CN1136918A - 一次注射疫苗的配制品 - Google Patents
一次注射疫苗的配制品 Download PDFInfo
- Publication number
- CN1136918A CN1136918A CN96102728A CN96102728A CN1136918A CN 1136918 A CN1136918 A CN 1136918A CN 96102728 A CN96102728 A CN 96102728A CN 96102728 A CN96102728 A CN 96102728A CN 1136918 A CN1136918 A CN 1136918A
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- Prior art keywords
- microgranule
- antigen
- mixture
- preparation
- core granule
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Abstract
一种微粒,其颗粒大小为0.5至300μm,它是通过用水溶性物质包裹抗原或抗原混合物以得到核心颗粒,再用可生物降解的聚合物包裹核心颗粒而制备的;一种一次注射疫苗配制品,它是通过将微粒分散到注射介质中制备的。
Description
本发明涉及微粒,其颗粒大小为0.5至300μm,相继用水溶性物质和生物降解性聚合物包裹抗原或抗原混合物即可制备之;本发明还涉及疫苗的配制品,它是通过将微粒分散到注射介质中制备的,由于它可在一段时间内,如几个月内延缓释放抗原,因此仅仅施予一次注射即可完成抗传染病的免疫接种作用(“一次注射疫苗的配制品”)。
迄今为止开发了大量能有效防治多种传染病的疫苗,然而大多数目前使用的疫苗都需要多次接种,这种需要给疫苗使用者带来了经济上的负担和不方便(M.T.Agoado and P.H.Lambert,Immunobiol.,184,113(1992);Aryward,B.,et al.,Vaccine.12.1155(1994)).尤其是已发现那些接受第一次接种的人当中仅有约30%返回接受第二次接种。因此当规定要接种三次时,经统计100个人当中仅有9人完成了免疫接种过程,这可清楚地阐明对通过一次注射接种即可完成免疫接种的疫苗的需要。
一次注射疫苗开发的现有技术方法基本上集中于使用微粒的思路,其中所需抗原被可生物降解的聚合物质包裹,此微粒在规定的时间期间内缓慢释放抗原以完成接种(R.Langer and J.Folkman,Nature.263.797(1976))。
在多种可生物降解的聚合物中,通常已知聚交酯(PLA)、聚乙交酯(PGA)、和聚(交酯一共-乙交酯)(PLGA)是安全的,因为它们在活体内经水解可成为无毒的乳酸和乙醇酸。已将那些聚合物用于制备缝线,手术后无需将之除去;也可用于配制经包裹的Leuprolide乙酸盐,其是一种促黄体素释放激素(LHRH)类似物,经食品与药品管理署(FDA)的允许可将它们供人使用(R.Langer and M.Mose. Science.249.1527(1990);D.K.Gilding and A.M.Reed.Polymer,20.1459(1979);and William Morris.et al.,Vaccine.12.5(1994)).这些聚合物降解速率随乙交酯/交酯的比率及其分子量的不同而不同,因此通过调节聚合物的分子量和乙交酯/交酯的比率以及颗粒的大小、胶囊配制品的包裹厚度即可使药物的释放在几个月内得以维持(S.J.Holland,et al.,J.Control.Rel.,4.155(1986))。
1988年以来,世界卫生组织(WHO)已发起大量研究以开发使用上述可生物降解的聚合物的破伤风类毒素的一次注射疫苗(M.T.Aguado,Vaccine,11,596(1993);Proceed.Intern.Symp.Control.Rel.Bioact.Mater.2lst.Controlled ReleaseSociety,Inc.,Y.Men.etal.,Paper No.126(1994);20th.B.Gander.et al.,Paper No.135(1993);19th.A.M.Hazrati.et al.,Paper No.220(1992);21st. M.Gilley.et al.,Paper No.218(1992);21st.ManmohanSingh.et al.,Paper No.1476(1994);21st.C.Yan.et al.,Paper No.127(1994)).
然而尽管作出这些努力,仍没有将一次注射疫苗的配制品投入实际应用,这主要是由于以包裹的配制品所形成的抗体的量仅约为经常规明矾配制所产生抗体量的1/10,而且结果不能再现(R.E.Spier.Vaccine.11.1450(1993);M.T.Aguado and P.H.,Lambert.Immunobiol.,184.113(1992))。已观察到这些问题的起因是:首先,用于溶解可生物降解的聚合物的有机溶剂通过使抗原变性而使抗原的抗原性降低或丧失;第二,当与水接触时,抗原形成了抗原性有所降低的凝聚体;第三,由于抗原和疏水的可生物降解的聚合物之间不必要的相互作用使得抗原性降低或丧失。
Alonso等人通过用PLA和PLGA包裹破伤风类毒素制备了一次注射疫苗,但由于在包裹过程中不可避免地将类毒素与有机溶剂相接触,因此发现在疫苗颗粒中保持的破伤风类毒素的抗原性仅为原始抗原性的0.5至20%(Maria.J.Alonso.et al.,Vaccine.12.229(1994))。在使用大鼠的实验中,这种疫苗的配制品显示了比使用明矾作佐剂不加强免疫的对照要低很多的抗体形成能力,这表明这种疫苗配制品作为一次注射疫苗是不可行的。Schwendeman等人通过对破伤风类毒素进行化学修饰,即通过将抗原的巯基S-烷基化来努力解决上述问题,但结果并不令人满意(S.P.Schwendeman.et al.,Proceed.Intern.Symp.Control.Rel.Bioact.Mater.,21st.Paper No.128.1994)。
Nellore等人报道了乙肝病毒一次注射疫苗的配制品,其包括微粒,此微粒是通过使用包括有机溶剂抽提或蒸发的方法用PGA包裹乙肝表面抗原(HBsAg)来制备的(R.V.Nellore.et al.,J.Parenteral Science & Technology.46.176(1992))。使用豚鼠的动物实验表明含有大小为1至10μm的较小颗粒的配制品显示出的抗体形成能力比使用明矾作佐剂不经加强免疫的对照要低很多,而颗粒大小为20至60μm和1至60μm的其它配制品基本上没有活性。在这些配制品中,包裹过程中使用的有机溶剂使HBsAg变性。
因此,为了通过用可生物降解的聚合物包裹抗原来制备有效的一次注射疫苗,人们必须使用在包裹步骤中不需要使用有机溶剂的可生物降解的聚合物,或者在包裹过程中必须防止抗原与有机溶剂接触。然而,还没有已知的不需要使用有机溶剂的可生物降解的聚合物。
典型地,已通过用可生物降解的聚合物包裹有机的、肽或蛋白质药物制备微粒。特别地,通过将药物溶解或分散于其中溶解了可生物降解的聚合物的有机溶剂中,并在表面活性剂的存在下将油相分散于水相中制备油-水(“O/W”)乳浊液即可制备油相。然后,使用如蒸发或抽提的常规方法除去有机溶剂,使生物可降解的聚合物固化即可得到微粒。在此过程结束时,药物分散于聚合物基质中而存在,所得微粒以于溶解有表面活性剂的水相中的分散相而存在。然而,此常规方法的缺点是:大多数可生物降解的聚合物易于被水水解;通常表面活性剂不适于注射,因此必须通过洗涤过程除去;洗涤过程之后此颗粒必须经受干燥过程以防止聚合物降解。
