CN101340930A - 在柔性容器中运动下灭活供体血液、血浆或红细胞浓缩物中病原体的方法 - Google Patents
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Abstract
本发明涉及灭活供体血液、血液血浆和红细胞浓缩物中病原体，例如细菌和病毒的方法，所述方法通过光动力处理和/或在柔性曝光袋中在强烈运动下利用紫外光辐射进行。
Description
技术领域
本发明的主题是灭活供体血液(血液)、血液血浆(血浆)和/或红细胞浓缩物(EK)中病原体，例如细菌和病毒的方法，所述方法通过光动力处理和/或利用紫外光辐射进行。
背景技术
已知的是，血液和血液制品在治疗上的应用具有风险，即受体感染病毒和细菌。例如病毒性乙型肝炎(HBV)和丙型肝炎(HCV)以及艾滋病病原体HIV-1和HIV-2。如果在制备相应的制品时没有进行灭活或消除病原体的步骤，这类风险一直存在。
以前和现在都做过很多努力，通过光动力方法净化血液制品。原理基于将所涉及的产品在光敏物质(光敏剂)存在下曝光。射入血液制品的光必须包含这样的波长范围，所述波长范围可以被光敏剂吸收并且可以激活光敏剂。被吸收的能量或者直接转移到相关目标结构(例如病毒的核酸或表面蛋白)，由此破坏目标结构，或者转移到溶解的氧分子上，由此激活氧分子。产生单线态氧，其具有显著的杀病毒和消毒活性。
所用的光敏剂理想地对病毒和其它病原体的基本成分具有高亲和性，例如对它们的核酸，并且对应该净化的制品成分只有很低或者根本没有亲和性。作为光动力学处理的结果，在这种情况下灭活病原体，而保留产品活性。作为处理血浆的适合光敏剂例如描述了吩噻嗪染料亚甲基蓝；核黄素(维生素B2)用来净化血小板浓缩物，并且试验了酞菁染料来净化EK。然而，用于光动力灭活EK中病原体的方法至今为止还没有超出实验室规模。
对于血液本身而言甚至更是如此。一个主要原因可能是，所射入的光必须具有一定的强度，从而可以激活所用的光敏剂，并且血液和EK对各个波长的光只具有极低的穿透性。血浆当然也存在同样的问题，尽管程度不同。
还已知的是，仅仅通过短波紫外(UV)光的辐射，即在约200至320nm的波长范围内，尤其200至小于300nm(UVB和UVC)的波长范围内，同样可以灭活病原体。超过320nm则辐射的能量太低，不能灭活微生物和病毒。与病原体灭活的化学、光化学和光动力学方法相反，仅仅用UV光的辐射基本上具有本身单独有效，而且不需要添加反应性化学品或光敏物质的优点。
用于直接病原体灭活UVC是最有效的。然而，它也有缺点，即它穿透含蛋白质溶液例如血浆或混浊的悬浮液(例如血液和EK)只至极低的穿透深度。UVC在第二次世界大战期间和其后不久被用于进行血浆和白蛋白溶液消毒，尤其灭活肝炎病毒。那时的程序是，溶液在流过装置中作为薄膜经过UVC光源。所述方法被证实不够安全并被放弃(Kallenbach NR，Cornelius PA，Negus D，et al.Inactivation of virusesby ultraviolet light.Curr.Stud.Hematol.Blood Transfus.1989，56，70-82)。
目前使用根据相同的原理运行的改进的方法，以进行治疗用血浆蛋白制品的消毒。在所有情况下，以前和现在的目的都是处理较大体积，即血浆库或者高达几百升或更多的蛋白质溶液(Hart H.Reid K，Hart W.Inactivation of viruses during ultraviolet light treatment of humanintravenous immunoglobulin and albumin.Vox Sang 1993；64(2)：82-88und Chin S.Williams B，Gottlieb P，et al.Virucidal short wavelengthultraviolet light treatment of plasma and factor VIII concentrate：protection of proteins by antioxidants；Blood 1995；86(11)：4331-4336)。
