CN1070697C - 制备一种新的微胶囊的方法 - Google Patents

制备一种新的微胶囊的方法 Download PDF

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CN1070697C
CN1070697C CN89103098A CN89103098A CN1070697C CN 1070697 C CN1070697 C CN 1070697C CN 89103098 A CN89103098 A CN 89103098A CN 89103098 A CN89103098 A CN 89103098A CN 1070697 C CN1070697 C CN 1070697C
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托马斯·R·泰斯
约翰·H·埃尔德里奇
理查德·M·吉利
杰伊·K·斯塔斯
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Abstract

一种将生物活性剂传送给动物的方法和可在这种方法中应用的组合物，这种方法需要的步骤是：将有效量的药剂包封在可生物相容的赋形剂中以形成其大小为小于约10微米的微胶囊并将有效量的微胶囊施用于动物。得到一种搏动方式的应答，及粘膜和全身的免疫性。

Description

制备一种新的微胶囊的方法
本发明涉及口服施用生物活性药剂的方法和制剂，该药剂被囊包在一种或多种生物相容的聚合物或共聚物赋形剂中，最好是一种可生物降解的聚合物或共聚物，这种微胶囊由于具有合适的大小及物化性质，使得它及其中所含的药剂能到达动物胃肠道的滤泡淋巴集结(也称为“派伊尔氏淋巴集结”)并被其有效地吸收，而不会由于药剂穿过胃肠道失去其有效性。在身体的呼吸道、泌尿生殖道、大肠和其他粘膜组织中也存在类似的滤泡淋巴集结。上述组织在下文都一般地称为与粘膜相关的类淋巴组织。
利用微包囊技术来保护敏感的生物活性药剂不会降解是众所周知的。一般说来，生物活性药剂被囊包在一系列保护性外壁物质的任一种中，它们的本质通常是聚合物。被囊包的药剂可以用聚合物单层外壁包裹(微胶囊)，或者也可以均一地分散于聚合物基质中(微球体)。(在下文中，术语微胶囊包括微胶囊和微球体二者)。微胶囊中的药剂量可根据需要而不同，其范围从少量可一直到高达微胶囊组合物的95％或更多。微胶囊的直径也可根据需要而不同。其范围从小于1微米至3毫米或更大。
派伊尔氏淋巴集结是位于小肠、大肠和兰尾壁中的类淋巴结的聚集体，它是身体防御系统的一个重要部分，防止外来传染媒介及其他物质的附着和穿透。抗原是诱导抗体生成和/或体内细胞介导的免疫系统的物质，包括外源蛋白或组织这类物质。由抗原和免疫系统相互作用而诱导的免疫应答就体内是否能够对于该抗原的随后侵袭而建立抗体或细胞免疫应答来说，可以是阳性的或阴性的。细胞介导的免疫应答包括杀伤外源细胞或组织，“细胞介导的细胞毒性”、以及迟滞型过敏这样一些应答。抗体属于一类称为免疫球蛋白(Ig)的蛋白质，它们是作为对抗原的应答而产生的，它们能与抗原特异性结合。抗体和抗原结合时形成复合物。此复合物有助于从体内清除抗原，促进活抗原的杀伤，例如传染媒介和外源组织或癌，并中和毒素或酶的活性。对于体内的粘膜表面来说，在围绕着这些位点的分泌物中，所存在的重要类抗体是分泌免疫蛋白A(sIgA)。分泌IgA抗体防止传染媒介和其他抗原对体内粘膜组织的附着和穿透。
在通常采用的免疫方法中，例如肌肉或皮下注射抗原或疫苗虽然有许多抗原通过粘膜组织进入体内，但很少能在粘膜分泌物中诱导出sIgA抗体。分泌IgA抗体最有效的诱导方法是，对与粘膜相关的类淋巴组织进行直接免疫，而胃肠道的派伊尔氏淋巴集结构成了体内这种组织的最大部分。
派伊尔氏淋巴集结具有IgA前体B细胞，这些细胞能够聚集于胃肠和上呼吸道的粘膜固有层区域，并分化成成熟的合成IgA的浆细胞。正是这些浆细胞实际分泌出抗体分子。Heremans和Bazin测定了用抗原口服免疫了的小鼠的IgA应答的发展，他们的研究表明，抗原特异性的IgA浆细胞是依次出现的，首先是在隔膜淋巴结中，然后是在脾中，最后是在胃肠道的粘膜固有层中(H.Bazin,G.Levi,G.Doria，“在口服施用抗原的无细菌小鼠肠外类淋巴组织中，IgA抗体形成细胞对于检测到的免疫应答的决定性贡献”，J.Immunol.105:1049,1970；P.A.Grabbe,D.R.Nash,H.Bazin,H.Eyssen,J.F.Heremans，“用铁蛋白对无细菌小鼠进行口服或非肠道免疫后肠道浆细胞中的IgA型抗体”，J.Exp.Med.130:723,1969)。后来的研究表明，口服施用抗原导致肠道中产生sIgA抗体，还在距肠道较远的粘膜分泌物中产生sIgA抗体，例如在支气管洗液、初乳、乳液、唾液和泪水中(J.Mestecky,J.R.McGhee,R,R.,Arnold,S.M.Michalek,S.J.Prince,J.L.Babb,“通过摄取细菌抗原而在人外分泌中选择性诱导免疫应答”，J.Clin.Invest.61:731,1978,P.C.Montgomery,B.R.Hosner,J.Cohen，“分泌抗体应答，由二硝基苯基化的Ⅲ型肺炎球菌诱导的抗DNP抗体，”Immunol.Commum.3:143,1974；L.A.Hanson,S.Ahistedt,B.Carlsson,B.Kaijser.P.Larsson,A.MattsbyBaltzer,A。Sohl Akerlund,C.Svanborg Eden和A.M.Dyennerholm，“针对肠细菌毒性抗原的分泌IgA抗体：它们的诱导及可能的关系”，Adv.Exp.Med.Biol.1007:165,1978)。因此很显然，派伊尔氏淋巴集结是前体IgA细胞的丰富来源，这些细胞在抗原刺激后，沿循环转移途径，同时在最初的抗原刺激区和较远的粘膜表面引起IgA的表达。这种循环形式提供了一种粘膜免疫系统，即作为对肠道遭遇到的环境抗原和潜在病原体的应答，不断地向粘膜位点输送敏化B细胞。
对本发明特别重要的是口服免疫来诱导保护性抗体的能力。已经知道，动物对抗原的摄取导致在支气管和鼻孔洗液中出现抗原特异性的sIgA抗体。例如，对自愿人员进行的研究表明，口服施用流感疫苗能有效地在鼻分泌物中诱导抗流感的分泌抗体。
广泛研究已经证实了口服免疫诱导普通的粘膜免疫系统的可行性。但在少数情况下需要大剂量才能达到有效免疫，因此使这种方法不大切合实际。很显然，任何一种涉及口服施用某成分的方法或制剂都要设计成使得该药剂通过胃肠道时保护至它不被降解。并达到将该成分送到派伊尔氏淋巴集结的目的。如果不是这样，该成分即使能够到达派伊尔氏淋巴集结处，也是在数量不足或不能达到有效的状态。
因此，需要有一种口服免疫的方法，它将有效地刺激免疫系统，并克服抗原通过胃肠道到达派伊尔氏淋巴集结时的降解问题。还存在一种更加具体的需要，即需要一种将抗原送至淋巴集结处，并使抗原一旦到体内后就释放的方法。还存在这样一种需要，即需要一种通过体内其他粘膜组织免疫的方法，该方法克服了抗原的降解问题，并达到将其送达与粘膜相关的类淋巴组织的目的。此外，需要保护施用于粘膜的生物活性试剂不被降解，改善和/或达到使它们通过与粘膜相关的类淋巴组织进入体内的目的，并在一旦进入体内后就释放生物活性试剂。
本发明涉及通过粘膜应用，更具体说是通过口服和气管内施用将生物活性药剂送至动物体内然后释放的方法和制剂。该药剂以微胶囊形式被包在生物相容的聚合物或共聚物中，最好是可生物降解的聚合物或共聚物，它们能通过肠胃道或存在于粘膜表面而不降解或很少降解，使得其中的药剂能够不改变地以有效量到达并进入淋巴集结或其他与粘膜相关的类淋巴组织。术语生物相容的定义为一种对身体无毒性、没有致癌作用、不会在体内组织中诱导炎症的聚合物。微胶囊聚合物赋形剂最好是可生物降解的，也就是说它应当能通过体内过程降解成容易被体内处理的产物，而不在体内积累下来。微胶囊还是一种其大小和物化性质使得它能够有效地和选择性地被淋巴集结摄取的组合物。因此，解决了使药剂到达淋巴集结或其他与粘膜相关的组织并被摄取的问题。
本发明的目的之一是提供一种给动物口服施用抗原的方法，该方法能使抗原到达派伊尔氏淋巴集结并被摄取，因而刺激粘膜免疫系统，而在通过动物胃肠道时不损失其有效性。
本发明的另一目的是提供一种给动物口服施用抗原的方法，该方法能使抗原到达派伊尔氏淋巴集结并被摄取，因而刺激全身免疫系统，同时不因为通过胃肠道而损失其有效性。
本发明进一步的目的是提供一种给动物施用抗原的方法，该方法使抗原到达与粘膜相关的类淋巴组织并被摄取，因而刺激粘膜免疫系统，同时不因为在粘膜表面的降解而损失其有效性。
本发明进一步的目的是提供一种给动物施用抗原的方法，该方法使抗原到达与粘膜相关的类淋巴组织并被摄取，因而剂激全身免疫系统，同时不因为在粘膜表面的降解而损失其有效性。
本发明进一步的目的是提供一种给动物口服施用生物活性药剂的方法，该方法使药剂到达派伊尔氏淋巴集结并被摄取，从而导致该药剂在局部或全身的浓度上升。
本发明进一步的目的是提供一种给动物施用生物活性药剂的方法，该方法使药剂到达与粘膜相关的类淋巴组织并被摄取，从而导致该药剂在局部或全身的浓度上升。
本发明进一步的目的是提供一种由核心生物活性组份和包囊聚合物或共聚物赋形剂组成的制剂，赋形剂具有生物相容性，并且最好是可生物降解的，该制剂能够用于上述的粘膜施用法中。
本发明进一步的目的是提供一种改进的疫苗传递系统，以避免对于免疫增效剂的需要。
本发明进一步的目的是提供一种改进的疫苗传递系统，用于通过从一次施用的微囊化抗原中搏动式释放抗原来诱导免疫作用。
本发明进一步的目的是提供一种改进的疫苗传递系统，此系统既避免了对于免疫增效剂的需要，又能够通过从一次施用的微囊化抗原中搏动式释放抗原来诱导免疫作用。
本发明进一步的目的是提供一种能够达到上述目的的组合物。
图1是通过终点滴定测定的小鼠中血浆IgA应答。
下面是对实施本发明方法的具体方案的说明。这些说明证实了抗原至粘膜相关类淋巴组织的定靶的和按计划的传递(所用抗原是三硝基苯基钥孔血盏蛋白和葡萄球菌肠毒素B的类毒素疫苗)。以及一种囊包在50∶50聚(DL-丙交酯-共-乙交酯)中用于小鼠的药物(苯壬四烯酯)。
但应当注意，除了聚(DL-丙交酯-共-乙交酯)以外还可使用其他聚合物。这些聚合物的例子包括但不限于：聚(乙交酯)、聚(DL-丙交酯-共-乙交酯)、共聚草酸酯、聚己内酯、聚(丙交酯-共-己内酯)、聚(酯酰胺)、聚原酸酯和聚(8-羟基丁酸)、以及聚酐。
另外，还可使用其他生物活性成分，其实例包括、但不限于：对抗病毒、细菌、原生动物、真菌疾病例如流感，呼吸合胞体、副流感病毒、流感嗜血杆菌、百日咳博德特氏菌、淋病奈氏球菌、肺炎链球菌和镰状疟原虫或其他由病原微生物导致的疾病等接种的抗原，或对抗由蠕虫病原体这类微生物导致的疾病接种的抗原，或对抗变态反应接种的抗原。另外可用的生物活性试剂包括但不限于：免疫调节剂、养分、药物、肽、淋巴因子和细胞素等。Ⅰ．微包囊A．装有染料的微胶囊的制备
