CN1035774A - 经浓缩的稳定微泡型超声成像剂 - Google Patents
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Abstract
本发明为一种微泡型超声成象剂，其特征在于该成象剂包括其直径板大多数小于10微米的微球体的分散体，其中所述的微球体由被不溶于水的生物相容的材料密封的气体气泡所组成。这样成像剂另外的特点是其浓度可大于100×106个微球体/ml，这个浓度能在20-25℃的温度下保持4个星期。
Description
本发明涉及用于诊断目的的人体超声成像，更具体地说，是涉及超声成像剂。
自从1968～1970以来，人们就发现对比回声-心动描记术可用来描绘心脏内部结构的轮廓，探明心脏内的旁路（Gramiak和Shah，1968;以及Feigenbaum等人，1970），心脏的超声成像与目前的诊断手段如血管成像术（使用射线不透过的颜料进行X射线成像，或使用射电核素成像剂进行射电成像）。然而，由于缺乏有效的用于临床的成像剂，超声成像进入实用的过程也大大地被延缓了。
超声成像使用一个超声扫描器产生和接收声波。扫描器置于覆盖被成像区域的人体表面，声波即被导向该区域。扫描器检测反射回来的声波，并把数据转换成图象。当超声能量在一种物质中传播时，这种物质的声学特性取决于该物质的密度及其传播速度。在不同物质的交界面处（如液体-固体交界面或液体-气体交界面），物质的声学特性的改变（如声阻的变化）是最突出的，当超声能量穿过这种介质时，声学特性的改变将导致更强的声波反射供超声扫描器检测。
超声成像剂可以由细小的固态或气体的微粒组成。一旦注入循环系统中后，它们能改善声波的反射，提高图象的清晰度。微泡型成像剂由微小的气（通常是空气）泡（以下简称为微泡）组成，并散布在一种适用于非肠道注入的载体液体中。这些“微小的气泡”由循环系统传送到待成像的器官。
人们曾经提出：在温暖的水凝胶溶液中形成散布的空气小泡，然后再把溶液冷却至凝固温度使气泡不致逸出。引入人体时，先把凝胶分散体加热直至液化，然后通过非肠道注入的方式引入人体，这时空气微泡还散布在液态凝胶（见梯克纳（Tickne）等人的4，276，885号美国专利和梯克纳等人的“国家技术信息服务报告（National Technical Information Serrice Report），HR-62917-1A，1977年4月）。
陷在凝胶中微泡引入血液中后的寿命一般不长。它们很快就散逸了。另外一个缺点是这些微泡还是太大，穿不过毛细管层，从而也就不适合于借助于体外静脉注射的心脏成像。
史蒂文·B·费斯顿博士（Dr.Steven B.Feinstem）对由声波产生微泡的成像剂的发现代表了本技术领域内的一个重要进展。费斯顿博士使用粘性水溶液（如70%的山梨醇或葡萄糖溶液）通过高能量的声波处理溶液产生散布的微泡，这些微泡的尺寸小于10微米，能穿过毛细血管层。这些微泡的持续时间虽然一般只有几分钟，但足以允许制备成像剂并通过静脉注射后进行心脏成像（见费斯顿等人，1984和费斯顿的第4，572，203号美国专利。
后来，费斯顿博士一直在寻求改善微泡的持续性的方法。他发现如用声波对热敏蛋白质如白朊进行处理，即可得到其稳定性得到改善的微泡（见费斯顿的PCT申请，WO84/02838，该申请与1985年12月5日递交的目前已被批准的美国专利申请（序号：805，975）相对应）。得到的微泡浓度为10-14×106个/毫升，微泡的尺寸为2-9微米（凯勒（Keller），费斯顿，沃森（Watsos），1987）。微泡的持久时间是24至48小时。
然而，费斯顿的声波产生的白朊微泡成像剂对商业制造来说还不够稳定。要使一种成像剂在一个中心地点制造然而再分别运送到美国和其他国家中的医院，其稳定性必须是几个星期或几个月（而不是几小时或几天）。为了能方便地进行商业制造、运输和使用前在医院中的存放，其稳定时间至少需要达到四个星期，最好是至少八个星期甚至更长。
