CN1079678C - 耐压充气微泡的长效水质分散液及其备方法 - Google Patents

耐压充气微泡的长效水质分散液及其备方法 Download PDF

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CN1079678C
CN1079678C CN93100154A CN93100154A CN1079678C CN 1079678 C CN1079678 C CN 1079678C CN 93100154 A CN93100154 A CN 93100154A CN 93100154 A CN93100154 A CN 93100154A CN 1079678 C CN1079678 C CN 1079678C
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米切尔·施奈德
严芬
帕斯卡尔·格勒尼耶
杰罗姆·皮杰尼尔
玛丽·贝纳代特·巴罗
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Abstract

通过用气体作为填充剂，这些气体在标准条件下在水中的溶解度(升气体/升水)除了分子量的平方根所得的商不大于0.003，可以使在超声回波检测术中用作对比剂的充气微囊得到显著的在压力下抗瘪陷的能力。

Description

耐压充气微泡的长效水质分散液 及其制备方法
本发明涉及充气微囊在水质载体液中的稳定分散液或组合物。这些分散液通常可用于要求气体均匀地分散于液体的多种用途。这些分散液的一个令人注目的应用是将其注入生物体，如用于超声波回波检测术及其它医学用途。本发明还涉及制备上述组合物的方法，包括制备中涉及的一些物质，如耐压充气微泡、微囊和微球。
众所周知，悬浮于液体中的空气或气体的微体或微球(此处定义为微囊)，例如微泡或微球，是回波检测术的极有效的超声反射体。在本说明书中，“微泡”这一术语特别是指悬浮于液体中充满空气或气体的空心球，得自以分离的形式在液体中引入空气或气体，该液体最好还含有表面活性剂以控制表面性质和气泡的稳定性。术语“微囊”或“微球”是指有物质边界或包衣即聚合物膜壁的充空气或气体的物体。微泡和微球均可用作超声波衬比剂(contrast agents)。将载体液中含充气微泡或微球(0.5-10μm范围内)的悬浮液注入活体血流，将极大地增强超声波回波的成像，从而有助于内部器官的显现。脉管和内部器官的成像可极大地有助于医学诊断，例如对心血管和其他疾病的检测。
用于回波检测术的在可注射的液状载体中的微泡悬浮液可以如下方法制备：释放在加压下溶于液体的气体，或通过产生气体产物的化学反应，或将含有空气或气体(捕获或吸附于其中)的可溶性或不溶性固体与该液体相混合。
例如，在US-A-4,446,442(Schering)中揭示了用(a)表面活性剂在水质载体液中的溶液和(b)作为稳定剂的增粘剂溶液来制备在无菌可注射液状载体中的微气泡悬浮液的一系列不同的技术。为产生气泡，该文所揭示的技术包括使(a)、(b)和空气的混合物以高速通过一小孔；或在临用前将(a)和一种生理学上可接受的气体一起注入(b)；或将酸加到(a)中，碳酸盐加到(b)中，在临用前将两种成分混合，使酸和碳酸盐反应，释放出CO2气泡；或将加压气体加到贮存下的(a)和(b)混合液中，当混合液用来注射时，该气体释放出来成为微泡。
EP-A-131,540(Schering)揭示了微泡悬浮液的制备方法，该法中将稳定的可注射载体液诸如生理盐水或糖溶液如麦芽糖、右旋糖、乳糖或半乳糖溶液与含有包入空气的同样糖的固体微粒(0.1-1μm范围内)混合。为了生成液状载体中的气泡悬浮液，在无菌条件下将液体和固体成分一起搅动，一旦形成后，悬浮液必须立即使用，即应在5-10分钟内注射以用于回波测定；事实上，因为它们是瞬间即逝的，经过这段时间后，气泡浓度就会变得太低而不能实际使用。
在克服瞬间即逝问题的努力中，产生了微球，即具有物质壁的微囊。如前所述，微泡只具有非物质壁的或瞬间即逝的外衣，即只被液体壁包围(由于表面活性剂的存在，其表面张力得到改善)，而微球或微囊则具有实体物质制成的有形外衣，例如有一定机械强度的聚合物膜。换言之，它们是在不同程度上将空气或气体紧紧地包围于其中的物质微囊。
例如，US-A-4,276,885(Tickner等)揭示了将含气体的表面膜微囊用来增强超声影像，该膜包括多种无毒和无抗原性的有机分子。在一个公开的实施方案中，这些微囊具有抗聚结的明胶膜，它们较佳的大小为5-10μm。这些微囊的膜据报导对于作回波测定是足够稳定的。
