CN116492301A - 一种疫苗耐热保护剂及其制备方法 - Google Patents
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Abstract
本发明公开了一种疫苗耐热保护剂，包括明胶3～5％、乳糖15～17％、酶解酪蛋白8％～12％、海藻糖1％～8％、甘氨酸1％～3％、聚乙烯吡咯烷酮1～8％、余量为水组成，通过高温灭菌、微孔滤膜过滤除菌、混合步骤制备。本发明通过优化疫苗耐热保护剂的组分，提高疫苗在冻干时对温度的耐受性，减少疫苗效力在冻干过程中的损失。对于在冷冻干燥过程中各种理化因素可能对病毒活性的损伤，具有较好的保护功能，有效解决了疫苗需冷冻运输、储存不便等问题。为冻干疫苗的生产提供了便利，同时也提高了产品质量及竞争力。疫苗的效力更加稳定，安全性好。
Description
技术领域
本发明属于生物技术领域，具体涉及一种疫苗耐热保护剂及其制备方法。
背景技术
生物活性制品的热敏感性一直是疫苗长期保存的瓶颈。储存、运输及使用过程中疫苗暴露在高温环境的现象依然存在，所以疫苗耐热性的提高亟待解决。
在食品、药品的冷冻干燥和贮藏过程中，很多因素，例如化学成分、冻结速率、冻结和脱水应力、玻璃化转变温度、干燥固体中剩余水分、贮藏环境的温度和湿度等都会影响其中活性组分的稳定性，甚至会导致失活。为了防止生物制品活性组分变性，需要添加合适的冷冻干燥保护剂和添加剂，配制成混合液后，才能进行有效的冷冻干燥和贮藏，以保持菌、毒种的生物学特性，稳定生物原料和半成品的生物活性，延长成品的有效期。
耐热保护剂考虑了活疫苗在较高温度和较长保存时间的情况下，冻干物质可能产生的物理和化学变化对活疫苗存活的影响。国外活疫苗冻干制品在2-8℃的保存期为12-36个月，而我国同类产品保存期只有3-6个月。国内疫苗企业常用的保护剂主要是蔗糖、牛奶、明胶等，组方简单，保护性能差。国内疫苗保护剂的研制相对滞后，使疫苗的长期保存和长途运输受到很大限制，加上基层防疫部门缺乏必要的冷冻和冷藏设施，容易因免疫失败而造成疫病流行。所以，耐热保护剂的研究非常急需。
另外，近年来疫病种类增多且暴发频繁，与之相适应的防疫模式也发生了根本性的变化。防疫质量成为制约这一变化的瓶颈之一，疫苗质量更是其中的关键问题。疫苗特别是活疫苗对于冷链运输以及储存温度要求非常高，而这一环节控制不好将直接影响疫苗质量，因此，对于耐热保护剂的开发显得尤为重要。
发明内容
本发明为了弥补现有技术的不足，提供了一种安全性好、稳定性高、便于储运的疫苗耐热保护剂及其制备方法。
本发明是通过如下技术方案实现的：
一种疫苗耐热保护剂，其特征在于：由等体积的A液和B液组成，
所述A液由以下重量分数的物质制成：乳糖15-17％、酶解酪蛋白8％-12％、海藻糖1％-8％，余量为水；
所述B液由以下重量分数的物质制成：明胶3-5％、甘氨酸1％-3％、聚乙烯吡咯烷酮1-8％，余量为水。
本发明选取多种特异性耐热保护作用的成分，通过合理的试验设计与配方优化，筛选出对疫苗有耐热保护效果的复合配方，解决了疫苗不耐受反复冻融及运输与保存过程中不耐热的问题。
进一步优选的，所述A液和B液中的水为蒸馏水。
上述疫苗耐热保护剂的制备方法，包括如下步骤：
(1)将乳糖、酶解酪蛋白、海藻糖溶解于水中，灭菌得到A液；
(2)将明胶、甘氨酸、聚乙烯吡咯烷酮溶解于水中，过滤除菌得到B液；
(3)将A液和B液按1:1的体积比混匀，得到所述耐热保护剂。
进一步优选的，步骤(1)中，灭菌条件为108-120℃下灭菌15-30min。
进一步优选的，步骤(2)中，过滤除菌是采用0.22μm的除菌过滤器。
本发明的耐热保护剂配置的疫苗在2-8℃下保存36个月，仍保持冻干后的外形，病毒含量超过国家生物制品规程的标准。冻干前后病毒损失率低，安全无应激，冻干产品耐老化效果好。
本发明耐热保护剂的使用降低了活疫苗产品的储运要求，解决了活疫苗不能在2-8℃下长期保存和运输的问题，提高了产品在保存和使用中的稳定性。
具体实施方式
