CN111658611B - 一种基于微乳的疫苗递送系统及其制备方法和应用 - Google Patents
一种基于微乳的疫苗递送系统及其制备方法和应用 Download PDFInfo
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- CN111658611B CN111658611B CN202010283350.9A CN202010283350A CN111658611B CN 111658611 B CN111658611 B CN 111658611B CN 202010283350 A CN202010283350 A CN 202010283350A CN 111658611 B CN111658611 B CN 111658611B
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Abstract
本发明提供一种基于微乳的疫苗递送系统,并提供其制备方法和应用。本发明的微乳通过吸附一系列金属离子化合物,并在制备的过程中加入抗原即可实现抗原包载得到稳定的疫苗制剂。本发明制备的疫苗可以高效地被抗原呈递细胞摄取,有效地传递到淋巴结并诱导抗原特异性的免疫反应,具有广阔的应用前景。
Description
技术领域
本发明涉及一种基于微乳的疫苗递送系统及其制备方法,属于医药技术领域。
背景技术
疫苗接种是现代医学的最伟大发明之一,也是许多疾病预防和根除的有效手段,用于控制多种感染性疾病。疫苗发展的三个重要方向包括:新抗原的发现、新的佐剂技术及新的载体平台。
传统减毒活疫苗和灭活疫苗本质上可能包含自然佐剂成分,其中可能包括颗粒形式的蛋白质、脂质和寡核苷酸。但是由于这些减毒和灭活疫苗本身的一些局限性,如减毒的病原微生物突变成强致病的微生物,灭活疫苗在制备中没有灭活完全,当这些疫苗作用于机体,可能会直接导致机体致病。亚单位疫苗是指通过化学分解、重组表达等手段,提取病原微生物具有免疫活性的片段而制成的疫苗。相对于灭活疫苗及减毒活疫苗,亚单位疫苗具有安全性更高、稳定性更好、可规模化生产等优势,成为现代疫苗开发和应用的主要趋势。但是亚单位疫苗也有免疫原性弱、保护作用时间短、起效慢等缺点,为弥补亚单位疫苗的这些缺点,在亚单位疫苗中广泛使用了佐剂。使用疫苗递送载体,能够提高免疫应答水平和改善疫苗制剂的稳定性。在过去十年中,纳米级(<1000nm)材料,如脂质体、ISCOMS、聚合物和可降解的纳米球,纳米粒等,作为疫苗抗原的递送载体而受到人们的关注,这种载体既可以稳定疫苗抗原,避免抗原的降解,其本身也有一定的佐剂效果,可以提高抗原在体内的免疫应答水平。
乳剂作为人类和动物疫苗的佐剂已有很长的历史。弗氏佐剂(Freund’sadjuvant),由美籍匈牙利细菌学家Freund于1935年研究成功,他首次证明了矿物油(石蜡)与分枝杆菌结合具有佐剂效应,这种佐剂被称为“弗氏完全佐剂”。而不含细菌的油包水(w/o)乳剂(弗氏不完全佐剂)随后用于兽医疫苗。虽然像弗氏不完全佐剂这样的乳剂也曾用于人类,其中包括流感病毒疫苗,但它们易引起不良反应。采用可降解油相角鲨烯替代矿物油而制成的水包油乳剂MF59,其佐剂化的流感疫苗已于1997年在欧盟批准上市,并且迄今已在30多个国家得到批准。现已在美国和欧洲临床批准使用的乳剂型佐剂还包括AS03和AF03。
金属离子化合物类佐剂具有极广的应用,其中铝盐,钙盐,锌盐,铁盐和锆盐经常作为抗原吸附剂。铝盐佐剂在疫苗中是应用较广的佐剂,包括硫酸钾铝、磷酸铝和氢氧化铝等,这种佐剂使抗原滞留,缓慢释放,并可引起局部炎症反应,从而吸引活性淋巴细胞,增强免疫应答,还可以增强补体系统,铝佐剂主要引起体液免疫应答而非细胞免疫应答;磷酸钙佐剂在法国已成功的用于白百破、小儿麻痹、卡介苗、麻疹、黄热病、乙肝、HIV的糖蛋白等疫苗的配制,其佐剂作用可能与铝佐剂相似,而钙是人体的天然结构成分,机体对其有很高的耐受性;氢氧化铁佐剂可以同时增强机体体液免疫和细胞免疫反应,因此将来可能会在疫苗的免疫佐剂应用中占有一席之地;氢氧化锌胶体单独或与ATP联合使用均能一定程度上增强对狂犬病毒抗原的免疫应答,加之锌元素的毒副作用极低,其开发应用也极具潜力。
在这里,我们将金属离子化合物吸附于微乳表面,促使其比表面积急剧增大,具有表面反应活性高、活性中心多、吸附能力强等特性,在相同金属离子化合物含量的情况下,可吸附更多的抗原,从而制成纳米级别颗粒用于疫苗递送。
发明内容
本发明的目的之一是提供一种由金属离子化合物、抗原和微乳形成的疫苗递送系统,其中金属离子化合物被微乳吸附。本发明通过高压均质、超声、高速搅拌等方法制备微乳,将金属离子化合物吸附于乳剂表面,再加入不同的抗原成分制成疫苗。本发明制备的疫苗可以将抗原运送至淋巴结,被抗原呈递细胞高效地摄取,并诱导抗原特异性的免疫反应。
本发明利用在pH值在4.0-10.0之间的条件下,乳剂中的油相和乳化剂中含有羧基、磷酸基、磺酸基、硫酸基、亚硫酸基、酚羟基、烯醇基等基团可部分或全部电离产生阴离子,金属阳离子与微乳表面的阴离子发生反应附着于微乳表面,金属阳离子可进一步吸附金属离子化合物阴离子部分从而制备吸附有金属离子化合物的微乳。据此,我们可在微乳表面吸附氢氧化铝、磷酸铝、氢氧化铁、磷酸钙等不同种类的金属离子化合物。吸附金属离子化合物的微乳并不影响原有微乳的稳定性,其分散性好,操作简单,易于临床使用。
术语“微乳”包括分散体、液滴,以及当水不溶性油相与水相混合时,由于疏水力使非极性残基(即长烃链)远离水并使极性头基团朝向水而形成的其他脂质结构。这些脂质结构包括但不限于单层、寡层和多层脂质囊泡、胶束和层状结构。
术语“金属离子化合物”,按本领域广义的理解,指的是由金属阳离子和阴离子构成的化合物。本发明所述的金属离子选自铝、铁、锆、钙、锰、镉、镁、铈、镉、钴、镓或锌的一种或多种,所述金属离子化合物呈无机盐或有机复合物的形式;优选的,所述金属离子化合物为金属离子的氢氧化物或磷酸化物;特别优选的,所述金属离子化合物为氢氧化铝、氢氧化铁、磷酸铝、磷酸钙或氢氧化锌的一种或多种。
术语“表面活性剂”一词是指任何既有极性头部基团(在能量上倾向于水溶剂化),又有疏水尾部(在水溶剂化程度上不好)的分子。术语“阳离子表面活性剂”是指具有阳离子头部基团的表面活性剂。术语“阴离子表面活性剂”是指具有阴离子头部基团的表面活性剂。术语“非离子表面活性剂”指具有不带电头部基团的表面活性剂。“两性离子表面活性剂”是指同时具有阳离子和阴离子头部基团的表面活性剂。
术语“医药上可接受”是指当给予宿主(例如动物或人类)时实质上不会产生不良过敏反应或不良免疫反应的成分。此类制剂包括任何医药上可接受的剂型。此类医药上可接受的剂型的实例包括但不限于浸渍、喷雾、外敷、注射和冻干剂型。
所述的微乳中,其所述水相可以包括任何类型的水相,包括但不限于水(例如水、蒸馏水、纯化水、注射用水、去离子水、自来水)和溶液(例如HEPES溶液),水相可进一步无菌且无热原。优选的,其所述水相为注射用水。
