CN110680916B - 一种含铝佐剂和罗非昔布组合的甲肝疫苗可溶性微针 - Google Patents
一种含铝佐剂和罗非昔布组合的甲肝疫苗可溶性微针 Download PDFInfo
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Abstract
本发明提供了一种含有铝佐剂和罗非昔布组合的甲肝疫苗可溶性微针阵列,包括载药针体和基底层。载药针体中含有甲肝疫苗、氢氧化铝和罗非昔布,各组分的固含量占比为:甲肝疫苗5%~15%,氢氧化铝佐剂16%~24%,罗非昔布6%~14%。基底层为药学上可接受的可溶性的基质材料。本发明提供的甲肝疫苗可溶性微针,既能显著提高甲肝疫苗的免疫效果,又能减缓因铝佐剂带来的炎症反应,大大提高了疫苗接种的有效性与安全性,提高了儿童用药的顺应性。
Description
技术领域
本发明涉及疫苗的微针给药技术领域,提供了一种含铝佐剂和罗非昔布组合的甲肝疫苗可溶性微针。
背景技术
甲型肝炎是由甲肝病毒(Hepatitis A virus,HAV)引起的急性自限性疾病,患者以低龄儿童为主。HAV在人群中主要通过粪口途径传播,全球每年约有150万人罹患甲肝。接种甲肝疫苗是预防和控制甲肝流行的最有效措施。
目前临床上应用的甲肝灭活疫苗、甲肝减毒疫苗均为注射剂,甲肝灭活疫苗包括贺福立适(HAVRIX)、维康特(VAQTA)、巴维信(AVAXIM)、爱巴苏(EPAXAL)、孩尔来福等。甲肝减毒疫苗包括LAl减毒株、H2减毒株等。然而,儿童对于注射剂所带来的疼痛和对针头的恐惧导致常伴随有较强的排斥心理,且注射剂会造成组织损伤和出血,操作不当会带来安全问题。综上所述,临床急需一种安全且不会给儿童带来痛苦的制剂。
经皮免疫(Transcutaneous immunization,TCI)是一种新型的免疫接种方式。皮肤作为人体最大的免疫器官,存在大量的与免疫反应相关的抗原提呈细胞(antigen-presentingcells,APC),例如树突状细胞(dendritic cells,DCs)和朗格汉斯细胞(Langerhans cells,LCs)。由于皮肤内存在的APC比肌肉内更丰富,使得经皮免疫比肌肉注射更节省剂量。微针阵列(microneedles array,下文所述的微针贴、可溶性微针均同此义)能通过刺穿皮肤角质层从而大大增强大分子药物的经皮吸收,且由于微针非常细小,在治疗过程中不会使患者感到痛苦,造成的皮肤孔洞能在较短的时间内自动修复,有望成为解决该问题的优良之选。按照微针的结构和释药方式,微针可以分为实心不溶性微针、涂层微针、可溶性微针、空心微针四类。其中可溶性微针具有载药量高、安全卫生、使用方便等优点,具有很好的应用前景。因此,考虑将甲肝疫苗载入可溶性微针中,不仅可以解决儿童用药的顺应性问题,而且能有效发挥经皮免疫的优势。
公开号为KR20170032810A的韩国专利公开了一种甲肝疫苗可溶性微针,该专利仅是常规的可溶性微针手段,并未在疫苗中加入佐剂,也未进行药效学和炎症反应实验。我们通过预实验发现,不加佐剂的甲肝疫苗可溶性微针的效果较差。
疫苗佐剂的使用能够提高机体对抗原的适应性免疫应答。然而,多数佐剂的作用机制尚未明确,佐剂在复杂的免疫级联反应中的首要效应很难阐明,这给新型疫苗佐剂的开发研究增加了难度(吴超,邹全明.新型疫苗佐剂的研究进展[J].中国生物工程杂志,2005,25(8):10-15.)。目前在国际上已被公认的人用佐剂也寥寥无几,包括铝盐、MF59、AS03、脂质体。其中脂质体对于甲肝疫苗效果有较好的促进作用,但脂质体存在稳定性差,成本高等缺陷(周洋,耿兴超,汪巨峰,等.疫苗佐剂最新研究进展[J].中国新药杂志,2013(1):34-42.)。