在此O/W乳浊液方法中,药物直接与有机溶剂接触,因此此方法不能被用来制备含接触有机溶剂后抗原性会降低的抗原的疫苗配制品。另外,此方法还有其它局限性,即不能用于水溶性药物。随后,开发的努力就转移到发现一种使用W/O/W乳浊液以克服上述困难的方法上。
例如,欧洲专利申请No.87309286.0公开了口服疫苗的配制品,它包含10μm或更小的颗粒,此颗粒是通过用PLA、PGA、PLGA等包裹多种抗原而制备,已知它可穿过Peyer氏小膜片。
另外,欧洲专利申请No.88302940.7公开了一种注射配制品,其通过用如PLGA的可生物降解的聚合物包裹如LHRH类似物的肽或蛋白质药物可使其在6个月的期间内保持其功效。更特别地,可如此制备微粒:将药物溶解或分散于水相;将水相与溶解有可生物降解聚合物和表面活性剂的有机溶剂混合以得到W/O乳浊液;将W/O乳浊液分散到含有表面活性剂的水相中以得到W/O/W乳浊液;然后除去有机溶剂即可制备得到含有药物的微粒。
根据此方法,药物与有机溶剂的接触相对于O/W乳浊液法而言有所降低。然而,不能防止内部水相和外部水相之间某种程度的混合,它可导致疫苗抗原性的降低。此外,除去表面活性剂的洗涤过程之后,通常要使用如冻干法的常规方法除去内部水相中的水。在此除去水的过程中,在生物聚合物层中会形成许多大孔,如果是包裹疫苗,这些孔在人体中会成为水通道,促进了抗原凝聚体的形成,与之相随的是抗原性的损失。
为了克服上述缺点,国际专利申请公开No.WO93/07861中公开了制备多相颗粒的方法,它包括:使用高度粘稠的食用油制备W/O/W乳浊液;用如PGA、PLA和PLGA的可生物降解的聚合物的乙腈溶液代替外部水相;将得到的乳浊液分散于矿物油;除去乙腈即可得到多相颗粒,其中W/O微乳被包裹在固体聚合物外壳内。然而,此方法的缺点是:它不可能从制备好的多相颗粒中除去如单硬脂酸铝和Spam80的表面活性剂,该表面活性剂是用来增加食用油的粘性和分散稳定性以防止药物从内部水相释放到外部水相中;在温度升至140℃以促进乳浊液分散的过程中药物会损失其抗原性。
相分离法(J.C.Wu et al.,J.Microencapsulation.11(3).297-308(1994))。包括将聚合物溶解到第一溶剂中;在其中加入不会溶解聚合物但可与第一溶剂混合的第二溶剂;因此得到核心-外壳型微粒,此微粒是因为聚合物溶解性降低,药物周围的聚合物固化而形成的。然而此方法与O/W乳浊液法一样不能防止抗原与第二有机溶剂接触。
另一个与使用乳浊液的上述方法相关的问题是蛋白质药物的活性可能会损失。正如在高能量的分散过程中一样机械外力使蛋白质易于变性。考虑到大多数抗原是蛋白质这就是一个严重的问题。
另一方面,喷雾干燥法(B.Gander et al.,J. Microencapsulation.12(1).83-97(1995))包括将药物溶解或分散于溶有可生物降解的聚合物的有机溶剂中,喷雾干燥此混合物以得到微粒。然而此方法也不能避免药物与有机溶剂的直接接触。
国际专利申请公开No.WO 94/12158和美国专利No.5,019,400建议用冷冻-和-抽提法制备经包裹的蛋白质药物(生长激素)颗粒。在此方法中,药物被分散于溶有可生物降解的聚合物的有机溶剂中(如二氯甲烷),将溶液喷射进低温液气中可形成冷冻颗粒。这些颗粒被收集到冷冻乙醇的表面,当冷冻乙醇熔化时,冷冻颗粒也在融化,颗粒中的有机溶剂被乙醇抽提,因而形成了被固化聚合物包装的微粒。此方法也使得抗原与有机溶剂直接接触,药物的释放期间仅为几天。因此,此方法不适于制备应在更长期间内释放抗原的一次注射疫苗。
国际专利申请公开No.WO 92/14449中公开了制备含有蛋白质药物的颗粒的方法,它包括:将粉末状蛋白质药物分散到熔化的脂肪酸酸酐中,冷却混合物以使混合物固化,粉碎此混合物以得到颗粒。脂肪酸酸酐在45至75℃的温度下熔化,这不象常规的有机溶剂会使蛋白质变性。然而在此过程中使用脂肪酸酸酐作为包裹材料难以得到颗粒大小适于注射的微粒。另外脂肪酸酸酐自身不能在长时间内释放药物,因此不适于用来制备一次注射疫苗配方。
欧洲专利申请No.88113933.1教导了包裹颗粒的配制,它是为蛋白质药物,除莠剂或肥料释放的零级或二相模式设计的,它是按下述方法制备的:用有吸收性的聚合物包裹药物、除莠剂或肥料,用聚合物再次包裹所得颗粒,此聚合物不能溶于水中但可穿过药物、除莠剂或肥料。然而在第二次包裹中所用的不溶于水的聚合物,即纤维素不是可生物降解的聚合物,它以不可控制的方式在仅一天的期间内释放药物。另外,此颗粒以水快速渗透进人体,因此,如果药物是抗原,通过形成凝聚体会损失其抗原性。而且,此方法不适于制备用于注射的微粒,因为第一次包裹的颗粒大小为125至10000μm,第二次包裹不得不厚到足以可防止因第一次包裹所用的吸水性聚合物的膨胀而引起的颗粒破裂。
如上所述,已有很多开发制备一次注射疫苗方法的尝试,此方法可避免蛋白质药物与有机溶剂,可生物降解的聚合物以及人体中水之间不必要的相互作用。除了这些努力之外仍未发现在包裹抗原的过程中能充分保护抗原之抗原性的方法;因此对开发一次注射疫苗配制品的需要持续存在(William Morris.et al.,Vaccine.12.5(1994))。
因此,本发明的目的是提供含有被聚合物包裹的完整抗原或抗原混合物的微粒。
本发明的另一目的是提供由微粒分散到注射介质中制备的一次注射疫苗配制品。
根据本发明,提供了平均颗粒大小为0.5至300μm的微粒,它是通过相继用水溶性物质和可生物降解的聚合物包裹抗原或抗原混合物而制备的;将微粒分散到注射介质中可制备一次注射疫苗配制品,仅注射一次该配制品即可完成抗传染病的免疫接种。
当结合图1理解,从本发明下列描述中可明显看出本发明的上述和其它的目的和特征,图1显示了颗粒特性和抗体形成之间的关系,其中根据本发明制备的三个疫苗配制品与常规的明矾配制品进行了比较。
本文提及的所有参考文献全都列入参考文献中。
通过使用水溶性物质覆盖抗原以得到粉末状颗粒(“核心颗粒”),再用疏水的可生物降解的聚合物覆盖核心颗粒以得到最终的微粒即可制备本发明的微粒。微粒呈大小为0.5至300μm的球形或椭球形。仅通过一次注射即可完成接种的一次注射疫苗配制品可经过将微粒分散到注射介质中制备。
可用于本发明的合适抗原是减毒、灭活或重组抗原,它可被用作一种疾病的疫苗(“单一抗原”)或同时用作两种或多种疾病的疫苗(“混合抗原”)。混合抗原可以是两种或多种抗原的混合物,或者是同时具有两种或多种疾病的抗原性的抗原,例如重组蛋白质。作为抗原,可以使用整个生物体,如完整的病毒或细菌细胞,或者使用生物体的一部分,如具有抗原性的某个蛋白质。
本发明举例说明的抗原包括肝炎、白喉、水痘、伤寒、百日咳、破伤风、结核、沙门菌病、霍乱、HIV、疱疹、黄热病、麻疹、脊髓灰质炎、风疹、流行性腮腺炎、狂犬病、蚀斑、血吸虫病、流感、肿瘤、锥虫病、利什曼病、麻风病、脑膜炎和疟疾的抗原。更特别地,它们包括乙肝表面抗原、破伤风类毒素、葡萄球菌肠毒素B类毒素、蓖麻蛋白类毒素和减毒的流感病毒。
在适当的水性溶剂如水或缓冲液中溶解水溶性物质得到溶液,将抗原溶解或分散到此溶液中,通过喷雾干燥或冷冻干燥法使混合物干燥即可制备核心颗粒。如有必要可在溶液中加入适当佐剂,其例子包括明矾;胞壁酰二肽、胞壁酰三肽和其衍生物;tymosin alpha;单磷酰基类脂A;皂苷;免疫刺激性的复合物;多聚电解质,如聚氧乙烯和聚氧丙烯的共聚合物;以及它们的混合物。