香豆素是一种水不溶性荧光染料，将它用一种不能生物降解的聚合物聚苯乙烯微包囊，这样制备的荧光微胶囊能用来跟踪微胶囊侵入派伊尔氏淋巴集结。制备这种微胶囊的方法如下：
首先制备聚合物溶液，即将4.95克聚苯乙烯(685D型，Dow Chemical Compary,Midland,MI)溶于29.5克二氯甲烷中(试剂级，Eastman Kodak,Rochester,NY)。然后在聚合物溶液中加入大约0.05克香豆素(Polysciences,Inc.,Warrington,PA)，用磁性搅拌棒搅拌混合物使其溶解。
在另一个容器中，通过将40克聚乙烯醇(Vinol 2050,Air Products and Chemicals,Allentown,PA)溶于360克去离子水中制备10％(重量)的聚乙烯醇(PVA)水溶液，即加工介质。制备了PVA溶液后，加入6克二氯乙烷使此溶液饱和。然后，将PVA溶液加至1升的树脂罐中(Ace,Glass,Inc.Vineland,NI)，该罐装配有真孔搅动轴和2.5英吋的聚四氟乙烯叶轮，通过Fisher型稳速电动机以大约380rpm搅动。
然后，将聚苯乙烯/香豆素混合物加至盛有PVA加工介质的树脂罐中，加入过程是这样完成的：将聚苯乙烯/香豆素混合物通过7mm孔径的长颈漏斗倒入，该漏斗直接通向树脂罐的混合物中。形成一种稳定的水包油型乳剂，然后在环境压力下搅拌大约30分钟，以产生合适大小的油微滴。然后封闭树脂罐，使树脂罐内的压力逐渐降至520mmHg柱，降压过程通过与压力计和放气阀相连的水力抽气器进行。树脂罐的内容物在减压下搅拌24小时，使所有的二氯甲烷挥发。在所有的二氯甲烷挥发后，离心收集硬化的微胶囊，于室温下在真空室中干燥72小时。B．装有抗原的微胶囊的制备
TNP-KLH是一种水溶性抗原，将它包囊在聚(DL-丙交酯-共-乙交酯)中，这是一种生物相容的可生物降解的聚酯。制备微胶囊的方法如下：
首先制备聚合物溶液，将0.5g 50∶50的聚(DL-丙交酯-共-乙交酯)溶于4.0g二氯甲烷中。然后，将300微升TNP-KLH水溶液(46mg TNP-LKH/ml；在透析后)加入其中，通过用Vortex-Genie2型(ScientificIndustries,Inc.Bohemia,NY)搅拌混合物使之均匀地分散于聚(DL-丙交酯-共-乙交酯)溶液中。
在另一个容器中，通过将4.8克PVA溶于55.2克去离子水中制备8％重量的PVA水溶液。在PVA溶解以后，将PVA溶液加至100毫升的树脂罐中(Kontes Glass,Inc.Vineland,NJ)，该罐装配有真孔搅拌装置和1.5英吋的聚四氟乙烯叶轮。将聚合物溶液通过7mm孔径的长颈漏斗倒入PVA加工介质中。在此加入过程中，以大约650rpm搅拌PVA溶液，然后使生成的水包油型乳液在树脂罐中搅拌大约10分钟，树脂罐中的内容物转移至装在4升烧杯中的3.5升的去离子水中，用2英吋的不锈钢叶轮以800rpm搅拌。产生的微胶囊在去离子水中搅拌大约30分钟，离心收集，用去离子水洗两次以除去所有残留的PVA，然后通过冰冻干燥收集。微胶囊产物由直径约为1-10微米的球形颗粒组成，以类似的方式可以制备其他微胶囊，例如葡萄球菌肠毒素B微胶囊。
抗原微胶囊的TNP-KLH内容物(也即微胶囊的核心装载物)通过在12毫升离心管中称出10mg抗原微胶囊进行测定。在管中加入3.0毫升二氯甲烷，通过搅拌使聚(DL-丙交酯-共-乙交酯)溶解。然后，在管中加入3.0ml去离子水并激烈搅拌1分钟。使离心管中的内容物离心，以分离有机层和水层。将水层转移至10ml容量瓶中。重复萃取并将水层合并于容量瓶中。用去离子水将容量瓶加至刻度。通过蛋白检测法对瓶中的TNP-KLH进行定量，并随后确定微胶囊中的TNP-KLH量。微胶囊中含有0.2％重量的TNP-KLH。以类似的方式，可对葡萄球菌肠毒素B微胶囊中的葡萄球菌肠毒素B进行定量。Ⅱ．装有染料的微胶囊在口服施用后对派伊尔氏淋巴集结的穿透
对于分泌IgA的应答能够起诱导位点作用的最大量组织是派伊尔氏淋巴集结。这些离散的淋巴网状组织集结位于沿着小肠和兰尾的整个长度上。将完整抗原直接定向传递入此组织中以达到较高的局部浓度，目前被认为是诱导传播性粘膜IgA应答的最有效的方式。可生物降解的微胶囊是达到此定点接种的理想载体。实例1聚苯乙烯微胶囊
通过给小鼠口服施用装有荧光染料香豆素的聚苯乙烯微胶囊，研究肠道淋巴网状组织对微胶囊的摄取和此穿透作用的尺寸限制。对未麻醉但固定好的BALB/C小鼠施用0.5ml 100mg/ml的不同大小的荧光微胶囊悬浮液(直径小于5微米或8-50微米)，利用饲喂针加自来水注入胃中。在施用后不同时间(0.5、1和2小时)，处死小鼠并分离小肠。分离出含有离散的淋巴集结的一些1厘米的肠道切段，洗掉肠腔内容物，翻卷后快速冰冻。制备好冰冻段并在荧光显微镜下检查冰冻切段，以观察由淋巴集结从肠腔中摄取的微胶囊的数目、位置和大小。
虽然有些微胶囊陷落于绒毛之间，因此在冲洗时未被洗出，但除了派伊尔氏淋巴集结之外，在其他任何位置都未观察到对组织的穿透。在口服施用后0.5小时，观察到微胶囊在小肠近端(在远端没有)的淋巴集结中，随着时间的延长，微胶囊通过蠕动转运，因此在2小时后它们已通过了胃肠道，并发现它们存在于肠胃的淋巴集结中。摄入细胞的微胶囊主要位于淋巴集结园顶的外周，而不在顶端，似乎是蠕动时在园顶和相邻绒毛之间的物理捕获促进了它们的摄取。比较小于5微米和8-50微米制剂的摄取效率证实，微胶囊直径大于10微米时不被派伊尔氏淋巴集结吸收，而直径为1-10微米的微胶囊被选择性地迅速摄取。这一结果提示，由可生物降解的外壁物质构成的微胶囊能作为有效的定点传递抗原的手段，将抗原送至淋巴网状组织以在粘膜表面诱导免疫作用。实例2、85∶15聚(DL-交酯-共-乙交酯)微胶囊：1．生物相容的和可生物降解的微胶囊至派伊尔氏淋巴集结的摄取。
对几组小鼠通过胃管以在自来水中的悬浮液方式施用含有荧光染料香豆素-6的可生物降解的微胶囊。这些研究中所选用的微胶囊外壁物质由85∶15聚(DL-丙交酯-共-乙交酯)组成，因为它在6个星期内能够抵抗严重的生物腐蚀。在施用后1-35天的不同时间，从单个小鼠中取出3个代表性的派伊尔氏淋巴集结，主要的隔膜淋巴结和脾，加工并制备系列冰冻段。
利用合适的激发光和栅栏式滤光镜在荧光显微镜下观察时，香豆素表现出深绿色荧光，因此能够目测到直径大大小于1微米的微胶囊。对所有切段进行观察，以对每个组织或器官中微胶囊的全部数量定量，利用有刻度的目镜测微尺确定每个内化微胶囊的大小，并记下它在组织或器官中的位置。
如表1所示，在口服施用后24小时，以及外伸到35天内的所有测试点，都在淋巴集结内观察到不同大小的内化微胶囊。除了派伊尔氏淋巴集结以外，在肠道组织的任一点上任何时候都未观察到任何大小的微胶囊的穿透。派伊尔氏淋巴集结内的微胶囊总数到第4天一直上升，然后在随后的31天内下降，降至最高数目的大约15％。
这与在1,2和4天的时间点上，在肠道绒毛表面可观察到游离的微胶囊是一致的。有趣的是，在口服施用微胶囊悬浮液大约10小时后，能在排泄的粪便中清楚观察到装有香豆素的微胶囊。借助于紫外光源跟踪这一清除作用，发现到24小时时，摄入微胶囊的绝大部份都被排出了。因此，在2和4天时间点上观察到的微胶囊的持续摄入派伊尔氏淋巴集结，只能归结为输入剂量截留于肠道绒毛间的粘液中的一小部分。此外，这些被截留微胶囊的摄取效率一定比肠腔中(但在粘液层上)的微胶囊的摄取要大好几个数量级。如果将这些结果延伸到人，则这些观察是很重要的，由于人的派伊尔氏淋巴集结组织比小鼠要大得多，物质通过人小肠的转移时间比小鼠也大得多，因此有理由相信，微胶囊在人的派伊尔氏淋巴集结的摄取效率也要高得多。
如表1所示，在所有测试的时间点，在派伊尔氏淋巴集结中观察到不同大小的微胶囊。在第1、2和4天的时间点上，小于2微米(45-47％)、2-5微米(31-35％)和大于5微米(18-23％)的微胶囊部份保持相对恒定。在第7天，可以明显观察到大小分布的漂移，在更晚的时间点上这一漂移甚至更明显，即小的(小于2微米)和中等(2-5微米)的微胶囊不再占优势，而大的(大于5微米)微胶囊所观察到的数目最多。此漂移与第7天及其后观察到的淋巴集结中微胶囊总数的下降是同时发生的。这些结果与微胶囊的运动趋向是一致的，即小的和中等大小的微胶囊趋于从派伊尔氏淋巴集结迁移出去，而大(大于5微米)微胶囊则更倾向于保留不动。
与微胶囊在淋巴集结结构中的位置相关的数据是与小的和中等微胶囊倾向于迁移离开派伊尔氏淋巴集结这一事实相一致的。在派伊尔氏淋巴集结中观察到微胶囊时，发现它总是在它进入派伊尔氏淋巴集结处比较靠近园顶上皮处(在200微米以内)，或是在类淋巴组织的更深处(距最近的可鉴别的园顶上皮处≥200微米)(表1)。在派伊尔氏淋巴集结组织深处观察到的微胶囊几乎都是小和中等直径的。在施用后的1天，92％的微胶囊位于靠近园顶上皮处。位于深处的微胶囊比例在第4天上升至总量的24％，此后随着时间下降，在笫14天及其后降至大约2％。因此，小的和中等的微胶囊穿过并迁移出派伊尔氏淋巴集结，而大(大于5微米)微胶囊在较长的期间内保留在园顶区。2．微胶囊至隔膜淋巴结和脾的迁移。
如表2所示，在施用后1天，在隔膜淋巴结中观察到少量微胶囊，其数目在7天内逐步上升。第7天后，数量逐渐下降，但在第37天仍可检测到。大小分布情况清楚地表明，直径大于5微米的微胶囊不进入此组织，在较早的时间点上，小的(小于2微米)微胶囊相对于中等(2-5微米)微胶囊的比率较高，这表明直径较小的微胶囊最容易进入此组织。此外，在较早的时间点上，大部分微胶囊都位于紧靠囊下窦中的囊下。在较晚的时间点上，分布状况移向淋巴结结构的深部，在第14天，90％的微胶囊都位于皮质和髓区中。观察到微胶囊首先是在囊下窦之中或附近测测出的。这一观察与它们是经引流派伊尔氏淋巴集结的淋巴管进入此组织是一致的。在第4天，可清楚分辨出位于此组织深处的微胶囊比率逐步增加，在第10天及其后，跟着是总数的逐步下降，这一观察表明微胶囊进入此组织中，并通过有效的淋巴排流而渗出。
对脾进行类似的检察，结果表明，直到施用后第4天才可检测到微胶囊。直到第14天，才在此器官中观察到微胶囊的峰值。与隔膜淋巴结中的情况一样，没有观察到直径大于5微米的微胶囊。在所有时间点上，都在皮层中的该器官深处观察到微胶囊。应当注意到，在脾中观察到微胶囊峰值的时间正是隔膜淋巴结中的大部分微胶囊位于深层并且总数正在下降的时间。这些结果与淋巴液由派伊尔氏淋巴集结流至隔膜淋巴结，以及由隔膜淋巴结通过胸导管流至血流中的已知模式是一致的。因此脾中存在的微胶囊似乎已穿越了派伊尔氏淋巴集结和隔膜淋巴结，并通过血流循环进入脾脏。
