CN115364206A - 一种联合抗肿瘤疫苗及其制备方法 - Google Patents
一种联合抗肿瘤疫苗及其制备方法 Download PDFInfo
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- CN115364206A CN115364206A CN202111374141.6A CN202111374141A CN115364206A CN 115364206 A CN115364206 A CN 115364206A CN 202111374141 A CN202111374141 A CN 202111374141A CN 115364206 A CN115364206 A CN 115364206A
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明公开了一种联合抗肿瘤疫苗，制备原料以重量百分比计包括：疫苗28‑41％，辅料10‑15％，PBS缓冲液补充余量。本发明通过将百白破疫苗，吸附白喉破伤风联合疫苗，芽孢杆菌卡介苗和灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗联用，通过一次接种达到多种疫苗联合增效的效果，提高机体免疫力，增加靶细胞免疫应答，提高抗肿瘤的效果；并且通过采用质量分数为80％的蛋黄卵磷脂，单硬脂酸甘油酯，薏苡仁油和吐温‑80的辅料组合，增加了各个疫苗之间的相容性和稳定性，减少了长时间储存下沉淀析出的问题；同时使疫苗有效成分在抗肿瘤疫苗中均匀分散，并且保持一定的分散稳定性，延长了疫苗的保存时效。
Description
技术领域
本发明涉及一种联合抗肿瘤疫苗及其制备方法，涉及A61K，具体涉及医用的配制品领域。
背景技术
肿瘤是威胁全人类生命安全的一大杀手，世界卫生组织指出部分肿瘤是可以通过预防的手段阻止的，并且部分恶性肿瘤也是可以治愈的，早发现早治疗可以较高的提高治愈率，并且早期开展对恶性肿瘤的治疗能够极大的提高患者的生命质量，缓解病痛。目前现有的治疗肿瘤的手段为放疗，化疗，外科手术等，但都会给患者机体带来极大的痛苦，并且还存在肿瘤清除不干净重复治疗的隐患，严重影响了患者的生活质量。采用疫苗接种是一种新兴的预防肿瘤的手段，但是单一种类的疫苗，作用于单一靶点，抗肿瘤效率低，疫苗管理成本高，也容易出错。
中国发明专利CN201710022717公开了一种口服肿瘤疫苗，通过抗酸剂与细胞囊泡联合使用，使其达到抑制肿瘤细胞生长的效果，延长生命的存活时间，但是口服药剂受消化系统和食物的影响，经过肠胃，可能对机体产生副作用。中国发明专利CN200910056537公开了一种广谱抗肿瘤复合疫苗，通过血液输送实现广谱的抗肿瘤效果，但是可能会对部分病变细胞的特异性不强，影响抗击肿瘤的效率，抗体的作用效果不佳。
发明内容
为了提高肿瘤预防的效率，减少对身体的毒副作用，本发明的第一个方面提供了一种联合抗肿瘤疫苗，制备原料以重量百分比计包括：疫苗28-41％，辅料10-15％，PBS缓冲液补充余量。
作为一种优选的实施方式，所述疫苗选自减毒活疫苗、灭活疫苗、类毒素疫苗、多肽疫苗、载体疫苗、核酸疫苗中的一种或几种的组合。
作为一种优选的实施方式，所述减毒活疫苗选自芽孢杆菌卡介苗、灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗、麻疹疫苗、鼠疫疫苗中的一种或几种的组合。
作为一种优选的实施方式，所述类毒素疫苗选自百白破疫苗、吸附白喉破伤风联合疫苗、葡萄球菌疫苗、霍乱类毒素疫苗中的一种或几种的组合。
作为一种优选的实施方式，所述疫苗为百白破疫苗，吸附白喉破伤风联合疫苗，芽孢杆菌卡介苗，灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗的组合。