所述的微乳中,其所述油相可以是任何化妆品或药物上可接受的油;优选的,所述油相选自可以从动物油、植物油、天然油、合成油、烃油、硅油、其半合成衍生物及其组合物;更优选的,所述微乳适用的油包括但不限于矿物油、角鲨烯油、C6-C30脂肪及其芳香酸及醇类、大豆油、中链甘油三酯、香精油、硅油、精油、水不溶性维生素、硬脂酸异丙酯、硬脂酸丁酯、棕榈酸辛酯、棕榈酸十六酯、贝氏酸三癸酯、己二酸二异丙酯、癸二酸二辛酯、邻苯二甲酸薄荷酯、辛酸十六酯、水杨酸辛酯、肉豆蔻酸异丙酯、新戊二醇二乙酸十六醇、油酸癸酯、己二酸二异丙酯,C12-15烷基乳酸酯、乳酸十六酯、乳酸月桂酯、新戊酸异硬脂酯、肉豆蔻酯、硬脂酸异硬脂酯、硬脂酸辛酯、烃类油、异戊二烯、液体石蜡、异十二烷、凡士林、阿甘油、菜籽油、智利油、椰子油、玉米油、棉籽油、亚麻籽油、葡萄籽油、芥末油,橄榄油、棕榈油、棕榈仁油、花生油、松子油、罂粟籽油、南瓜仁油、米糠油、红花油、茶油、松露油、植物油、杏(仁)油、荷荷巴油(西蒙脱石籽油)、葡萄油、澳洲坚果油、小麦胚芽油、杏仁油、菜籽油、葫芦油、大豆油、芝麻油、榛子油、玉米油、向日葵油、大麻油、博伊斯油、苦杏仁油、鳄梨油、核桃油、鱼油、浆果油、多香果油、杜松子油、种子油、杏仁籽油、茴香籽油、芹菜籽油、孜然籽油、肉豆蔻籽油、叶油、罗勒叶油、月桂叶油、桂皮叶油、鼠尾草叶油、桉树叶油、柠檬草叶油、白千层叶油、牛至叶油、广藿香叶油、薄荷叶油、松针油、迷迭香叶油、留兰香叶油、茶树叶油、百里香叶油、冬绿叶油、花油、洋甘菊油、鼠尾草油、丁香油、天竺葵花油、牛膝草花油、茉莉花油、薰衣草花油、麦卢卡花油、马贺兰花油、桔子花油、玫瑰花油、依兰花油、树皮油、桂皮油、肉桂树皮油、檫树树皮油、木材油、樟木油、雪松木材油、玫瑰木油、檀香油、根茎(姜)木材油、树脂油、乳香油、没药油、果皮油、佛手柑皮油,柚子皮油、柠檬皮油、酸橙皮油、桔子皮油、桔子皮油、根油、缬草油、油酸、亚油酸、异硬脂醇、甲基苯基聚硅氧烷、西米硅酮、二甲基硅氧烷、苯基三甲基硅氧烷(或其有机改性版本)、聚合硅氧烷的烷基化衍生物、十六烷基二甲基硅氧烷、十二烷基三甲基硅氧烷、聚合硅氧烷的羟基化衍生物、挥发性硅油、环和线性硅油、环甲基硅油、环甲基硅油、六甲基环三硅油、八甲基环四硅油、十甲基环戊烷硅油、挥发性线性二甲基硅油、异十六烷、异二十烷、异四乙酸、聚异丁烯、异辛烷、异十二烷、萜烯、单萜烯、倍半萜、胭脂红、天青、薄荷脑、樟脑、重楼、百里酚、橙花醇、芳樟醇、柠檬烯、香叶醇、紫苏醇、橙花醇、法尼醇、依兰烯、红没药醇、法尼烯、驱蛔萜、藜芦油、香茅醛、柠檬醛、香茅醇、甘蓝素、雅罗,愈创木烯、洋甘菊、及其半合成衍生物或其组合物;特别优选的,其所述油相为角鲨烯,大豆油,中链甘油三酯,油酸的一种或一种以上的组合物。
本发明基于微乳的疫苗递送系统中的表面活性剂可以是药学上可接受的离子表面活性剂、药学上可接受的非离子表面活性剂、药学上可接受的阳离子表面活性剂、药学上可接受的阴离子表面活性剂或药学上可接受的两性表面活性剂。《Applied Surfactants:Principles and Applications》中描述了表面活性剂的示例性应用。(Tharwat F.Tadros,Copyright 8 2005WILEY-VCH Verlag GmbH&Co.KGaA,Weinheim ISBN:3-527-30629-3),通过引用特别并入。
此外,表面活性剂可以是医药上可接受的离子聚合表面活性剂、医药上可接受的非离子聚合表面活性剂、医药上可接受的阳离子聚合表面活性剂、医药上可接受的阴离子聚合表面活性剂或医药上可接受的两性离子聚合表面活性剂。聚合表面活性剂的实例包括但不限于具有多个(至少一个)聚乙二醇(PEO)侧链的聚(甲基丙烯酸甲酯)主链的接枝共聚物、聚羟基硬脂酸、烷氧基化烷基苯酚甲醛缩合物、具有脂肪酸的聚烷基乙二醇改性聚酯、聚酯、其半合成衍生物或其组合物。
表面活性成分或表面活性剂是两亲性分子,由非极性疏水部分(通常是直链或支链碳氢化合物或含8-18个碳原子的氟碳链)组成,附着在极性或离子的亲水部分上。亲水部分可以是非离子的、离子的或两性离子的。在水环境中,烃链与水分子的相互作用较弱,而极性或离子的头部基团则通过偶极或离子偶极相互作用与水分子的相互作用较强。根据亲水基团的性质,表面活性剂可分为阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂、非离子表面活性剂和聚合物表面活性剂。
优选的,所述微乳中合适的表面活性剂包括但不限于乙氧基化壬基酚、乙氧基化十一醇、聚氧乙烯山梨醇单月桂酸酯、聚氧乙烯山梨醇酐棕榈酸酯、聚氧乙烯山梨醇酐单硬脂酸酯,聚氧乙烯山梨醇酐单油酸酯、脱水山梨醇脂肪酸酯类(司盘类)、乙氧基化氢化蓖麻油、十二烷基硫酸钠、乙氧基和丙氧基二嵌段共聚物、环氧乙烷-环氧丙烷嵌段共聚物、以及基于环氧乙烷和环氧丙烷的四官能嵌段共聚物、甘油单酯、己酸甘油酯、辛酸甘油酯、椰酸甘油酯、芥酸甘油酯、羟基酯甘油酯、异硬脂酸甘油酯、兰酸甘油酯、月桂酸甘油酯、亚油酸甘油酯、肉豆蔻酸甘油酯、油酸甘油酯、PABA甘油酯、棕榈酸甘油酯、蓖麻油酸甘油酯、硬脂酸甘油酯、硫乙醇酸甘油酯、二月桂酸甘油酯、二油酸甘油酯、肉豆蔻酸甘油酯、甘油四油酸酯、硬脂酸甘油酯、甘油酰硬脂酸酯、甘油二月桂酸酯、甘油二油酸酯、甘油二酸酯、甘油二酸甘油酯、甘油四油酸酯、硬脂酸甘油酯、聚氧乙烯脂肪醚、聚氧乙烯月桂醚、聚氧乙烯硬脂醚、聚氧乙烯肉豆蔻醚、类固醇、胆固醇、β-甾醇、双酚醇、醇脂肪酸酯、肉豆蔻酸异丙酯、脂肪酸异丙酯、正丁酸异丙酯、正己酸异丙酯、正癸酸异丙酯、棕榈酸异丙酯、辛基十二烷基肉豆蔻酸酯、烷氧基化醇、烷氧基化酸、烷氧基化酰胺、烷氧基化糖衍生物、天然油和蜡的烷氧基化衍生物、聚氧乙烯-聚氧丙烯嵌段共聚物、壬氧醇-14、PEG-8月桂酸酯、PEG-6椰酰胺、PEG-20甲基葡萄糖倍半乳糖酸酯、PEG-40羊毛脂、PEG-40蓖麻油、PEG-40氢化蓖麻油、聚氧乙烯脂肪醚、甘油二酯、聚氧乙烯硬脂醚、聚氧乙烯肉豆蔻醚、聚氧乙烯月桂醚、二月桂酸甘油酯、二硬脂酸甘油酯、月桂酸甘油酯、肉豆蔻酸甘油酯、二月桂酸甘油酯、其半合成衍生物及其组合物。
