CN1226842A - 通过泡沫形成来保存的方法 - Google Patents
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Abstract
一种通过在待脱水流体物质中形成稳定泡沫来保存敏感的生物分散液、悬液、乳液和溶液的方法,该方法既有助于干燥流体中一种或多种生物活性底物,又有助于制备易分开的、适用于进一步商业用途的干燥产物。稳定泡沫是这样形成的:除去部分水形成粘稠液体,然后进一步对浓缩的液体抽真空使其在进一步远低于100℃的温度下干燥期间,并引起“沸腾”。换句话说。将减小的压力施用于粘稠的生物活性物溶液或悬液,使溶液或悬液在沸腾时起泡,在起泡过程中进一步除去溶剂,最终产生稳定的开腔或闭腔泡沫。
Description
发明领域
本发明涉及敏感的生物活性溶质(例如酶、蛋白质、病毒、血清、疫苗、脂质体和细胞悬液)以及其悬液、乳液和分散液的保存方法。
发明背景
生物活性物质的长期保存对我们来说是一种独特的挑战,因为生物活性物质是我们这个星球上最脆弱的、最易受环境影响的结构(这是它的本质特点)。当然,也有极少数水合物是稳定的,它们能被分离纯化并储藏在室温溶液中较长时间。
从商业和实践的角度来看,以干形式储藏生物活性物质具有许多优点。成功干燥的试剂、物质和组织的重量减少,保存所需的空间减少,但是它们的保存期限却增加。干物质的室温保存比低温保存方案及其费用更经济。
目前生产干的生物活性物质的方法主要包括喷雾干燥(参见美国专利No.5,563,318,该专利涉及喷雾干燥的一种变化方案)和流化床干燥,因为简单的干燥方法实际上不能放大成类似工业上有用的规模。降温保存方法可能有脱水作用,它包括冷冻干燥和/或深低温冷冻。冷冻干燥不大适用于保存敏感的生物活性物质,因为形成的冰晶会产生冷冻诱导的低温损伤,而且成本非常高。
在生物活性物质经蜕变(transmute)干燥但仍可恢复生物活性形式的许多过程中,特别存在的问题始终是简单的空气干燥或真空干燥步骤很难放大。干燥是扩散限制型过程,因此对于超过10微升的水分含量来说,水分的除去就变得更加复杂,这是一点;而且待干燥的底物越大,其中心部份的有效干燥就越困难。干燥时间与水的扩散系数成反比,与样品大小的平方成正比。我们总不能老是求助于喷雾干燥技术,因为该技术中的一些具有典型的高温对柔弱的生物活性物质有破坏作用。而且,用已知的干燥方法来制备干燥的物质有时会产生稠密的、难溶的团块,这些团块在大规模(full-scale)商业性生物和药物应用中不能很好地作进一步处理。
因此,需要有一种通过干燥来保存敏感生物活性物质的可放大的方法。
发明概述
为了满足这一需求,本发明涉及一种通过从待干燥流体物质形成稳定泡沫来保存敏感的生物悬液和溶液的方法,这种方法既有助于流体中一种或多种生物活性底物的干燥,又有助于制得适用于进一步商业用途的易溶的干燥产物。稳定的泡沫是这样形成的:除去生物活性样品中的部分水,形成粘稠的液体,然后对浓缩的液体抽真空,使其在进一步在远低于100℃的温度下进行干燥的过程中引起“沸腾”。换句话说,使粘稠的生物活性物溶液或悬液受减压作用,使溶液或悬液在沸腾过程中产生泡沫,在起泡过程中进一步除去水分,最终产生稳定的开腔或闭腔泡沫。这些泡沫很容易通过切割、研磨或其它分隔方法来细分,而且起泡作用本身通过使液体蒸发面积或其它溶剂放散(evolutin)面积最大化而增强了水分的除去。
发明详述
本发明是一种通过从待干燥流体物质形成稳定泡沫来保存敏感的生物分散液、悬液和溶液的方法,这种方法既有助于干燥流体中一种或多种生物活性底物,又有助于制得适用于进一步商业用途的容易细分的干燥产物。稳定的泡沫是这样形成的:除去部分水,形成粘稠液体,进一步对浓缩的液体抽真空,使其在进一步在远低于100℃的温度下进行干燥的过程中引起粘稠液体“沸腾”。换句话说,使粘稠的生物活性物溶液或悬液受减压作用,使溶液或悬液在沸腾过程中产生泡沫,在起泡过程中进一步除去水分,最终产生稳定的开腔或闭腔泡沫。这些泡沫很容易通过切割、研磨或其它分隔方法来细分,而且起泡作用本身通过使液体蒸发面积最大化而增强了水分的除去。(通常,待干燥物质的溶剂部分是水性的,然而,应当理解本发明适用于各种类型的溶液和悬液,包括那些含有非水性溶剂或这些溶剂的混合物的溶液和悬液)。
一旦理解了本发明中干燥过程与减压沸腾的结合,就可以看出在最简单的实例中本发明的装置是一种真空泵和温度控制干燥器的新组合装置。这一组合的其它任选特征包括:测定温度和热流控制的传感器,根据从这些及其它传感器收集的数据来计算其它过程参数的微处理器等。这种装置能够实现新的用于干燥的二维的真空和温度的设置方案。
