进行色谱并收集不含非所需种类的部分，或者通过部分酸或酶水解除去高分子量的种类，其后通过透析或超滤进行纯化。另外获得所需分子量范围的共聚物-1的方法是通过制备氨基酸是被保护的所需种类，然后直接除去保护即得所需种类。本发明的组合物可以通过本领域常规的已知方法配制。优选地，将组合物冻干并制成适于皮下注射用的水溶液。可任选地，也可将共聚物-1配制成本领域已知的用于制备肽类药物的口服、鼻用、口腔用或直肠用制剂的各种形式。
典型地，每日以20mg的剂量将共聚物-1给予多发性硬化症患者。
本发明通过下述实施例说明，但并非限定本发明。
实施例1
制备低毒性共聚物-1的色谱法
按照本领域已知的方法如美国专利3849550的方法制备两组共聚物-1。
如下文所述将一组用色谱分离。
在Superformance 26Merck药筒中按照生产商的说明制备凝胶过滤用柱-FRACTOGEL TSK HW55(600×26mm)。将此柱用水平衡，注射丙酮溶液用于总体积测定。用0.2M的乙酸铵缓冲液(pH5.0)平衡该柱。将30ml共聚物-1样品(20mg/ml，在0.2M pH值为5.0的乙酸铵中)装上柱，每10分钟收集一次级分。在120-130分钟之间分离含有平均分子量为7-8KDa的级分(A批)。
分子量分析
在UVIKON 810分光光度计上测定275nm的紫外吸收。将样品稀释以获得低于1个吸收单位的紫外吸收。在校准后的凝胶过滤柱(Superose 12)上测定两批产品的分子分布。
发明共聚物-1的A批平均分子量为7-8KDa。该批产品的2.5％具有高于32KDa的分子量，但是在该批产品中不存在分子量高于40KDa的共聚物-1种类。
共聚物-1的另一批(不进行色谱法)平均分子量为12KDa。该批产品的2.5％具有高于42KDa的分子量，该批产品中总共聚物-1种类的5％具有高于40KDa的分子量。
实施例2
毒性分析
A：体内
将平均分子量为7.3和8.4KDa(低于2.5％的共聚物-1种类超过40KDa)和22KDa(多于5％的共聚物-1种类超过40KDa)的三批共聚物-1进行如下毒性试验。在每种情况下每个实验组使用5只小鼠。
方法
将共聚物-1溶于蒸馏水中得到含2mg/ml的活性成分的溶液。将0.5ml测试溶液注射到每只小鼠的外侧尾静脉。观察48小时期间中小鼠的死亡率和相关临床症状。注射后10分钟、24小时和48小时记录观察结果。如果在48小时后，全部动物仍存活并且没有观察到不良症状，则指明该组为“无毒”。但是，如果有一只或多只的小鼠死亡或者表现出不痕症状，则指明该组为“毒性”。
平均分子量为7.3和8.4KDa批的产品都被指明是“无毒”，而平均分子量为22KDa的组在48小时后，5只小鼠中有3只死亡，因此指明其为“毒性”。
B：体外
RBL-脱颗粒试验
I.引言
噬碱细胞释放的组胺(或者5-羟色胺)是一种直接过敏性的体外模型。将大鼠噬碱白细胞系(RBL-2H3)培养成特征为高敏、均一、易于在培养物及再生体系中维持的细胞系(E.L.Basumian，C.Isersky，M.G.petrino和R.P.Siraganian.欧洲免疫学杂志11，317(1981))。组胺释放的生理剌激包括抗原结合到膜结合IgE分子上，导致后者交联，然后引发复杂的生化级联。除了这些生理性免疫球蛋白介导的引发剂以外，也可通过不同的非IgE介导刺激诱导脱粒。其中有各种肽类和合成聚合物，例如聚赖氨酸(R.P.Siraganan.药理学动向，10月，432(1983))。因此，用RBL脱粒试验筛选出可引起脱粒从而导致有害的局部和/或全身副作用的共聚物-1。
II.试验方法原理
将大鼠噬碱白细胞(RBL-2H3)用[3H]-5-羟色胺加载，然后与100μg待测共聚物-1一起培养。可诱导非特异性脱粒的共聚物-1组可将[3H]-5-羟色胺释放到培养基中。通过液闪计数仪计数培养基中的放射性，在沉淀细胞中测定结合到细胞中的总放射标记的5-羟色胺。脱粒百分数是以从总结合中的释放出的5-羟色胺百分比计算的。