其中,所述非离子表面活性剂包括但不限于泊洛沙姆、聚乙二醇胆固醇、聚乙二醇聚乳酸(PEG-PLA)、聚乙二醇聚羟基乙酸(PEG-PLG)、聚乙二醇聚乳酸-羟基乙酸共聚物(PEG-PLGA)、聚乙二醇维生素E琥珀酸酯(TPGS)、聚乙二醇660-12-羟基硬脂酸酯(HS-15)、聚氧乙烯-8-辛酸/癸酸甘油酯(Labrasol)、聚乙二醇-二硬脂酰乙醇胺(DSPE-PEG)、乙二醇单乙基醚(Transcutol)、乙氧基化表面活性剂、乙氧基化醇、乙氧基化烷基酚、乙氧基化脂肪酸、乙氧基化单醇酰胺、乙氧基化山梨醇酯、乙氧基化脂肪胺、环氧乙烷-环氧丙烷共聚物、双(聚乙二醇双[咪唑基羰基])、壬氧醇-9、双(聚乙二醇双[咪唑基羰基])、 癸二醇单十二烷基醚、N-癸酰基-N-甲基葡萄糖胺、N-癸酰基α-D-吡喃糖苷、癸基β-D-麦芽吡喃糖苷、N-十二烷基-N-甲基葡萄糖酰胺、N-十二烷基α-D-麦芽糖苷、正十二烷基β-D-麦芽糖苷、七甘醇单癸醚、七甘醇单十二醚、七甘醇单十四醚、正十六烷基β-D-麦芽糖苷、六甘醇单十二醚、六甘醇单十六醚、六甘醇单十八醚、六甘醇单十八醚单十四烷基醚、Igepal CA-630、Igepal CA-630、甲基-6-O-(N-庚基氨基)-α-D-吡喃葡糖苷、非乙二醇单十二烷基醚、N-壬酰基-N-甲基葡糖胺、N-壬酰基-N-甲基葡糖胺、八甘醇单十二烷基醚、八甘醇单十六烷基醚、辛基乙二醇单十八烷基醚、辛基乙二醇单十四烷基醚、辛基β-D-吡喃糖苷、五甘醇单癸醚、五甘醇单十二烷基醚、五甘醇单十六烷基醚、五甘醇单己基醚、五甘醇单十八烷基醚、五甘醇单辛基醚、聚乙二醇二缩水甘油醚、聚乙二醇醚W-1、聚氧乙烯10十三烷基醚、聚氧乙烯100硬脂酸酯、聚氧乙烯20异十六烷基醚、聚氧乙烯20油酸醚、聚氧乙烯40硬脂酸酯、聚氧乙烯50硬脂酸酯、聚氧乙烯8硬脂酸酯、聚氧乙烯双(咪唑基羰基)、聚氧乙烯25-丙二醇硬脂酸酯、奎拉贾树皮皂甙、15-S-12型Tergitol、15-S-30型Tergitol、15-S-5型Tergitol、15-S-7型Tergitol、15-S-9型Tergitol、NP-10型Tergitol、NP-4型Tergitol、NP-40型Tergitol、NP-7型Tergitol、NP-9型Tergitol、TMN-10型Tergitol、TMN-6型Tergitol、十四烷基β-D-麦芽糖苷、四乙二醇单癸醚、四乙二醇单十二烷基醚、四乙二醇单十四烷基醚、三乙二醇单癸醚、三乙二醇单十二烷基醚、三甘醇单十六烷基醚、三甘醇单辛基醚、三甘醇单十四烷基醚、Triton CF-21、TritonCF-32、Triton DF-12、Triton DF-16、Triton GR-5M、Triton QS-15、Triton QS-44、TritonX-100、Triton X-102、Triton X-15、Triton X-151、Triton X-200、Triton X-207、 Tyloxapol、n-十一烷基β-D-吡喃糖苷、其半合成衍生物或其组合物。
所述的阳离子表面活性剂包括但不限于季铵化合物、烷基三甲基氯化铵化合物、二烷基二甲基氯化铵化合物、阳离子含卤素化合物,例如十六烷基氯化吡啶、苯扎氯铵、苄基二甲基十六烷基氯化铵、苄基二甲基十四烷基氯化铵、苄基十二烷基二甲基溴化铵、苄基三甲基四氯碘酸铵、二甲基十八烷基溴化铵、十二烷基二甲基溴化铵、十二烷基三甲基溴化铵、十六烷基二甲基溴化铵、吉拉德试剂T、十六烷基三甲基溴化铵、N,N′,N′-聚氧乙烯(10)-N-脂-1,3-二氨基丙烷、溴化苄铵、三甲基(十四烷基)溴化铵、1,3,5-三嗪-1,3,5(2H,4H,6H)-三乙醇胺、1-癸胺、N-癸基-N,N-二甲基-氯化物、双癸基二甲基氯化铵、2-(2-(p-(二异丁基)甲氧基)乙氧基)乙基二甲基苄基氯化铵、2-(2-(p-(二异丁基)苯氧基)乙氧基)乙基二甲基苄基氯化铵、烷基1或3苄基-1-(2-羟基乙基)-2-咪唑啉氯化物、烷基双(2-羟乙基)苄基氯化铵、烷基脱甲基苄基氯化铵、烷基二甲基3,4-二氯苄基氯化铵(100%C12)、烷基二甲基3,4-二氯苄基氯化铵(50%C14、40%C12、10%C16)、烷基二甲基3,4-二氯苄基氯化铵(55%C14、23%C12、20%C16)、烷基二甲基苄基氯化铵、烷基二甲基苄基氯化铵(100%C14)、烷基二甲基苄基氯化铵(100%C16)、烷基二甲基苄基氯化铵(41%C14,28%C12)、烷基二甲基苄基氯化铵(47%C12,18%C14)、烷基二甲基苄基氯化铵(55%C16,20%C14)、烷基二甲基苄基氯化铵(58%C14,28%C16)、烷基二甲基苄基氯化铵(60%C14,25%C12)、烷基二甲基苄基氯化铵(61%C11,23%C14)、烷基二甲基苄基氯化铵(61%C12,23%C14)、烷基二甲基苄基氯化铵(65%C12,25%C14)、烷基二甲基苄基氯化铵(67%C12,24%C14)、烷基二甲基苄基氯化铵(67%C12,25%C14)、烷基二甲基苄基氯化铵(90%C14,5%C12)、烷基二甲基苄基氯化铵(93%C14,4%C12)、烷基二甲基苄基氯化铵(95%C16,5%C18)、烷基二甲基苄基氯化铵、烷基二癸基二甲基氯化铵、烷基二甲基苄基氯化铵(C12-16)、烷基二甲基苄基氯化铵(C12-18)、二烷基二甲基苄基氯化铵、烷基二甲基二甲基苄基氯化铵、烷基二甲基乙基溴化铵(90%C14,5%C16,5%C12)、烷基二甲基乙基溴化铵(大豆脂肪酸中的混合烷基和烯基油)、烷基二甲基乙基苄基氯化铵、烷基二甲基乙基苄基氯化铵(60%C14)、烷基二甲基异丙基苄基氯化铵(50%C12,30%C14,17%C16,3%C18)、烷基三甲基氯化铵(58%C18,40%C16,1%C14,1%C12)、烷基三甲基氯化铵(90%C18,10%C16)、烷基二甲基(乙基苄基)氯化铵(C12-18)、二-(C8-10)-烷基二甲基氯化铵、二烷基二甲基氯化铵、二烷基甲基苄基氯化铵、二烷基二甲基氯化铵、二异癸基二甲基氯化铵、二异辛基二甲基氯化铵、十二烷基双(2-羟乙基)辛基氯化氢铵、十二烷基二甲基苄基氯化铵、十二烷基氨甲酰甲基二乙基苄基氯化铵、七烷基羟乙基咪唑啉氯化物、六氢-1,3,5-三(2-羟乙基)-s-三嗪、六氢-1,3,5-三(2-羟乙基)-s-三嗪、肉豆蔻氯化铵(和)季铵盐14、N,N-二甲基-2-羟丙基氯化铵聚合物、N-十四烷基二甲基苄基氯化铵一水合物、辛基癸基二甲基氯化铵、辛基十二烷基二甲基氯化铵、辛基苯氧基乙氧基乙基二甲基苄基氯化铵、氧二乙基双(烷基二甲基氯化铵)季铵化合物、二氯代烷基二甲基氯化物、三甲氧基硅丙基二甲基十八烷基氯化铵、三甲氧基硅季铵盐、三甲氧基十二烷基苄基氯化铵、其半合成衍生物及其组合物。
合适的阴离子表面活性剂包括但不限于羧酸盐、硫酸盐、磺酸盐、磷酸盐、磷脂酸、鹅去氧胆酸、鹅去氧胆酸钠盐、胆酸、牛或羊胆汁、脱氢胆酸、去氧胆酸、去氧胆酸甲酯、地高辛、N,N-二甲基十二烷基胺N-氧化物、月桂酸钠、甘胆酸钠、水合甘胆酸、一水甘胆酸、3-硫酸甘胆酸二钠盐、甘胆酸乙酯、N-月桂酰肌氨酸钠、N-月桂酰肌氨酸溶液、N-月桂酰肌氨酸溶液、十二烷基硫酸锂、Lugol溶液、4型Niaproof、1-辛烷磺酸钠、1-丁烷磺酸钠、1-癸烷磺酸钠、1-癸烷磺酸钠、1-十二烷磺酸钠、1-庚烷磺酸钠无水、无水1-庚烷磺酸钠、1-壬磺酸钠、1-丙磺酸钠、2-溴乙烷磺酸钠、水合胆酸钠、胆酸钠、脱氧胆酸钠、十二烷基硫酸钠、无水己磺酸钠、辛基硫酸钠、无水戊烷磺酸钠、牛磺胆酸钠、牛磺脱氧胆酸钠、牛磺脱氧胆酸钠水合物、牛磺胆酸3-硫酸盐二钠盐、十二烷基硫酸盐、熊去氧胆酸、C6-C30脂肪及其芳香酸的盐、其半合成衍生物及其组合物。