适用于该真空-沸腾-泡沫-形成革新方法的生物液体实际上是无限的。确实何溶液或悬液均可用本发明的真空沸腾方法来脱水,但是该方法在保存敏感的生物物质方面有明显的优点(即,由于较低的干燥温度而避免了破坏)。对于掺入了玻璃化增强剂、其它保护剂以及基本上任何类型溶剂的溶液,当它受低于大气压作用并在沸腾过程中产生泡沫时,它受的干燥作用会增强。保护剂可以包括(没有限制):糖(包括蔗糖)、碳水化合物、多糖、水溶性聚合物、肽或蛋白质等,只要保护剂能增强生物活性物质经受干燥和保存的能力,而且不干扰特定的生物活性。
在本发明的一个重要实例中,泡沫的形成包括两个步骤:(a)通过真空下沸腾使含有生物活性剂的溶液或分散液充分脱水,形成稳定的不会被破坏的泡沫,和(b)随后将泡沫二次干燥至泡沫稳定并且不会在保存时被破坏。
如上所述,本发明提供了一种可改变规模的保存敏感的生物活性物质(蛋白质、酶、血清、疫苗、病毒、脂质体和细胞悬液)方法,该方法采用了独特的工程化干燥方法。采用这种方法,就可以用水或水性溶液使样品重新水合,以使该过程逆转并恢复成原始的生物活性。该方法适用于保存药物、流体或实际上其它任何生物活性产物或溶质。
在本发明的方法中,相当大量的生物活性液体(溶液或悬液)通过真空下沸腾而脱水形成了稳定的泡沫。泡沫的形成是一个动态的过程,它取决于形成泡沫过程中温度和真空度的改变速度,以及含有生物活性物质的溶液或悬液的初始浓度和组成。通过加入表面活性剂或其它合成或生物聚合物,可进一步增强泡沫的稳定性,只要那些添加剂不干扰打算转化成干形式的溶质的生物活性。可采用二次干燥,并任选地冷却形成的与初始的干泡沫,以确保保存时的泡沫稳定性。冷却可用来将起泡物质转变成玻璃态。根据本发明制得的泡沫可以不经分割而整个保存或进行细分或研磨,当要使用它们时,只需使它们重新水合以恢复它们的原始生物活性即可。
下列实施例用来描述。
实施例1
使含有59.4单位活性/毫升的50%异柠檬酸甘油酯脱氢酶水溶液(购自SigmaChemical Co.)在0.1M Tris HCl缓冲液(pH=7.4)中透析5小时。在透析后,0.1MTris HCl溶液中异柠檬酸酯脱氢酶的活性为26+1.8单位/毫升。活性随着透析时稀释而引起的酶浓度的降低而降低。
将100微升的混合物放在1.5毫升塑料管中并在室温下干燥进行保存,该混合物含有50微升50%(重量)的蔗糖溶液和50微升在0.1M Tris HCl缓冲液(pH7.4)中的异柠檬酸酯脱氢酶悬液。首先,使样品在低真空度(流体静压P=0.2大气压)下干燥4小时。第二,使样品在高真空度(P<0.01大气压)下沸腾4小时。在这一步中,试管内形成了稳定的干泡沫。第三,使样品在真空、室温下,在DRIERITE上保存8天。
在保存规定天数后,用500微升水使样品重新水合。含有干泡沫的样品的重新水合是容易的,它可在几秒种内完成。通过在340nm用分光光度计测定还原NADP的能力来测定重建样品的活性。反应混合物包括:2毫升0.1M Tris HCl缓冲液,pH=7.4;10微升0.5%(重量)NADP+;10微升10mM MnSO4溶液;10微升50mM 1-异柠檬酸酯;以及10微升异柠檬酸酯脱氢酶溶液。活性为2.6±0.2单位/毫升,这意味着在室温下干燥和随后的保存中活性没有损失。
实施例2
将100微升的混合物放在1.5毫升塑料管中并在室温下干燥进行保存,该混合物含有50微升50%(重量)的蔗糖溶液和50微升冰晶核细菌悬液(由GenencorInternational,Inc.提供)。首先,使样品在低真空度(流体静压P=0.2大气压)下干燥4小时。第二,使样品在高真空度(P<0.01大气压)下沸腾4小时。在真空下沸腾后,试管内形成了稳定的干泡沫。第三,使样品在真空、室温下在DRIERITE上保存8天。在保存8天后,用500微升水使样品重新水合。含有干泡沫的样品的重新水合是容易的,它可在几秒钟内完成。然后测定样品的冰成核活性与对照样品比较。我们发现用本发明方法保存的样品每1000个细菌的冰成核活性与对照样品没有显著区别。
尽管本发明已参照上述特定实施例和细节进行了描述,但是本发明的范围只能取决于在附加的权利要求中所提出的陈述。
1.一种通过干燥来保存生物活性物质的方法,方法包括下列步骤:使含有生物活性剂的溶液、分散液或悬液受相应于残余流体静压低于24托的真空作用,该真空度足以使所述溶液、分散液或悬液引起沸腾,从而使得所述沸腾的溶液、分散液或悬液在沸腾期间干燥产生物理上稳定的泡沫。
2.根据权利要求1所述的方法,其中所述流体静压在0到7.6托之间。