在另外的一些实验中，通过组织化学和免疫组织化学技术检查含有吸附的85∶15DL-PLG微胶囊的派伊尔氏淋巴集结、隔膜淋巴结和脾的组织切段。除了其他的观察以外，这些研究清楚表明，吸入到派伊尔氏淋巴集结的微胶囊存在于巨噬细胞样细胞中。这些细胞中的胞内碳水化合物，最可能是糖原，以及主要组织相容性复合物(MHC)Ⅱ类抗原可以通过高碘酸希夫氏试剂(PAS)被染色。进一步，发现在隔膜淋巴结和脾中观察到的微胶囊，都已进入到这些PAS和MHCⅡ类阳性细胞中。因此，含有抗原的微胶囊于派伊尔氏淋巴集结中被具抗原的副卫细胞(APC)内化，这些APC将抗原胶囊传播至其他类淋巴组织中。
这些结果表明，由口服施用微胶囊疫苗诱导的免疫应答的质量可由颗粒大小来控制。直径小于5微米的微胶囊由派伊尔氏淋巴集结APC中渗出，并将抗原释放至作为全身免疫应答诱导位点的类淋巴组织中。与此相反，直径在5-10微米的微胶囊在派伊尔氏淋巴集结及APC中保留较长时间，并将抗原释放至sIgA诱导位点中。实例3．派伊尔氏淋巴集结对10种组合物微胶囊摄取的比较。
通过实验来鉴别对实际的受控释放传递系统有用的微胶囊聚合物赋形剂，它应当具有这样的物化性质，此性质使微胶囊能被定靶吸入与粘膜相关的类淋巴组织中。对于后一点而论，研究结果表明，疏水颗粒更易于被网状内皮系统的细胞吞噬。因此，检查了10种不同的聚合物的1-10微米微胶囊由派伊尔氏淋巴集结的吸收。这10种聚合物都具有一定程度的疏水性。这些研究选用的外壁物质由在吸水性、生物降解及疏水性方面都不同的聚合物组成。这些聚合物包括聚苯乙烯、聚(L-丙交酯)、聚(DL-丙交酯)、50∶50聚(DL-丙交酯-共-乙交酯)、85∶15聚(DL-丙交酯-共-乙交酯)、聚(羟基丁酸)、聚(异丁烯甲酯)、乙基纤维素、纤维素醋酸氢酞酸和三乙酸纤维素。如表3所示，由10种赋形剂中的7种制备的微胶囊，在口服施用含有20mg微胶囊的悬浮液48小时后，被吸收并主要存在于派伊尔氏淋巴集结的园顶正中。没有观察到一个微球体穿透除派伊尔氏淋巴集结外的其他组织中。只有一个例外即乙基纤维素，发现其吸收效率与赋形剂的相对疏水性相关。在小鼠的3个代表性派伊尔氏淋巴集结中观察到1500个微胶囊，该小鼠施用有最疏水的化合物基团(聚苯乙烯、聚(异丁烯甲酯)、聚(羟基丁酸))，而施用疏水性相对小的聚酯(聚(L-丙交酯)、聚(DL-丙交酯)、85∶15聚(DL-丙交酯-共-乙交酯)、50∶50聚(DL-丙交酯-共-乙交酯))时只观察到200-1000个微胶囊，纤维素类不被吸收。
已经发现，微胶囊的物化特性通过它们由肠腔吸收至派伊尔氏淋巴集结的效率而调节微胶囊的定靶性能，而且这是一种表面现象，因此，通过对聚合物进行化学修饰或以包衣方式改变微胶囊的表面特性，能用来调节微胶囊将生物活性试剂定靶传递至与粘膜相关的类淋巴组织和APC上的效率。可以采用的包衣实例包括但不限于：化学试剂、聚合物、抗体、生物粘结剂、蛋白、肽、碳水化合物、植物凝集素等天然和人工来源的物质。Ⅲ．用微胶囊疫苗诱导的抗体应答材料和方法
小鼠：研究中所用小鼠为BALB/C小鼠，8-12周令。
三硝基苯基-钥孔血兰素来自钥孔(Megathuracrenulate)的血兰素(KLH)购自Calbiochem(SanDiego,CA)。根据Rittenburg和Amkraut的方法(M.B.Rittenburg和A.A。Amkraut，“三硝基苯基血兰素的免疫原性：初级和次级抗-半抗原沉淀素的产生，”J.Immunol.97:421,1966)，用2,4,6-三硝基苯磺酸使之与三硝基苯基半抗原结合(TNP-KLH)。用15400的摩尔消光系数和350nm的波长通过分光光度法测得取代比例为TNP861-KLH，对于在此波长下KLH的影响作了30％的修正。
葡萄球菌肠毒素B疫苗：根据Warren等人所述的方法(J.R.Warren,L.Spero.和J.F.Metzger“福尔马林失活的葡萄球苗肠毒素B的抗原性”，J.Immunol.111:885，1973)，制备福尔马林化的葡萄球菌肠毒素B(SEB)疫苗。简而言之，1克肠毒素溶于0.1M磷酸钠缓冲液PH7.5中，使其成为2mg/ml。肠毒素溶液中加入甲醛，使甲醛：肠毒素的摩尔比例为4300∶1。将溶液置于缓慢摇动的保温摇床中，环境温度控制在37℃，每天监测pH使之维持在7.5±0.1。30天以后，浓缩该类毒素，使用加压过滤单元(Amicon)将其洗入硼酸盐缓冲液中(BBS)，通过过滤消毒。对3-3.5kg的兔子肌肉注射1mg类毒素物质，体质未降低，这证实了肠毒素已转化为类毒素。
免疫：以合适的浓度将微囊化和非微囊化的抗原悬浮于8份过滤消毒的自来水和2份碳酸氢钠溶液中(7.5％的溶液)，在施用0.5ml悬浮液之前把受体小鼠绑缚过夜，用插管针通过胃插管法给予施用(J.L.Babb,H.Kiyono,S.M.和Michalek,J.R.McChee，“免疫应答的LPS调节：免疫应答对于口服施用的T依赖抗原的抑制”，J.Immunol.127:1052,1981)。
生物体液的收集
1．血浆：对后眶丛穿刺，用毛细刻度收管收集血液。凝块形成后收集血清，离心去除红细胞和血小板，热失活，检测前保存于-70℃。
2．肠道分泌物：以15分钟的间隔，给小鼠施用四倍剂量(0.5ml)的灌洗液(25mM NaCl,40mM Na2SO4,10mM KCl,20mM NaHCo3,48.5mM聚(乙二醇)，530mosM的摩尔渗透压浓度〕(C.O.Elson,W.Ealding,和J.Lefkowitz，“一种能够重复测定小鼠肠道分泌物IgA抗体的灌洗技术”，J.Immunol.Meth.67:101,1984)。最后剂量的灌洗液施用后15分钟，使小鼠麻醉，再过15分钟后，通过ip注射给它们施用0.1mg毛果芸香碱。在随后的10-20分钟内，刺激肠道内容物的排放。将其收集入培养皿中。其中含有3ml在50mM EDTA中的0.1mg/ml大豆胰蛋白酶抑制剂(Sigma St.Louis,MO)，激烈搅拌后离心以去除悬浮物质，上清液转移至园底聚碳酸酯离心管中，加入30微升20毫摩尔的苯基甲基磺酰氟(PMSF,Sigma)，然后通过高速离心澄清(27000×g,20分钟，4℃)。澄清以后，PMSF和1％迭氮钠各加入20微升，将其配制成FCS的10％溶液，从而为任一种残留的蛋白酶提供一种可供选择的底物。
3．唾液：在肠道排放的同时还分泌大量唾液，通过毛细作用收集0.25ml至巴斯德吸管中，加入胰蛋白酶抑制剂、PMSF、叠氮钠和FCS各20微升，然后澄清。
4．支气管肺泡洗液：用1.0ml PBS对肺进行灌洗，从而得到支气管肺泡洗液。将动物饲喂针插入气管内，通过缝合进行固定。引入PBS并抽取5次以得到洗液，加入胰蛋白酶抑制剂、PMSF、迭氮钠、和FCS各20微升，然后通过离心澄清。
5．免疫化学试剂：从市场购得对鼠IgM、IgG和IgA具特异性的固相吸收和亲和纯化的多克隆山羊IgG抗体(SouthernBiotechnology Associates,Birmingham,AL)。通过它们与适当纯化的单克隆抗体和骨髓瘤蛋白的结合能力来测试其在放射免疫检测中的特异性。
6．固相放射免疫检测法：利用氯胺T法(W.M.Hunter,“放射免疫检测法”，《实验免疫学手册》，M.Weir编，Blackwell Scientific Publishing,Oxford,1978.14.1页)，用无载体Na125I(Amersham)标记纯化的抗体。用1μg/ml的结合TNP的牛血清清蛋白(BSA)或葡萄球菌肠毒素B包衣Immulon Removawell检测条(Dynatech)，包衣过程在BBS中于4℃下过夜进行。对照条不预以包衣，但所有条却用1％BSA(在BBA中)于室温下封闭2小时，该溶液用作为所有样品和125I标记试剂的稀释液。适当稀释生物体液样品，加入到3个一样的洗涤过的小孔中，于室温下保温6小时。洗涤以后，每孔中加入100000CPm的125I标记的同型特异性的抗免疫球蛋白抗体，于4℃保温过夜。通过洗涤去除未结合125I标记的抗体，然后用伽玛5500型分光计(BeckmanInstruments,Inc.,San Ramon,CA)对小孔计数。在检测TNP特异性抗体时，在包衣有1μg/孔同型特异性抗体的小孔上，用含有已知量免疫球蛋白的2倍系列稀释的标准血清(Miles Scientific,Naperville,IL)来定标。通过计算机得到定标曲线和未知部分的插入(利用“Logit-log“或”Four Parameter Logistic”BASICTechnology Center,Vanderbilt MedicalCenter,Nashville,TN)。对于特异于葡萄球菌肠毒素B的抗体，其结果以血清稀释度的倒数给出，该稀释度所产生的信号比同样稀释度的预抽血对应组大3倍(终点滴定度)。
A．通过注射施用疫苗微胶囊1．通过微胶囊化产生的佐剂效应实例1由微胶囊腹腔施用产生的佐剂效应
我们实验室的研究结果已经表明，在许多实验系统中，微胶囊化对其中掺入的抗原或疫苗产生显著增强的免疫应答。通过直接比较提供了一个实例，即在用可溶性或微胶囊化的类肠毒素免疫以后，比较对于葡萄球菌肠毒素B(即葡萄球菌食物中毒的致病剂)的循环抗体应答的水平和同型分布。给几组小鼠施用不同剂量的、参入在50∶50聚(DL-丙交酯-共-乙交酯)微胶囊中的类毒素疫苗，或以可溶形式通过腹腔(IP)注射施用。在免疫后的第10和20天，收集血浆样品，用同型特异性的放射免疫检测法通过终点滴定检测抗毒素活性(表4)。可溶类毒素的最佳剂量(25μg)所诱导的针对毒素的特性免疫应答很弱，只在IgM同型中检测到。与此相反，施用25μg掺入微胶囊中的类毒素不仅诱导了IgM应答，还诱导了IgG应答，在免疫后第20天可在1/2560的稀释血清中检测到。此外，可以微胶囊形式施用更大剂量的类毒素而不降低应答幅度，而使用50μg剂量的可溶性类毒素则不行。事实上，测量微胶囊达到的释放表明，微胶囊的释放水平使得可以施用4-5倍剂量而不产生很强的局部麻痹，因此导致显著增强的免疫作用。在第二(表5)和第三次免疫(表6)以后，此佐剂活性甚至更为显著。
第二次免疫后的第20天，施用50μg微胶囊化类毒素的小鼠比施用最佳剂量可溶性类毒素的小鼠的IgG抗毒素免疫应答高512倍。进一步，要用最佳剂量的可溶性类毒素进行第3次免疫，才能将针对毒素的抗体应答水平提高到与用100μg微胶囊化类肠毒素单独一次免疫后所观察到的相等的水平。实验室常用的蛋白抗原也记载过相等的佐剂活性，例如半抗原化的钥孔血兰素和流感病毒疫苗。实例2微胶囊皮下施用产生的佐剂效应
发现目前的传递系统在肌肉或皮下(SC)注射后具有活性。如表7所示，这是通过直接比较对几组小鼠作IP和SC注射后免疫应答的时间进程和水平而进行研究的。