虽然通过注射的方式接种时脂质体对于甲肝疫苗效果有较好的促进作用,然而通过预实验发现,将上述四种已得到国际公认的佐剂加入甲肝疫苗处方中制成的可溶性微针中,脂质体对于甲肝疫苗效果没有促进作用,这可能由于可溶性微针的制备过程中需要将液态的基质溶液干燥固化后才能得到可溶性微针阵列片,脂质体需在溶液中才稳定,脱水后就失去了效果。铝佐剂对于提高甲肝疫苗可溶性微针的免疫应答效果最显著,且优于MF59和AS03。然而铝佐剂、MF59和AS03加入甲肝疫苗可溶性微针后均会引起皮肤局部炎症等不良反应,这与文献报道的结果一致(周洋,耿兴超,汪巨峰,等.疫苗佐剂最新研究进展[J].中国新药杂志,2013(1):34-42.)。
目前,尚未有文献报道,可将抗炎成分加入到甲肝疫苗可溶性微针中,来抑制铝佐剂副作用这一创新思路。
综上所述,如何开发出一种同时含有抗炎成分和铝佐剂的甲肝疫苗可溶性微针,使其既能发挥经皮免疫优势,又能避免因疫苗佐剂导致的炎症反应,从而提高了儿童用药的顺应性,是本领域技术人员急需解决的技术难题。
发明内容
本发明目的在于提供了一种含铝佐剂和罗非昔布组合的甲肝疫苗可溶性微针,通过在甲肝疫苗可溶性微针中加入特定比例的铝佐剂和抗炎药罗非昔布,既显著增强了甲肝疫苗的免疫效果,又避免产生了明显的炎症反应,解决了上述现有技术存在的瓶颈。
本发明的研发思路如下:首先,考察加入不同的佐剂对甲肝疫苗可溶性微针的效果差异,择选出合适的佐剂;其次,考察加入不同的抗炎药对含有佐剂的甲肝疫苗可溶性微针的炎症抑制效果差异,择选出合适的抗炎药;最后,考察佐剂与抗炎药以不同比例组合时对甲肝疫苗可溶性微针的效果差异,择选出最优比例。
为实现上述研发思路,本发明采用的技术方案具体如下:
本发明提供了一种含铝佐剂和罗非昔布组合的甲肝疫苗可溶性微针,包括载药针体和基底层,载药针体中含有甲肝疫苗、氢氧化铝和罗非昔布,基底层为药学上可接受的可溶性的基质材料。
优选的,针体中各组分的固含量占比为:甲肝疫苗5%~15%,氢氧化铝佐剂16%~24%,罗非昔布6%~14%。
更优选的,针体中各组分的固含量占比为:甲肝疫苗10%,氢氧化铝佐剂20%,罗非昔布10%。
优选的,基质材料为透明质酸(HA)、海藻糖、果糖、半乳糖、麦芽糖、硫酸软骨素、甲基乙烯基醚-顺丁烯酸酐共聚物(Gantrez)中的一种或几种。
优选的,甲肝疫苗为灭活疫苗、减毒疫苗中的一种。
本发明还提供了一种如前所述的甲肝疫苗可溶性微针的制备方法,包括如下步骤:将甲肝疫苗、氢氧化铝、罗非昔布与基质材料按比例混合后,加水使之成为均一混悬液且粘度适宜注模;将混悬液均匀涂覆至微针模具上,通过离心或抽真空使之进入微针模具孔洞,排除气泡,烘干或自然晾干,脱模,即得。
本发明提供的含铝佐剂和抗炎药组合的甲肝疫苗可溶性微针,与现有技术相比,有益效果在于:
1.将甲肝疫苗制成可溶性微针,避免了注射给药带来的疼痛、组织损伤、出血、恐惧等影响儿童用药顺应性的隐患。
2.将氢氧化铝与罗非昔布按照特定的比例载入可溶性甲肝疫苗微针中,既能显著提高甲肝疫苗的免疫效果,又能减缓因铝佐剂带来的炎症反应,大大提高了疫苗接种的有效性与安全性。
具体实施方式
为了使本技术领域的人员更好的理解本发明方案,下面将对本实施例中的技术方案进行具体说明。必须说明的是,下述实施例仅用来解释本发明,而不是对发明进行限制,在本发明的精神和权利要求的保护范围内,对本发明作出的任何修改和改变,都落入到了本发明的保护范围。
实施例1:可溶性微针的制备工艺
利用MEMS工艺制备的微针阵列阳模具,材质为硅,微针为四棱锥形,高度600μm、底部为300×300μm的正方形,微针阵列之间的间距为600μm,数量为20×20共400根针。应用PDMS硅橡胶材料,取主剂和固化剂质量比为10:1混匀,浇在上述阳模具上,90℃加热固化2h后,脱模,得到PDMS阴模具。