3.根据权利要求1所述的方法,其中在使所述溶液、分散液或悬液受高真空度作用步骤之前,通过在残余流体静压高于7.6托的低真空度下从液体状态蒸发,或从部分冷冻状态蒸发,或用反向渗透或其它膜技术来对所述溶液、分散液或悬液脱水或浓缩,以减少施加所述高真空度必需的时间,并增加所述溶液、分散液或悬液在高真空度下沸腾之前的粘度。
4.根据权利要求1所述的方法,其中通过在升高温度下对所述稳定泡沫施加真空或干空气中的一种来进行二次干燥。
5.根据权利要求4所述的方法,其中在二次干燥步骤后将样品冷却到温度低于干泡沫的玻璃化温度。
6.根据权利要求5所述的方法,其中在施加所述高真空度之前先在所述溶液、分散液或悬液中加入表面活性剂,使在二次干燥时增加泡沫稳定性。
7.根据权利要求6所述的方法,其中所述溶液、分散液或悬液含有选自糖、碳水化合物、多糖、聚合物、肽、蛋白质及其混合物的保护剂,其中所述保护剂增强了生物活性物质经受干燥和保存的能力。
8.根据权利要求1所述的方法,其中所述方法还包括通过所述泡沫与合适溶剂接触来使所述稳定泡沫重新水合。
9.根据权利要求8所述的方法,其中所述重新水合是在高于重新水合前泡沫保存温度的温度下进行。
10.根据权利要求9所述的方法,其中重新水合前的泡沫保存温度至少和环境温度一样高。
11.根据权利要求8所述的方法,其中所述重新水合在等于或低于重新水合前泡沫保存温度的温度下进行。
12.根据权利要求8所述的方法,其中重新水合前的泡沫保存温度低于或等于环境温度。
13.根据权利要求8所述的方法,其中所述溶剂是包括低温保护剂的水性溶液。
14.根据权利要求7所述的方法,其中所述糖是蔗糖。
Claims (14)
1.一种通过干燥来保存生物活性物质的方法,方法包括下列步骤:
a)对至少一种生物活性剂的溶液、分散液或悬液进行抽真空;和
b)在所述抽真空期间干燥所述溶液、分散液或悬液,其中抽真空和干燥步骤的组合产生了含有所述生物活性剂的稳定的泡沫。
2.根据权利要求1所述的方法,其中所述真空度在0到25℃饱和水蒸气压24托之间。
3.根据权利要求1所述的方法,其中在步骤a)之前先使含至少一种生物活性剂的所述溶液或悬液蒸发,以增加其粘度,减少抽真空时间。
4.根据权利要求1所述的方法,其中在步骤b)后还要在真空下进行二次干燥。
5.根据权利要求4所述的方法,其中在二次干燥步骤之后将样品冷却到温度低于干样品的玻璃化温度。
6.根据权利要求5所述的方法,其中所述溶液或悬液中加入了至少一种表面活性剂,使在抽真空时增强泡沫形成。
7.根据权利要求6所述的方法,其中所述溶液或分散液含有至少一种选自糖、碳水化合物、多糖、聚合物、肽或蛋白质的保护剂,其中所述保护剂增强了生物活性物质经受干燥和保存的能力。
8.根据权利要求7所述的方法,其中所述方法还包括步骤d),使这样形成的所述泡沫重新水合。
9.根据权利要求8所述的方法,其中所述重新水合是在高于重新水合前泡沫保存温度的温度下进行。
10.根据权利要求9所述的方法,其中重新水合前的泡沫保存温度至少和环境温度一样高。
11.根据权利要求8所述的方法,其中所述重新水合是在等于或低于重新水合前泡沫保存温度的温度下进行。
12.根据权利要求8所述的方法,其中重新水合的前泡沫保存温度低于或等于环境温度。
13.根据权利要求12所述的方法,其中重新水合通过泡沫与浓缩的低温保护剂组合物水溶液接触来实现。
14.根据权利要求7所述的方法,其中所述糖是蔗糖。
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- 1997-07-14 CN CN97196422A patent/CN1116104C/zh not_active Expired - Fee Related
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- 1997-07-14 AU AU36606/97A patent/AU714328B2/en not_active Ceased
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CN103140145A (zh) * | 2010-08-13 | 2013-06-05 | 高级生物营养公司 | 用于生物材料的干的贮存稳定用组合物 |
CN106434840A (zh) * | 2016-12-02 | 2017-02-22 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测维生素b12的微孔板、其试剂盒及其制备方法 |