沿着小鼠背上四个位点通过SC注射施用100μg微球体类肠毒素，所刺激的IgG抗毒素应答峰值与IP注射后观察到的相当，观察到抗毒素抗体出现的动力学有些迟滞。然而，仍选到了非常高的抗体水平，这证实在除腹膜以外的地方注射也是可行的。如表8所示，在第2次免疫之后，IP和SC途经的峰值滴度再一次相当，尽管SC途径的应答迟滞仍然是明显的。2．由微胶囊化产生的佐剂效应的机理实例1．微胶囊化产生的佐剂效应不是聚合物固有的佐剂活性的结果
在研究1-10μm DL-PLG微球体介导针对包囊抗原的增强的体液免疫应答的机理时，必须考虑3种可能的机制。首先，其长期的慢性释放(贮存)与未包囊抗原的一次大剂量相比较，可能对增强免疫起作用，第二，我们的实验已经表明，这种大小范围的微球体很容易被处理和展示抗原的细胞所吞噬。因此，还必须考虑较大剂量的非降解抗原的直接定靶传递的效果，即将它们递到负责启功针对T细胞依赖抗原免疫应答的细胞。第三，微囊通过它们以类似于细菌脂多糖或胞壁酰二肽等佐剂的方式活化免疫系统细胞的能力、可能具有固有的免疫增强活性。通过这后一种机理增强免疫的特点是由该佐剂与抗原同时施用时表达的。
为了测定微球体是否具有通过这些颗粒非特异性活化免疫系统的能力而介异的天然佐剂效果，将针对100μg微胶囊化的类肠毒素的抗体应答与施用等剂量的与不含抗原的对照微球体混合的类肠毒素后诱导的抗体应答相比较。如表9所示，对10只BALB/C小鼠的一些组，通过IP注射施用各种形式的抗原，通过终点滴定RIA，测定血浆中IgM和IgG特异于肠毒素的抗体应答。
由最佳剂量可溶性类肠毒素(25μg)的快速浓注产生的血浆抗体应答水平很低，其特征是由第10天的峰值为800的IgM滴度和第20天的峰值为800的IgG滴度组成。而施用等剂量的微囊类肠毒素对于IgM和IgG同型体都诱导很强的应答，并在免疫30天后还保持上升。将可溶性类肠毒素和其重量、大小和组成都与包囊抗原相同的对照微球体一起施用，所诱导的血浆抗毒素应答并不显著高于通过单用可溶性抗原诱导的水平。在对照微球体之前1天或之后1、2或5天施用可溶性抗原，也不改变此结果。因此，这些数据表明，施用在1-10μm DL-PLG微球体中的抗原时表现的免疫增强作用并不是由于微球体天然具有活化免疫系统的能力的结果。相反，这些数据与贮存效应，抗原至展示抗原的副卫细胞的定靶传递或这两种机理的结合是一致的。实例2、延滞1-10μm微胶囊的抗原释放速率可提高抗体应答水平及延迟峰值应答的时间
制备四种抗原释放速率不同的含类肠毒素的微胶囊，比较它们在IP注射后诱导血浆抗毒素应答的能力。在此次研究中，微胶囊的抗原释放速率是两种机理的函数：通过外壁基质上孔的扩散及外壁基质的水解(生物腐蚀)。批号为#605-026-1和#514-140-1的产品具有不同的穿过孔的初始释放速率，第二阶段的释放则是其通过水解而降解的函数。与此相反，批号为#697-143-2和#928-060-00的产品具有紧密而均匀的外壁基质，很少有穿过孔的释放，它们的释放基本上是外壁水解速率的函数。然而，后两批产品中组成微胶囊的丙交脂与乙交酯的比例不同，85∶15DL-PLG对水解具有更大的抗性，这导致类肠毒素的释放速率更慢。
由批号为#605-026-1(48小时时释放60％)的产品诱导的免疫应答在第20天达到峰值为6400的IgG滴度(表10)。批号为#514-140-1的产品(在48小时时释放30％)刺激的IgG抗体也在第20天达到峰值，但在第20和30天所出现的浓度更高。
用批号为#697-143-2的产品(在48小时时释放10％)进行免疫，结果是在第30和45天达到IgG抗体的峰值水平，而且比早期释放的任一批号所诱导的都高得多(102,400)。通过用丙交酯与乙交酯比例为85∶15来进一步延迟抗原释放速率，批号为#928-060-00(在48小时时释放0％)的产品，将峰值抗体水平延迟到45和60天，但没有观察到进一步的免疫增强作用。
这些结果与延迟和维持抗原释放能刺激更高的抗体应答是一致的。然而，由这些不同微球体诱导的应答模式的某些方面表明，贮存效应并不是免疫增强的唯一机理。初始释放愈快，则峰值抗体滴度愈低。此结果与下面的模式是一致的：即在最初48小时内通过越孔扩散释放的抗原，其效应并不比施用可溶性抗原更强。显著延迟释放的启动，使得巨噬细胞有时间含噬微球体，因此能对抗原进行有效的处理和展示，而所产生应答的高度由传至展示细胞中的抗原量确定。然而，如果抗原释放的延迟越过了所有抗原都传至展示细胞中的时间点，则不会使应答导致进一步增强，而只会延迟峰水平。2．在一次性注射后疫苗按预定加强方式由微胶囊的搏动释放
当一个人通过注射接受若干疫苗中的任一种时，为了诱导出良好的免疫应答，还需要施用2到3次或更多次疫苗。一般说来，第一次注射是为了提供初级应答，第2次注射是为了提供次级应答，第3次注射是为了提供三级应答。需要进行多次注射，因为为了刺激很强的免疫应答，需要使抗原与免疫系统细胞进行重复的作用。因此，病人在接受第一天疫苗注射后，他为了得到保护作用，就必须多次回到医生那儿接受第二次、第三次及其后的注射，而病人却经常再也不回到医生那儿去接受继后的注射。
注射入患者体内的疫苗制剂可能由抗原和佐剂组成。例如，可使抗原与明矾结合。在第一次注射时，使用抗原/佐剂结合物是很重要的，因为佐剂能帮助刺激免疫应答。在第二次和第三次注射时，抗原的施用将改善身体对抗原的免疫应答。但在第二次和第三次以及随后的施用中，不一定需要佐剂。
Alza Corporation描述了为刺激免疫应答而使抗原和免疫增强剂(佐剂)持续释放的方法(US4455142)。本发明与Alza的专利至少在两个重要的方面不同。首先，不需要免疫增强剂来提高免疫应答，第二，抗原并不是从传递系统中持续释放。
本发明涉及将疫苗(抗原)配制于微胶囊中(或微球体)，从而使抗原囊包在可生物降解的聚合物中，例如聚(DL-丙交酯-共-乙交酯)。更具体地说，制备了不同的微胶囊疫苗，然后将它们混合在一起，使得注射一次本发明的胶囊疫苗混合物，就能改善初级免疫应答，然后在后面的时间点上以搏动方式释放抗原，以产生二级、三级及其后的应答。
微囊混合物由小的和大微囊组成。小的微囊小于10微米，优选小于5μm，最好选1-5μm，它们能增强初级应答(不需要佐剂)，因为小微囊能有效地被巨噬细胞识别和摄取。然后，巨噬细胞内的微囊释放抗原，这些抗原随后被加工并展示于巨噬细胞的表面，以产生初级应答。较大的微囊大于5μm，最好大于10μm，但不能大到不能通过例如注射施用的地步，最好小于250μm，它们用不同的聚合物制备，使得它们以不同的速率被生物降解，并因此以搏动方式释放抗原。
根据本发明，用于初级应答的抗原微胶囊组合物基本上与用于二级、三级及随后应答的抗原微囊组合物一样。也就是说，抗原被囊包在同一类的可生物降解的聚合物中。抗原微囊的大小和博动释放性质然后使针对抗原的免疫应答达到最强。
优选的可生物降解的聚合物是那些降解速率可仅仅通过改变其单体比例就能变化的聚合物，别如，聚(DL-丙交酯-共-乙交酯)，使得用于二级应答的抗原微囊比用于随后的抗原微囊生物降解更快，以提供抗原的搏动释放。
总之，通过控制由基本相同组合物组成的微囊的大小，能够使针对抗原的免疫应答达到最强。另一重要的问题是，抗原微囊混合物中应具有一些小的微囊(小于10μm的微囊，最好小于5μm，以1-5μm为好)，以使初级应答达到最强。使用具有免疫增强作用的传递系统，例如小的微囊，在企图诱导针对免疫原性较低的化合物的免疫应答时更为重要，这些化合物有例如杀死的疫苗、亚基疫苗、低分子量疫苗如肽等等。实例1共同施用游离和微胶囊化的疫苗
研究了一株日本脑炎病毒疫苗(Biken)。所用病毒是大阪大学微生物疾病研究基金会(Suita,Osaka,Japan)的产品。生产者推荐了一种三剂量的免疫系列法，疫苗的2次剂量以1-2周的间隔施用，第三次剂量在第1次免疫1个月后施用。我们对用日本脑炎(JE)疫苗采取标准的三剂量法对小鼠免疫后的抗病毒免疫应答，和一次性施用由一份未包囊疫苗和两份包囊疫苗组成的JE疫苗对小鼠免疫的抗病毒应答作了比较。JE微囊大于10μm。通过ELISA检测法，检测针对JE疫苗的血清抗体滴度。从而比较通过这两种方法用JE疫苗免疫小鼠的结果。ELISA法能通过JE疫苗组分的特异性检测血清抗体的存在与否，但它不能检测血清中的中和病毒的抗体水平。因此，通过病毒细胞致病效应(CPE)抑制检测法和病毒噬斑减少检测法测定抗体的病毒中和活性。在此给出了这些检测结果。
对四个实验组进行了研究，该四个实验组由下述组成：(1)未接受免疫的未处理对照小鼠；(2)在第0天接受3.0mg JE疫苗(未包囊)的小鼠，(3)在第0、14和42天接受3.0mgJE疫苗(未包囊)的小鼠(标准程予)、(4)在第0天接受3.0mg JE疫苗(未包囊)和3.0mg JE疫苗(胶囊化)的小鼠。未处理对照组提供了免疫动物可与之作比较的病毒中和滴度的背景，在第0天接受一次3.0mg剂量JE疫苗的动物也提供了中和滴度的背景，接受未包囊及包囊疫苗的动物可与之进行比较。这种比较提供的证据表明：包囊疫苗的施用扩大了单独一次3.0mg剂量的未包囊疫苗的免疫能力。接受3次剂量的未包囊疫苗的动物所提供的对照，包囊疫苗组可与之进行比较，从而确证由未包囊和包囊组成的疫苗单独一次注射，能产生与标准的三剂量免疫法差不多的活性。
在第21,49和77天从每个实验组的10只动物中抽取血清样品，测试它们对于JE病毒的标准攻击(100TCID50)诱导的细胞致病效应的抑制能力。表11给出了CPE抑制检测法的结果，以能够抑制50％病毒CPE的最高血清稀释度表示。如表中所示，在任一测试点上，未处理的对照动物(第一组)的血清没有显著的病毒中和活性。在0天接受单独一次3.0mg剂量JE疫苗的10只动物(第2组)中，有一只没有产生任何可测出的病毒中和抗体。剩下的九只小鼠中，选到的最高滴度是254，这是在第49天达到的。这一实验组在第49天的抗病毒滴度的几何平均值达到最高峰。在接受了剂量疫苗标准免疫的10只动物中(第3组)，有8只在第49-77天的抗体活性降低。在第40-77天，这一组滴度的几何平均值下降了50％以上。接受包囊JE疫苗的所有10只动物(第4组)都产生了血清抗病毒活性。在第21-77天，这一组的滴度的几何平均值上升。这一组在第49天达到的平均滴度比第3剂量疫苗组(第3组)低得多(P=0.006)；然而，滴度在第49-77天持续上升，这一点与3剂量疫苗组刚好相反。在第77天的样品中，这两组的平均滴度没有显著差别(P=0.75)。这一现象表明，包囊疫苗组在第77天达到的血清抗病毒滴度可与之比拟。与3剂量疫苗组(第3组)不同，接受包囊疫苗的动物(第4组)在所有检查的时间点上，其血清都持续表现出病毒中和活性的上升。与标准疫苗处理组相反，在第49-77天，接受包囊JE疫苗的小鼠的平均血清中和滴度上升两倍。接受微胶囊疫苗的小鼠在第21天的平均抗病毒滴度，与在0天接受单次剂量JE疫苗的小鼠在第21天的平均滴度没有显著差别(P=0.12)；然而，在第49天和77天，这两组的平均滴度有显著不同(分别为P=0.03和P=0.03)。这些数据表明，通过施用单独一次剂量的包囊JE疫苗所达到的血清病毒中和滴度，与通过标准疫苗施用法所产生的相似。虽然，本研究中采用的赋形剂制剂达到的抗病毒滴度并不象标准疫苗上升得那样快。但血清中的中和抗体活性达到的滴度确实可与用标准的三剂量疫苗法所达到的相比拟。