用于消毒多个在每种情况下体积高达几百毫升的单一单元的供血、血浆或EK，上述流过装置并不适合。然而，这正是血库每天实际需要的。
UVB既是杀微生物剂又是杀病毒剂，尽管和UVC相比在程度上不同。UVB穿透含蛋白质溶液和混浊悬浮液比UVC稍好，然而，其穿透深度，例如在血浆中的穿透深度也只在几个毫米的范围内。
血浆和EK大多数从单个供血中分离，或者也从单个供体通过机器单采血液成分术而得到。制品的体积通常为约200至350ml。供血的体积大多数为450至500ml。所述制品在扁平塑料袋中通常深冻(血浆)或者在约4℃(供血，EK)储藏。
期望的是，在这类袋中将所述制品消毒。然而，在此存在上述问题，即其对UV光几乎是不透过性的，除此之外，血液和EK对可见光是不透过性的。
出人意料地发现，上面的问题通过根据权利要求1的方法得以解决。优选的实施方案是从属权利要求的主题，或者在下文中描述。
发明内容
根据本发明，使制品，即供体血液(血液)、血液血浆(血浆)和/或红细胞浓缩物(EK)在其曝光袋中以适合的方式运动，从而实现样品在容器中连续循环。所述运动在此如此强烈，使得在液体或悬浮液内部形成区域性的层，所述层如此薄，使得可以被所施用的光穿透。所述运动必须同时使得袋中的溶液或悬浮液被有效混合。如果满足下列前提，则两者都得以实现：
1.所述曝光袋高度柔性，并且在曝光期间不固定所述曝光袋，例如不夹在玻璃板或石英板之间。因此，其适应所述曝光袋运动时所产生的血浆或悬浮液(血液、EK)的形状变化。
2.所述曝光袋被填充至最大填充体积的最多30％，尤其最多15％。
3.使所述袋强烈运动，例如水平(来回线性或者圆形或椭圆形)或者垂直(摇摆)运动。
强烈运动在此(单独或结合地)理解为：
1.它超出了仅仅引起液体或悬浮液混合的运动。
2.在强烈运动的液体或悬浮液内部，至少暂时、甚至在不同的位置上形成区域，所述区域如此薄，使得UV光或可见光(后者适用于混浊或有颜色的液体或悬浮液，例如EK)可以穿透它。
3.强烈运动时运动方向的逆转如此突然，使得曝光袋中所述制品的较大部分由于惯性继续向原来的方向运动，因此剩余部分可以形成薄层，该薄层可以被所施用的光穿透。
结合同时进行的连续混合，最后使全部制品(和其中包含的病原体)曝光，由此将其消毒。
所述曝光袋在水平的填充状态下只有几个mm厚，例如小于10mm，优选小于5mm，并且打算容纳例如200至500ml的样品体积。然而，所述曝光袋的最大容量(体积)为其中实际包含的待处理样品体积的至少3倍，通常至少6.66倍，优选至少10倍或者甚至至少20倍。
试验研究
所述实验说明方法的有效性，但是不限于所述病毒的灭活。对于所述实验中使用的来自供血的血浆或EK也没有限制，根据本发明的方法还可以用于以其它方式制备的制品。所有描述的实验均进行了3至6次。给出的结果分别表示这些实验的平均值。
血浆单元和红细胞浓缩物
所用的血浆单元和EK通过常用方法从单个供血制备。其体积为约250至300或高达350ml，并且保存在用于血液制品的常用塑料袋中。剩余的白细胞或血小板通过过滤除去。将EK悬浮在稳定剂介质SAG-M中。血浆在低于-30℃的温度下储存，用于实验时在水浴中融化。EK储存在4至8℃的冷藏室内。
病毒学研究