下面结合具体实施例对本发明的技术方案进行详细说明，以便于对本发明的理解，但并不是对本发明的限制。
实施例1：疫苗耐热保护剂的制备
(1)将乳糖15％、酶解酪蛋白8％、海藻糖1％溶解于蒸馏水中，110℃、20min灭菌得到A液；
(2)将明胶3％、甘氨酸1％、聚乙烯吡咯烷酮4％溶解于蒸馏水中，采用0.22μm的除菌过滤器过滤除菌得到B液；
(3)将A液和B液等体积混匀，得到所述耐热保护剂。
实施例2：疫苗耐热保护剂的制备
(1)将乳糖15％、酶解酪蛋白8％、海藻糖1％溶解于蒸馏水中，110℃、20min灭菌得到A液；
(2)明胶4％、甘氨酸2％、聚乙烯吡咯烷酮4％溶解于蒸馏水中，采用0.22μm的除菌过滤器过滤除菌得到B液；
(3)将A液和B液等体积混匀，得到所述耐热保护剂。
实施例3：疫苗耐热保护剂的制备
(1)将乳糖17％、酶解酪蛋白10％、海藻糖2％溶解于蒸馏水中，110℃、20min灭菌得到A液；
(2)将明胶4％、甘氨酸2％、聚乙烯吡咯烷酮4％溶解于蒸馏水中，采用0.22μm的除菌过滤器过滤除菌得到B液；
(3)将A液和B液等体积混匀，得到所述耐热保护剂。
实施例4：疫苗耐热保护剂的制备
(1)将乳糖17％、酶解酪蛋白10％、海藻糖2％溶解于蒸馏水中，110℃、20min灭菌得到A液；
(2)将明胶3％、甘氨酸1％、聚乙烯吡咯烷酮4％溶解于蒸馏水中，采用0.22μm的除菌过滤器过滤除菌得到B液；
(3)将A液和B液等体积混匀，得到所述耐热保护剂。
疫苗耐热保护剂的效力分析
(1)实验方法：本发明保护剂作为实验组；另选现有技术中一种常用的普通保护剂作为对照组。
(2)实验疫苗：甲肝减毒活疫苗。
(3)将甲肝减毒活疫苗与上述实施例1、2、3、4所述方法分别制备得到疫苗耐热保护剂混合后，采用下列方法制备出成品：
1)将保护剂与抗原按照1:4的体积比混合培苗，得到冻干液；每瓶中含有溶液2.6ml；
2)将冻干液进行冻干，所述冻干工艺包括：
冻干液在7小时内缓慢降到-48℃下保持5小时；逐渐升温至-25℃后保持24小时；升温至-20℃保持2小时，升温至-15℃保持2小时，升温至-10℃保持2小时，升温至0℃保持2小时；升温至5℃保持2小时；升温至26℃保持10小时。
(4)实验结果：
本实施方案的实验结果如表1所示。
用普通保护剂病毒在冻干过程中损失0.5～1个滴度；在37℃温度下存放5天后测病毒含量，病毒损失相当大，在3～4个滴度。本发明的耐热保护剂不仅可以减少病毒在冻干过程中的损失(几乎无损失)，同时大大提高了病毒的耐老化能力，即在7℃放7天后病毒含量损失在1个滴度以内。
虽然本发明的具体实施方式进行了详细地描述，但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内，本领域技术人员不经创造性劳动即可做出的各种修改和变形仍属本专利的保护范围。
表1
Claims (5)
1.一种疫苗耐热保护剂，其特征在于：由等体积的A液和B液组成，所述A液由以下重量分数的物质制成：乳糖15-17％、酶解酪蛋白8％-12％、海藻糖1％-8％，余量为蒸馏水；所述B液由以下重量分数的物质制成：明胶3-5％、甘氨酸1％-3％、聚乙烯吡咯烷酮1-8％，余量为蒸馏水。
2.一种权利要求1所述疫苗耐热保护剂的制备方法，其特征在于，包括如下步骤：(1)将乳糖、酶解酪蛋白、海藻糖溶解于水中，灭菌得到A液；(2)将明胶、甘氨酸、聚乙烯吡咯烷酮溶解于水中，过滤除菌得到B液；(3)将A液和B液按1:1的体积比混匀，得到所述耐热保护剂。
3.根据权利要求2所述的制备方法，其特征在于：步骤(1)中，灭菌条件为108-120℃下灭菌15-30min。
4.根据权利要求2所述的制备方法，其特征在于：步骤(2)中，过滤除菌是采用0.22μm的除菌过滤器。
5.根据权利要求2所述的制备方法，其特征在于：所得到的耐热保护剂储存于1-6℃环境下。
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