III.结果
分析平均分子量在6,250-14,500之间的四批共聚物-1的分子量大于40KDa种类的和RBL脱粒的百分数％。结果汇总于下表。
 平均分子量(道尔顿)  分子量大于40KDa种类的百分数(％)   5-羟色胺释放百分数(％)
 6,250  ＜2.5   12.4
 7,300  ＜2.5   21.0
 13,000  ＞5   66.9
 14,500  ＞5   67.8
从中可看出，当高分子量种类的百分数低时(＜2.5)，5-羟色胺的释放百分数(表示毒性)则低，反之亦然。
实施例3
三氟乙酰基-共聚物-1的制备
按照Teitelbaum等在《欧洲免疫学杂志》第1卷第242页(1971)中描述的方法由溶于3.5升二烷中的酪氨酸的N-羧酸酐(18g)、丙氨酸(50g)、γ-谷氨酸苄酯(35g)的N-羧酸酐和三氟乙酰赖氨酸制备保护起来的共聚物-1。
通过加入0.01-0.02％二乙胺引发聚合过程。将反应混合物于室温搅拌24小时，然后倒入10升水中。过滤产物(被保护的共聚物-1)，用水洗涤并干燥。室温下用33％氢溴酸的冰醋酸溶液搅拌处理被保护的共聚物-1 6至12小时以除去谷氨酸盐中γ苄基保护基。将产物倒入过量水中，过滤，洗涤并干燥，得到三氟乙酰基-共聚物-1。
实施例4
三氟乙酰基-共聚物-1的制备
按照Teitelbaum等在《欧洲免疫学杂志》第1卷第242页(1971)中描述的方法由溶于3.5升二烷中的酪氨酸的N-羧酸酐(18g)、丙氨酸(50g)、γ-谷氨酸苄酯(35g)和三氟乙酰赖氨酸制备保护起来的共聚物-1。
通过进入0.01-0.02％二乙胺引发聚合过程。将反应混合物于室温搅拌24小时。然后倒入10升水中。过滤产物(被保护的共聚物-1)，用水洗涤并干燥。
用33％HBr的冰醋酸溶液处理被保护的共聚物-1以从谷氨酸残基的5-甲酸酯中除去Ω苄基保护基并且将聚合物分裂成较小的多肽。获得分子量为7,000±2,000道尔顿的共聚物-1所需时间取决于反应温度和被保护的共聚物-1的大小。在20-28℃之间的温度于不同时间段如10-50小时对每批产品进行测试反应。计算有关这些小规模反应的分子量结果，描绘分子量对时间的曲线。由该曲线计算获得平均分子量为7000±2,000道尔顿的共聚物-1所需时间并将其应用于较大规模的反应中。平均而言，在26℃操作的时间为17小时。将产物倒入过量水中，过滤，洗涤并干燥，得到三氟乙酰基-共聚物-1。
低毒性共聚物-1的制备
将20g三氟乙酰基-共聚物-1分散在1升水中，加入100g哌啶。室温搅拌混合物24小时，过滤。将粗共聚物-1溶液分配到透析袋中，于10-20℃水中透析，直至达到pH＝8。然后将其在约0.3％乙酸中透析，再用水透析直至达到pH＝5.5-6.0。然后将溶液浓缩并冻干。

Claims (29)

1.一种共聚物-1组合物，包含多肽的混合物，由谷氨酸、赖氨酸、丙氨酸和酪氨酸组成，其中所述混合物具有的平均分子量为约4-9千道尔顿，其中所述多肽的混合物在分子量和序列上是非均一的，且其中，该组合物适用于治疗多发性硬化症。
2.权利要求1的组合物，其中以摩尔分级为基的所述混合物中超过75％的多肽具有的分子量在约为2-20千道尔顿范围内。
3.权利要求1的组合物，其中以摩尔分级为基的所述混合物中少于5％的多肽具有的分子量超过40千道尔顿。
4.权利要求3的组合物，其中以摩尔分级为基的所述混合物中超过75％的多肽具有的分子量在约为2-20千道尔顿范围内。
5.权利要求4的组合物，其中所述混合物具有的平均分子量为6.25-8.4千道尔顿。
6.权利要求1的组合物，其中所述混合物具有的平均分子量为约4-8.6千道尔顿。
7.权利要求1的组合物，其中所述混合物具有的平均分子量为约5-9千道尔顿。
8.权利要求1的组合物，其中以摩尔分级为基的所述混合物中少于2.5％的多肽具有的分子量超过40千道尔顿。