本发明中的基底层选用可溶性基质材料,首选透明质酸,但并不局限于此,还可以选择海藻糖、果糖、半乳糖、麦芽糖、硫酸软骨素、甲基乙烯基醚-顺丁烯酸酐共聚物中的一种或几种。
将各组分按规定的处方配比混合后,用蒸馏水溶胀成均一混悬液,使其粘度恰好有利于浇注入模。取适量的混悬液涂覆于按实施例1制备的阴模具上,放入离心机中,1000g离心力下离心5min,使得混悬液进入模具孔洞。取出模具,于37℃烘箱干燥8h后,脱模,即得甲肝疫苗可溶性微针阵列。
实施例2:微针的免疫效果和局部炎症反应测试方法
使用脱毛后的6-8周龄ICR小鼠,给药方式为在小鼠背部施加微针贴,微针贴的施加时间为5min,给药后2h时取给药部位皮下组织液,使用白介素-6ELISA试剂盒(产自Bender Medsystem公司)测定皮下组织液中炎症因子白介素-6浓度,测试步骤按照试剂盒说明操作。
给药后第八周尾静脉取血,使用小鼠Ig G ELISA试剂盒(KPL公司)检测小鼠分离血清中的抗HAV Ig G抗体水平,测试步骤按照试剂盒说明操作。
实施例3:不同佐剂的效果比较
为了考察不同佐剂对甲肝疫苗微针阵列效果的影响,对比了氢氧化铝、MF59、AS03、脂质体这四种国际上已获得批准的佐剂对于甲肝疫苗微针的效果。根据预实验结果,采用的处方配比(w.t.)为:10%甲肝疫苗、20%佐剂、70%基质材料;处方比例不变,仅变动佐剂的组分,按照实施例1的方法制备微针阵列,并按照实施例2的方法测试各处方微针阵列的免疫效果和局部炎症反应,实验结果见表1。
表1.不同佐剂达到的效果(n=5,x±s)
佐剂 | 白介素6水平(pg/ml) | 抗HAV Ig G抗体水平(pg/ml) |
空白对照 | 526.3±25.4 | 0 |
不含佐剂组 | 589.1±29.2 | 1.43±0.33 |
氢氧化铝 | 858.3±60.7 | 3.27±0.55 |
MF59 | 887.9±62.0 | 1.80±0.28 |
AS03 | 903.9±75.5 | 1.95±0.30 |
脂质体 | 728.6±47.8 | 1.42±0.28 |
从表1中可以看出:
1)仅氢氧化铝(即铝佐剂,下同)的加入能够显著增加疫苗的免疫效果,而脂质体对于甲肝疫苗效果没有促进作用,分析其原因在于,可溶性微针的制备过程中需要将液态的基质溶液干燥固化后才能得到可溶性微针阵列,脂质体须在溶液中才稳定,脱水后会失去效果。
2)铝佐剂对于提高甲肝疫苗可溶性微针的免疫应答效果最显著,且优于MF59佐剂和AS03佐剂。
3)表1中所有佐剂的加入都导致炎症因子水平(白介素-6)的上升,故有待通过特定的方法在不降低铝佐剂效果的前提下减缓其炎症反应。
实施例4:不同抗炎药的效果比较
为了考察不同抗炎药对含铝佐剂的甲肝疫苗微针阵列致炎效应的减缓作用,选取HA(Mw≈30w)作为基质材料,对比等剂量的抗炎成分布洛芬、阿司匹林、对乙酰氨基酚、罗非昔布、萘普生、双氯芬酸、吲哚美辛、尼美舒利各自对于含氢氧化铝的甲肝疫苗微针致炎效应的减缓作用。根据预实验结果,采用的处方配比为:10%甲肝疫苗、20%氢氧化铝、10%抗炎成分、60%基质材料,处方比例不变,仅变动佐剂的组分,按照实施例1的方法制备微针阵列,并按照实施例2的方法测试各处方微针阵列的免疫效果和局部炎症反应,实验结果见表2。
表2.不同抗炎成分达到的效果(n=5,x±s)
佐剂 | 白介素6水平(pg/ml) | 抗HAV Ig G抗体水平(pg/ml) |
空白对照 | 526.3±25.4 | 0 |
不含抗炎成分组 | 858.3±60.7 | 3.27±0.55 |
布洛芬 | 785.9±71.0 | 2.98±0.30 |
阿司匹林 | 804.6±71.2 | 3.09±0.68 |
对乙酰氨基酚 | 954.0±81.8 | 3.30±0.18 |