用于制备核心颗粒的水溶性物质不会造成与蛋白质抗原之间不必要的相互作用,在实际操作中,它不会溶于第二次包裹步骤中使用的有机溶剂。水溶性物质的例子包括水溶性糖类,如葡萄糖、木糖、半乳糖、果糖、乳糖、麦芽糖、蔗糖、藻酸盐、葡聚糖、透明质酸、硫酸软骨素和水溶性纤维素衍生物,如羟丙甲基纤维素、羟丙基纤维素(HPC)、羧甲基纤维素(CMC)和羧甲基纤维素钠(CMC-Na);蛋白质,如白蛋白和明胶;氨基酸,如甘氨酸、丙氨酸、谷氨酸、精氨酸、赖氨酸及其盐类;及其混合物;优选为HPC、CMC、CMC-Na、明胶及它们的混合物。
所使用的水溶性物质的量是抗原总重量的1至50倍,优选为5至15倍。
如此制备的核心颗粒其大小为0.1至200μm,优选为0.5至20μm。为了制备最终的微粒,可通过使用适当的装置,如磁力搅拌器,均化器,微量流体仪和超声发生器将核心颗粒分散于其中溶有疏水性可生物降解的聚合物的有机溶剂中。
所使用的可生物降解的聚合物的量为核心颗粒重量的1至100倍,优选为5至30倍。核心颗粒的包裹层由不溶于有机溶剂的水溶性物质制成,因此,通过阻止抗原与有机溶剂接触即可防止抗原之抗原性的降低或丧失。
用于本发明的疏水、可生物降解的聚合物的例子包括聚(交酯-共-乙交酯)(PLGA)、聚乙交酯(PGA)、聚交酯(PLA)、共聚草酸盐、聚已内酯、聚(交酯-共-已内酯)、聚酯酰胺、聚原酸酯、聚(β-羟丁酸)和聚酐;而优选PLGA和PLA。
本技术熟知的任何有机溶剂都可用于溶解生物降解性的聚合物,它们包括四氯化碳、二氯甲烷、丙酮、氯仿、乙酸乙酯和乙腈。
本发明的微粒由经可生物降解的聚合物包裹的核心颗粒组成,它得自有机悬浮液中,其中核心颗粒均匀分散于可生物降解聚合物的有机溶液中(“核心颗粒分散系统”)。核心颗粒分散系统是有利的,根据常规方法从中可制备微粒,同时可避免抗原与有机溶剂或可生物降解的聚合物接触。另外,与有机溶剂接触的核心颗粒表面积足够低以致抗原与有机溶剂的物理接触不会发生。
尤其是可根据下列常规方法中的任何一种从核心颗粒分散系统中制备本发明的微粒。
1)溶剂蒸发法
众所周知此方法可用以制备微粒,但本发明与现有技术的不同在于使用了可防止抗原与有机溶剂接触的核心颗粒分散系统以替代其中溶解或分散了抗原的水溶液。
尤其是微粒可如下制备:将核心颗粒分散系统分散到含有表面活性剂的水溶液中以得到O/W乳浊液,然后从核心颗粒分散系统中除去有机溶剂,或者将核心颗粒分散系统分散到溶剂中(此溶剂与核心颗粒分散系统不能互溶,对于可生物降解的聚合物而言是非溶剂)以制备O/O乳浊液,从核心颗粒分散系统中除去有机溶剂。当使用乙腈作为核心颗粒分散系统的有机溶剂时,可使用矿物油作为溶剂,它与核心颗粒分散系统不能互溶,对于可生物降解的聚合物而言是非溶剂。
2)溶剂抽提法
众所同知此方法也可用以制备微粒,但本发明与现有技术的不同在于使用了核心颗粒分散系统。尤其是通过使用溶剂(此溶剂与核心颗粒分散系统不能溶和,对于可生物降解的聚合物而言是非溶剂),如矿物油和石蜡油抽提核心颗粒分散系统中的有机溶剂即可制备微粒。
3)快速冷冻和溶剂抽提法
本发明与现有技术的不同在于使用了核心颗粒分散系统。尤其是使用超声装置将核心颗粒分散系统喷射进低温液气相中可形成冷冻颗粒。此颗粒被收集到冷冻乙醇的表面,当冷冻乙醇熔化时,冷冻颗粒也在融化,颗粒中的有机溶剂被抽提到乙醇相中,同时形成了被可生物降解的聚合物包裹的微粒。
4)喷雾干燥法
最优选将此方法用于本发明,尤其是使用喷雾干燥器喷射核心颗粒分散系统即可制备微粒。由于其产量高速度快,此方法是有利的。另外,此方法的有利之处还在于无需除去水,因为此方法中不使用水;此方法也无需表面活性剂;洗涤和干燥的过程可以省略。
由此制备的微粒其颗粒大小为0.5至300μm,优选为1至180μm。颗粒大小小于180μm的那些微粒可分散到注射介质中以制备注射配制品供皮下、肌内、腹膜内注射。颗粒大小大于180μm的那些颗粒可用于制备口服施用的配制品。
因此,本发明进一步提供了一注射疫苗的配制品,它是通过将微粒分散到适当的注射介质中而制备的。此疫苗配制品可仅含有一种抗原,或同时含有两种或多种抗原。使用含有两种或多种抗原混合物的核心颗粒,或者使用每种含有的抗原不相同的两种或多种核心颗粒的混合物即可制备含有两种或多种抗原的疫苗配制品。
本发明的一次注射疫苗的配制品仅通过一次注射即可完成抗其中所含抗原的免疫接种,此疫苗配制品中抗原的量相同于或少于需要几次注射以完成免疫接种的常规明矾配制品中抗原的量。
可用于本发明的注射介质的例子包括有或无分散剂和/或防腐剂的缓冲液、食用油、矿物油、鱼肝油、角鲨烯、角鲨烷、一、二-或三甘油酯及其混合物;所说的食用油是谷物油、芝麻油、橄榄油、黄豆油、红花油、棉籽油、花生油、或其混合物。
下列实施例旨在进一步阐明本发明而不会限制其范围。
另外,除非另有说明,以下给出的固体混合物中的固体,液体混合物中的液体以及液固混合物中的固体百分数分别根据的是wt/wt、vol/vol和wt/wt。
实施例中所用的材料和方法如下所述:.抗原
重组的乙肝表面抗原(HBsAg),它溶于磷酸盐缓冲的盐水中(PBS),此抗原是根据韩国专利申请No.93-2735(公开日:1994年4月9日)的方法制备的。.可生物降解的聚合物
美国BPI生产的PLGA(50/50).抗原的量:由Lowry法测定。.抗原性:使用AUZYME试验试剂盒(Abbot.U.S.A.)测定。.抗体效价
使用AUSAB试验试剂盒(Abbott.U.S.A)从11只豚鼠的血清中得到效价的几何平均数。.豚鼠
重300-400g,在施用样品2天前确证其血中没有抗体。使用心脏穿刺技术从豚鼠心脏中收集血液。
实施例1:使用冷冻干燥法制备核心颗粒
将重组HBsAg溶于10mM PBS中至浓度为300μg/ml,在其中加入羟丙基纤维素以使浓度分别为0.3mg/ml(样品1),1.5mg/ml(样品2)和3.0mg/ml(样品3)。使用干冰和丙酮将每种溶液在-70℃下冷冻30分钟,然后使用压力为0.05毫米汞柱,冷凝器温度为-80℃的EYELA FD-81冷冻干燥器(Tokyo Rikakikai.Japan)冻干24小时以得一被羟丙基纤维素包裹的核心颗粒。由此得到的核心颗粒其平均颗粒大小分别为1.0、1.2和1.5μm。
实施例2:使用喷雾干燥法制备核心颗粒
将重组HBsAg溶于10mM PBS中至浓度为300μg/ml,在其中各加入羟丙基纤维素(样品4)、羧甲基纤维素钠(样品5)和明胶(样品6)中的每一种至浓度为3.0mg/ml。将每种溶液以3ml/分钟的流速提供给喷雾干燥器(Buchi190)以得到分别被羟丙基纤维素、羧甲基纤维素钠和明胶包裹的核心颗粒。在此步骤中,推进剂氮气的流速为6001/分钟,流入空气的温度为70℃。由此制备的核心颗粒其平均颗粒大小分别为4.6、6.3和4.9μm。
试验实施例1:核心颗粒中抗原的保护
为了确证被水溶性物质包裹的核心颗粒是否可保护抗原的抗原性以使之不与有机溶剂接触,将实施例1和2中制备的核心颗粒分散到可溶解PLGA但不能溶解羟丙基纤维素的乙酸乙酯或乙腈中,使用磁力搅拌器混合所得溶液以使核心颗粒与有机溶剂接触。分离核心颗粒并干燥之以除去有机溶剂。将干燥的核心颗粒溶解于缓冲液中(10mM磷酸盐、PH7.5),用AUZYME试剂盒测定抗原性并与韩国专利公开No.93-2735中于低温状态下保存的重组HBsAg溶液相比较。
另外,如下所述使用末被水溶性物质包裹的HBsAg作为对照。将重组HBsAg溶于10mM PBS中至浓度为300μg/ml,在此溶液中加入相同体积的表1所列多种有机溶剂中的每一种。使用磁力搅拌器将所得溶液混合10分钟,从溶液中分离出水相,根据与上述相同的方法测定其抗原性,分离沉淀,干燥并加入PBS以检测抗原性。然而由于沉淀变性为不可溶形式,因而它不能溶解于PBS中。
结果,经羟丙基纤维素包裹的核心颗粒中的抗原与有机溶剂接触之后仍可保持其抗原性,而未被聚合物包裹的抗原与有机溶剂接触之后完全失去了其抗原性。
表1
样品 | 水溶性聚合物 | 有机溶剂 | 抗原性(%) | 不溶的沉淀物 | 注 |