US-A-4,718,433(Feinstein)公开了不含明胶的充空气微球。这些微囊是通过蛋白质溶液如5％血清白蛋白的声处理(5-30KHz)而制备的，直径在2-20μm范围内，主要是2-4μm。声处理后通过成膜蛋白质的变性来使微囊稳定化，例如用加垫或化学方法，如与甲醛或戊二醛反应。用此技术得到的稳定的微囊的浓度据报导为：2-4μm范围内的约8×106/ml，4-5μm范围内的106/ml，以及5-6μm范围内的少于5×105/ml。这些微囊的稳定时间据说为48小时或更长，使在静脉注射后可方便地形成左心影像。例如，声处理的白蛋白微泡注入外周血管可经肺途径，导致左心室腔和心肌组织的超声心动图变暗。
近来，EP-A-324,938(Widder)报告了用于注射超声回波检测术的更为改进的微囊。在此文件中揭示了小于10μm的高浓度(＞108/ml)、包以蛋白质的充气微囊，它们的寿命为数月或更长。这些微球的水悬液是通过可加热变性蛋白如人血清白蛋白的超声空化而制备的，该处理也导致成膜蛋白一定程度的发泡及其后的加热硬化。其它蛋白质如血红蛋白和胶原蛋白据说也可用于该方法。
EP-A-324,938公开的微球悬浮液的高度贮存稳定性使其本身能出售，即以水载体形式出售，这具有很大的商业价值，因为不再需要在使用前制备。
在水质微泡悬浮液的制备上最近也揭示了类似的优点，即揭示了可稳定贮存的干粉状组合物，在加水时会产生长效气泡悬浮液，见于PCT/EP91/00620申请，在该申请文件中，将含成膜脂类的脂质体冻干，冻干的脂类暴露于空气或一种气体中一段时间后，当在其中单纯加入水质液状载体时，便会产生长效气泡悬浮液。
在水质微泡悬浮液贮存稳定性方面尽管获得很多进展(不论是前体或终制备阶段)，但至今仍存在当悬浮液置于超压下时空泡的持久性问题，例如，在压力变化时的情况，如注射入患者血流中连续受心脏搏动(特别是在左心室)所产生的压力变化。本发明者们实际上在诸如麻醉家免上观察到，在注射后一段时间内压力变化不足以显著地改变气泡的数目。相反，在狗和病人身上，充满普通气体如空气、甲烷或CO2的典型微泡或微球在注射后大约几秒钟内就会由于血压效应而完全瘪陷。这一观察被其他人所证实，例如，S.Got-tlieb等在J.Am.Soc.of Echocardiography 3(1990)：238报导了用声处理法制备的交联的蛋白微球在受到60乇超压后失去全部回波源性质。因此，解决这一问题，并延长微泡和包膜微球悬浮液在压力下的使用寿命，以确保能在体内安全和可重现地进行回波测定，已变得十分重要。
现时应提到的是，另一种回波描记影像增强剂已被提出，由于它们包含具有多孔结构的普通微球，孔中含空气或气体，从而能抗超压。这样的微球公开于诸如WO-A-91/12823(DELTABIOTECHNOLOGY)，EP-A-327490(SCHERING)和EP-A-458079(HOECHST)。普通多孔微球的缺点是形成囊状物的充气自由空间一般太小，不能得到好的回波响应，而且这些球缺乏适当的弹性。因此，一般仍选用空心微囊，并对瘪陷问题的解决进行探索。
通过使用符合权利要求书中列出的标准的气体或气体混合物，现已解决了这个问题。简言之，发现在具有符合下面方程式的物理性质的气体存在下，制成至少部分填充该气体的回波源微囊，在注射后，在足以获得可重现的回波图象测定时间内，微囊明显地能抗御＞60乇压力：
Figure C9310015400081
在上述方程式中，“S”指在水中的溶解度，“BUNSEN”系数，即在标准条件(1巴，25℃)及1大气压给定气体的分压下被单位体积水溶解的气体的体积(见Gas Encyclopaedia，Elsevier 1976)，因为在这样的条件和限定下，空气的溶解度为0.167，其平均分子量(Mw)的平方根为5.39，上式简化为：
在下文实施例中公开了充填各种不同气体及其混合物的回波源微泡和微球的试验以及它们在体内外对压力增加的相应抗力(见表)。在表中，水溶解度因子也取自前述Gas Encyclopaedia，“L′AirLiquide”，Elsevier Publisher(1976)。
按照本发明的水质悬浮液中的含气体微囊，包括至今已公开的用作回波检测术衬比剂的多数微泡和微球。较佳的微球是在EP-A-324,938，PCT/EP91/01706和EP-A-458745中公开的那些；较佳的微泡是PCT/EP91/00620中的那些。这些微泡便利地得自水质液体和含有片状的冻干磷脂和稳定剂的干粉(微囊前体)；微泡是通过将此粉末与水质液状载体混合搅拌而形成的。EP-A-458745的微球具有孔隙率受控制的界面沉积的有弹性的聚合物膜。它们一般是这样获得的：使聚合物溶液在含水液态载体中的乳浊液内形成(聚合物溶液)微液滴，接着使聚合物从其溶液中沉淀出来，在微液滴/液体界面形成产生薄膜的膜，此过程导致先形成充填液体的微囊，其液体核心最后被气体取代。
为了实施本发明的方法，即用符合前述关系的气体形成或充填微囊，这些微囊在水质载体中的悬浮液构成所需的回波源添加物，可以采用以下二步途径作为第一个实施方案，包括(1)在任何合适的气体存在下，用任何适当的常规技术，从合适的起始物质制备微囊，(2)用一种符合本发明限定的新的气体(第二气体)取代制备微囊原先用的气体(第一气体)(气体交换技术)。