罗非昔布 | 405.6±40.1 | 7.97±0.75 |
萘普生 | 768.7±72.5 | 3.28±0.22 |
双氯芬酸 | 635.6±61.7 | 3.59±0.47 |
吲哚美辛 | 707.2±70.9 | 3.00±0.29 |
尼美舒利 | 715.9±70.6 | 3.86±0.73 |
从表2中可以看出:
1)只有罗非昔布的加入,使得炎症因子水平显著降低至405.6±40.1pg/ml,且低于空白对照组的526.3±25.4pg/ml,表明罗非昔布的加入比不加佐剂组的炎症反应更低;此外,罗非昔布组的抗HAV Ig G抗体水平达到7.97±0.75pg/ml,远高于不加佐剂组、仅加佐剂不加抗炎成分组、既加佐剂又加其它抗炎成分组,表明罗非昔布与铝佐剂联用能显著增强甲肝疫苗微针的免疫效果,产生了协同增效作用。
2)其他抗炎成分,均不同时具备上述两种功效。
实施例5:不同处方比例对免疫效果和炎症反应的影响实验
基于预实验和经验判断,当微针阵列产生的白介素6水平在600.0以内、抗HAV IgG抗体水平高于3.00时,该微针符合实际使用的要求。
为了考察了处方中甲肝疫苗、氢氧化铝、罗非昔布的含量变化对免疫效果和炎症反应的影响,设计了一系列的处方比例,按照实施例1的方法制备微针阵列,并按照实施例2的方法测试各处方微针阵列的免疫效果和局部炎症反应。实验结果见表3。
表3.微针中各组分固含量重量百分比以及各组实验结果(n=5,x±s)
从表3中可以看出:
1)处方1表明,微针中仅含甲肝疫苗,不含氢氧化铝和罗非昔布时,白介素6水平为589.1±29.2pg/ml,抗HAV Ig G抗体水平为1.43±0.33,此时微针的免疫效果较差,还有一定的炎症反应。
2)处方2~7考察了当甲肝疫苗和铝佐剂为定值时,罗非昔布含量的变化对微针的免疫效果与炎症反应的影响,可知罗非昔布含量仅为6%~14%(即处方4、5、6)时,微针符合实际使用要求。在处方3-5中,随着罗非昔布浓度上升,白介素水平降低,然而在处方5-7中,随着罗非昔布浓度进一步上升,白介素水平反而升高,是因罗非昔布的加入导致微针机械强度的降低,无法有效刺入皮内所致。
3)处方8~11考察了当甲肝疫苗和罗非昔布为定值时,铝佐剂含量的变化对微针的免疫效果与炎症反应的影响,可知铝佐剂含量仅为16%~24%(即处方9、10)时,微针符合实际使用要求。
4)处方12~15考察了当铝佐剂和罗非昔布为定值时,甲肝疫苗含量的变化对微针的免疫效果与炎症反应的影响,可知甲肝疫苗含量仅为5%~15%(即处方13、14)时,微针符合实际使用要求。
综上分析可知,本发明的甲肝疫苗微针,能够同时兼具增强免疫效果和降低炎症反应的优选处方为:甲肝疫苗5%~15%,氢氧化铝佐剂16%~24%,罗非昔布6%~14%;其中,最优处方为:甲肝疫苗10%,氢氧化铝佐剂20%,罗非昔布10%(即处方5)。
Claims (3)
1.一种甲肝疫苗可溶性微针,由载药针体和基底层组成,其特征在于,所述的载药针体中各组分及其固含量占比为:甲肝疫苗10%,氢氧化铝佐剂20%,罗非昔布10%,基质材料60%;
所述的基底层为药学上可接受的可溶性的基质材料;
所述的基质材料为透明质酸。
2.根据权利要求1所述的甲肝疫苗可溶性微针,其特征在于,所述的甲肝疫苗为灭活疫苗、减毒疫苗中的一种。
3.一种如权利要求1~2中任一项所述的甲肝疫苗可溶性微针的制备方法,包括如下步骤:
将甲肝疫苗、氢氧化铝、罗非昔布与基质材料按比例混合后,加水使之成为均一混悬液且粘度适宜注模;将混悬液均匀涂覆至微针模具上,通过离心或抽真空使之进入微针模具孔洞,排除气泡,烘干或自然晾干,脱模,即得甲肝疫苗可溶性微针阵列。
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