原始HBsAg溶液 | - | - | 100 | - | - |
1 | 羟丙基纤维素(0.3mg/ml) | 乙腈 | 78 | - | - |
乙酸乙酯 | 75 | - | - | ||
2 | 羟丙基纤维素(1.5mg/ml) | 乙腈 | 80 | - | - |
乙酸乙酯 | 80 | - | - | ||
3 | 羟丙基纤维素(3.0mg/ml) | 乙腈 | 91 | - | - |
乙酸乙酯 | 88 | - | - | ||
4 | 羟丙基纤维素(3.0mg/ml) | 乙酸乙酯 | 90 | - | - |
5 | 羧甲基纤维素钠(3.0mg/ml) | 85 | - | - | |
6 | 明胶(3.0mg/ml) | 82 | - | - | |
对照 | 未使用 | 乙腈 | 0 | 形成 | - |
乙酸乙酯 | 0 | 形成 | - | ||
四氯化碳 | 0 | 形成 | - | ||
氯仿 | <<1.0 | 形成 | *1) | ||
二氯甲烷 | <<1.0 | 形成 | *1) | ||
苯 | <<1.0 | 形成 | *1) | ||
己烷 | <<1.0 | 形成 | *1) |
实施例3:微粒的制备
将PLGA(50/50)溶解于乙酸乙酯中至浓度为1%,将实施例1中制备的样品3的核心颗粒分散于其中至浓度为1mg/ml。以3ml/分钟的流速速将所得溶液提供给喷雾干燥器(Buchi 190)即可得到又经PLGA包裹的最终微粒。在此步骤中,氮气的流速是6001/分钟,流入空气的温度为60C。
由此制备的微粒其平均颗粒大小为7μm,PLGA/核心颗粒的重量比为10。由Lowry法测定的抗原量是6μg蛋白质/mg颗粒。
实施例4:微粒的制备
根据与实施例3中所述相同的方法,使用实施例2的样品4作为核心颗粒可制备经PLGA包裹的微粒。PLGA/核心颗粒的重量比为10。
由此制备的微粒其平均颗粒大小为9μm,抗原的量为3μg蛋白质/mg颗粒。
实施例5:微粒的制备
将实施例2的样品4分散到乙酸乙酯中至浓度为2mg/ml,根据与实施例3所述相同的方法制备经PLGA包裹的微粒,PLGA/核心颗粒的重量比为5。
由此制得的微粒其平均颗粒大小为7μm,抗原的量为6μg蛋白质/mg颗粒。
实施例6:微粒的制备
将实施例2的样品4分散到乙酸乙酯中至浓度为0.5mg/ml,根据与实施例3所述相同的方法制备经PLGA包裹的微粒,PLGA/核心颗粒的重量比为20。
由此制得的微粒其平均颗粒大小为10μm,抗原的量为1.5μg蛋白质/mg颗粒。
实施例7:微粒的制备
使用超声发生器将实施例2中制备的5mg样品4(核心颗粒)分散于其中溶解有200mg PLGA的1ml乙酸乙酯中。使用磁力搅拌器将核心颗粒分散系统与1ml 1%聚乙烯醇(PVA)水溶液相混合,将所得混合物分散于100ml 0.3%的PVA水溶液中可得到O/W乳浊液。持续混合乳浊液5小时以蒸发乙酸乙酯,使用0.5μm的滤器分离由此形成的微粒,洗涤,再干燥。
平均颗粒大小为110μm。
试验实施例2:水溶性物质的活体内作用
将实施例3中制备的微粒分散于PBS中(样品7),给豚鼠腹膜内注射样品7一次,所用抗原的量为40μg蛋白质/头。注射后2个月内以15天为间隔抽取豚鼠的血样,检测每份样品中所形成抗体的浓度(mIU/ml)。作为对照,可按下述制备仅由PLGA包裹而未经水溶性物质包裹核心的颗粒。根据实施例1的方法,冷冻不使用水溶性物质作为核心包被的原始的HBsAg溶液,根据实施例3的方法从中制备仅由PLGA直接包裹的HBsAg颗粒(比较样品)。根据与上述相同的方法将比较样品施用给豚鼠,然后测定所形成的抗体浓度。结果样品7显示出的抗体浓度比比较样品要高,这一点可从表2中看出。此结果表明未经水溶性物质包裹核心的抗原因其与有机溶剂和可生物降解的聚合物之间不必要的相互作用会使其丧失抗原性。
表2
Ab浓度(mIU/ml)样品 | 注射后的时间(月) | ||||
0 | 0.5 | 1 | 1.5 | 2 | |
样品7比较样品 | 0.00.0 | 2.41.1 | 10.68.1 | 24.610.2 | 34.014.3 |
试验实施例3:一次注射疫苗配制品的活体内作用
进行下列实验是为了确证本发明的疫苗配制品作为一次注射疫苗配制品是否有较高的作用。
将实施例5中制备的微粒分散在1.0ml注射介质中(含有0.02%(重量)吐温80的PBS)以形成疫苗配制品(样品8),使用26G注射器,以抗原量为20μg蛋白质/头的量皮下注射豚鼠一次。注射后5个月内以15天或一个月为间隔抽取豚鼠血样,测定每份样品中所形成的抗体的浓度(mI U/ml)。
如下制备使用明矾为佐剂的比较配制品。将含有HBsAg的PBS与明矾分散溶液(SuperfosBialsector,Vedbaek,Denmark)相混合以制备所含HBsAg的量为10μg蛋白质/1.5mg明矾的疫苗配制品。
使用26G注射器,以抗原量为10μg蛋白质/ml/注射的量将疫苗配制品给两组豚鼠各注射一次(初次注射)。此后,即初次注射后15天使用相同量的抗原使一组豚鼠经受第一次加强免疫(比较例1)。根据与上述相同的方法使另一组豚鼠在接受第一次加强免疫后1.5个月再经受第二次加强免疫(比较例2)。
另外,使用明矾配制品和与上述相同的方法使第三组豚鼠仅仅接受初次注射,所用抗原的量为20μg蛋白质/ml/注射(比较例3,样品9)。
如上所述测定比较例1,2和3中所形成的抗体的浓度(mI U/ml),并与样品8的结果相比较。
结果示于表3,从中可以看出通过注射样品8所形成抗体的浓度比通过三次注射明矾配制品所形成抗体的浓度要高。此结果表明本发明的疫苗配制品作为一次注射疫苗配制品具有较高的作用,也即一次注射使用20μg蛋白质的有创造性的疫苗配制品比三次注射使用30μg蛋白质的明矾配制品显示出更高的免疫接种作用。
表3
Ab浓度(mIU/ml)样品 | 注射后的时间(月) | ||||||||
0 | 0.5 | 1 | 1.5 | 2 | 2.5 | 3 | 4 | 5 | |
样品8比较例1比较例2比较例3(样品9) | 0.00.00.00.0 | 2.53.3-6.8 | 18.99.618.010.7 | 40.030.6-9.2 | 90.072.092.214.4 | 97.086.0-18.0 | 113.086.099.819.5 | 132.5108.6-22.0 | 149.4131.5-30.2 |
试验实施例4:疫苗配制品的颗粒特性和抗体形成之间
的关系
为了研究是否可根据可生物降解的聚合物和核心颗粒的重量比来控制抗体形成的时间和量,可进行下列试验。
将实施例4、5和6中制备的每种微粒悬浮于PBS中以制备一次注射疫苗配制品(样品10、8和11),以抗原量为20μg蛋白质/头的量皮下注射豚鼠一次,注射后5个月内以15天为间隔抽取豚鼠血样,测定每份样品中所形成抗体的浓度(mI U/ml)。
另外,以抗原量为20μg蛋白质/头(样品9)的量将试验实施例3中制备的明矾配制品给豚鼠注射一次,根据与上述相同的方法测定所形成抗体的浓度(mIU/ml)。
图1显示出注射后抗体浓度随时间而变化,其中PLGA/核心颗粒的重量比为5的样品8显示出最高的抗体浓度增加速率。因此,这证实了通过调节可生物降解的聚合物包裹的厚度即可控制抗体形成的速率。因此,通过使用具有不同特性的多种颗粒可制备含有混合抗原的一次注射疫苗或者可以不同方式释放抗原的一次注射疫苗。
如上述实施例所述,本发明的一次注射疫苗配制品仅通过一次注射施用即可完成免疫接种,并比常规的疫苗配制品具有更高的抗体形成能力。
着眼于上述特定的实施方案描述了本发明,应理解本技术熟练人员所作的多种修饰和改变也落入附加的权利要求书所限定的发明范围中。
Claims (19)