所述的两性表面活性剂包括但不限于N-烷基甜菜碱、十二烷基氨基丙基二甲基甜菜碱、烷基二甲基甘氨酸盐、N-烷基氨基丙酸盐、CHAPS、CHAPSO、3-(癸基二甲氨基)丙磺酸盐内盐、3-(十二烷基二甲氨基)丙磺酸盐内盐、3-(N,N-二甲基肉豆蔻胺基)丙磺酸盐、3-(N,N-二甲基十八烷基氨基)丙磺酸盐、3-(N,N-二甲基辛基氨基)丙磺酸盐内盐、3-(N,N-二甲基棕榈基氨基)丙磺酸盐、大豆卵磷脂、蛋黄卵磷脂、磷脂酰甘油、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰胆碱、鞘磷脂、其半合成衍生物及其组合物。
更优选的,其所述乳化剂为吐温80,聚乙二醇-二硬脂酰乙醇胺(DSPE-PEG),蛋黄卵磷脂,司盘85的一种或一种以上的组合物。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,其所述微乳的油相和乳化剂中含有羧基、磷酸基、磺酸基、硫酸基、亚硫酸基、酚羟基、烯醇基、硼酸基的一种或一种以上的组合物,上述油相和乳化剂包括但不限于C6-C30脂肪及其芳香酸、油酸、亚油酸、异四乙酸、烷氧基化酸、百里酚、双酚醇、聚乙二醇-二硬脂酰乙醇胺(DSPE-PEG)、阴离子表面活性剂、两性表面活性剂。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,其所述微乳粒径小于1000nm,优选小于300nm,特别优选小于200nm。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,其所述微乳pH值在4.0-10.0之间,优选pH值在5.0-9.0之间,特别优选为pH值在6.0-8.0之间。
适用于本发明微乳疫苗中使用的附加剂包括但不限于一种或多种溶剂,例如医药上可接受的防腐剂、pH调节剂、缓冲液、有机溶剂、螯合剂,抗氧剂、填充剂、着色剂、赋形剂等,可将所述附加剂掺入先前乳化的微乳中,或将所述附加化合物添加到所述原始混合物中以进行乳化。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,所述防腐剂包括但不限于十六烷基氯化吡啶、苯扎氯铵、苯甲醇、氯己定、咪唑烷基脲、苯酚、山梨酸钾、苯甲酸、甲酚、氯甲酚、对苯甲酸酯、苯氧乙醇、山梨酸、α-生育酚、抗坏血酸,抗坏血酸棕榈酸酯、丁基羟基茴香醚、丁基羟基甲苯、抗坏血酸钠、焦亚硫酸钠、柠檬酸、依地酸、其半合成衍生物及其组合。所述的防腐剂包括但不限于苯甲醇、氯己定(双(对氯苯基二胍基)己烷)、扑尔敏(3-(-4-氯氧基)-丙烷-1,2-二醇)、卡松CG(甲基和甲基氯异噻唑啉酮)、尼泊金酯(苯甲酸甲酯、乙酯、丙酯和丁酯)、苯氧乙醇(2-苯氧基乙醇)、Phenonip(对羟基苯甲酸苯氧乙醇酯,甲酯,乙酯,丁酯和丙酯)、Phenoroc、Liquipar Oil、Liquipar PE、NipaguardMPA、尼泊金多磺酸甲酯(羟苯甲酸丙二醇酯、甲酯和丙酯)、尼泊金肽(羟苯甲酸甲酯、乙基和丙酯)、尼泊金酯(羟苯甲酸甲酯、丁基、乙基和丙酯)、Elestab 388和Killitol的一种或多种。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,所述pH调节剂包括但不限于HEPES、二乙醇胺、乳酸、单乙醇胺、三乙胺、氢氧化钠、磷酸钠、其半合成衍生物及其组合。此外,所述微乳可包含螯合剂,所述螯合剂的实例包括但不限于乙二胺、乙二胺四乙酸(EDTA)、植酸、多聚磷酸、柠檬酸、葡萄糖酸、乙酸、乳酸和二巯基丙醇的一种或多种。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,所述缓冲剂包括但不限于2-氨基-2-甲基-1,3-丙二醇、2-氨基-2-甲基-1-丙醇、L-(+)-酒石酸、ACES、ADA、乙酸、乙酸铵溶液、碳酸氢铵溶液、柠檬酸二铵溶液、甲酸铵溶液、一水草酸铵、磷酸二铵溶液、磷酸一铵溶液、磷酸二钠四水溶液、硫酸铵溶液、酒石酸铵二元酸盐溶液、BES缓冲盐水溶液、BICINE缓冲溶液、BIS-TRIS、碳酸氢钠缓冲液、硼酸、CAPS、CHES、乙酸钙水合物、柠檬酸盐浓溶液、柠檬酸、二乙醇胺、EPPS、甲酸水溶液、甘氨酸-甘氨酸-甘氨酸、甘氨酸-甘氨酸、甘氨酸、HEPES缓冲盐水、咪唑缓冲液、脂蛋白复性缓冲液、乙酸锂二水合物、柠檬酸锂三盐基四水合物、MES溶液、MOPS、醋酸镁溶液、柠檬酸镁三盐基非水合物、甲酸镁溶液、磷酸镁二盐基三水合物、草酸二水合物、PIPES、磷酸盐缓冲盐、过氧化物酶结合物洗涤缓冲液、哌嗪、D-酒石酸钾、乙酸钾溶液、碳酸氢钾、碳酸钾、氯化钾、柠檬酸钾一元酸盐、柠檬酸钾三元酸盐溶液、甲酸钾溶液、一水草酸钾、磷酸二氢钾、邻苯二甲酸钾、酒石酸钾钠溶液、酒石酸钾钠四水合物、四硼酸钾四水合物、四草酸钾二水合物、丙酸溶液、STE缓冲溶液、5,5-二乙基巴比妥钠、乙酸钠溶液、碳酸氢钠、酒石酸钠一水合物、碳酸钠、柠檬酸钠溶液、甲酸钠溶液、草酸钠、磷酸氢二钠溶液、磷酸二氢钠溶液、磷酸钠溶液、焦磷酸钠二元溶液、焦磷酸钠四元十水溶液、酒石酸钠二元溶液、十水四硼酸钠、TAPS、TES、TM缓冲液、TNT缓冲液、三甘氨酸缓冲液、三乙酸二乙酯EDTA缓冲液、三甘氨酸十二烷基硫酸钠缓冲液、三磷酸乙二胺四乙酸缓冲液、三嗪、三乙醇胺、三乙胺、醋酸三乙胺缓冲液、磷酸三乙基铵溶液、乙酸三甲基铵溶液、磷酸三甲基铵溶液、Tris-EDTA缓冲液、醋酸盐、碱。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,所述有机溶剂包括但不限于C1-C12醇、二醇、三醇、磷酸二烷基酯、磷酸三烷基酯(如磷酸三正丁酯)、乙醇、甲醇、异丙醇、甘油、中链甘油三酯、乙醚、乙酸乙酯、丙酮、二甲基亚砜(DMSO)、乙酸、正丁醇、丁二醇、香料醇、异丙醇、正丙醇、甲酸、丙二醇,山梨醇、工业甲基化酒精、三醋酸甘油、己烷、苯、甲苯、二乙醚、氯仿、1,4-二氧烷、四氢呋喃、二氯甲烷、丙酮、乙腈、二甲基甲酰胺、二甲亚砜、甲酸、其半合成衍生物及其任何组合物。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,所述微乳还包含附加剂,所述附加剂包括但不限于抗氧剂(如维生素c,维生素E等),矫味剂(如葡萄糖、木糖醇等),渗透压调节剂(如甘油等),增稠剂(如卡拉胶、果胶等)、填充剂(如淀粉等)、着色剂(柠檬黄、日落黄等)、赋形剂(阿拉伯胶、糖浆等)等。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于微乳通过吸附金属离子化合物,再直接通过表面吸附或疏水相互作用等与抗原形成疫苗。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,所述抗原包括但不限于蛋白、多肽、核酸、寡糖、多糖、肿瘤细胞裂解物、细菌裂解物、细菌细胞膜、支原体细胞膜、衣原体细胞壁、螺旋体、立克次体微荚膜、病毒包膜、外泌体、病毒或细菌裂解液抗原、病毒或细菌外膜囊泡抗原、肿瘤细胞膜囊泡抗原、肿瘤细胞外泌体抗原、模式抗原鸡卵清白蛋白(OVA)等的一种或一种以上组合物。