或者，根据第二个实施方案，可在符合本发明限定的新气体的氛围下用合适的常用方法直接制备所需的悬浮液。
如果采用二步法，可先从微囊除去原来的气体(例如在负压下抽去)，然后引入第二气体与抽空的产物接触，或者在第二气体可从微囊取代第一气体的条件下将仍含第一气体的微囊与第二气体接触(气体取代)。例如，微囊悬浮液或其前体(此处，前体可指制成微囊包衣的物质，或当与水质载体液搅拌时可在液体中产生微泡的物质)可置于减压下以抽去气体，然后通入所需进行取代的气体恢复至周围压力。这一步可重复一次或多次以确保原来的气体被新气体取代。这一实施方案特别适用于制备干贮存的前体，如用于干粉，它在与适量载体液混合时产生回波源添加物气泡。因此，在一个较好的例子中，该例子中微泡是从水相和干的层状磷脂例如脱水冻干脂质体加稳定剂的粉末(此粉末随后在液状水载体相中搅拌分散)而生成的，最好是将干粉贮存在按本发明选择的气体的气氛中。这种制剂将可无限期地保存在这种状态，若将其在注射前分散于无菌水中，可在任何时候用于诊断。
或者(当对液体载体相中的微囊悬浮液实行气体交换时特别是这样)用第二气体中洗液体载体相直至交换(部分或全部)足以达到所需目的。通过从气体管子中鼓泡，或有时候在轻微的搅拌下，仅仅用新气体流(连续的或断续的)扫过含微囊的液体表面，就可以达到冲洗目的。在这种情况下，替换的气体在含悬浮液的烧瓶中可只加一次，并按原样保持一定时间，或者可更新一次或一次以上，以确保更新的程度(气体交换)近于完全。
或者，在如前所述第二个实施方案中，可用通常的前体(起始物质)开始，完成回波添加物悬浮液的全部制备，这些前体是现有技术所提到的，制备时也按现有技术的常用方法，但在本发明所需气体或气体混合物的存在下进行操作，而不是在现有技术中常用的那些气体，如空气、氮气、CO2和类似气体中进行。
应当注意到，该制备方式一般涉及以第一类气体制备微囊，然后用第二类气体取代原来的气体，后者是为了将不同的回波源性质赋予所述微囊，这样的制备方式有以下优点：正如从下文实施例的结果将会很好地看到，用于制备微囊(特别是有聚合物包衣的微球)的气体的性质对所述微囊的总体大小(即平均直径)有一定影响：例如在精确设定的条件下在空气中制得的微球的体积可以准确地控制在所需的范围内，例如适合于左心室和右心室回波描记的1-10μm范围。在用其它气体，特别是符合本发明要求的气体时，这并不是太容易的，因此当希望获得其大小在给定范围内的微囊；但其所充气体的性质使直接制备变成不可能或非常困难时，可以极有利地依靠二步制备途径，即先制备含有一种气体的微囊，该气体使微囊有较精确的直径和数目控制，然后通过气体交换用第二种气体来取代第一种气体。
在接下来的实验部分的描述(实施例)中，将悬浮于水或其他水溶液中的充气微囊，置于高于周围气压的压力下。注意到当超压达到一定值时，该值一般是微球参数和工作条件如温度、加压速率、载体液的性质及其所溶解气体的含量(这一参数的相对重要性将在下文详述)、气体充填物的性质、回波源物质的类型等一系列条件下的典型值，这时微囊开始瘪陷，气泡数随压力进一步增加而不断减少，直至声反射器效应的完全消失。这一现象可用光学方法观察(浊度测定)，因为它同时发生相应的光密度改变，即当气泡不断瘪陷时，介质的透光度增加。为此，将微囊的水悬浮液(或其适当的稀释液)放在分光光度计比色皿中，保持在25℃(标准条件)下施加正的流体静力超压下并逐渐增大，于600或700nm处连续测定吸光度。压力是由一蠕动泵(GILSON′s Mini-puls)产生的，该泵向联于分光光度计比色皿的可变高度的液柱输料，比色皿是密封不漏的。用水银压力计(经校正，用乇表示)测量压力。实验发现加压速率与泵的速度(rpm)呈线性相关，上述范围内的吸光度与载体液中微囊浓度成正比。
图1表示在上述范围内用光密度表示的微泡浓度(微泡数)和加于微泡悬浮液的压力之间的关系，制图的数据取自实施例4的实验。
图1显示吸光度的改变与压力的关系是一条S型曲线。低于某一定的压力值时，曲线接近平坦，表明微泡是稳定的。然后，出现相当快的吸光度降低，这表明存在一个相当狭的临界区，在该临界区内，任何压力增加对微泡的数量均有极引人注目的影响。当所有微泡消失时，曲线又变平坦。曲线上的临界点选在较高和较低光密度读数的中间，即“全部”微泡(ODmax)和“无”微泡(ODmin)测量值的中间，实际上相应于开始存在的微泡消失约50％之外，即光密度读数为起始读数约一半之处，在图上相应于加压悬浮液的透光度最大处的高度(基线)而设定。这一点也在曲线斜率最大处附近，定义为临界压力PC。实验发现，对于一种给定的气体来说，PC不仅依赖于上述各参数，而且还特别依赖于已溶于载体液中的气体(一种或几种)的浓度：气体浓度越高，临界压力越高。就此而论，人们可因此而通过一种可溶性气体(可与填充微囊的气体相同或不同)来使载体相饱和，从而增加微囊在压力下的抗瘪陷能力。例如，用CO2饱和溶液作载体液，可制成抗超压能力很高(＞120乇)的充气微囊。不幸，这一发现在诊断领域的价值是有限的，因为一旦衬比剂注入患者血流(其中气体含量当然失去控制)，就在血液中稀释到这样的程度，使原来溶解在注射样品中的气体的作用变得微不足道。