为了进一步证实这些结果，将每个实验组的每份等体积血清样品进行混合以得到合并的样品。将这些样品交给一个独立的实验室以测定其抗病毒活性。通过用JE病毒标准攻击的噬斑减少检测法测试这些样品。表12给出了这些测定结果，证实了上面所述的发现。虽然，接受包囊疫苗的动物达到滴度峰值不象标准疫苗组那样快，但包囊疫苗诱导的中和病毒的抗体活性确实能与之相比拟。进一步，包囊疫苗在一个更长的时间段上维持比标准疫苗更高的抗病毒滴度。这些结果进一步支持了这一结论：单次施用微胶囊化的疫苗产生的结果可与三剂量标准疫苗法产生的相比拟。实例2小于10微米和大于10微米疫苗微胶囊的共同施用
共聚物微囊传递系统的一个优点是它们能够控制所渗入物质释放的时间和/或速率。对于疫苗来说，将能够以这样的方式使抗原按计划释放，使得一次施用后达到最高的抗体应答。搏动释放是一种可以采用的释放方式，预期它能够改善针对疫苗的抗体应答(类似于传统的加强剂免疫法。
通过下述方式研究了采用搏动释放的可能性：对各组小鼠皮下施用100μg类肠毒素，实验组包括1-10μm组(50∶50DL-PLG；1.51％重量的类肠毒素)，20-125mm组(50∶50DL-PLG；0.64％重量的类肠毒素)，或前两种微胶囊的混合组，每一大小范围中所含的类肠毒素是等量的。以10天间隔对各组小鼠抽血，采用固相吸收的肠毒素，用同型特异性放射免疫检测法通过终点滴定测定血浆中的IgG应答(图1)。在施用1-10μm类肠毒素微胶囊后在第10天检测到血浆IgG应答，在笫30和40天滴度上升到最高值102,400，到第60天下降至25,600。与此相反，施用20-125μm微胶囊后，对于类毒素的应答延迟至第30天，然后在第50和60天滴度上升至51,200。同时以1-10和20-125μm微胶囊施用等量的类毒素产生的IgG应答，在最初30天基本上与单独施用1-10μm微胶囊刺激的相同。然而，从第40天起，在同时接受1-10加上20-125μm微胶囊的小鼠中测量到的应答稳步上升，在第60天的滴度达到819,200。此水平比通过单独施用这两种大小所诱导的应答之和高得多。
通过一起施用1-10和20-125μm含有类肠毒素的微胶囊得到的抗体应答，与抗原的两期(搏动)释放是一致的。第一次博动是由于组织细胞对1-10μm颗粒的迅速吞噬和加速降解导致的，由于高浓度抗原有效地进入这些副卫细胞，更有可能是由于它们的活化，从而导致增强的初级免疫应答。第二期抗原释放是由于20-125μm微胶囊的在物降解导致的，它们由于太大而不能被吞噬细胞所吞食。第二次搏动将抗原释放至已引发的宿主中，刺激一种记忆性免疫应答。因此，利用50∶50DL-PLG共聚物，能够构建一种一次注射疫苗的传递系统，它能够加强抗体应答(1-10μm微胶囊)，它还能传递一种定时的和长持继期的辅助加强剂免疫(20-125μm微胶囊)。此外，通过改变共聚物的比例，能够制备甚至更迟释放的制剂，从而能提供第三甚至第四次加强作用，而不需要额外的注射。
因此，本发明的可注射微胶囊可以通过多种途径用于接种。在这些途径中，包括多次注射小的微囊，以1-5μm的为好，它可被巨噬细胞吞食并不需使用免疫增强剂，以及游离抗原与微囊形式的微胶囊化抗原(直径为10μm或更大)的组合，前者诱导初级应答，后者通过博动抗原释放以加强二级和三级应答，从而通过一次施用提供免疫作用。另外，还可使用小微胶和大微囊的组合物，前者负责初级应答，后者负责二级及随后的应答，从而既不需要免疫增强剂，也无需进行多次注射。B口服施用疫苗微胶囊实例1．口服施用含有TNP-KLH的微球体同时诱导对TNP的循环和粘膜抗体应答
用50∶50DL-PLG作为赋形剂，制备含有半抗原化的蛋白抗原三硝苯基-钥孔血蓝素(TNP-KLH)的微胶囊。根据大小分离这些微胶囊，选择直径为1-5μm范围的进行评价。这些微胶囊含有0.2％重量的抗原。通过连续4天由胃管施用在碳酸氢盐缓冲的灭菌自来水中的0.5ml 10mg/ml的悬浮液(10μg抗原)，测定它们在吞食后作为有效的抗原传递系统的能力。为了进行比较。对另一组小鼠用0.5ml 20μg/ml未包囊的TNP-KLH溶液作平行的口服免疫。对照小鼠仅仅口服施用稀释液。
在最后免疫后的第14和28天，由每组5只绑缚小鼠中收集血清、唾液和肠分泌物。通过同型特异性的放射免疫检测法测试这些样品，测定IgM、IgG和IgA同型特异于TNP的和总的抗体的水平(表13)。唾液和肠分泌物样品中的抗体几乎全都是IgA类的。这些结果与前面的研究是一致的。并提供证据表明，用来收集这些分泌物的方法不会导致血清的污染。没有一种免疫方法显著改变任一测试体液中的总的免疫球蛋白水平。在模仿免疫的对照小鼠中，在血清中检测到天然产生的抗TNP的IgM和IgG同型抗体，在血清和肠分泌物中检测到IgA同型抗体，它们的水平虽低，但是可以检测到。然而，连续3天以相等剂量施用30μg微胶囊化的TNP-KLH后，在免疫后的第14天，在分泌物中出现大量抗原特异性的IgA抗体，在血清中出现所有的同型体(见表13最后一行)。这些抗体水平在第28天进一步上升。与此相反，口服施用同样数量的未包囊抗原，在所有的测试体液中，都不能诱导任一同型体的特异性抗体。
这些结果在好几方面值得注意。首先，在血清和粘膜分泌物中诱导出大量抗原特异性的IgA抗体，此应答在常用的全身免疫法之后是很弱或没有的。因此，可期望此免疫方法在粘膜上导致显著增强的免疫作用，而粘膜正是许多细菌和病毒病原体的入口或病理位点。第二，微胶囊化的抗原制剂在口服施用时是一种有效的免疫原，而同样量的未包囊抗原却不是。因此，微胶囊化导致效率急剧地上升，这是由于对派伊尔氏淋巴集结的定靶传递和增加摄入的结果。第三，免疫应答的诱导期似乎具有一个长的时间。虽然在无佐剂时用蛋白抗原进行全身免疫的特征是抗体在7-14天内出现峰值，但口服施用含有抗原的微胶囊诱导的应答在第28天比第14天更高。这一结果表明，外壁物质的生物腐蚀和抗原释放是在一较长的时期内一直发生的，因此，诱导的应答延缓期更长。实例2口服施用含有SEB类毒素的微胶囊同时诱导循环和粘膜的抗SEB类毒素抗体
上述结果表明：(a)微胶囊化产生了很强的佐剂活性，(b)直径小于5μm的微囊进入派伊尔氏淋巴集结后传播到隔膜淋巴和脾，这一现象提示，通过用掺入合适大小的可生物降解微胶囊中的疫苗进行口服免疫以诱导全身免疫应答是可行的。这种可能性得到如下实验的证实：用100μg可溶形式或在微胶囊(用50∶50DL-PLG作为赋形剂)中的葡萄球菌类肠毒素B对几组小鼠免疫。这些小鼠以30天的间隔三次通过胃管施用可溶性或微胶囊化的类毒素，每次免疫后第10和20天收集血浆样品。表14中的数据给出了在第一、第二和第三次口服免疫后20天的时间点上，血浆中IgM和IgG抗毒素应答的终点滴度。
接受掺入微胶囊疫苗的小鼠，在每次免疫后特异于毒素的血浆抗体呈现稳步的上升，而可溶性类肠毒素无此效果。此实验与上述表4、5和6的实验一样操作并行实验，而且使用同样批号的微胶囊产品。因此，这些数据直接证实，对于诱导血清的抗毒素应答来说，用微胶囊化的葡萄球菌类肠毒素B比以最佳剂量非肠道注射可溶性类肠毒素更加有效。
在同组小鼠中检查分泌IgA应答。这一批号的含有类肠毒素的微胶囊的特点(即其大小范围的不均一性，从小于1微米至大约10微米)，可能使得部分微胶囊固定在派伊尔氏淋巴集结中时就释放类毒素。因此，在第三次口服免疫后第10和20天，收集唾液和肠洗液样品，检测其中的毒素特异性的IgA同型抗体(表15)。与口服施用可溶性类毒素时不能激发应答相反，吞食等量的掺入在微胶囊中的类毒素疫苗，在唾液和肠分泌物二者中都能导致显著的抗类毒素的SIgA应答。应当指出，来自每只小鼠的肠分泌物在收集时稀释到总量为5ml。虽然很难确定这样稀释收集的材料其稀释因子究竟是多大，但可以有把握地假设，在围绕肠壁的粘液中，SIgA浓度至少比测定值高出10倍以上，而在本文的测定中还并未计算这一点。
这些数据清楚地证实了微胶囊化类肠毒素口服施用时在肠和较远的粘膜位点处诱导抗毒素SIgA应答的有效性。进一步，通过使用直径范围在小于1至10μm的混合微胶囊，有可能同时诱导这种粘膜应答和较强的循环抗体应答。这表明通过使用微胶囊化技术，可使大量疫苗制成更加有效而且方便施用的产品。C、气管内施用疫苗微胶囊实例1、气管内施用含有SEB类毒素的微胶囊来同时诱导循环和粘膜抗毒素抗体
类似于胃肠道中派伊尔氏淋巴集结的滤泡淋巴集结也存在于其它解剖学位置的与粘膜相关的类淋巴组织中，例如呼吸道。其功能与派伊尔氏淋巴集结相似，吸收肺膜中的物质，并作为诱导以大量SIgA为特征的抗体应答的位点。研究了通过与支气管相关的类淋巴组织进行免疫的可行性。对几组小鼠的气管中直接施用50ml.PBS.其中含有50μg微胶囊化或未包囊的SEB类毒氘在免疫后的第10、20、30和40天，收集血浆、唾液、肠洗液和支气管泡洗液样品。
检测血浆样品中的抗毒素特异性抗体揭示，施用游离的SEB类毒素不会诱导出任何同型抗体的可测出的应答(表16)。与此相反，气管由滴注等剂量微胶囊化的SEB疫苗诱导出毒素特异性的所有同型抗体。此应答在第30天达到最高水平，并一直维持到第40天。IgM、IgG和IgA的滴度分别为400,51,300和400。
与在血浆中观察到的应答相似，微胶囊化类毒素在支气管泡洗液中诱导出了毒素特异性的抗体，但未包囊的疫苗则没有(表17)。与血浆中的应答相比较，支气管分泌物中的抗毒素抗体出现的动力学有些延迟，在第20天，只测出IgG同型体的应答，而且与最终达到的最高水平比较还很低。然而，在第30天，IgG和IgA抗毒抗体达到最高滴度(分别为1280和320)，并一直维持到第40天。用此免疫法未在支气管泡洗液中检测到IgM类抗体，此结果与下述现象是一致的，即在肺中不存在分泌IgM的浆细胞，并且此大分子抗体不能通过分子量限度大约为200,000的毛细肺泡膜由血清中渗出。
这些数据证实，微胶囊化能在将抗原施用至呼吸道中以后，产生针对SEB类毒素抗原的免疫应答，而未包囊的抗原都无此效果。在循环和浸润呼吸道的分泌物二者中都可观察到这种应答。应当注意，此免疫法对于诱导出IgA类抗体是有效的。此抗体被认为是在上呼吸道中的局部合成产物，该区域不受到IgG类抗体的保护，IgG只从循环血液中进入较低的肺部。因此，通过气溶胶的吸入，用微胶囊化抗原进行气管内免疫。将是一种诱导保护上呼吸道抗体的有效方式。D．通过混合的免疫途径施用疫苗微胶囊