优选的,其所述抗原为模式抗原鸡卵清白蛋白(OVA),黑色素瘤抗原肽GP100的一种或一种以上的组合物。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,吸附金属离子化合物的微乳本身即具有佐剂作用,且还可加入不同的佐剂联合进一步提高免疫反应,所述附加佐剂包括但不限于:抗原相关分子模式类佐剂:Toll样受体激动剂:肽聚糖、脂磷壁酸、MPLA、咪喹莫特、瑞喹莫特、CpG-ODN、细菌鞭毛蛋白、Poly I:C;RIG-I样受体激动剂:3pRNA、短的双链RNA;NOD样受体激动剂:胞壁酰二肽(MDP)、N一乙酰葡萄糖胺;C-型凝集素受体:β-葡聚糖、海藻糖二硼酸盐;STING激动剂:cGAMP;细菌毒素及其衍生物:霍乱毒素(CT)、大肠杆菌不耐热肠毒素(LT)、霍乱毒素B亚单位;皂苷类:QS21、番茄苷、Quil-A;细胞因子:GM-CSF、IL-2、IL-12、IL-6、IFN-γ、Flt-3、淋巴细胞趋化因子;其他佐剂:热激蛋白、A151、GTP-GDP、氟化钠、烷基聚丙烯酯多聚体、二甲基双十八烷基季胺溴化物(DDA)的一种或一种以上组合物。
优选的,其所述附加佐剂为CpG 1826,A151的一种或一种以上组合物。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,所述微乳包括如下重量份的组分:水相适量,油相0.01%-50%,乳化剂0.001%-10%,金属离子化合物的重量份为0.0001%-1%,抗原的重量份为1%-0.0001%。
优选的,所述的基于微乳的疫苗递送系统,其特征在于,所述微乳包括如下重量份的组分:水相适量,油相0.1%-5%,乳化剂0.01%-2%,金属离子化合物的重量份为0.001%-1%,抗原的重量份为0.1%-0.0001%。
优选的,所述的基于微乳的疫苗递送系统,其特征在于,所述微乳包括如下重量份的组分:注射用水适量,角鲨烯0.1%-5%,吐温80 0.01%-2%,司盘85 0.01%-2%,DSPE-PEG 0.01%-2%,氢氧化铝0.01%-1%,模式抗原鸡卵清白蛋白OVA 0.1%-0.001%。
优选的,所述的基于微乳的疫苗递送系统,其特征在于,所述微乳包括如下重量份的组分:注射用水适量,大豆油0.1%-5%,中链甘油三酸酯0.1%-5%,蛋黄卵磷脂0.01%-2%,DSPE-PEG 0.01%-2%,氢氧化铁0.1%-0.001%,黑色素瘤抗原肽GP100 0.01%-0.0001%。
更优选的,所述的基于微乳的疫苗递送系统,其特征在于,所述微乳包括如下重量份的组分:注射用水适量,角鲨烯0.1%-2%,吐温80 0.1%-2%,司盘85 0.1%-2%,DSPE-PEG 0.1%-2%,氢氧化铝0.01%-0.1%,模式抗原鸡卵清白蛋白OVA 0.1%-0.01%。
更优选的,所述的基于微乳的疫苗递送系统,其特征在于,所述微乳包括如下重量份的组分:注射用水适量,大豆油0.1%-2%,中链甘油三酸酯0.1%-2%,蛋黄卵磷脂0.1%-2%,DSPE-PEG 0.1%-2%,氢氧化铁0.01%-0.001%,黑色素瘤抗原肽GP1000.01%-0.001%。
优选的,所述的基于微乳的疫苗递送系统,其特征在于还含有附加佐剂CpG 1826,A151的一种或多种,其含量为0.1%-0.001%。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,所述微乳的制备方法包括以下步骤:
(1)将亲油性乳化剂溶于油相中,将亲水性乳化剂溶于水相中,二者充分混合后形成微乳;
(2)将pH缓冲液和/或金属离子化合物的阴离子部分加入上述微乳中;
(3)将金属离子化合物的阳离子部分加入到步骤(2)制得的混合物中;
(4)抗原加入到步骤(2)或是步骤(3)制得的混合物中,混合均匀即得。优选的,所述微乳的制备方法包括以下步骤:
(1)将亲油性乳化剂溶于油相中,将亲水性乳化剂溶于水相中,二者混合形成初乳,初乳再经充分混合,例如高压均质、超声或高速搅拌等混合方法形成微乳;
(2)将pH缓冲液和/或金属离子化合物的阴离子部分加入上述微乳中;
(3)在涡旋、搅拌、超声条件下,或者通过微量注射泵加入金属离子化合物的阳离子部分到步骤(2)制得的混合物中;
(4)抗原加入到步骤(2)或是步骤(3)制得的混合物中,即得。
本发明的目的之一是提供一种基于微乳的疫苗递送系统,其特征在于,所述微乳的制备方法包括以下步骤:
(1)将亲油性乳化剂溶于油相中,将亲水性乳化剂溶于水相中,二者充分混合后形成微乳;
(2)将金属离子化合物的阳离子部分加入上述微乳中;
(3)将pH缓冲液和/或金属离子化合物的阴离子部分加入到步骤(2)制得的混合物中;
(4)抗原加入到步骤(2)或是步骤(3)制得的混合物中,混合均匀即得。
优选的,所述微乳的制备方法包括以下步骤:
(1)将亲油性乳化剂溶于油相中,将亲水性乳化剂溶于水相中,二者混合形成初乳,初乳再经充分混合,例如高压均质、超声或高速搅拌等混合方法形成微乳;
(2)将金属离子化合物阳离子部分加入上述微乳中;
(3)在涡旋、搅拌、超声条件下,或者通过微量注射泵加入pH缓冲液和/或金属离子化合物的阴离子部分到步骤(2)制得的混合物中;
(4)抗原加入到步骤(2)或是步骤(3)制得的混合物中,即得。
本发明选择OVA作为模型抗原,通过体内外实验证明,该疫苗载体可诱导抗原特异性的体液和细胞免疫。本发明选择OVA或黑色素瘤抗原肽GP100作为模型抗原,CpG1826或A151作为模型佐剂,通过体外实验证明,该疫苗载体可实现抗原和核酸佐剂的共载。作为本发明优选的实施方案之一,制备的疫苗载体可被DC2.4抗原提呈细胞高效地摄取。本发明的疫苗递送系统使用微乳吸附金属离子化合物,稳定性更高,不易聚集,分散性好,更适合于临床使用。本发明的疫苗递送系统粒径可小于200nm,符合淋巴结递送的要求,能够有效地靶向淋巴结,实现疫苗的靶向递送。本发明的疫苗载体可被抗原提呈细胞高效摄取,有利于下一步免疫应答的发生。传统的铝胶佐剂容易引起注射部位肉芽肿,在肾脏功能衰退等一些特殊情况下易在体内积聚,机体内高剂量的铝首先影响大脑和骨组织,引起严重的神经综合征和透析性痴呆症。铝毒性还与肌萎缩性脊髓侧索硬化症和老年痴呆症有关。当本发明制备含铝的微乳疫苗时,本发明的疫苗的铝含量远远低于商品化铝凝胶(2%,美国InvivoGene公司),可以减少金属离子蓄积的危险和局部的副作用,毒性低,提高了患者的适应性。
相比于现有技术,本发明具有以下优点:
本发明将金属离子化合物吸附于乳剂表面,提供了一种制备乳剂吸附金属离子化合物的普适性方法。
本发明将金属离子化合物吸附于乳剂表面作为疫苗载体,乳剂分散性好,稳定性高,粒径可控范围大,可包载大分子抗原实现淋巴递送。
本发明可将亲水性抗原和疏水性抗原包载于同一载体内,实现不同性质的多种抗原的共递送,诱导机体产生针对病原体的全面、有效的免疫应答。
本发明可采用全部由FDA批准的辅料进行制备,其安全性高,且价廉易得,适合于工业生产;且制备方法简单迅速,条件温和,无有机试剂的加入,不会造成抗原蛋白的变性,可以有效地保持抗原蛋白的构象和活性。
本发明方法简单,采用高压均质、超声或高速搅拌等混合方法制备微乳,再在涡旋、搅拌、超声条件下或者通过微量注射泵加入金属离子化合物阳离子或阴离子部分以及抗原,可用于大规模生产,有利于工业转化,具有广阔的应用和市场前景。
附图说明
以下,结合附图来详细说明本发明的实施方案
图1游离CpG 1826(CpG 1826),20μl氢氧化铝微乳包载2.4μg CpG 1826(NE-80μg/ml),20μl氢氧化铝微乳包载4.8μg CpG 1826(NE-160μg/ml)的葡聚糖凝胶电泳图;
图2游离A151(A151),20μl氢氧化铁微乳载有3.0μg A151的氢氧化铁微乳(NE-A151)的葡聚糖凝胶电泳图;
图3实施例1制备的氢氧化铝微乳电镜图;
图4实施例9制备的载有黑色素瘤抗原肽GP100的氢氧化铁微乳电镜图;
图5游离的FITC标记的OVA(Free OVA)和载有FITC标记的OVA的氢氧化铝微乳(NE-OVA)在DC2.4细胞上的摄取结果;
图6游离的FITC标记的GP100(Free-GP100)和载有FITC标记的GP100的氢氧化铁微乳(NE@Fe-GP100)在DC2.4细胞上的摄取结果;
图7游离的OVA(OVA),载有OVA的氢氧化铝微乳(NE-OVA),游离的OVA与CpG(OVA+CpG)免疫动物后的CTL结果;
图8游离的OVA与CpG(OVA+CpG),载有OVA与CpG的氢氧化铝微乳(NE-OVA-CpG)免疫后的动物血清抗体IgG(图8a)、IgG1(图8b)和IgG2a(图8c)情况。
具体实施方式
以下实施例是对本发明的进一步说明,但绝不是对本发明范围的限制。下面参照实施例进一步详细阐述本发明,但是本领域技术人员应当理解,本发明并不限于这些实施例以及使用的制备方法。而且,本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰,但这些都将包括在本发明的范围内。
实施例1
氢氧化铝微乳的制备方法:将0.2g司盘85溶解在0.5g角鲨烯中,将0.2g吐温80溶于注射用水中,混合形成初乳,初乳经高压均质形成微乳40ml,取微乳1ml向其中加入5mgDSPE-PEG粉末,搅拌使其溶解,加入312.5μl 37.5mM硫酸铝水溶液,涡旋下加入1.75ml100mM pH为8的HEPES缓冲液调节至中性,即得。
实施例2
氢氧化铝微乳的制备方法:将0.35g蛋黄卵磷脂与0.01g吐温80溶于注射用水中,与0.5g角鲨烯混合形成初乳,初乳经高压均质形成微乳40ml。取以上乳液1ml,加入123μl37.5mM硫酸铝水溶液,涡旋下加入615μl 100mM pH为8的HEPES缓冲液调节至中性,即得。
实施例3
氢氧化铝微乳的制备方法:将0.1g油酸、0.2g司盘85溶解在0.5g角鲨烯中,将0.2g吐温80溶于注射用水中,混合形成初乳,初乳经高压均质形成微乳40ml。取以上乳液1ml,加入100μl 37.5mM硫酸铝水溶液,涡旋下加入550μl 100mM pH为8的HEPES缓冲液调节至中性,即得。
实施例4
磷酸铝微乳的制备方法:将0.2g司盘85溶解在0.5g角鲨烯中,将0.2g吐温80溶于溶于注射用水中,混合形成初乳,初乳经高压均质形成微乳40ml,取微乳1ml向其中加入5mgDSPE-PEG粉末,搅拌使其溶解,加入1ml 5mM硫酸铝水溶液,涡旋下加入1ml 10mM磷酸钠水溶液,即得。
实施例5
磷酸钙微乳的制备方法:将0.2g司盘85溶解在0.5g角鲨烯中,将0.2g吐温80溶于注射用水中,混合形成初乳,初乳经高压均质形成微乳40ml,取微乳1ml向其中加入5mgDSPE-PEG粉末,搅拌使其溶解,加入1ml 10mM氯化钙水溶液,涡旋下加入1ml 6.6mM磷酸钠水溶液,即得。
实施例6
载有OVA的氢氧化铝微乳的制备方法:取180μl实施例1制备的含氢氧化铝的微乳,向其中加入20μl 2mg/ml的OVA水溶液,37度下孵育半小时,即得。
实施例7
载有OVA、CpG1826的氢氧化铝微乳的制备方法:取160μl实施例1制备的含氢氧化铝的微乳,向其中加入20μl 2mg/ml OVA的水溶液和20μl 200μg/ml CpG1826的水溶液,37度下孵育半小时,即得。
实施例8
载有孵清溶菌酶的氢氧化铝微乳的制备方法:将0.2g司盘85溶解在0.5g角鲨烯中,将0.2g吐温80溶于注射用水中,混合形成初乳,初乳经高压均质形成微乳40ml,取微乳1ml向其中加入5mg DSPE-PEG粉末,搅拌使其溶解,加入1.75ml100mM pH为8的HEPES缓冲液,100μl 4mg/ml的孵清溶菌酶水溶液,涡旋下加入312.5μl 37.5mM硫酸铝水溶液,即得。
实施例9
载有黑色素瘤抗原肽GP100的氢氧化铁微乳的制备方法:将0.5g大豆油、0.5g中链甘油三酸酯以及0.5g蛋黄卵磷脂混合均匀,加入注射用水,混合形成初乳,初乳经高压均质形成微乳40ml,取微乳1ml向其中加入5mg DSPE-PEG粉末,搅拌使其溶解,加入3μl(200mM)三氯化铁水溶液,加入约20μl(0.1M)氢氧化钠溶液调节pH至近中性,加入10μl 7mg/ml的黑色素瘤抗原肽GP100水溶液,混合均匀,即得。
实施例10
载有OVA和核苷酸CpG 1826的氢氧化铝微乳的制备方法:取20μl实施例6制备的含氢氧化铝的微乳,加入10μl含有2.4μg或4.8μg CpG 1826的水溶液,振摇半小时制得载有OVA和核苷酸CpG 1826的氢氧化铝微乳,然后进行葡聚糖凝胶电泳实验以检测微乳对核酸的包载能力。结果所示如图1,20μl微乳可以包载2.4μg CpG 1826。图中CpG1826表示游离CpG 1826;NE-80μg/ml表示20μl微乳包载2.4μg CpG 1826,终浓度为80μg/ml;NE-160μg/ml表示20μl微乳包载4.8μg CpG 1826,终浓度为160μg/ml。
实施例11
载有核苷酸A151和黑色素瘤抗原肽GP100的氢氧化铁微乳的制备方法:取20μl实施例9制备的氢氧化铁微乳,加入3μg核苷酸A151,振摇半小时制得载有核苷酸A151和黑色素瘤抗原肽GP100的氢氧化铁微乳,然后进行葡聚糖凝胶电泳实验以检测微乳对核酸的包载能力。结果所示如图2,20μl微乳可以包载3μg A151。图中A151表示游离A151,NE-A151表示20μl微乳包载3μg A151。