另一可再现地比较作为微球填充剂的各种气体的性能的易得到的参数是压力间距的宽度(ΔP)，该间隔由微泡数(表示为光密度)等于原微泡数的75％和25％的两个压力值限定。如今，令人吃惊地发现，对于压力差DP＝P25-P75超过约25-30乇的气体来说，血压对充气微囊的杀灭效应减到最小，即微泡数的实际减少缓慢到不会损害回波测量的显著性、精确度和再现性。
此外还发现，在图1所示的实验中，PC和ΔP值也依赖于压力升高的速率，即压力增大速率在一定范围内(例如在每分钟几十至几百乇的范围内)，速率越高，PC和ΔP值越大。由于这个原因，在标准温度条件下所作的比较也在恒定增压速率100乇/分钟下进行。然而应当注意，对于很高的速率，压力增大速率对PC和ΔP值的影响不再增大；例如在每分钟几百壬的速率下测得的乇的速率下测得的值并不明显区别于由心跳决定的条件下测得的值。
尽管为何某些气体遵循前述性质而另一些则否的原因尚未完全阐明，但看来有些关系可能存在于其中，这些关系除分子量和水溶性外，还涉及溶解动力学，可能还有其他参数。然而这些参数并非实践本发明所必须知道的，因为可按前面讨论的标准容易地测定气体是否符合条件。
特别适于本发明的气体种类为卤代烃如氟利昂和稳定的氟化硫属化物如SF6，SeF6等。
上面提到，根据本发明，用作微囊载体的液体中气体的饱和度对压力变化下微囊的稳定性具有重要性。实际上，微囊分散在载体液中制备本发明的回波悬浮液，当该载体液被气体(最好是用以充填微囊的气体)饱和并处于平衡状态时，微囊在压力变化下的抗瘪陷能力明显提高。从而，用作衬比剂的产品以干品售出，在临用前与载体液混合(例如见上文提到的PCT/EP/00620公开的产品)，用饱和了气体的水质载体来配制是很有利的。或者，当销售可立即使用的微囊悬浮液作为回波描记衬比剂时，可方便地用饱和了气体的水质溶液作载体液来制备；在这种情况下，悬浮液的保存寿命将会提高很多，产品可在相当长时间内保持基本不变(微泡数无显著改变)，例如几周至几月，特殊情况下甚至几年。用气体将液体饱和的最容易的方法，是简单地在室温下将气体鼓泡通入液体一段时间。
实施例1
按EP-A-324938所述，制备充填空气或各种气体的白蛋白微囊，将5％人血清白蛋白(HSA)(得自Blood Tsansfusion Service，Red-Cross Organization，Bern，Switzerland)装入校准的10ml注射器，将近距离声波定位器探针(Sonifier Model 250，Branson U1-trasonic Corp.USA制)插入溶液至注射器4ml刻度处，声处理25秒(能量定位8)。然后，将探针提高到溶液水平面上直至6ml刻度处，并在脉冲方式下(周期＝0.3)重新进行声处理40秒。于4℃下静置过夜后，由于浮力，形成含大多数微囊的上层，含未用的变性蛋白质白蛋白碎片和其它不溶物的底层则弃去。将微囊再悬浮于新鲜白蛋白溶液后，使混合物在室温下再静置，最后收集上层液。前述过程在大气下进行时得到充填空气的微球。为了得到充填其他气体的微球，先用一种新的气体冲洗白蛋白溶液，再在这种气体的气流吹拂溶液表面的情况下，进行上述操作过程；然后在操作结束时将悬浮液置于一玻璃瓶中，在密封前用所需气体充分冲洗此玻璃瓶。
用饱和溶有空气、处于平衡状态的蒸馏水将充填不同气体的各种微球悬浮液稀至1∶10，然后如前所述，将它们放入光学比色皿，在持续地增大悬浮液所受压力下记录吸光度。在测量过程中，悬浮液温度保持于25℃。
结果见于下面的表1，表中列出了对以名称或分子式定义的一系列气体测得的临界压力PC值，这些气体的特性参数即分子量(MW)和水溶性，以及原始的微泡数目和微泡平均大小(体积的平均直径)。
                                    表    1样品        气体      MW    溶解度    微泡数    微泡大小   PC(乇)   S气体/
                                (108/ml)     (μm)                  
Figure C9310015400151
AFre1       CF4      88     .0038     0.8        5.1       120     .0004AFre2       CBrF3   149     .0045     0.1        11.1      104     .0004ASF1        SF6     146     .005      13.9       6.2       150     .0004ASF2        SF6     146     .005      2.0        7.9       140     .0004AN1         N2       28     .0144     