1.一种微粒,其颗粒大小为0.5至300μm,它是通过用水溶性物质包裹抗原或抗原混合物以得到核心颗粒,再用可生物降解的聚合物包裹核心颗粒而制备的。
2.如权利要求1的微粒,其中抗原是减毒、灭活或重组抗原。
3.如权利要求1的微粒,其中核心颗粒进一步包括佐剂或无机盐。
4.如权利要求1的微粒,其中抗原是选自包含下列疾病组的一种或多种疾病的抗原,这些疾病是:肝炎、白喉、水痘、伤寒、百日咳、破伤风、结核、沙门菌病、霍乱、HIV、疱疹、黄热病、麻疹、脊髓灰质炎、风疹、流行性腮腺炎、狂犬病、蚀斑、血吸虫病、流感、肿瘤、锥虫病、利什曼病、麻风病、脑膜炎和疟疾。
5.如权利要求3的微粒,其中佐剂是明矾;胞壁酰二肽、胞壁酰三肽及其衍生物;tymosin alpha;单磷酰基类脂A;皂苷;免疫刺激性的复合物;多聚电解质;或它们的混合物。
6.如权利要求1的微粒,其中水溶性物质所使用的量是抗原重量的1至50倍。
7.如权利要求1的微粒,其中水溶性物质是糖类、蛋白质、氨基酸或其混合物。
8.如权利要求7的微粒,其中糖类是纤维素聚合物、葡萄糖、木糖、半乳糖、果糖、乳糖、麦芽糖、蔗糖、藻酸盐、葡聚糖、透明质酸、硫酸软骨素或其混合物。
9.如权利要求8的微粒,其中纤维素聚合物是羟丙基纤维素、羟丙甲基纤维素、羧甲基纤维素、羧甲基纤维素钠或其混合物。
10.如权利要求7的微粒,其中蛋白质是明胶,白蛋白或其混合物。
11.如权利要求7的微粒,其中氨基酸是甘氨酸、丙氨酸、谷氨酸、精氨酸、赖氨酸、或盐类或其混合物。
12.如权利要求1的微粒,其中核心颗粒的颗粒大小为0.1至200μm。
13.如权利要求1的微粒,其中所使用的可生物降解的聚合物的量是核心颗粒重量的1至100倍。
14.如权利要求1的微粒,其中可生物降解的聚合物是聚乙交酯、聚交酯、聚(交酯-共-乙交酯)或其混合物。
15.如权利要求1的微粒,其中可生物降解的聚合物是共聚草酸盐、聚已内酯、聚(交酯-共-已内酯)、聚酯酰胺、聚原酸酯、聚(β-羟丁酸)、聚酐或其混合物。
16.一次注射疫苗配制品,它是通过将权利要求1至15中提到的任何一个微粒分散到注射介质中而制备的。
17.如权利要求16的一次注射疫苗配制品,其中注射介质是任选含有分散剂和/或防腐剂的缓冲液。
18.如权利要求17的一次注射疫苗配制品,其中注射介质是食用油、矿物油、鱼肝油、角鲨烯、角鲨烷、一、二、或三甘油酯或其混合物。
19.如权利要求18的一次注射疫苗配制品,其中食用油是谷物油、芝麻油、橄榄油、黄豆油、红花油、棉籽油、花生油或其混合物。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105338961A (zh) * | 2013-05-22 | 2016-02-17 | Ucb生物制药私人有限公司 | 制备包含治疗性蛋白质的颗粒的方法 |
CN107375921A (zh) * | 2017-06-12 | 2017-11-24 | 商丘美兰生物工程有限公司 | 一种甘草皂苷脂质体免疫佐剂及其制备方法 |
Families Citing this family (115)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6090925A (en) | 1993-03-09 | 2000-07-18 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
US5981719A (en) | 1993-03-09 | 1999-11-09 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
KR100236771B1 (ko) * | 1997-04-01 | 2000-02-01 | 성재갑 | 히아루론산을 이용한 약물의 서방성 미세입자 제형 |
KR0162872B1 (ko) * | 1996-04-01 | 1998-12-01 | 김은영 | 용매추출법을 이용한 생분해성 고분자 미립구의 개선된 제조방법 및 이를 이용한 국소염증 질환 치료용 미립구의 제조방법 |
US7276251B2 (en) * | 1997-04-01 | 2007-10-02 | Lg Life Sciences, Ltd., Inc. | Sustained-release composition of drugs encapsulated in microparticles of hyaluronic acid |
TW586934B (en) * | 1997-05-19 | 2004-05-11 | Sumitomo Pharma | Immunopotentiating composition |
US6156347A (en) * | 1998-01-21 | 2000-12-05 | Bio-Dar Ltd. | Controlled release chromium picolinate |
US7087236B1 (en) | 1998-09-01 | 2006-08-08 | Merrion Research I Limited | Method for inducing a cell-mediated immune response and improved parenteral vaccine formulations thereof |
GB9819272D0 (en) * | 1998-09-03 | 1998-10-28 | Andaris Ltd | Microparticles |
JP3802348B2 (ja) | 1999-01-18 | 2006-07-26 | エルジー ライフ サイエンシズ エルティーディー. | タンパク質薬物または抗原を含む、親油性微細粒子およびそれを含む剤形 |
KR100359252B1 (ko) * | 1999-12-21 | 2002-11-04 | 주식회사 엘지생명과학 | 항원을 포함하는 고체상 미세입자 및 이를 포함하는 제제 |
US6723342B1 (en) | 1999-02-08 | 2004-04-20 | Fmc Corporation | Edible coating composition |
US6432448B1 (en) | 1999-02-08 | 2002-08-13 | Fmc Corporation | Edible coating composition |
US6217895B1 (en) * | 1999-03-22 | 2001-04-17 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
PT1218001E (pt) * | 1999-09-03 | 2009-03-31 | Sigma Tau Ind Farmaceuti | L-carnitina ultrafina, métodos de preparação da mesma, composições contendo a mesma, e métodos de utilização da mesma |
US6500462B1 (en) | 1999-10-29 | 2002-12-31 | Fmc Corporation | Edible MCC/PGA coating composition |
GB0000891D0 (en) * | 2000-01-14 | 2000-03-08 | Allergy Therapeutics Ltd | Formulation |
CN1242750C (zh) * | 2000-02-08 | 2006-02-22 | 分子农业生物学院 | 可生物降解的且生物相容的封装有肠炎沙门氏菌的聚合物微球体 |