作为一种优选的实施方式，所述百白破疫苗，吸附白喉破伤风联合疫苗，芽孢杆菌卡介苗，灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗的重量比为(10-15)：(5-8)：(10-13)：(3-5)。
作为一种优选的实施方式，所述百白破疫苗，吸附白喉破伤风联合疫苗，芽孢杆菌卡介苗，灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗的重量比为12：6：13：5。
作为一种优选的实施方式，所述辅料中原料以重量份包括：脂质材料10-30份，乳化剂2-10份，注射用油60-80份。
作为一种优选的实施方式，所述辅料中原料以重量份包括：脂质材料20份，乳化剂6份，注射用油70份。
作为一种优选的实施方式，所述脂质材料选自单硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸、油酸、中链脂肪酸甘油酯和长链脂肪酸甘油酯中的一种或几种的组合。
作为一种优选的实施方式，所述脂质材料为单硬脂酸甘油酯。
作为一种优选的实施方式，所述乳化剂选自蛋黄卵磷脂Lipoid E80、豆磷脂Lipoid S75、豆磷脂Epikuron 170、乳化剂Plironic F68、吐温80、脱氧胆酸钠中的一种或几种的组合。
作为一种优选的实施方式，所述乳化剂为蛋黄卵磷脂Lipoid E80和吐温80的组合。
作为一种优选的实施方式，所述蛋黄卵磷脂Lipoid E80和吐温80的重量比为(4-7)：(1-2)。
作为一种优选的实施方式，所述蛋黄卵磷脂Lipoid E80和吐温80的重量比为5：1。
作为一种优选的实施方式，所述蛋黄卵磷脂Lipoid E80中蛋黄卵磷脂的质量分数大于80％。
作为一种优选的实施方式，所述注射用油选自山茶油、大豆油、葡萄籽油、芝麻油、蓖麻油、薏苡仁油中的一种或几种的组合。
作为一种优选的实施方式，所述注射用油为薏苡仁油。
作为一种优选的实施方式，所述辅料为蛋黄卵磷脂Lipoid E80，单硬脂酸甘油酯，薏苡仁油和吐温-80的组合。
申请人在实验过程中发现，将多种疫苗进行组合作用，通过加入质量分数为80％的蛋黄卵磷脂，单硬脂酸甘油酯，薏苡仁油和吐温80的组合可以增加各个疫苗之间的相容性和稳定性，猜测可能的原因是：百白破疫苗和吸附白喉破伤风联合疫苗中都含有氢氧化铝作为疫苗的佐剂，增强机体免疫反应的强度和持久性，但是氢氧化铝佐剂在长时间的储存过程中容易沉淀析出，影响疫苗的储存稳定性，本申请通过加入辅料，可以将疫苗分散成粒径均匀的乳剂粒子，将疫苗有效成分与氢氧化铝佐剂进行整体的包裹，减少外界环境对疫苗有效成分和氢氧化铝佐剂的影响，从而提高联合疫苗的储存稳定性。同时采用质量分数为80％的蛋黄卵磷脂和薏苡仁油作为乳剂粒子的包裹壁，与基体注射细胞的成分近似，可以增强细胞摄取抗原的能力，有效增强对靶细胞的免疫应答。
作为一种优选的实施方式，制备原料以重量百分比计还包括能量补充剂20-35％；优选的，所述能量补充剂包括静脉注射用脂肪乳剂和维生素E，重量比为(20-30)：(0.5-3)。
作为一种优选的实施方式，所述静脉注射用脂肪乳剂和维生素E的重量比为25：3。
作为一种优选的实施方式，所述PBS缓冲液的pH为7.2-7.4。
作为一种优选的实施方式，所述PBS缓冲液中氯化钠，氯化钾，磷酸氢二钠，磷酸二氢钾的重量比为(8-9)：(0.2-0.5)：(2.2-3)：(0.3-5)。
作为一种优选的实施方式，所述PBS缓冲液中氯化钠，氯化钾，磷酸氢二钠，磷酸二氢钾的重量比为8.5：0.2：2.2：0.3。
作为一种优选的实施方式，所述PBS缓冲液的制备方法包括以下步骤：称取8.5gNaCl，0.2gKCl，2.2gNa2HPO4和0.3gKH2PO4，加蒸馏水溶解定容至1000ml，即得。