0.4        7.8        62     .0027A14         空气      29     .0167     3.1        11.9       53     .0031A18         空气      29     .0167     3.8        9.2        52     -A19         空气      29     .0167     9.5        9.5        51     -AMe1        CH4      16     .032      0.25       8.2        34     .008AKr1        Kr        84     .059      0.02       9.2        86     .006AX1         Xe       131     .108      0.06       17.2       65     .009AX2         Xe       131     .108      0.03       16.5       89     .009
从表1的结果可以看出，较低溶解度和较高分子量的气体，其临界压力PC增高，因此可以预期，充填这些气体的微囊在体内将提供较持久的回波源信号；也可看出，微泡平均大小一般随气体溶解度增大而增大。
实施例2
为了试验体内回波源性，将实施例1中制备的一些微球悬浮液的等分试样(1ml)注入实验家兔的颈静脉。用Acuson 128-XP5回波检测仪和7.5MHz传感器，以灰色标度法进行左心室和右心室成像。通过在一段时间内记录信号来测定左心室衬比增强的持续时间。结果集中于下面的表2，该表也列出了所用气体的PC。
                   表   2样品(气体)      对比持续时间(秒)      PC(乇)AMe1(CH4)            0                 34A14(空气)            10                 53A18(空气)            11                 52AX1(Xe)              20                 65AX2(Xe)              30                 89ASF2(SF6)          ＞60               140
从上面的结果，可以看到，在所试气体的临界压力和回声源信号持续时间之间存在明确的相关性。
实施例3
充空气半乳糖微粒回声源悬浮液(Echovist，SCHERINC AG)是这样得到的：将3g固体微粒在8.5ml 20％半乳糖溶液中振摇5秒钟。在其他制备中，将部分Echovist颗粒上的空气抽去(0.2乇)，用SF6氛围替代，藉此，在加入20％半乳糖溶液后得到含有缔合了六氟化硫的微粒悬浮液。将此悬浮液等分试样(1ml)经颈静脉注射给予实验家兔，如前一实施例所述进行心脏成像。在此种情况下，回波源微粒不穿过肺毛细血管。因此成像限于右心室，信号总持续时间无特殊意义。下面表3的结果显示注射后几秒钟时信号峰强度值。
                    表    3
样品号              气体           信号峰(任意单位)
Ga11                空气                 114
Ga12                空气                 108
Ga13                SF6                 131
Ga14                SF6                 140
可以看到，用水溶性低的惰性气体六氟化硫制备的回波源悬浮液比充填空气的类似悬浮液产生回波源信号较强。鉴于下述情况，这些结果是特别令人感光趣的：EP-A-441,468和357,163(SCHERING)分别公开了充填各种气体包括SF6的穴状化合物和笼状化合物微粒对于回波检测目的的应用，但是这些文件没有报告SF6在回波源响应上有超出其他更普通气体的特殊优点。
实施例4
用下面阐明的一般方法制备了一系列充气微泡的回波源悬浮液：
将9/1摩尔比氢化大豆卵磷脂(Nattermann PhospholipidsGmbH，Germany)和磷酸三十二烷酯(DCP)的混合物1克溶于50ml氯仿，放在100ml(圆底烧瓶中，在旋转蒸发器(Rotavapor ap-paratus)上蒸发至干。然后加入20ml蒸馏水，于75℃下将混合物缓缓搅拌一小时，这就形成多层脂质体(MLV)的悬浮液，此后将该悬浮液于75℃下相继挤压通过3μm和0.8μm的聚碳酸酯膜(Nucle-pore)。冷却后，将挤出的悬浮液1ml等分试样用9ml浓乳糖溶液(83g/l)稀释，稀释的悬浮液于-45℃下冷冻。然后将冷冻样品置于瓶中，在高真空下冷冻干燥得到自由流动的粉末，瓶中最后充以空气或下面表4所指的一种气体。然后将粉状样品再悬浮于作为载体液的10ml水，这一步在充填所述瓶子所用的同样气体流下进行。将悬浮液在旋涡式混合器上剧烈振动1分钟。