另外，为了进行最有效的成像，成像剂中的微泡浓度最好是能达到的最高浓度。但是，成像剂中所希望的小尺寸微泡的数量会随着经声波处理的白朊溶液的存贮时间的增加而下降。微泡的碰撞与尺寸过大的微泡的结合都将引起小微泡的数量消耗。因此，一个重要的目标就是要找到一种能增加成像剂中的微泡浓度的装置。一种微泡浓度非常高的成像剂以本质上就好得多，能提供一个安全因数。如果微泡的浓度高于有效成像所需的最低值，那么，损失一些具有有用尺寸的气泡也是可以接受的。
本发明提出了一种经浓缩的常温稳定的超声成像剂，其特点在于包括一种可用于非肠道引入的水溶液介质，该水溶液介质中散布着直径极大多数小于10微米微球体，这些微球体由不溶于水的生物相容（biocampatible）材料密封成的微泡组成，上述成像剂的均匀散布浓度大于100×106个微球体/毫升，并能在20至25℃的温度范围内在四个星期内维持上述浓度。上面说到的不溶于水的生物相容物质可以是类似白朊的材料。
上面所述的本发明的成像剂的平均散布浓度大于100×106（即108）个微球体/毫升，它代表了本技术领域内的一个显著进展。这个高浓度可以在通常的室温（20-25℃）下维持较长的时间（4至8星期甚至更长）。在某些最佳实施例中，微球体的密度可达到300-500×106个微球体/毫升。令人惊 
的是，这些高浓度能维持的时间超过八个星期。因此，本发明的成像剂适用于以商业为基础的制造和运输。运到以后，医院可以把它们保存好几个星期，此时，它们还能按要求被用于诊断。
本发明的成像剂最好由一种热可变属性的生物兼容蛋白质通过逐步的声波处理步骤制成。与费斯顿的方法一样，先对一种蛋白质水溶液进行声波处理形成气体微泡，同时加热该溶液，使一小部分的蛋白质降低可溶性。但是，经改进的声波处理步骤采用一种全新的顺序声波处理，它将产生浓度增加的高稳定微泡。在上面的这个初始声波处理阶段，近距离声波发生器的喇叭型辐射器直接与溶液接触（亦即刚浸入溶液的上表面之下）。进行这一初始声波处理时将察觉不到溶液起泡。在下一阶段的声波处理将加速泡沫的形成。此时，近距离声波发生器的喇叭型辐射器缩至环境空气中溶液的表面以上但是临近溶液表面的一个位置。将大量地发生起泡和气溶（aerosolate）现象。微泡的数目因此大量增加，这些微泡被属性已变的蛋白质所密封，这样可得到高度稳定的微球体散布。此外，微球体的稳定度允许它们能被浓缩和/或分馏。经过这样的处理之后，气泡的浓度将变成二倍甚至二倍于原浓度，同时大尺寸的气泡将被剔除掉。
举个例子来说，经初始生产步骤后微球的浓度可能是从50至150×166个微球/毫升。经过一种浮层分离浓缩步骤之后，微球的浓度可以上升至200至600×106个微球/毫升。经过另一种浮层分离步骤之后，尺寸大于70微毫的大部分微泡可以去除，这样就生成了基本上由直径极大多数小于10微米的微球体构成的成像剂。举例来说，至少80%的微球体的直径在1-9微米的范围内。
下面的附图说明了制备本发明的超声成像剂的一种最佳方法。
图1A至1D。示出了顺序声波处理步骤中的各个步骤。
图2.是沿图1中的线2-2的剖面图，示出了近距离声波发生器的喇叭型辐射器与盛有待声波处理的白朊溶液的唧筒的内壁的位置关系。
图3.示出了一个分离器容器，其中微球散布的溶液被汇集起来进行浮层分离浓缩。
图4，4A和4B，示出了分馏微球散布体从而去除尺寸过大的微球体的一种方法。
图5.是一张实验数据表，示出了刚制造后的成像剂中的微球体浓度和它们的存贮稳定度。
实施本发明的起始材料是一种合适的生物相容（biocompatible）材料的水溶液。这种密封材料必须是热敏的，这样在声波处理期间通过加热就能部分地降低可溶性。更具体地说，在声波处理的同时，一小部分溶解了的生物兼容材料被加热或被用其他手段处理使其可溶性降低。这样将生成少量的固态材料，这些固态材料在微球体周围形成一个密封层。最好选用一种热敏型蛋白质如白朊、血红蛋白、胶原蛋白等等。用于人类时，最好选用人体蛋白质，人体血浆白朊（HSA）特别合适。作为5%的无菌水溶液。HSA可从市场上买到，它可直接作为制备微球体的起始材料。此外，其他浓度的白朊和其他类型的热-可变属性型蛋白质也可选用。HSA的浓度可以从（比方说）1%至25%（重量百分比）。