US6375972B1 (en) * | 2000-04-26 | 2002-04-23 | Control Delivery Systems, Inc. | Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof |
GB0017999D0 (en) * | 2000-07-21 | 2000-09-13 | Smithkline Beecham Biolog | Novel device |
US20060177416A1 (en) | 2003-10-14 | 2006-08-10 | Medivas, Llc | Polymer particle delivery compositions and methods of use |
SE517422C2 (sv) * | 2000-10-06 | 2002-06-04 | Bioglan Ab | Farmaceutiskt acceptabel stärkelse |
DE60136002D1 (de) | 2000-10-06 | 2008-11-13 | Pacira Pharmaceuticals Inc | Parenteral verabreichbare mikropartikel-zubereitung mit kontrollierter freisetzung |
SE517421C2 (sv) | 2000-10-06 | 2002-06-04 | Bioglan Ab | Mikropartiklar, lämpade för parenteral administration, väsentligen bestående av stärkelse med minst 85 % amylopektin och med reducerad molekylvikt, samt framställning därav |
SE518007C2 (sv) | 2000-11-16 | 2002-08-13 | Bioglan Ab | Förfarande för framställning av mikropartiklar |
SE518008C2 (sv) * | 2000-11-16 | 2002-08-13 | Bioglan Ab | Parenteralt administrerbara mikropartiklar och förfarande för framställning av desamma |
EP1339395A2 (en) | 2000-11-28 | 2003-09-03 | Fmc Corporation | Edible pga (propylene glycol alginate) coating composition |
US20070142325A1 (en) * | 2001-01-08 | 2007-06-21 | Gustavsson Nils O | Starch |
WO2004030608A2 (en) * | 2001-06-05 | 2004-04-15 | The Regents Of The University Of Michigan | Nanoemulsion vaccines |
US6967234B2 (en) * | 2002-12-18 | 2005-11-22 | Ethicon, Inc. | Alkyd-lactone copolymers for medical applications |
US7030127B2 (en) * | 2001-06-29 | 2006-04-18 | Ethicon, Inc. | Composition and medical devices utilizing bioabsorbable polymeric waxes |
US7034037B2 (en) * | 2001-06-29 | 2006-04-25 | Ethicon, Inc. | Compositions and medical devices utilizing bioabsorbable polymeric waxes and rapamycin |
US7105181B2 (en) * | 2001-10-05 | 2006-09-12 | Jagotec, Ag | Microparticles |
SE0201599D0 (sv) * | 2002-03-21 | 2002-05-30 | Skyepharma Ab | Microparticles |
US7326426B2 (en) * | 2002-03-29 | 2008-02-05 | Ethicon, Inc. | Compositions and medical devices utilizing bioabsorbable liquid polymers |
US7005136B2 (en) | 2002-03-29 | 2006-02-28 | Ethicon, Inc. | Bone replacement materials utilizing bioabsorbable liquid polymers |
US8871241B2 (en) * | 2002-05-07 | 2014-10-28 | Psivida Us, Inc. | Injectable sustained release delivery devices |
KR100479735B1 (ko) * | 2002-05-25 | 2005-03-30 | 이현철 | 대식세포특이 나노입자-면역조절제-면역원 복합체를이용한 치아우식증을 예방하는 비경구용 백신 |
US7368125B2 (en) * | 2002-06-05 | 2008-05-06 | Ethicon, Inc. | Amphiphilic polymers for medical applications |
US7026374B2 (en) * | 2002-06-25 | 2006-04-11 | Aruna Nathan | Injectable microdispersions for medical applications |
US7101566B2 (en) * | 2002-06-28 | 2006-09-05 | Ethicon, Inc. | Polymer coated microparticles for sustained release |
FR2842737B1 (fr) * | 2002-07-25 | 2006-01-27 | Centre Nat Rech Scient | Particules revetues en surface de hyaluronane ou d'un de ses derives et leur utilisation a titre de vecteurs biologiques pour des matieres actives |
US20040047835A1 (en) * | 2002-09-06 | 2004-03-11 | Cell Therapeutics, Inc. | Combinatorial drug therapy using polymer drug conjugates |
US6872799B2 (en) | 2002-12-18 | 2005-03-29 | Ethicon, Inc. | Functionalized polymers for medical applications |
