CN108175854B - 一种乙脑疫苗的冻干制剂 - Google Patents
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Abstract
本发明公开了一种乙脑疫苗的冻干制剂，制剂含有乙脑疫苗原液和疫苗稳定剂，所述疫苗稳定剂由人血白蛋白和甘露醇组成。本发明的有益效果是：(1)辅料中成分组成简单，无来源于动物源的成分，风险更低。(2)有效控制了冻干过程中的疫苗活性损失率。(3)本制剂制成成品后，通过稳定性研究，制品表现出良好的稳定性。
Description
技术领域
本发明属于病毒生物学技术领域，具体涉及一种乙脑疫苗的冻干制剂。
背景技术
流行性乙型脑炎简称乙脑，是由黄病毒科虫媒病毒----乙脑病毒引起的一种侵害中枢神经系统的急性传染病。常造成患者死亡或留下神经系统后遗症。乙脑是一种由蚊类传播的人畜共患疾病，人和许多动物(家畜、家禽和鸟类)感染乙脑病毒后都可成为乙脑的传染源。乙脑主要通过蚊虫叮咬而传播。乙脑疫苗是预防流行性乙型脑炎的有效措施。
灭活全病毒疫苗制品通常采用皮下或肌内给药途径，利用这些部位丰富的免疫细胞特别是抗原递呈细胞(Antigen Presenting cells，APCs)以及将其他部位的免疫细胞和免疫相关细胞因子募及到这些部位的能力，诱导机体快速产生保护性免疫应答。因此，这种类型的疫苗制品通常都是采用注射针剂的制剂方式，包括水针和冻干粉针。相对而言，冻干粉针具有效期更长、保存和运输更方便以及各项关键质量指标在效期内的一致性更好等优点，成为灭活全病毒疫苗制品的优选剂型。
疫苗辅料是指疫苗制品调配处方时所用的赋形剂和附加剂，是疫苗制剂中不可缺少的重要成分，它可以赋予疫苗剂型及必要的物理、化学、药理和生物学特性，对疫苗制剂的稳定性、生物活性、保证制品质量、开发新剂型与新品种、满足预防使用的要求等都有积极的关键性作用。
2000年世界卫生组织(WHO)公布的疫苗接种后相关不良反应有关信息中提出，在美国，接种乙型脑炎灭活疫苗的人群中，每1万名接种者中就有1～64人出现过敏反应、严重的全身性荨麻疹、面部血管性水肿或呼吸窘迫，其原因与制品中的明胶稳定剂有关。最新研究表明，在单价麻疹、腮腺炎和风疹疫苗接种后有过敏反应的个体具有对明胶稳定剂的免疫球蛋白E抗体。由此可见，疫苗在接种后引起的不良反应中，有相当比例是由于生产过程中使用的原辅料所致。因此在生物制品中，原辅料成分不再被看做是无活性的物质，生物制品生产用原辅料的理化性质和安全性对生物制品的有效性和安全性有着直接影响。
人血白蛋白主要用作注射剂的辅料，作为处方中蛋白的稳定剂。也可在冷冻干燥过程中作为防冻剂，以防止表面吸附其他蛋白。甘露醇可用作生物制品的稳定剂和冻干保护剂。在制备冻干人用乙脑疫苗过程中，除了上述辅料外，还需要添加明胶、海藻糖和表面活性剂等成分，以增强冻干过程和保存过程中的保护效果，降低疫苗效价的损失率，但由此引入的成分会对制品的安全性造成较大影响。
因此，开发一种组成更简单、安全性更高、稳定和副作用少的疫苗制剂是非常有意义的。
发明内容
本发明的一个目的在于提供一种成分简单、冻干效果好的疫苗稳定剂。
本发明的另一个目的在于提供一种辅料成分简单、安全性良好的乙脑疫苗制剂。
本发明所采用的技术方案为：
一种疫苗稳定剂，其由人血白蛋白和甘露醇组成。
作为优选的，所述疫苗稳定剂中，人血白蛋白和甘露醇的质量比例为：(1-10):(10-100)。
一种乙脑疫苗冻干制剂，该制剂配方包含有乙脑疫苗抗原和疫苗稳定剂，所述疫苗稳定剂如权利要求2所述。
作为优选的，按冻干前的质量百分比计，所述乙脑疫苗冻干制剂中各组分的浓度如下：
进一步优选的，所述乙脑疫苗冻干制剂中，人血白蛋白的浓度为0.3～1.0％。
进一步优选的，所述乙脑疫苗冻干制剂中，甘露醇的终浓度为3～6％。
进一步优选的，缓冲液为pH为7.2～8.0的磷酸盐缓冲液。