市场上能得到的近距离声波发生设备即可用来实施本发明。从理论上讲，声波发生器的振动频率在一个相当大的范围内（如5至30KHz）内变动，但大多数从市场上买得到的近距离声波发生器工作在20KHz或10KHz。20KHz的近距离声波发生器完全适用于本发明。这样的近距离声波发生器从超声加热设备公司（Heat Systems-Ultrasonics，Inc.，Farmingdale，New York）和其他一些公司买到。W-380型或其它类似类型的超声设备可以和一个平端的高增益喇叭型辐射器一起使用。如W-380型超声设备上，送入声波发生器的辐射器的功率可以在制造商标定的功率设置1-10之间变化。一般可使用中间的功率设备（即4-8）。振动频率和馈入的功率必须足以在待处理的溶液中产生气窝现象（carvitatioa）。
待声波处理的溶液可以以很小的增量加以处理，如每次单独处理8ml的溶液。进行初始声波处理时，平端形声波发射器的喇叭型辐射器与溶液接触，最好刚浸过溶液的上表面。为了进行初始声波处理而不产生可察觉的泡沫，浸入是应该的。功率设置可定在4-6之间，初始声波处理不到一个钟（即15到45秒）即可完成。
初始阶段声波处理完成以后，喇叭型辐射器马上缩至溶液之上但临近溶液的上表面的一个位置。在这一阶段（第二阶段），进行声波处理时人为地使溶液产生大量泡沫;这一点与避免产生泡沫常规声波处理不同。在本发明中，产生泡沫和气溶对于得到改进浓度和稳定性的成像剂是非常重要的。
为了增加泡沫，声波发生器的喇叭型辐射器的功率输入可以增加至第二个阶段。举例来说，功率设置可以由最初的设定值4移至设定值6。第二阶段的声波处理可以在一分钟之内（即15至45秒）内完成。第一和第二阶段的声波处理的总时间的数量级可以是一分钟。举例来说，每个阶段都使用25至35秒的声波处理。第二阶段声波处理产生的泡沫可以通过溶液的云雾状外观及形成的泡沫马上可以监察到。
通过进行顺序声波处理（包括起泡沫阶段后面的气窝阶段），密封微泡（上面也称为“微球体”）的浓度大大地增加了。超过25×106个微球/毫升的浓度（如从50×106至150×106个微球体/毫升）很容易达到。此外，产生的小球的直径的极大部分小于10微米。比方说，80%甚至更多的微球体具有的直径在1微米至9微米的范围内，其平均直径为4至6微米。
当与作为环境气体的空气接触进行声波处理时，微球体将有空气芯。空气是最方便的环境气体，但是如果需要的话，声波处理也可以在其他气体（如氮、氧、二氧化碳等等）环境下进行。
初始生产以后，微球体散布必须进行进一步处理以增加浓度和/或去除尺寸过大的微球体。由于微球体是有浮力的，因此，它们有上升至分散体表面的趋向。把分散体不加搅动放置几个小时（如4至12小时）后，大多数微球体上升至表面，集中在清澈液体上方的一层中。由于微球体都“浮层分离”在一上层中，清澈的液体部分可以从微球体的下方放掉，这样，就得到一种微球体密度更高的分散体。举个例子来说，体积为50%在75%的溶液可以在这个浓缩处理中被排放掉。
不管上述的浓缩步骤的以前还是以后，都对尺寸过大的微球体进行浮层分离。大尺寸（如直径大于10微米）的微球体具有较大的浮力，因此，它们将较快地升至溶液的表面。放置一个较短的时间（如15-45分钟）后，尺寸最大的那些微球体可以以散布体上方的一液层中有选择地收集出来，此时，所有的小尺寸微球体还在散布体之中。放出大尺寸微球体层下方的微球体散布层，就实现了分馏。这时，大尺寸的微球体还留在其中进行分馏的容器之中。
通过两个阶段的声波处理的结合以及浮法分离浓缩制成的成像剂具有的平均散布浓度大于300×106（举个例子来说，可达300×106至900×106）个微球体/毫升。保存在环境空温（20-25℃）下时，这些高浓度可维持很长一段时间。高于200×106（典型情况下高于300×106）个微球体/毫升的高浓度至少可以维持四个星期，一般为八个星期甚至更长。