9.权利要求8的组合物，其中以摩尔分级为基的所述混合物中超过75％的多肽具有的分子量在约为2-20千道尔顿范围内。
10.权利要求9的组合物，其中所述混合物具有的平均分子量为6.25-8.4千道尔顿。
11.权利要求1的组合物，其中所述混合物具有基本上如附图1或附图2的曲线所示的分子量分布，其中平均分子量为约7.7千道尔顿。
12.一种药物组合物，其包含：
用于治疗多发性硬化症的治疗有效剂量的共聚物-1组合物，其中该共聚物-1组合物包含多肽的混合物，由谷氨酸、赖氨酸、丙氨酸和酪氨酸组成，其中所述混合物具有的平均分子量为约4-9千道尔顿，其中所述多肽的混合物在分子量和序列上是非均一的；和
药学上可接受的赋形剂。
13.权利要求12的药物组合物，其中以摩尔分级为基的所述混合物中超过75％的多肽具有的分子量在约为2-20千道尔顿范围内。
14.权利要求12的药物组合物，其中以摩尔分级为基的所述混合物中少于5％的多肽具有的分子量超过40千道尔顿。
15.权利要求14的药物组合物，其中以摩尔分级为基的所述混合物中超过75％的多肽具有的分子量在约为2-20千道尔顿范围内。
16.权利要求15的药物组合物，其中所述混合物具有的平均分子量为6.25-8.4千道尔顿。
17.权利要求12的药物组合物，其中所述混合物具有的平均分子量为约4-8.6千道尔顿。
18.权利要求12的药物组合物，其中所述混合物具有的平均分子量为约5-9千道尔顿。
19.权利要求12的药物组合物，其中以摩尔分级为基的所述混合物中少于2.5％的多肽具有的分子量超过40千道尔顿。
20.权利要求19的药物组合物，其中以摩尔分级为基的所述混合物中超过75％的多肽具有的分子量在约为2-20千道尔顿范围内。
21.权利要求20的药物组合物，其中所述混合物具有的平均分子量为6.25-8.4千道尔顿。
22.权利要求12的药物组合物，其中所述混合物具有基本上如附图1或附图2的曲线所示的分子量分布，其中平均分子量为约7.7千道尔顿。
23.权利要求12-22中任一项的药物组合物在制备治疗患有多发性硬化症患者的药物中的用途。
24.一种制备分子量为4-9千道尔顿的共聚物-1组合物的方法，该方法包括：
将摩尔比为1∶5∶2∶4的酪氨酸的N-羧酸酐、丙氨酸的N-羧酸酐、γ-谷氨酸苄酯和三氟乙酰赖氨酸的混合物进行聚合，形成被保护的多肽的混合物；
将该被保护的多肽脱保护，形成未保护的多肽混合物；和
将由谷氨酸、赖氨酸、丙氨酸和酪氨酸构成的未保护的多肽的共聚物-1组合物分离，其中所述共聚物-1组合物具有的平均分子量为4-9千道尔顿。
25.权利要求24的方法，其中所述的共聚物-1组合物具有的平均分子量为6.25-8.4千道尔顿。
26.平均分子量为约4-9千道尔顿的共聚物-1组合物，该组合物可由包括下列步骤的方法制备：
将摩尔比为1∶5∶2∶4的酪氨酸的N-羧酸酐、丙氨酸的N-羧酸酐、γ-谷氨酸苄酯和三氟乙酰赖氨酸的混合物进行聚合，形成被保护的多肽的混合物；
将该被保护的多肽脱保护，形成未保护的多肽混合物；和
将由谷氨酸、赖氨酸、丙氨酸和酪氨酸构成的未保护的多肽的混合物分离，其中所述的混合物具有的平均分子量为4-9千道尔顿。
27.权利要求26的组合物，其中所述的混合物具有的平均分子量为6.25-8.4千道尔顿。
28.一种共聚物-1组合物，包含多肽的混合物，由谷氨酸、赖氨酸、丙氨酸和酪氨酸组成，其中所述混合物具有的平均分子量为约4-9千道尔顿，其中所述多肽的混合物在分子量和序列上是非均一的，且其中，根据RBL-脱颗粒试验，该组合物与分子量大于9千道尔顿的共聚物-1组合物相比，显示出较低的毒性。
29.权利要求28的组合物，其中所述的混合物具有的平均分子量为6.25-8.4千道尔顿。
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