实施例12
基于微乳的疫苗递送系统的微乳的粒径测定:使用Zetasizer Nano ZS90激光粒度分析仪测定实施例1-9的含金属离子化合物的微乳或包载抗原的疫苗递送系统的粒径分布,分别取0.1ml的实施例1-9的微乳溶液,加入0.9ml纯水溶液进行稀释,将样品放入样品池内,测定温度设为25℃。其结果如表一所示,结果显示纳米粒粒径在100-150nm之间,PDI符合要求,分布均一。
表1实施例1-9含金属离子化合物的微乳的粒径
实施例编号 | Size(nm) | PDI |
1 | 120.0 | 0.228 |
2 | 144.4 | 0.140 |
3 | 124.2 | 0.135 |
4 | 128.9 | 0.210 |
5 | 116.0 | 0.256 |
6 | 125.3 | 0.183 |
7 | 145.5 | 0.210 |
8 | 131.9 | 0.124 |
9 | 133.0 | 0.212 |
实施例13
氢氧化铝微乳的透射电镜:将实施例1制备的氢氧化铝微乳样品置于铜网上,静置5min,然后用磷钨酸染色1min,之后用滤纸吸走铜网上多余的染液,室温晾干样品,在200kv条件下,透射电镜观察样品。结果如图3所示,由实验结果可知微乳均为圆整的颗粒,粒径在100nm以下。
实施例14
载有黑色素瘤抗原肽GP100的氢氧化铁微乳的透射电镜:将实施例9制备的载有黑色素瘤抗原肽的氢氧化铁微乳样品置于铜网上,静置5min,然后用磷钨酸染色1min,之后用滤纸吸走铜网上多余的染液,室温晾干样品,在200kv条件下,透射电镜观察样品。结果如图4所示,由实验结果可知微乳均为圆整的颗粒,粒径在100nm以下。
实施例15
氢氧化铝微乳疫苗系统在DC2.4细胞的摄取:在十二孔板中,每孔种入1×106个DC2.4细胞,放入孵箱4-6小时,细胞贴壁后,向每孔中加入5μg FITC标记的OVA,或按实施6制备的载有相同量的FITC标记的OVA的氢氧化铝微乳。37度条件下摄取1.5小时后,弃去上清液,用PBS轻轻冲洗细胞表面2次,再用PBS直接吹打,2000rpm 3min离心洗涤细胞2次,最后用400μl PBS重悬细胞,用流式细胞仪检测。结果如图5所示,游离的OVA几乎不能被DC2.4细胞摄取,但是本发明的疫苗传递系统在DC2.4细胞上的摄取率约为70%,远远高于游离的OVA,具有显著性差异(****,P<0.0001),可见通过该给药系统包裹抗原显著提高了免疫细胞对抗原的摄取效率。图中Free OVA表示游离FITC标记的OVA,NE-OVA表示载有FITC标记OVA的氢氧化铝微乳。
实施例16
氢氧化铁微乳疫苗系统在DC2.4细胞的摄取:在十二孔板中,每孔种入1×106个DC2.4细胞,放入孵箱4-6小时,细胞贴壁后,向每孔中加入2μg FITC标记的黑色素瘤抗原肽GP100,或按实施例9制备的载有相同量FITC标记的黑色素瘤抗原肽GP100的氢氧化铁微乳。37度条件下摄取1.5小时后,弃去上清液,用PBS轻轻冲洗细胞表面2次,再用PBS直接吹打,2000rpm 3min离心洗涤细胞2次,最后用400μl PBS重悬细胞,用流式细胞仪检测。结果如图6所示,游离的黑色素瘤抗原肽几乎不能被DC2.4细胞摄取,但是本发明的疫苗传递系统在DC2.4细胞上的摄取率约为60%,远远高于游离的多肽,具有显著性差异(***,P<0.001),可见通过微乳包裹抗原显著提高了免疫细胞对抗原的摄取效率。图中Free-GP100表示游离FITC标记的GP100,NE@Fe-GP100表示载有FITC标记GP100的氢氧化铁微乳。
实施例17
氢氧化铝微乳疫苗系统的细胞毒性T淋巴细胞(CTL)实验和免疫抗体检测:第0天、第7天、第14天免疫,小鼠脚掌注射25ul的实施例6制备的载有OVA的氢氧化铝微乳,实施例7制备的载有OVA和CpG的氢氧化铝微乳,游离的OVA或游离的OVA与CpG,其中包含5ug OVA,0.5ug CpG,第21天通过CFSE染色的方法检测体内CTL反应。结果如图7所示,游离OVA和OVA的氢氧化铝微乳不能诱导抗原特异性细胞免疫反应,而载有OVA和CpG的氢氧化铝微乳可以产生较强的抗原特异性细胞免疫反应,其CTL显著高于游离OVA+CpG组,具有显著性差异(*,P<0.05)。结果表明,本发明的疫苗系统可显著提高CD8+T细胞免疫应答,在肿瘤、病毒感染等领域具有广阔的应用前景。图中OVA表示游离的OVA,NE-OVA表示载有OVA的氢氧化铝微乳,OVA+CpG表示游离的OVA与CpG,NE-OVA-CpG表示载有OVA与CpG的氢氧化铝微乳。
实施例18
氢氧化铝微乳疫苗系统的免疫抗体检测:第0天、第7天、第14天免疫,小鼠脚掌注射25ul的实施例7制备的载有OVA与CpG的氢氧化铝微乳,游离的OVA与CpG,其中包含5ugOVA,0.5ug CpG,第21天眼眶取血,检测血清中OVA特异性抗体。结果如图8所示,其中图a、图b和图c是IgG、IgG1和IgG2a的抗体检测结果,由实验结果可知,氢氧化铝微乳疫苗系统可以产生较强的抗原特异性免疫反应,IgG水平显著高于游离的OVA+CpG组,具有显著性差异(****,P<0.0001),表征Th2型免疫应答的IgG1也显著高于游离的OVA+CpG组,具有显著性差异(****,即P<0.0001),表征Th1型免疫应答的IgG2a水平显著高于游离的OVA+CpG组,具有显著性差异(***,即P<0.001),证明本发明的疫苗系统具有显著提高抗原免疫原性的优点。图中OVA+CpG表示游离的OVA与CpG,NE-OVA-CpG表示载有OVA与CpG的氢氧化铝微乳。
以上所述仅是本发明的优选实施例而已,并非对本发明做任何形式上的限制,虽然本发明已以优选实施例揭露如上,然而并非用以限定本发明,任何熟悉本专业的技术人员,在不脱离本发明技术方案的范围内,当可利用上述揭示的技术内容做出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化与修饰,均仍属于本发明技术方案的范围内。
Claims (14)
1.一种基于微乳的疫苗递送系统,其特征在于,所述微乳包括水相、油相、乳化剂、金属离子化合物和抗原,其中所述金属离子化合物吸附于微乳表面,同时包载抗原,所述微乳pH值在4.0-10.0之间,所述微乳的油相和乳化剂中含有羧基、磷酸基、磺酸基、硫酸基、亚硫酸基、酚羟基、烯醇基、硼酸基的一种或多种,可部分或全部电离产生阴离子,金属离子化合物含有金属阳离子,该金属离子化合物与微乳表面的阴离子发生反应附着于微乳表面。
2.根据权利要求1所述的基于微乳的疫苗递送系统,其特征在于,所述基于微乳的疫苗递送系统的各组分的重量份为:油相0.01%-50%,乳化剂0.001%-10%,所述金属离子化合物的重量份为0.0001%-1%,所述抗原的重量份为0.0001%-1%。