CN106434840B (zh) * | 2016-12-02 | 2019-08-09 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测维生素b12的微孔板、其试剂盒及其制备方法 |
CN106591415A (zh) * | 2017-01-03 | 2017-04-26 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测生物素的微孔板、其试剂盒及其制备方法 |
CN106676161A (zh) * | 2017-01-03 | 2017-05-17 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测烟酸的微孔板、其试剂盒及其制备方法 |
CN106676160A (zh) * | 2017-01-03 | 2017-05-17 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测泛酸的微孔板、其试剂盒及其制备方法 |
CN106701887A (zh) * | 2017-01-03 | 2017-05-24 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测叶酸的微孔板、其试剂盒及其制备方法 |
CN106591415B (zh) * | 2017-01-03 | 2019-12-10 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测生物素的微孔板、其试剂盒及其制备方法 |
CN106701887B (zh) * | 2017-01-03 | 2020-01-17 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测叶酸的微孔板、其试剂盒及其制备方法 |
CN106676161B (zh) * | 2017-01-03 | 2020-01-21 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测烟酸的微孔板、其试剂盒及其制备方法 |
CN106676160B (zh) * | 2017-01-03 | 2020-02-21 | 北京中检葆泰生物技术有限公司 | 一种用于微生物法定量检测泛酸的微孔板、其试剂盒及其制备方法 |
Also Published As
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EA001138B1 (ru) | 2000-10-30 |
AU3660697A (en) | 1998-02-09 |
NZ333738A (en) | 2000-09-29 |
KR20000023779A (ko) | 2000-04-25 |
HUP9903917A3 (en) | 2000-06-28 |
TR199900127T2 (xx) | 1999-04-21 |
EA199900268A1 (ru) | 1999-10-28 |
DE914202T1 (de) | 2000-02-17 |
NO990158L (no) | 1999-01-14 |
IL127971A (en) | 2001-09-13 |
JP2000515856A (ja) | 2000-11-28 |
HUP9903917A2 (hu) | 2000-03-28 |
WO1998002240A1 (en) | 1998-01-22 |
BR9711808A (pt) | 2000-01-18 |
IL127971A0 (en) | 1999-11-30 |
AU714328B2 (en) | 1999-12-23 |
KR100457748B1 (ko) | 2004-11-17 |
PL331174A1 (en) | 1999-06-21 |
CN1116104C (zh) | 2003-07-30 |
EP0914202A4 (en) | 2004-09-01 |
CA2260233A1 (en) | 1998-01-22 |
EP0914202A1 (en) | 1999-05-12 |
CZ7999A3 (cs) | 1999-11-17 |
US5766520A (en) | 1998-06-16 |
NO990158D0 (no) | 1999-01-14 |
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