将血浆或EK的等分试样分别掺入水泡性口炎病毒(VesicularStomatitisvirus)(VSV，Indiana株，ATCC VR 158)或辛德比斯病毒(Sinbis-Virus)(ATCC VR-68)或猪疱疹病毒(Suid Herpesvirus)(SHV-1，伪狂犬病病毒，Aujeszky株，ATCC VR-135)。通过CPE测试法(CPE＝致细胞病变效应)确定病毒滴度。以TCID50(TCID＝组织培养感染剂量)给出。非洲绿猴肾细胞株系(Vero)细胞作为指示细胞。所实施的实验中原始病毒浓度为约105至107TCID50。
曝光装置，曝光袋
所用的曝光装置装备有发射UVC光(波长：254nm)的管。辐射从所放置的曝光袋的两侧进行，即从上面和下面。第二个曝光装置装备有发射UVB光(280至320nm)的管。辐射同样从两侧进行。第三个曝光装置装备有发射波长范围在635nm左右的强烈红光的LED(发光二极管)。所有三种装置在运行中放置在每分钟高达100转的轨道震荡器(制造商Buehler公司，Tuebingen；SM 25型)上。所用的曝光袋由较薄的UV穿透性和高柔性塑料膜制成。
实验实施例1
通过UVC对血浆中VSV的灭活：震荡速度和辐射期间血浆自由活动性的影响
在曝光袋中的血浆单元中掺入VSV，并且用UVC辐射2分钟。一个样品在100rpm下震荡，并且在辐射期间牢固地夹在两块石英板之间。其它样品仅仅放在石英板上，以便在震荡期间袋的内部可以运动。震荡器的转速在30至100rpm之间变化。表1中总结出了结果。在牢固夹住的样品中，病毒滴度仅仅降低了约0.3log10的系数。
表1
| 震荡频率(rpm) | 病毒滴度(log10TCID50) | 注释 |
| 0 | 6,21±0,69 | 对照 |
| 30 | 5,78±0,27 | 松散放置 |
| 50 | 4,59±0,04 | 松散放置 |
| 75 | 0,92±0,24 | 松散放置 |
| 100 | 0,35±0,52 | 松散放置 |
| 100 | 5,92±0,11 | 夹紧 |
对于松散放置的样品，转速对病毒灭活的程度有直接的影响：转速为30或50rpm期间，灭活系数与未处理的对照样品相比只是约1.1或2.4log10，在75rpm时升至约5.1，在100rpm时升至约6.6log10。这个实验的结果证明了，血浆在处理期间必须强烈震荡，从而可以使UV光辐射变得高效。为了使得震荡效应也起作用，样品必须松散放置，从而在震荡期间形成可以被穿透的薄层。
实验实施例2
通过利用UVC的辐射对血浆中VSV、辛德比斯病毒和SHV-1的灭活：
灭活动力学
在血浆单元中掺入VSV、辛德比斯病毒或SHV-1，并且辐射1至5分钟。松散放置在轨道震荡器上的样品以100rpm运动，辐射对照样品5分钟，但是不震荡。表2中总结出了实验结果。经过震荡的样品中，VSV的滴度在3分钟内减少了大于6.5log10的系数，而在未震荡的对照样品中，灭活系数不超过1.5log10。辛德比斯病毒被证明比VSV稳定；但是在此，经过震荡和未震荡的样品之间再次显示出了大的差异：在5分钟的辐射时间之后，经过震荡的样品中病毒滴度减少了约5.1log10，而在未震荡的样品中只减少了0.30log10。使用SHV-1时也得到了类似的结果：经过震荡的样品中病毒滴度在4到5分钟内减少了4.3至4.5log10的系数，而在未震荡的样品中辐射5分钟之后只减少了0.3log10。
表2
实验实施例3
通过利用UVB的辐射对血浆中VSV的灭活：灭活动力学
在血浆单元中掺入VSV，并且辐射1至5分钟。松散放置在轨道震荡器上的样品以100rpm运动。辐射对照样品5分钟，但是不震荡。从表3看出，经过震荡的样品中，病毒滴度在5分钟内减少6.36log10的系数，而在未震荡的对照样品中，只减少约1.5log10。结果表明，所发现的现象(通过强烈震荡使松散放置的样品中病原体灭活升高)不只限于UVC。
表3
| UVB(分钟) | 震荡 | 病毒滴度(log10TCID50) |