在25℃下，将各种悬浮液以预先与空气平衡的蒸馏水作1∶20稀释，然后如实施例1所揭示的于25℃下进行加夺测试，通过在分光光度计比色皿中测定光密度，该皿受到逐渐增加的流体静压直至全部微泡瘪陷。结果集中于下面的表4，该表除了给出临界压力Pc外，还给出ΔP值(见图1)。
                          表    4
样品号       气体      Mw       水中溶解度      微泡数     PC     ΔP
                                               (108/ml)   (乇)    (乇)
LFre1        CF4      88         .0038          1.2       97      35
LFre2        CBrF3   149         .0045          0.9      116      64
LSF1         SF6     146         .005           1.2       92      58
LFre3        C4F8   200         .016           1.5      136     145
L1           空气      29         .0167          15.5      68      17
L2           空气      29         .0167          11.2      63      17
LAr          空气      40         .031           14.5      71      18
LKr1         Kr        84         .059           12.2      86      18
LXe1         Xe       131         .108           10.1      92      23
LFre4        CHClF2   86         .78             -        83      25
上述结果清楚地表明，对压力增加的最高抗力是由水溶性最低的气体提供的。在这方面，微泡的情况和微球的情况相同。而且，有较高分子量的较低水溶性气体提供最平坦的微泡瘪陷/压力曲线(即ΔP最宽)，如前所述，这也是影响体内回波响应持久性的重要因素。
实施例5
将实施例4的一些微泡悬浮液如实施例2所述，注入实验家兔的颈静脉，按以前所述作左心室成像。记录能检测到有用的回波信号的持续时间，结果列于表5，表中C4F8表示八氟环丁烷。
                    表    5
样品号          气体类型         对比持续时间(秒)
L1                空气                  38
L2                空气                  29
LMe1              CH4                  47
LKr1              氪                    37
LFre1             CF4                 ＞120
LFre2             CBrF3                92
LSF1             SF6          ＞112
LFre3            C4F8        ＞120
这些结果表明，在微泡的情况下，符合本发明标准的气体将比至今所用大多数气体在长得多的时间内提供超声回波信号。
实施例6
用恰如实施例4所述的各种不同气体制备微泡悬浮液，只是用从Avanti Polar Lipids，Birmingham，Alabama，USA得到的等摩尔量的二花生酰磷脂酰胆碱(C20脂肪酸残基)代替卵磷脂磷脂成分。磷酯与DCP的摩尔比仍为9/1。然后如实施例4所述对悬浮液作加压测试，得到表6A所列结果与表4的结果作比较。
                                  表    6A样品号          气体类型         气体         水中         微泡数      PC      ΔP