US6866860B2 (en) | 2002-12-19 | 2005-03-15 | Ethicon, Inc. | Cationic alkyd polyesters for medical applications |
US20040120981A1 (en) * | 2002-12-20 | 2004-06-24 | Aruna Nathan | Crosslinked alkyd polyesters for medical applications |
CA2510320C (en) * | 2002-12-20 | 2012-10-09 | St. James Associates Llc/Faber Research Series | Coated particles for sustained-release pharmaceutical administration |
US7446131B1 (en) * | 2004-06-10 | 2008-11-04 | The United States Of America As Represented By The Secretary Of Agriculture | Porous polymeric matrices made of natural polymers and synthetic polymers and optionally at least one cation and methods of making |
KR100729954B1 (ko) | 2004-12-01 | 2007-06-20 | 주식회사 엘지생명과학 | Sec1 변이 단백질의 제형 및 그것의 제형화 방법 |
EP1726299A3 (en) * | 2005-05-27 | 2007-04-18 | StratoSphere Pharma AB | Cores and microcapsules suitable for parenteral administration as well as process for their manufacture |
WO2007038246A2 (en) * | 2005-09-22 | 2007-04-05 | Medivas, Llc | Solid polymer delivery compositions and methods for use thereof |
CA2623198C (en) | 2005-09-22 | 2014-08-05 | Medivas, Llc | Bis-(a-amino)-diol-diester-containing poly(ester amide) and poly(ester urethane) compositions and methods of use |
US20070134332A1 (en) * | 2005-11-21 | 2007-06-14 | Medivas, Llc | Polymer particles for delivery of macromolecules and methods of use |
EP1962894A4 (en) * | 2005-12-07 | 2012-11-14 | Medivas Llc | PROCESS FOR ASSEMBLING A BIOLOGICAL POLYMER-AGENT DELIVERY COMPOSITION |
JP5445130B2 (ja) * | 2006-05-02 | 2014-03-19 | メディバス エルエルシー | 眼の外部または内部への眼科用薬剤の送達法 |
EP2021141A4 (en) * | 2006-05-09 | 2013-07-03 | Medivas Llc | BIODEGRADABLE WATER SOLUBLE POLYMERS |
CA2709412A1 (en) * | 2007-07-24 | 2009-01-29 | Medivas, Llc | Biodegradable cationic polymer gene transfer compositions and methods of use |
US9415006B2 (en) * | 2008-05-23 | 2016-08-16 | The Regents Of The University Of Michigan | Immunogenic compositions comprising nanoemulsion and hepatitis B virus immunogen and methods of using the same |
CN102186484A (zh) * | 2008-08-13 | 2011-09-14 | 梅迪沃什有限公司 | Aabb-聚(酯肽)可生物降解聚合物及其使用方法 |
US20110020392A1 (en) * | 2008-10-14 | 2011-01-27 | Salubrious Pharmaceutical, Llc | Process for treatment of rheumatoid arthritis, tremors/parkinson's disease, multiple sclerosis and non-viral based cancers |
US9072688B2 (en) * | 2008-10-31 | 2015-07-07 | The Invention Science Fund I, Llc | Compositions and methods for therapeutic delivery with frozen particles |
US8725420B2 (en) * | 2008-10-31 | 2014-05-13 | The Invention Science Fund I, Llc | Compositions and methods for surface abrasion with frozen particles |
US8545855B2 (en) * | 2008-10-31 | 2013-10-01 | The Invention Science Fund I, Llc | Compositions and methods for surface abrasion with frozen particles |
US8603494B2 (en) * | 2008-10-31 | 2013-12-10 | The Invention Science Fund I, Llc | Compositions and methods for administering compartmentalized frozen particles |
US8721583B2 (en) | 2008-10-31 | 2014-05-13 | The Invention Science Fund I, Llc | Compositions and methods for surface abrasion with frozen particles |
US9050317B2 (en) | 2008-10-31 | 2015-06-09 | The Invention Science Fund I, Llc | Compositions and methods for therapeutic delivery with frozen particles |
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WO2013073454A2 (ja) * | 2011-11-17 | 2013-05-23 | 国立大学法人 富山大学 | 生理活性物質徐放制御組成物 |