本发明的第二个方面提供了一种联合抗肿瘤疫苗的制备方法，包括以下步骤：
(1)将上述原料混合，置于超声波下进行超声，超声功率为85-100W，超声时间为15-30min；
(2)然后以每秒10％的下降速率，将超声功率降至50-60W，然后继续超声10-30min，即得。
与现有技术相比，本发明具有以下有益效果：
(1)本发明所述联合抗肿瘤疫苗，通过将百白破疫苗，吸附白喉破伤风联合疫苗，芽孢杆菌卡介苗和灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗联用，通过一次接种达到多种疫苗联合增效的效果，提高机体免疫力，增加靶细胞免疫应答，提高抗肿瘤的效果。
(2)本发明所述联合抗肿瘤疫苗，通过采用变频超声制备的方法，使疫苗有效成分在抗肿瘤疫苗中均匀分散，并且保持一定的分散稳定性，延长了疫苗的保存时效。
(3)本发明所述联合抗肿瘤疫苗，通过采用质量分数为80％的蛋黄卵磷脂，单硬脂酸甘油酯，薏苡仁油和吐温-80的辅料组合，增加了各个疫苗之间的相容性和稳定性，减少了长时间储存下沉淀析出的问题。
具体实施方式
下面通过实施例对本发明进行具体描述。有必要在此指出的是，以下实施例只用于对本发明作进一步说明，不能理解为对本发明保护范围的限制，该领域的专业技术人员根据上述本发明的内容做出的一些非本质的改进和调整，仍属于本发明的保护范围。
另外，如果没有其它说明，所用原料都是市售得到的。
实施例1
一种联合抗肿瘤疫苗，制备原料以重量百分比计包括：疫苗36％，辅料15％，能量补充剂32％，PBS缓冲液补充余量。
所述疫苗为百白破疫苗，吸附白喉破伤风联合疫苗，芽孢杆菌卡介苗，灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗的组合，重量比为12：6：13：5。
所述百白破疫苗购自长春长生生物科技股份有限公司。
所述吸附白喉破伤风联合疫苗购自汉生物制品研究所。
所述芽孢杆菌卡介苗购自成都生物制品研究所有限责任公司。
所述灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗购自赛诺菲巴斯德公司。
所述辅料为蛋黄卵磷脂Lipoid E80，单硬脂酸甘油酯，薏苡仁油和吐温80的组合，重量比为5：20：70：1。
所述蛋黄卵磷脂Lipoid E80中蛋黄卵磷脂的质量分数为80％，购自上海芃硕生物科技有限公司。
所述薏苡仁油购自上海源叶生物科技有限公司。
所述能量补充剂为静脉注射用脂肪乳剂和维生素E的组合，重量比为25：2。
所述静脉注射用脂肪乳剂购自科伦药业公司。
所述维生素E购自北京百灵威科技有限公司。
所述PBS缓冲液的制备方法包括以下步骤：称取8.5gNaCl，0.2gKCl，2.2gNa2HPO4和0.3gKH2PO4，加蒸馏水溶解定容至1000ml，即得。
一种联合抗肿瘤疫苗的制备方法，包括以下步骤：
(1)将上述原料混合，置于超声波下进行超声，超声功率为90W，超声时间为20min；
(2)然后以每秒10％的下降速率，将超声功率降至55W，然后继续超声20min，即得。
实施例2
一种联合抗肿瘤疫苗及其制备方法，具体步骤同实施例1，不同点在于制备原料以重量百分比计包括：疫苗41％，辅料10％，能量补充剂28％，PBS缓冲液补充余量。
所述疫苗为百白破疫苗，吸附白喉破伤风联合疫苗，芽孢杆菌卡介苗，灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗的组合，重量比为15：8：13：5。
所述能量补充剂为静脉注射用脂肪乳剂和维生素E的组合，重量比为25：3。
实施例3
一种联合抗肿瘤疫苗及其制备方法，具体步骤同实施例1，不同点在于制备原料以重量百分比计包括：疫苗28％，辅料10％，能量补充剂20.5％，PBS缓冲液补充余量。