图1A中示了一个10ml的唧筒，其顶部开口，其下部的排放端有一柱塞式阀门。唧筒中的5%的白朊（HSA）溶液加至8ml刻度。近距离声波发生器的喇叭型辐射器插入唧筒中的7ml刻度，在图1B中被标为位置T1。在这个位置上，喇叭型辐射器已浸入溶液的上部，图1B中也示出了溶液的液面。进行初始声波处理时，溶液基本上不起泡沫。
初始声波处理之后，不用关掉声波发生器，立即把喇叭型辐射器抽至10ml刻度（即图1C中所示的位置T2）。声波发生器的喇叭型辐射器的功能输入在它被换至位置T2时就能增加。抽出以后，白朊溶液中马上出现泡沫，溶液的外观也变成乳白色。溶液在第二阶段中将沿声波发生器向上发生起泡。图1D中示出了起泡溶液的外观，其中的微泡直径与它们的微米范围内的实际尺寸相比被大大地放大了。
被进行声波处理的溶液中既包含溶解了的空气也包括夹杂空气。溶液绕着喇叭型辐射器与环境大气接触（这一点辐射器和唧筒内壁的缝隙可以以图2中的剖面图中看得很清楚）。这种空气接触将便于发生溶液在声波处理的第二阶段起泡和气溶。
多批经声波处理过的溶液可以汇集在一起进行浓缩处理。举个例子来说，多个散布体增量可以引入一个分离容器中，这种分离容器可以是大唧筒或者是底部设有可用排放阀控制的出口的分离漏斗。图3中以大唧筒的形式示出了这样的一种分离容器。把汇集起来的溶液不加搅动存放几个小时（如存放过夜），则微球体都会升至溶液的顶部，形成一层浮法分离的微球体。在待收集的微球体层下方，清澈的白朊溶液中几乎不含有微球体。因此，通过底部排放口就能排放掉大部分的溶液，比方说，能放掉一半至四分之三的溶液。但是，最好还应保留足够体积的溶液，以允许被浓缩的微球体自由重新散布。
图4中示出了由重新散布的微球浓缩成的微球体。这些微球体足够稳定，它们在浓缩层中并不永久地粘在一起，而是作为分离的完整微球体存在。轻轻地搅动就能使它们重新散布。
当重新散布到一种基本均匀的状态后，就可以进行分流以剔除尺寸过大的微球体。把这种重新散布体存放一个短时间（如30分钟）后，最大直径的微球体将优先地升至液面并集中在一个液层中，如图4A所示。出现这种情况后，大尺寸微球体下面的微球体散布体可以从排放阀中排放掉。当集中了的大尺寸微球体低达排放阀时，关紧排放阀，使这个大尺寸液层留在分离容器中，如图4B所示。最后得到的产物是经浓缩和分馏的白朊微球体产物，其中至少80%的微球体具有的直径在1-9微米的范围内。最佳的结果是至少90%的微球体的直径在2-8微米之间。
下面再在各个标题之下另外给出一些指示性细节。
声波处理：
取一个底部排放口装有柱塞的、截面为椭圆形的唧筒，用5%的人体血浆白朊无菌溶液加至8ml。把一个截面面积小些的声波发生器的能量输出装置置于唧筒中，使该能量输出装置和底部在7ml刻度处。把能量设定定在6，工作30秒;然后，把能量输出装置的底端移至10ml刻度处（此时声波发生器依然开着），再把能量设定移至8。再进行25秒的声波处理。最后，关掉声波发生器，移开能量输出装置，再把唧筒中的溶液放入一个60ml的唧筒或带有柱塞控制的底部排放口的分离漏斗。上面的大唧筒或分离漏斗可汇集5-6小唧筒的溶液。
浓缩：
使记集起来的液体在一个分离容器中不加搅动存放过液（8-12小时）。当差不多所有的微球体升至液面并在液面处形成一液层时，从底部排放掉三分之一体积的溶液。
分馏：
使微球体重新悬浮，并用它们充满一个60ml的唧筒。放置30分钟，然后把差不多所有的液体（留下最后的3-4ml）放入一个收集容器中，留下的是尺寸过大的微球体。取一点样品，计算一下浓度，平均直径和小于10μ的百分比。如果小于10μ的百分比低于99.5%，重新进行分馏。如果需要重新散布，其浓度可根据5%HSA来调整。
结果：
表A中列出的浓度测量三次代表性操作中使用了上面描述的各步骤。声波处理后的初始散布浓度的数量级为130-140×106/ml，除法分离浓度后的可达340-450×106/ml。
为进行生产控制，也可以用一台考尔脱（Coulter）计数器对微球体进行计数，这样的计数器（即PAII型考尔脱计数器）可以从考尔脱电子公司（Coulter Electronics，Inc.，Highleah，Florida）买到。上面所述的微球计数值是这样确定的：