                            分子量       溶解度       (108/ml)   (乇)     (乇)LFre1            CF4              88        .0038          3.4       251      124LFre2            CBrF3           149        .0045          0.7       121      74LSF1             SF6             146        .005           3.1       347      ＞150LFre3            C4F8            200        .016           1.7       ＞350    ＞200L1                空气             29        .0167          3.8       60       22LBu1              丁烷             58        .027           0.4       64       26LAr1              氩               40        .031           3.3       84       47LMe1             CH4              16        .032           3.0       51       19LEt1             C2H6            44        .034           1.4       61       26LKr1             Kr                84        .059           2.7       63       18LXe1             Xe               131        .108           1.4       60       28LFre4            CHClF2           86        .78            0.4       58       28
与表4结果相比较，上述结果显示，至少对于低溶解度气体，通过加长磷脂脂肪酸残基的链，可以令人注目地增加回波源悬浮液对压力增加的稳定性。重复前述实验但用较高级同系物即二山萮酰磷脂酰胆碱(C22脂肪酸残基)代替磷脂成分，进一步证实了这一结论。在这种情况下，微泡悬浮液在加压下抗瘪陷能力仍进一步增强。
按前面关于家兔试验所描述的方法，在狗身上测试本实施例的某些微泡悬浮液(5ml样品注入颈前静脉后作心室成像)。与实施例4揭示的制剂的情况相比，注意到有效体内回波源响应明显增强，即磷脂成分中脂肪酸残基链长的增加提高回波源剂在体内的使用寿命。
下表显示从一系列有不同链长脂肪酸残基的磷脂悬浮液制得的微泡(SF6)在左心室中的相对稳定性(＜注射剂量：1ml兔)。
                    表  6B磷脂       链长       PC      ΔP     对比持续时间
       (Cn)      (乇)     (乇)        (秒)DMPC        14        57       37          31DPPC        16        100      76          105DSPC        18        115      95          120DAPC        20        266      190        ＞300
上文提到，为了测量这些实施例描述的对压力的抗力，维持恒定的升压速率为100乇/分钟，这样做的理由可由下面给出的结果说明。下表表明各气体的PC值作为升压速率的函数而变。这些样品中所用的磷脂是DMPC。
         PC(乇)气体样品     升压速率(乇/分钟)
         40        100       200SF6         51        57        82空气         39        50        62CH4         47        61        69Xe           38        43        51氟利昂22     37        54        67
实施例7
用实施例1给出的方法，在空气下以控制球体大小的方式，制备一系列白蛋白微球在水中的悬浮液。然后，在大气压下，通过气体交换吹拂方式，用其它气体取代某些样品中的空气。在照例用蒸馏水稀释至1∶10后，将样品按实施例1作加压测试。从下面的表7收集的结果可以看出，在某些情况下，二步制备方式比实施例1的一步制备方式给出具有更好抗压能力的回波发生剂。
                               表    7样品号      气体类型      气体分子量      水中溶解度      起始微泡数     PC