本发明的有益效果是：
(1)稳定剂中成分组成简单，无人源外的动物源成分，无需添加明胶、右旋糖酐、海藻糖、表面活性剂等复杂的高风险成分。
(2)有效控制了冻干过程中的疫苗活性损失率。
(3)本发明制剂具有良好的稳定性。
具体实施方式
下面结合实施例对本发明作进一步的说明，但并不局限于此。
实施例1
1.1按照以下配方配制疫苗半成品，检测其冻干效果：
人血白蛋白0.5(w/w)％；
甘露醇5.0(w/w)％；
乙脑病毒抗原原液50mL；
补充pH7.2～8.0的磷酸盐缓冲液至100mL。
1.2乙脑疫苗的制备方法
把纯化的乙脑病毒抗原原液按照上述配方配制成半成品；
将半成品分装到2ml管制瓶，每管0.5ml，置小型冻干机进行冷冻干燥。
1.3疫苗检定方法
效价测定：按《中国药典》2010年版三部冻干乙型脑炎灭活疫苗(Vero细胞)效价测定法测定；
水分：按《中国药典》2010年版三部附录ⅦD法测定；
异常毒性试验：按《中国药典》2010年版三部附录Ⅻ法测定；
热稳定试验：将疫苗放置在37±1℃的恒温箱中储存1周，到期后采用上述效价测定法进行效价测定；
长期稳定性试验：将疫苗放置在4±2℃的药品保存箱中储存，于0个月、3个月、6个月、9个月和12个月取出，采用上述效价测定法进行效价测定。
1.4研究结果
1.4.1按照配方类别冻干前后效价损失率
将批号为1005、1006和1007共三批纯化后的乙脑病毒抗原原液按照配方配制成疫苗原液后进行冻干，冻干前的疫苗原液和冻干后的成品制剂均进行效价测定，比较冻干前后疫苗活性。
表1冻干前后疫苗效价(T值)的比较
注:括号内为T值
本配方的冻干效价T值变化在可接受范围内。
1.4.2冻干后检定结果
将批号为1005、1006和1007共三批冻干后制剂进行效价、水分和异常毒性试验项目的检定。
表2冻干制剂的质量指标检定结果
注:括号内为T值
1.4.3冻干制剂的热稳定性研究结果
将批号为1005、1006和1007共三批冻干制剂放入37±1℃保存，1周后将样品取出，进行效价测定。
表3数据显示在经过1周的加速热稳定考察后，疫苗效价合格，符合《中国药典》三部(2010版)对冻干乙脑疫苗的相关要求。
表3冻干制剂的热稳定性研究结果
注:括号内为T值
1.4.4冻干制剂的长期稳定性研究结果
将批号为1005、1006和1007共三批冻干制剂放入4±2℃保存，按照表4保存不同时间后将样品取出，进行效价测定。
表4冻干制剂的长期稳定性研究结果
注:括号内为T值
从表中的数据可以看出，冻干制剂的长期稳定性较好。
实施例2
2.1、不同甘露醇用量对疫苗制剂的影响
设置人血白蛋白浓度为0.5％，并将其中的甘露醇浓度进行调整，观察甘露醇的浓度对疫苗的影响。具体的比较结果见表5：
表5不同甘露醇浓度对冻干效果的影响
表5数据显示，在1.0～10％的甘露醇浓度范围内，外观，复溶时间和水分含量均符合《中国药典》三部(2010版)对冻干乙脑疫苗的相关要求，但在3～6％的甘露醇浓度范围内，外观和复溶时间均表现最优。
2.2不同人血白蛋白用量对疫苗制剂的影响
设置甘露醇浓度为5％，将其中的人血白蛋白浓度进行调整，观察人血白蛋白的浓度对疫苗的影响。具体的比较结果见表6：
表6不同人血白蛋白浓度对冻干效果的影响
表6数据显示在0.1～1.0％的人血白蛋白浓度范围内，冻干制剂的外观良好。
实施例3不同组合的疫苗稳定剂对疫苗制剂的影响
以上实验表明：本发明的疫苗稳定剂有效控制了冻干过程中的疫苗活性损失率。
Claims (1)
1.一种乙脑疫苗冻干制剂，其特征在于，该制剂配方包含有乙脑疫苗抗原和疫苗稳定剂，所述疫苗稳定剂由人血白蛋白和甘露醇组成，所述冻干制剂中，按冻干前的质量百分比计，人血白蛋白的浓度为0.3～1.0%，甘露醇的浓度为3～6%。
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