所述疫苗为百白破疫苗，吸附白喉破伤风联合疫苗，芽孢杆菌卡介苗，灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗的组合，重量比为10：5：10：3。
所述能量补充剂为静脉注射用脂肪乳剂和维生素E的组合，重量比为20：0.5。
实施例4
一种联合抗肿瘤疫苗及其制备方法，具体步骤同实施例1，不同点在于所述辅料为蛋黄卵磷脂Lipoid E80，薏苡仁油和吐温80的组合。
实施例5
一种联合抗肿瘤疫苗及其制备方法，具体步骤同实施例1，不同点在于所述能量补充剂为静脉注射用脂肪乳剂。
性能测试
1.抑瘤率：
实验对象：上海斯莱克实验动物责任有限公司提供的小鼠，对实施例1-3的样品进行小鼠生物实验，试验组小鼠分为6组，每组10只，对照组小鼠10只；
剂量设置：原液注射0.1ml/鼠或0.2ml/鼠；
给药方案：接种后1、4、7、10天、皮下注射；
试验对照：对照组小鼠给以注射与试验组等体积等浓度的生理盐水；
试验步骤：取生长旺盛的瘤源，于小鼠腋皮下接种0.2ml/每鼠，次日按实验设计方案给药，实验结束时处死各组动物，剖取肿瘤称重，按下列公式计算肿瘤抑制率：
肿瘤抑制率％＝[(对照组平均瘤重—给药组平均瘤重)/对照组平均瘤重]×100％
瘤源：Lewis肺癌模型由上海医药工业研究院药理评价研究中心传代维持。
实施例1-3按照上述测试标准进行测试，实验结果见于表1。
2.粒径稳定性：观察测量实施例1-5的起始乳剂粒径为300nm，放置一段时间后观察乳剂粒径出现变化的时间。实验结果见于表2。
表1
表2
Claims (10)
1.一种联合抗肿瘤疫苗，其特征在于，制备原料以重量百分比计包括：疫苗28-41％，辅料10-15％，PBS缓冲液补充余量。
2.根据权利要求1所述联合抗肿瘤疫苗，其特征在于，所述疫苗选自减毒活疫苗、灭活疫苗、类毒素疫苗、多肽疫苗、载体疫苗、核酸疫苗中的一种或几种的组合。
3.根据权利要求2所述联合抗肿瘤疫苗，其特征在于，所述减毒活疫苗选自芽孢杆菌卡介苗、灭活脊髓灰质炎和b性流感嗜血杆菌联合疫苗、麻疹疫苗、鼠疫疫苗中的一种或几种的组合。
4.根据权利要求2所述联合抗肿瘤疫苗，其特征在于，所述类毒素疫苗选自百白破疫苗、吸附白喉破伤风联合疫苗、葡萄球菌疫苗、霍乱类毒素疫苗中的一种或几种的组合。
5.根据权利要求1或2所述联合抗肿瘤疫苗，其特征在于，所述辅料中原料以重量份包括：脂质材料10-30份，乳化剂2-10份，注射用油60-80份。
6.根据权利要求5所述联合抗肿瘤疫苗，其特征在于，所述脂质材料选自单硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸、油酸、中链脂肪酸甘油酯和长链脂肪酸甘油酯中的一种或几种的组合。
7.根据权利要求5所述联合抗肿瘤疫苗，其特征在于，所述乳化剂选自蛋黄卵磷脂Lipoid E80、豆磷脂Lipoid S75、豆磷脂Epikuron 170、乳化剂Plironic F68、吐温80、脱氧胆酸钠中的一种或几种的组合。
8.根据权利要求5所述联合抗肿瘤疫苗，其特征在于，所述注射用油选自山茶油、大豆油、葡萄籽油、芝麻油、蓖麻油、薏苡仁油中的一种或几种的组合。
9.根据权利要求1或2所述联合抗肿瘤疫苗，其特征在于，制备原料以重量百分比计还包括能量补充剂20-35％；优选的，所述能量补充剂包括静脉注射用脂肪乳剂和维生素E，重量比为(20-30)：(0.5-3)。
10.一种根据权利要求1-9任一项所述联合抗肿瘤疫苗的制备方法，其特征在于，包括以下步骤：
(1)将上述原料混合，置于超声波下进行超声，超声功率为85-100W，超声时间为15-30min；
(2)然后以每秒10％的下降速率，将超声功率降至50-60W，然后继续超声10-30min，即得。
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