对代表物产品的稳定性测试是在长达20星期的研究中进行的。最初的浓度大致是4.31×108（431×106）个微球体/毫升，对浓度的测量是以大致为一周的间隔来进行的。其结果总结在表B中。这样用考尔脱计数器测得的数据在图5中被画成了图表。样品保存在环境室温（20-25℃）下。大致为400×106个微球体/毫升的浓度维持了20个星期，这就证实了样品在室温下的高度稳定性。
微球体的稳定性受异常的高温或低温的影响。然而，即在低达4℃和高至37℃时，超过200×106个微球体/毫升的浓度还能维持8个星期或更长。不管怎么说，在进行商业运输或长期存放时应避免极高或极低的温度。最好保存在室温下。在运输过程中可以使用温度保护措施。
表A
浓度测量值
实验 微球体数/ml 微球体数/ml
（声波处理前） （声波处理后）
A 135×106386×106
B 141×106483×106
C 133×106440×106
表B
星期 微球体浓度（×108）
0 4.31
1 4.49
2 4.20
3 3.91
4 3.86
5 4.25
6 4.06
7 4.12
8 3.92
9 3.94
10 3.97
11 3.48
12 3.48
13 4.09
14 3.70
15 4.92
17 4.15
18 3.99
19 4.14
Claims (10)
1、一种经浓缩的室温稳定型超声成像剂，其特征在于包括一种能进行非肠道引入的水溶液介质，这种水溶液介质中含有直径极大多数小于10微米的微球体的散布体，上述的微球体由不溶于水的生物兼容材料密封住气体气泡而组成，上述的成像剂平均散布浓度大于100×106个微球体/毫升，这样的浓度能在20-25℃的温度上维持4个星期。
2、一种如权利要求1所述的成像剂，其特征在于至少80%的上述微球体具有的直径在1-9微米的范围内。
3、一种如权利要求1或2中所述的成像剂，其特征在于上述微球体的平均散布浓度大于299×106个/毫升，在20-25℃的温度下这样的浓度能维持4个星期以上。
4、一种如权利要求1、2或3中所述的成像剂，其特征在于所述的微泡被人体血浆白朊所密封。
5、一种经浓缩的室温下稳定的超声成像剂，其特征在于包括一种可通过非肠道引入的热变属性型生物相容蛋白质的水溶液，该孔溶液中包含其中至少80%的直径在1-9微米之间的微球体的分散体，上述的微球体由被热可变属性的生物相容蛋白质密封的气体微泡组成，上述成像剂的平均散布浓度大于200×106个微球体/毫升，并能在20℃-25℃的温度上维持这样的浓度4个月以上。
6、一种如权利要求5所述的成像剂，其特征在于其平均散布浓度可达300至600×106个微球体/毫升，这样的浓度在20℃-25℃之间温度上至少可以保持8个星期。
7、一种根据权利要求5或6所述的成像剂，其特征在于所述的蛋白质是人体血浆白朊。
8、一种根据权利要求5、6或7中所述的成像剂，其特征在于90%或者90%以上的微球体的直径在2至8微米的范围内。
9、一种经浓缩的室温下稳定的用于静脉注射的超声成像剂，其特征在于包括人体血浆白朊的无菌水溶液，该水溶液中含有至少80%的直径在1-9微米的范围内的微球体的分散体，上述的微球体由被一层不溶于水的上述白朊所密封的空气泡所组成，所述成像剂的平均分散浓度为300-600×106个微球体/毫升，这样的浓度在20℃至25℃的室温下维持8个星期。
10、一种根据权利要求9的成像剂，其特征在于至少90%的所述微球体的直径在2-8微米的范围内。
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| US07/139,576 US4844882A (en) | 1987-12-29 | 1987-12-29 | Concentrated stabilized microbubble-type ultrasonic imaging agent |
| US139,576 | 1987-12-29 |