在人和动物中已经发明，使全身免疫与抗原的粘膜接触相结合，对于促进粘膜免疫应答来说比其他任何结合都更加有效(N.F.Pierce，布J.L.Gowans.“大鼠中针对霍乱类毒素的肠免疫应答的细胞动力学”，J.Exp.Med.142:1550,1975)。三组小鼠用100μg微胶囊化的SEB类毒素通过IP免疫引发，30天后通过IP，口服或IT途径，用100μg微胶囊化的SEB类毒素进行攻击。这项实验是为了直接确定，对于所诱导的SIgA的水平来说，用微胶囊化的抗原进行混合免疫是否更加有利。
在微胶囊化加强剂免疫后20天，收集血浆、肠洗液和支气管泡洗液样品，通过终点滴定放射免疫检测法，测定抗SEB毒素的同型抗体的水平和分布(表18)。在血浆和分泌物样品中，IP引发的小鼠通过IP加强后，出现高水平的抗毒素的IgG抗体，但对于在任何测试体液中诱导可测出的IgA抗体来说则完全无效。与此相反，通过口服或IT途径用微胶囊化的SEB类毒素作第二次免疫后，能有效地加强血浆中特异性IgG抗体的水平(每组中进行第二次免疫前的滴度是51200)，在肠和支气管泡洗液中也能诱导高水平sIgA抗体的出现。对IP诱发的小鼠进行口服加强，能诱导在肠分泌物中分泌抗SEB毒素的sIgA抗体，其水平可与需要三步口服免疫的相比拟(表18与表15相比较)。对先经IP免疫的小鼠进行气管内加强，对于诱导传播性粘膜应答尤其有效，并在支气管泡和肠分泌物两种样品中，都同时诱导高水平IgG和sIgA抗体的出现。
这些结果对于针对许多通过定位于呼吸道的急性传染而施加其病理效应的传染媒介进行免疫来说尤其重要。存在于呼吸道中的抗体来自两种不同的来源。在浸润鼻咽和支气管树的粘液中，主要成分是分泌IgA(C.A.Soutar，“正常人呼吸道中含有免疫球蛋白的浆细胞和其它细胞的分布及其中所含免疫球蛋白的类别”，Thorax31:58,1976；H.B.Kaltreider和M.K.L.Chan，“得自不同水平犬呼吸道液体中类别特异性的免疫球蛋白组成”,J.Immunol.116:423,1976)，它们是局部浆细胞的产物，这些细胞位于上呼吸道的固有层中。与鼻咽和支气管树相反，细支气管和肺泡中主要含有IgG，它是由循环血液通过渗出作用被动产生的(H.Y.Reynolds,H.H.Newball，“通过人肺的灌洗得到的蛋白质和呼吸细胞的分析”J.Lab.Clin.Med.84:559,1974)。因此，肺部的有效保护既需要循环IgG又需要粘膜sIgA抗体。
这些数据表明，对于同时诱导循环和粘膜抗体应答来说，用微囊化抗原进行混合途径免疫将证明是最有效的。虽然在本文报导的实验中，所检查的不同的引发和加强步骤都需要施用微胶囊化的抗原，但有可能使用微胶囊传递系统提供的可控制的博动释放中的灵活性，来设计单独一次施用的方法，它将同时刺激最强的全身和分泌免疫作用。例如，在一次拜访医生的过程中，就可通过注射和吞食两种途径施用微胶囊化的抗原。通过改变两种剂量中丙交酯与乙交酯的比例，全身施用的剂量在几天内就能释放以引发免疫系统，而第二(口服)剂量则在较迟的时候由派伊尔氏淋巴集结中释放，以刺激加强的粘膜应答。Ⅳ．药物的吸收
下述实例表明，小的微胶囊(小于5μm，优选1-5μm)除了抗原之外，还能改善药物至体内的吸收。苯壬四烯酯，即(AII-E)-9-(4-甲氧基-2,3,6-三甲基)苯基-3,7-二甲基-2,4,8-壬四烯酸，乙基酯)被用微胶囊包在50∶50聚(DL-丙交酯-共-乙交酯)中。微胶囊直径为0.5-4μm，含有37.2％重量的etretinate。这些etretinate微胶囊及未包囊的etretinate，用在水中的1％重量的Tween80作为载体通过口服管饲法喂给小鼠。只喂给50mg etretinate/Kg的独单一次剂量。以一定的时间间隔收集服药小鼠的血液，利用高效层析法定量测定此血液血清中的苯壬四烯酯和/或其代谢物(表19)。结果表明，用etretinate微胶囊处理的小鼠，其苯壬四烯酯的血液水平比用未包囊苯壬四烯酯处理的小鼠高很多。与小于5μm的疫苗微胶囊相似，相信此微胶囊是通过胃肠道中类淋巴组织(派伊尔氏淋巴集结)将苯壬四烯酯带到血流中去的。这一相同的方法也应当选用于提高其它药物的吸收，尤其可以发挥其作用的是传递生物药物制品，例如肽、蛋白质、核酸等等。
表1口服施药后香豆素-6 85:15 DL-PL-PLG球体穿透入并通过派伊尔氏淋巴集结
 时间     观察到(天数)    的总数           直径大小(％)小       中       大＜2um    2-5um    ＞5um 区域的大小(％)圆顶    深
    1    2962    3254    3527    19614    1421    9128    6335    52     47      35      1845      32      2346      31      2321      29      4116      29      557      27      665      24      716      19      79     92      883      1776      2488      1198      298      2100     097      3
表2口服施药后香豆素-6 85∶15 DL-PLG微球体迁移进入和通过肠系膜的淋巴结
 时间     观察到(天数)    的总数           直径大小(％)小        中        大＜2um    2-5um    ＞5um 区域的大小(％)圆顶    深
     1      82     834     977    12014     5421     2028     1535      9     50      50       076      24       073      27       067      32       083      17       075      25       067      32       044      56       0     100      095      573     2764     369     915     950    1000    100
表3在口服施药后，由与肠相关的类淋巴组织的派伊尔氏淋巴集结定靶吸收的1至10μm微球体与多种赋形剂
    微球体赋形剂     可生物降解的 由派伊尔氏淋巴集结吸收
聚苯乙烯聚甲基丙烯酸甲酯聚羟基丁酸聚DL-丙交酯聚L-丙交酯85∶15聚DL-丙交酯-共-乙交酯50∶50聚DL-丙交酯-共-乙交酯乙酸纤维素氢酞酸三乙酸纤维素乙基纤维素     不不可以可以可以可以可以不不不     很好很好很好好好好好不吸收不吸收不吸收
表4对于有微胶囊包裹的依可溶的葡萄球菌肠毒素B为转移的初级抗毒素应答
                                        血浆抗毒滴定度类毒素剂量(μg)      形式
                                            第10天第20天IgM    IgG                                  IgM    IgG100              微胶囊包裹的    1,280  320  1,280  10,24050               微胶囊包裹的      640  320  1,280   5,12025               微胶囊包裹的      320 ＜20    640   2,56050               可溶的           ＜20 ＜20   ＜20    ＜2025               可溶的            320 ＜20    160    ＜2012.5             可溶的             40 ＜20   ＜20    ＜20
表5对于有微胶囊包裹的依可溶的葡萄球菌肠毒素B为转移的次级抗毒素应答
                                        血浆抗毒滴定度
                                    第10天    第20天类毒素剂量(μg)/免疫接种             形式       IgM    IgG    IgM    IgG100              微胶囊包裹的    320  163,840  160  81,92050               微胶囊包裹的    640   81,920  640 163,84025               微胶囊包裹的  2,560   40,960  640  81,92050               可溶的          160     ＜20   80    ＜2025               可溶的          320      160  160     32012.5             可溶的          160       40   40      60
表6对于微胶囊包裹的依可溶的葡萄球菌肠毒素B为转移的第三级抗毒素应答
                                        血浆抗毒素滴定度
                                                  第10天    第20天类毒素剂量(μg)/免疫接种
                    形式        IgM    IgG    IgM    IgG100             微胶囊包裹的       1,280 655,360  640  327,68050              微胶囊包裹的       2,560 327,680  280  327,68025              微胶囊包裹的       2,560 327,680  640  163,84050              可溶的               640   1,280  640      64025              可溶的               320  10,240   80   10,24012.5            可溶的               160   1,280   40    1,280
表7由多种非肠道的免疫途径诱导的初级全身抗毒素应答
                                        血浆IgG抗毒素滴定度微胶囊包裹的类毒素剂量(μg)   免疫途径      第15天    第30天    第45天
      100                 腹膜内的    12,800    102,400   204,800