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Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4338335A (en) * | 1980-02-05 | 1982-07-06 | Merck & Co., Inc. | Vaccine stabilizer containing L-glutamic acid and L-arginine |
US4744933A (en) * | 1984-02-15 | 1988-05-17 | Massachusetts Institute Of Technology | Process for encapsulation and encapsulated active material system |
US5417986A (en) * | 1984-03-16 | 1995-05-23 | The United States Of America As Represented By The Secretary Of The Army | Vaccines against diseases caused by enteropathogenic organisms using antigens encapsulated within biodegradable-biocompatible microspheres |
IL84167A (en) * | 1986-10-24 | 1991-04-15 | Southern Res Inst | Oral delivery of bioactive agents to and through the peyer's patch by use of microencapsulation |
SE8701479L (sv) * | 1987-04-09 | 1988-10-10 | Carbomatrix Ab | Metod foer inneslutning av biologiskt verksamma preparat samt anvaendning daerav |
US4897268A (en) * | 1987-08-03 | 1990-01-30 | Southern Research Institute | Drug delivery system and method of making the same |
US5015476A (en) * | 1989-08-11 | 1991-05-14 | Paravax, Inc. | Immunization implant and method |
IT1243390B (it) * | 1990-11-22 | 1994-06-10 | Vectorpharma Int | Composizioni farmaceutiche in forma di particelle atte al rilascio controllato di sostanze farmacologicamente attive e procedimento per la loro preparazione. |
US5344644A (en) * | 1991-08-01 | 1994-09-06 | Takeda Chemical Industries, Ltd. | Water-soluble composition for sustained-release |
GB9310781D0 (en) * | 1993-05-25 | 1993-07-14 | Davis Stanley S | Preparation of microparticles |
ATE173160T1 (de) * | 1994-02-17 | 1998-11-15 | Pankaj Modi | Arzneimittel, impfstoffe und hormone in polylaktidbeschichteten mikropartikel |
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1995
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- 1996-03-15 JP JP8085962A patent/JP2739570B2/ja not_active Expired - Fee Related
- 1996-03-15 AR ARP960101761A patent/AR002969A1/es active IP Right Grant
- 1996-03-15 BR BR9601032A patent/BR9601032A/pt not_active Application Discontinuation
- 1996-03-15 EP EP96104177A patent/EP0737472A1/en not_active Withdrawn
- 1996-03-15 CN CNB961027282A patent/CN1213736C/zh not_active Expired - Fee Related
- 1996-03-15 PE PE1996000176A patent/PE57797A1/es not_active Application Discontinuation
- 1996-03-15 CA CA002171881A patent/CA2171881A1/en not_active Abandoned
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105338961A (zh) * | 2013-05-22 | 2016-02-17 | Ucb生物制药私人有限公司 | 制备包含治疗性蛋白质的颗粒的方法 |
CN107375921A (zh) * | 2017-06-12 | 2017-11-24 | 商丘美兰生物工程有限公司 | 一种甘草皂苷脂质体免疫佐剂及其制备方法 |
CN107375921B (zh) * | 2017-06-12 | 2019-10-29 | 商丘美兰生物工程有限公司 | 一种甘草皂苷脂质体免疫佐剂及其制备方法 |
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KR100201352B1 (ko) | 1999-06-15 |
TW495361B (en) | 2002-07-21 |
KR960033469A (ko) | 1996-10-22 |
PE57797A1 (es) | 1998-03-14 |
US5753234A (en) | 1998-05-19 |
CN1213736C (zh) | 2005-08-10 |
AR002969A1 (es) | 1998-05-27 |
MX9600938A (es) | 1997-07-31 |
BR9601032A (pt) | 1998-01-06 |
JPH08253426A (ja) | 1996-10-01 |
EP0737472A1 (en) | 1996-10-16 |
CA2171881A1 (en) | 1996-09-16 |
JP2739570B2 (ja) | 1998-04-15 |
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