3.根据权利要求1-2任一所述的基于微乳的疫苗递送系统,其特征在于,所述的金属离子化合物中的金属离子选自铝、铁、锆、钙、锰、镉、镁、铈、镉、钴、镓或锌的一种或多种,所述金属离子化合物呈无机盐或有机复合物的形式。
4.根据权利要求1-2任一所述的基于微乳的疫苗递送系统,其特征在于,其所述金属离子化合物为氢氧化铝、氢氧化铁、磷酸铝、磷酸钙或氢氧化锌的一种或多种。
5.根据权利要求1-2任一所述的基于微乳的疫苗递送系统,其特征在于,所述油相为任何化妆品或医药上可接受的油。
6.根据权利要求1-2任一所述的基于微乳的疫苗递送系统,其特征在于,其所述乳化剂选自阴离子表面活性剂、非离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂的一种或一种以上的组合物。
7.根据权利要求1-2任一所述的基于微乳的疫苗递送系统,其特征在于,其所述微乳粒径小于1000nm。
8.根据权利要求1-2任一所述的基于微乳的疫苗递送系统,其特征在于,其所述微乳粒径小于300nm。
9.根据权利要求1-2任一所述的基于微乳的疫苗递送系统,其特征在于,其所述微乳粒径小于200nm。
10.根据权利要求1-2任一所述的基于微乳的疫苗递送系统,其特征在于,其所述微乳还含有附加剂,所述附加剂包括防腐剂、pH调节剂、缓冲液、有机溶剂、螯合剂、抗氧剂、填充剂、着色剂的一种或多种。
11.根据权利要求1-2任一所述的基于微乳的疫苗递送系统,其特征在于,所述抗原选自蛋白、多肽、核酸、寡糖、多糖、肿瘤细胞裂解物、肿瘤细胞膜囊泡抗原、细菌裂解物、细菌细胞膜、支原体细胞膜、衣原体细胞壁、螺旋体、立克次体微荚膜、病毒包膜、外泌体、病毒裂解液抗原、细菌外膜囊泡抗原的一种或一种以上组合物。
12.根据权利要求1-11任一所述的基于微乳的疫苗递送系统的制备方法,其特征在于,包括以下步骤:
(1)将亲油性乳化剂溶于油相中,将亲水性乳化剂溶于水相中,二者充分混合后形成微乳;
(2)将pH缓冲液和/或金属离子化合物的阴离子部分加入上述微乳中;
(3)将金属离子化合物的阳离子部分加入到步骤(2)制得的混合物中;
(4)抗原加入到步骤(2)或是步骤(3)制得的混合物中,混合均匀即得。
13.根据权利要求1-11任一所述的基于微乳的疫苗递送系统的制备方法,其特征在于包括以下步骤:
(1)将亲油性乳化剂溶于油相中,将亲水性乳化剂溶于水相中,二者充分混合后形成微乳;
(2)将金属离子化合物的阳离子部分加入上述微乳中;
(3)将pH缓冲液和/或金属离子化合物的阴离子部分加入到步骤(2)制得的混合物中;
(4)抗原加入到步骤(2)或是步骤(3)制得的混合物中,混合均匀即得。
14.根据权利要求1-11任一所述的基于微乳的疫苗递送系统或根据权利要求12-13任一所述的制备方法制备的疫苗递送系统在制备预防性和/或治疗性免疫药物中的应用。
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CN111658611B (zh) * | 2020-04-13 | 2021-06-01 | 四川大学 | 一种基于微乳的疫苗递送系统及其制备方法和应用 |
CN112843020A (zh) * | 2021-01-29 | 2021-05-28 | 燕山大学 | 一种用于增强瘤内递送的抗肿瘤纳米药物的制备方法 |
CN113679831B (zh) * | 2021-08-17 | 2023-07-28 | 四川大学 | 一种注射用水包油型乳剂黏膜疫苗及其制备方法和应用 |
CN117338948A (zh) * | 2022-06-28 | 2024-01-05 | 四川大学 | 一种ace2特异性结合肽修饰的递药系统及其制备方法和应用 |
CN116395718A (zh) * | 2023-04-12 | 2023-07-07 | 中国科学院长春应用化学研究所 | 一种弱碱性钠盐纳米药物、其制备方法及其应用 |
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FR2733151B1 (fr) * | 1995-04-20 | 1997-05-23 | Seppic Sa | Composition therapeutique comprenant un antigene ou un generateur in vivo d'un compose comprenant une sequence d'acides amines |
ATE515258T1 (de) * | 1999-02-05 | 2011-07-15 | Alk Abello As | Mukosales verabreichungssytem |
EP2286792A1 (en) | 1999-02-26 | 2011-02-23 | Novartis Vaccines and Diagnostics, Inc. | Microemulsions with an adsorbent surface, comprising a microdroplet emulsion |
JP5890096B2 (ja) * | 2007-12-21 | 2016-03-22 | ゾエティス・エルエルシー | 熱処理バクテリンおよびそのような熱処理バクテリンから調製された乳剤ワクチン |
WO2011031850A1 (en) | 2009-09-10 | 2011-03-17 | Merial Limited | New vaccine formulations comprising saponin-containing adjuvants |
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CN104147599B (zh) * | 2014-06-24 | 2017-03-01 | 华中科技大学 | 一种疫苗佐剂、其制备方法及应用 |
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CN108187040B (zh) * | 2018-01-10 | 2021-11-09 | 浙江洪晟生物科技股份有限公司 | 一种疫苗佐剂及其制备方法 |
WO2019241873A1 (en) * | 2018-06-22 | 2019-12-26 | Cuprous Pharmaceuticals Inc. | Metal containing products and compositions to induce immunogenic cell death and uses thereof |
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