      100                 皮下的       6,400     25,600   204,800表8由多种非肠道的免疫途径诱导的次级全身抗毒素应答微胶囊包囊的类抗毒素                  血浆IgG抗毒素滴定度剂量(μg)/免疫接种      免疫途径     第15天     第30天      第45天100                     IP-IP      819,200   1,638,400  3,276,800100                     SC-SC      409,600   819,200    3,276,800表9微球体不具有内在的佐剂活性
                                       血浆抗毒素滴定度类毒素剂量
                  形式        第10天       第20天         第30天(μg)
                             IgM    IgG  IgM    IgG   IgM     IgG25            在微球体中的抗原 6,400  6,400  400  12,800   800  25,60025            水溶的抗原         800   ＜50  200     800   100    ＜5025            抗原加无效剂微球体 800   ＜50  200    ＜50   200      50表10由非肠道的免疫作用μm微球体以不同速度释放的抗原诱
导的全身抗毒素应答类毒素                  丙交酯/乙   在48小时    血浆IgG抗毒素滴定度(所在天数)。剂量(μg)      形式     交酯比率    释放的抗原  10     15         20      30       45     60100           可溶的      --         --        ＜50   ＜50       ＜50    ＜50     ＜50  ＜50100           微球体    50∶50      60％        400   --        6,400    3,200    --     --100           微球体→  50∶50      30％        400   --       12,800    6,400    --     --100           微球体    50∶50      10％        --    6,400      --    102,400 102,400  51,200100           微球体    85∶15       0％        --    3,200      --     51,200 102,400 102,400表11从JE疫苗免疫研究中得到的在血清样本上CPE抑制作用测定的结果
                      可减少50％病毒诱导的CPE
                      的血清稀释剂(所在天数)动物               21               49               77第1组-未处理的对照物GMTa           ＜10               11               11平均值           ＜10               11               11最大值           ＜10               16              ＜20最小值           ＜10             ＜10              ＜10第2组=3.0mg未包胶囊的JE疫苗IP(在第10天)GMT               44               73                50平均值             55               95                71最大值            127              254               160最小值           ＜10               13              ＜10第3组=3.0mg未包胶囊的JE疫苗IP(在第0、14和42天)42GMT               507            3,880             1,576平均值            934            5,363             2,951最大值          4,064         ＞10,240          ＞10,240最小值            160              806               254第4组-3.0mg未包胶囊的+3.0mg包微胶囊的JE疫苗IP(在0天)GMT                77              718             1,341平均值            803            1,230             2,468最大值            320            5,120            10,240最小值             13              160               254aGMT=几何平均滴定度表12由JE疫苗免疫研究中在汇集的血清样本上进行的空斑-减数测定得到的结果血清稀释至组别   处理     天数    50％终点    80％终点1a   对照物     0        ＜10         ＜101     对照物    14        ＜10         ＜101     对照物    21        ＜10         ＜101     对照物    42        ＜10         ＜101     对照物    49        ＜10         ＜101     对照物    84        ＜10         ＜102b未包胶囊的JE  0        ＜10         ＜102  未包胶囊的JE 14         160           202  未包胶囊的JE 21         NDC          ND2  未包胶囊的JE 42         320           802  未包胶囊的JE 49         320           402  未包胶囊的JE 84         640          1603d未包胶囊的JE  0        ＜10         ＜103  未包胶囊的JE 14         160           403  未包胶囊的JE 21       2,560          6403  未包胶囊的JE 42       1,280          6403  未包胶囊的JE 49       5,120        2,5603  未包胶囊的JE 84       2,560        1,2804e包微胶囊的JE  0        ＜10         ＜104  包微胶囊的JE 14         160           204  包微胶囊的JE 21         320           804  包微胶囊的JE 42       5,120          6404  包微胶囊的JE 49       5,120          6404  包微胶囊的JE 84      10,000        2,560a未处理的对照物b在0天接受3.0mg未包胶囊的JE疫苗IP的动物cND=未测定的(样品量不足)d在0.14和42天接受3.0mg未包胶囊的JE疫苗IP的动物e在0天接受3.0mg未包胶囊的和3.0mg微胶囊的JE疫苗IP的动物。表13通过用微胶囊的TNP-KLH的口服免疫作用诱导在BALB/C小鼠血清粘膜分泌物中的TNP-特异抗体
                                                          通免疫球蛋白/ml样本
          免疫作用                             IgM                IgG              IgA免疫原        后的天数       生物样本        总数      抗-TNP    总数    抗TNP    总数    抗TNP对照物        14天           洗肠液            ＜1      ＜1         62   ＜1     79,355    25
                         唾液             ＜40     ＜10       ＜40  ＜10      2,651  ＜10
                         血清          445,121        6  5,503,726    37  1,470,553   32未包胶囊的    14天           洗肠液              4        1        131   ＜1     64,985    17TNP-KLA                      唾液             ＜40     ＜10       ＜40  ＜10      1,354  ＜10
                         血清          298,733       11  6,000,203    29  1,321,986   21TNP-KLH       14天           洗肠液              3      ＜1        130   ＜1     95,368   222微胶囊
                         唾液             ＜40     ＜10       ＜40  ＜10      1,461    88
                         血清          360,987    1,461  5,312,896   572  1,411,312 1,077未包胶囊的    28天           洗肠液            ＜1      ＜1         94   ＜1     88,661     64TNP-KLA                      唾液             ＜40     ＜10       ＜40  ＜10      1,278  ＜10