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| CN1035774A true CN1035774A (zh) | 1989-09-27 |
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| US4276885A (en) * | 1979-05-04 | 1981-07-07 | Rasor Associates, Inc | Ultrasonic image enhancement |
| DE3141641A1 (de) * | 1981-10-16 | 1983-04-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Ultraschall-kontrastmittel und dessen herstellung |
| US4718433A (en) * | 1983-01-27 | 1988-01-12 | Feinstein Steven B | Contrast agents for ultrasonic imaging |
| US4572203A (en) * | 1983-01-27 | 1986-02-25 | Feinstein Steven B | Contact agents for ultrasonic imaging |
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- 1987-12-29 US US07/139,576 patent/US4844882A/en not_active Expired - Lifetime
-
1988
- 1988-10-13 IL IL88039A patent/IL88039A/xx active Protection Beyond IP Right Term
- 1988-11-02 CA CA000581985A patent/CA1325590C/en not_active Expired - Lifetime
- 1988-12-23 JP JP63323826A patent/JPH0662445B2/ja not_active Expired - Fee Related
- 1988-12-28 KR KR1019880017665A patent/KR960005709B1/ko not_active IP Right Cessation
- 1988-12-28 CN CN88105824A patent/CN1028963C/zh not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042700C (zh) * | 1996-06-25 | 1999-03-31 | 谢峰 | 含有全氟化碳或六氟化硫的右旋糖酐白蛋白声学造影剂及其制作方法 |
| CN104519989A (zh) * | 2012-06-26 | 2015-04-15 | 通用电气医疗集团股份有限公司 | 制备包含气体微泡的组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| US4844882A (en) | 1989-07-04 |
| CA1325590C (en) | 1993-12-28 |
| JPH0662445B2 (ja) | 1994-08-17 |
| JPH01203337A (ja) | 1989-08-16 |
| IL88039A (en) | 1992-07-15 |
| KR960005709B1 (ko) | 1996-05-01 |
| KR890009418A (ko) | 1989-08-01 |
| CN1028963C (zh) | 1995-06-21 |
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