| 对照 | - | 7,00±016 |
| 2 | + | 4,70±0,08 |
| 3 | + | 3,68±0,12 |
| 4 | + | 2,23±0,23 |
| 5 | + | 0,64±0,08 |
| 5 | - | 5,52±0,08 |
实验实施例4
通过利用亚甲基蓝和光的光动力处理对血浆中VSV的灭活
在血浆单元中掺入VSV，混入0.25μM/L光敏剂亚甲基蓝(MB)并且在转数为100rpm的轨道震荡器上利用红色LED光辐射最长达30分钟。对照样品在同样浓度MB的存在下曝光20分钟，但在此期间不运动。如表4所示，经过震荡样品中病毒灭活程度远大于未震荡样品。后者在20分钟后病毒滴度减少约4.4log10的系数；30分钟之后减少约5.8log10。与此相反，未运动的样品中在20分钟之后减少系数不大于约2.7log10。
表4
| MB/光(分钟) | 震荡 | 病毒滴度(Log10TCID50) |
| 对照 | - | 6,72±0,24 |
| 10 | + | 4,95±0,68 |
| 20 | + | 2,30±0,88 |
| 30 | + | 0,94±0,87 |
| 20 | - | 4,04±0,54 |
实验实施例5
通过利用亚甲基蓝和光的光动力处理对EK中VSV的灭活
在EK等分试样中掺入VSV，混入5μM/L光敏剂亚甲基蓝(MB)并且在转数为100rpm的轨道震荡器上利用红色LED光辐射最长达30分钟。与此相反，对照样品在曝光期间不运动。表5示出了明显的实验结果。很明显，经过震荡的EK样品中病毒灭活大大快于未震荡EK样品。在处理过程中运动的样品中，病毒在30分钟后几乎完全被灭活(灭活系数6.7log10)。与此相反，未运动的样品中在30分钟之后减少系数只有约2.7log10。
实验实施例4和5的结果证明了，如果样品在曝光期间被强烈震荡，则也大大提高血浆或红细胞浓缩物的光动力处理的效率。
表5
| MB/光(分钟) | 震荡 | 病毒滴度(Log10TCID50) |
| 对照 | - | 7,04±0,26 |
| 10 | + | 2,62±0,31 |
| 20 | + | 0,89±0,21 |
| 30 | + | 0,30±0,12 |
| 10 | - | 5,07±0,26 |
| 20 | - | 5,25±0,31 |
| 30 | - | 4,35±0,27 |
Claims (25)
1.用于灭活供体血液、血液血浆和/或红细胞浓缩物中病原体的方法，所述方法包括下列步骤：
-提供供血或从供体血液和/或通过机器单采血液成分术得到的制品，
(a)添加适合的光敏物质，并且通过光辐射来进行光动力处理，所述光包含或仅仅由在所述光敏物质吸收范围内的波长组成，或
(b)利用波长为200至320nm的紫外(UV)光辐射所述制品，
-其中所述制品由大量可单独操作并且分开储藏的单元组成，和
-所述制品分别位于柔性光穿透性(方案(a))或UV穿透性(方案(b))扁平曝光袋中，
其特征在于，
-所述曝光袋被填充了曝光袋最大填充体积的小于30体积％，和
-使所述曝光袋在光动力处理和/或利用UV光辐射期间这样运动，使得曝光袋中的内含物被循环并且通过运动形成变化层厚度的地带。
2.根据权利要求1的方法，其特征在于，所述病原体是病毒和/或细菌。
3.根据前述权利要求中至少一项的方法，其特征在于，所述地带通过运动具有区域，所述区域有规律地暂时得到小于1mm，优选小于0.05mm的层厚度。
4.根据前述权利要求中至少一项的方法，其特征在于，所述运动，尤其运动的幅度这样实现，以使得在所述制品内部形成层厚度有规律地暂时小于0.05mm的区域。
5.根据前述权利要求中至少一项的方法，其特征在于，所述曝光袋与袋内含物接触或可以接触的底侧和顶侧面积总和合计大于袋内含物总内表面积的90面积百分比，优选大于99面积百分比。