                         血清          301,223       21  5,788,813    67  1,375,322    63TNP-KLH       28天           洗肠液              4      ＜1        122     2     82,869   422微胶囊                       唾液             ＜40     ＜10       ＜40  ＜10      1,628    130
                         血清          320,192     1,904 5,951,503  2,219 1,277,505 1,198表14在用可溶的或微胶囊的(50∶50 DL-PLG)葡萄球菌类毒素的初级次级和第三级口服免疫作用之后第20天的血浆IgM和IgG抗毒素水平
                             在口服免疫  作用之后第
                             20天的血浆抗毒素滴定度肠类毒素剂量               初级          次级         第3级(μg)/免疫样种   形式     IgM   IgG    IgM   IgG     IgM    IgG100              微球体    80 1,280    320 5,120    1,280 40,960100              可溶的  ＜20  ＜20    80   ＜20      640   ＜20第15在用可溶的或包微胶囊的肠内类毒素的口服免疫作用的第三级口服免疫作用之后的第10和20天在小鼠唾液和肠液中的毒素一特异IgA抗体在第3级口服免疫作用之后的IgA-肠内毒素的滴定度肠类毒素剂量                  10天            20天(μg)/免疫接种  形式    唾液    洗肠液    唾液    洗肠液100             微球体  1,280   1,024     640      256100             微球体     40     ＜8      10      ＜8
            可溶的第16通过用可溶的或包微囊的葡萄球菌肠毒素B的类毒素的气管内免疫作用诱导的血清抗毒素抗体水平
                              在气管内免疫作用之后的下列天数的血浆抗素毒滴定度肠类毒素                          10                20          30                      40剂量(μg)        形式       IgM   IgG   IgA   IgM   IgG   IgA   IgM   IgG   IgA   IgM   IgG  IgA50              包微囊的   ＜50  ＜50  ＜50   200 25,600  400   400 51,200  400   400 51,200 40050              可溶的     ＜50  ＜50  ＜50  ＜50   ＜50 ＜50  ＜50   ＜50 ＜50  ＜50   ＜50＜50表17通过用可溶的或包微胶囊的葡萄球菌肠毒素B的类毒素气管内免疫作用诱导的支气管一肺泡的洗涤物抗体水平
                                气管内免疫作用之后在下列天数支气管
                                     肺泡的洗涤物抗毒素滴定度肠内类毒素                        10                20              30             40剂量(μg)          形式    IgM   IgG   IgA   IgM   IgG   IgA  IgM  IgG  IgA  IgM  IgG  IgA50           包微胶囊的    ＜5   ＜5   ＜5   ＜5    80   ＜5  ＜5 1,280 320  ＜5 1,280 32050           可溶的        ＜5   ＜5   ＜5   ＜5   ＜5   ＜5  ＜5   ＜5 ＜5  ＜5   20   50表18应用包微胶囊的SEB类毒素的免疫作用原始记录通过混合途径在多种生物流体中诱导的抗-SEB毒素抗体的应答
                              在次级免疫作用之后第20天的抗毒素滴定度免疫的途径
       包微胶囊的SEB毒素      血浆           洗肠液          洗支气管液初级   次级  剂重(μg)/免疫接种 IgM    IgG     IgA   IgM   IgG   IgA   IgM   IgG     IgA1P     1P          100        3,200 1,638,400 ＜50  ＜20 10,240 ＜20   ＜5  10,240   ＜51P    Oral         100        1,600   204,800 ＜50  ＜20   640  640    ＜5   2,560 1,2801P    1T           100        1,600   819,200 ＜50  ＜20  2,560 2,560  ＜5  20,480 2,560表19在用包微胶囊的和未包胶囊的Etretinate口服投药之后在小鼠血清中的Etretinate的浓度
                                   Etretinate浓度，ng/mL次数/小时               微胶囊                未包胶囊的药物1                       4,569                         1913                         634                         1586                         242                        ＜3124                        ND                           NDND=未检测

Claims (28)

1．配制一种激发免疫功能的组合物的方法，该方法包括将治疗有效量的一种激发免疫功能的生物活性剂，用可生物相容的赋形剂包裹成其大小为1至10微米的微胶囊。
2．根据权利要求1的方法，其中所说的生物活性剂是一种淋巴因子。单核因子或细胞因子
3．根据权利要求1的方法，其中所述的生物活性剂是一种抗原。
4．根据权利要求1的方法，其中所述的生物活性剂是一种免疫调节剂。
5．根据权利要求1的方法，其中所述的生物活性剂包含一种佐剂。
6．根据权利要求1的方法，其中所述的生物活性剂是一种病毒抗原、细菌抗原、原生动物抗原或一种真菌抗原。
7．根据权利要求1的方法，其中所述的生物活性剂是一种流感抗原、呼吸合胞体抗原、副流感病毒抗原、百日咳博德特氏菌抗原、淋病奈瑟菌抗原、肺炎链球菌抗原、镰状疟原虫抗原、蠕虫病原体抗原或对抗变态反应接种的抗原。
8．根据权利要求1的方法，其中所述的生物活性剂是一种流感病毒或葡萄球菌肠毒素B。
9．根据权利要求1的方法，其中所述的生物活性剂是一种细胞素和一种佐剂的混合物。
10．根据权利要求1的方法，其中所述的细胞活性剂是一种肽、蛋白质或核酸。
11．根据权利要求1的方法，其中所述的微胶囊的大小是由5微米至10微米。
12．根据权利要求1的方法，其中所述的微胶囊的大小是由1微米至5微米。
13．根据权利要求1的方法，其中所述的微胶囊的大小是由5微米至10微米，以及其中所述的生物活性剂是一种抗原。
14．根据权利要求1的方法，其中所述的微胶囊的大小是由1微米至5微米以及其中所述的生物活性剂是一种抗原。
15．根据权利要求1的方法，其中所述的可生物相容的赋形剂是聚(丙交酯-共-乙交酯)、聚(丙交酯)、聚(乙交酯)、共聚草酸酯、聚己内酯、聚(丙交酯-共-己内酯)、聚(酯酰胺)、聚原酸酯、聚(β-羟基丁酸)或聚酸酐。
16．根据权利要求1的方法，其中所述的微胶囊包括大多数其大小为1至5微米的第一种微胶囊和其大小为5微米至10微米的第二种微胶囊。
17．配制一种激发免疫功能的组合物的方法，该方法包括将治疗有效量的具有其大小为1至10微米并含有一种激发免疫功能的生物活性剂的第一种生物可相容的微胶囊和具有其大小为5至250微米并含有一种激发免疫功能的生物活性剂的第二种可生物相容的微胶囊相混合，所述的第二种微球体能够以博动方式释放药剂。
18．根据权利要求17的方法，其中所述的第一种微胶囊具有的大小为1微米至5微米之间。
19．根据权利要求18的方法，其中所述的第二种可生物相容的微胶囊具有的大小是10微米至250微米之间。
20．配制用于增加口服生物药效率的组合物的方法，该方法包括将治疗有效量的一种药物用一种可生物相容的赋形剂包裹成具有1至10微米大小的微胶囊。
21．根据权利要求20的方法，其中所述的药物是一种肽、蛋白质或核酸。
22．根据权利要求20的方法，其中所述的微胶囊的大小是由5微米至10微米。
23．根据权利要求20的方法，其中所述的微胶囊的大小是由1微米至5微米。
24．根据权利要求20的方法，其中所述的可生物相容的赋形剂是聚(丙交酯-共-乙交酯)、聚(丙交酯)、聚(乙交酯)、共聚草酸酯、聚己内酯、聚(丙交酯-共-己内酯)、聚(酯酰胺)、聚原酸酯、聚(β-羟基丁酸)或聚酸酐。
25．配制一种增加口服的生物药效率的组合物的方法，该方法包括将治疗有效量的一种营养素用一种可生物相容的赋形剂包裹成具有1微米至10微米大小的微胶囊。
26．根据权利要求25的方法，其中所说的胶囊所具有的大小范围是5微米至10微米。
27．根据权利要求25的方法，其中所说的胶囊所具有的大小范围是1微米至5微米。
28．根据权利要求25的方法，其中所说的生物相容的赋形剂是聚(丙交酯-共-乙交酯)，聚(丙交酯)，聚(乙交酯)，共聚草酸酯，聚乙内酯，聚(丙交酯-共-己丙酯)，聚(酯酰胺)，聚原酸酯，聚(β-羟基丁酸)或聚酸酐。
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