6.根据前述权利要求中至少一项的方法，其特征在于，在实施方案(b)情况下，所述辐射是或包含小于320nm至280nm的UVB和/或小于280nm至200nm的UVC，尤其小于260nm至220nm的UVC，优选仅仅由具有上述范围波长的辐射构成。
7.根据前述权利要求中至少一项的方法，其特征在于，每个单元来源于一个至6个供体，尤其来自一个供体。
8.根据前述权利要求中至少一项的方法，其特征在于，所述辐射利用光能为0.3至10J/cm2，优选0.5至5J/cm2的UVB来进行。
9.根据权利要求1～7中至少一项的方法，其特征在于，所述辐射利用光能为0.01至5J/cm2，优选0.1至2J/cm2的UVC来进行。
10.根据前述权利要求中至少一项的方法，其特征在于，所述曝光袋的体积为最高5000ml。
11.根据前述权利要求中至少一项的方法，其特征在于，所述曝光袋可运动地保持在装置中并且尤其不是夹在两个平面之间，使所述曝光袋在所述装置中运动并且被辐射。
12.根据前述权利要求中至少一项的方法，其特征在于，在总曝光持续时间的至少四分之三，尤其至少六分之五时间内所述曝光袋是运动的。
13.根据前述权利要求中至少一项的方法，其特征在于，所述曝光袋通过震荡、倾斜和/或通过旋转来运动。
14.根据前述权利要求中至少一项的方法，其特征在于，所述制品是血浆并且超过80重量％由血液血浆组成。
15.根据权利要求1～13中至少一项的方法，其中所述制品是EK制品，并且其血细胞比容为10至75重量％，优选20至60重量％。
16.根据前述权利要求中至少一项的方法，其特征在于，所述光敏物质是一种或多种吩噻嗪染料，尤其硫堇、亚甲基蓝、甲苯胺蓝和/或天青染料A、B和C。
17.根据权利要求1～15中至少一项的方法，其特征在于，所述光敏物质是一种或多种酞菁染料化合物。
18.根据权利要求1～15中至少一项的方法，其特征在于，所述光敏物质是一种或多种卟啉化合物。
19.根据权利要求16～18中至少一项的方法，其特征在于，所述光动力处理仅仅利用在所用一种或多种光敏剂吸收范围(+/-20nm)的波长来进行。
20.根据前述权利要求中至少一项的方法，其特征在于，所述曝光袋被填充至最大填充体积的最多15％。
21.根据前述权利要求中至少一项的方法，其特征在于，所述血液血浆根据步骤(a)在不存在光敏剂的情况下被处理。
22.根据前述权利要求中至少一项的方法，其特征在于，所述震荡利用轨道震荡器、平台震荡器、摇摆式震荡器或翻滚式振荡器来进行。
23.根据前述权利要求中至少一项的方法，其特征在于，所述曝光袋在一侧放置，使得在运动或震荡期间或者通过运动或震荡，所述曝光袋的高度不断变化，所述高度基于在其上放置所述曝光袋的平面和与曝光袋的上表面相交点之间的距离(表面法线)计，考虑所述曝光袋的整个上表面。
24.根据前述权利要求中至少一项的方法，其特征在于，所述曝光袋的平均填充高度为小于5mm，并且通过运动不断产生波谷，产生小于平均填充高度的一半的层厚度，优选小于1mm或者甚至小于0.05mm的层厚度。
25.根据前述权利要求中至少一项的方法，其特征在于，使所述曝光袋在辐射期间不断地至少在x方向和任选地也在y方向(y方向与x方向成直角)以大于0.2mm，优选大于1cm，尤其1至15cm或2至8cm的幅度运动，并且与之无关地，所述运动的方向变化频率大于0.5Hz，优选1至10Hz。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107833751A (zh) * | 2017-10-27 | 2018-03-23 | 吉林化工学院 | 一种复合膜电极制备方法及光电性质检测方法 |
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