                                                       (108/ml)     (乇)A14           空气            29             .0167           3.1         53A18           空气            29             .0167           3.8         52A18/SF6      SF6           146             .005            0.8       115A18/C2H8    C2H6         30             .042            3.4         72A19           空气            29             .0167           1.9         51A19/SF6      SF6          146             .005            0.6         140A19/Xe        Xe             131             .108            1.3         67A22/CF4      CF4           88             .0038           1.0         167A22/Kr        Kr              84             .059            0.6         85
实施例8
将本发明的方法应用于现有技术所描述的，例如WO92/11873例1，一个实验。将3g PluronicF68(聚氧乙烯-聚氧丙烯共聚物，分子量为8400)、1g二棕榈酰磷脂酰甘油(钠盐，AVANTI PolarLipids)和3.6甘油加入80ml蒸馏水。在约80℃下加热后，得到澄清的匀质溶液。将此表面活性剂溶液冷却至室温，体积调节至100ml。在某些实验中(见表8)，用二花生酰磷脂酰胆碱(920mg)和80mg二棕榈酰磷脂酸(钠盐，AVANTI Polar lipids)的混合物代替二棕榈酰磷脂酰甘油。
用经一三通阀联接的二个注射器得到微泡悬浮液。一个注射器装上5ml表面活性剂溶液，而另一个装上0.5ml空气或气体。三通阀在与含气体的注射器联接前，先充满表面活性剂溶液。通过交替地开启两个活塞，表面活性剂溶液在两个注射器之间来回转移(每个方向5次)，形成乳状悬浮液。用以空气饱和平衡的蒸馏水稀释(1∶10-1∶50)后，按实施例1测定制剂对压力的抗力，升压速率为240乇/分钟，得到如下结果：
                   表    8磷脂           气体      Pc(mm Hg)      DP(mm Hg)DPPG           空气         28             17DPPG           SF6         138            134DAPC/DPPA/9/1  空气         46             30DAPC/DPPA9/1   SF6         269            253
可见，即使对于已知的制剂，用本发明的方法并用其他气体取代空气，可得到相当大的改进，即对压力的抗力增大。在带负电荷的磷脂(例如DPPG)的情况下和在中性及带负电荷磷脂混合物(DAP/DPPA)的情况下，均是如此。
上述实验进一步证明，用本发明的方法已有利地解决了已经认识到的微泡和微球在暴露于压力下时(即当悬浮液注入生物体时)容易瘪陷的问题。有较高抗瘪陷能力、较稳定的悬浮液可有利地制备出来，为在人或动物体内进行的回波测定提供重观性较好和安全性有所改进的悬浮液。

Claims (21)

1.超声回波检测用衬比剂，所述衬比剂包含充填气体或气体混合物的微囊在水质液状载体相中的悬浮液，所述微囊是由溶解的磷脂形成的迅逝的气/液界面包围的微泡或由有机聚合物膜形成的物质包衣包围的微球，其特征在于：所述气体或气体混合物包含至少一种生理上可接受的卤代烃气体或氟化硫属元素化物，其中至少一部分在标准条件下以升气体/升水计的水中溶解度与分子量道尔顿的平方根之比低于0.003，所述微球包含SF6或CF4并具有交联或聚合非蛋白质两亲基团的壳除外。
2.如权利要求1所述的衬比剂，其中卤代烃气体或氟化硫属元素化物是SF6或选自CF4、CBrF3、C4F8、CClF3、C2F6、C2ClF5、CBrClF2、C2Cl2F4或C4F10的氟利昂。
3.如权利要求1所述的衬比剂，其中至少部分磷脂是层状或薄片状。
4.如权利要求3所述的衬比剂，其中液状载体相还包含稳定剂。
5.如权利要求3所述的衬比剂，其中至少一种磷脂是二酰基磷脂酰化合物，其中酰基是C16脂肪酸残基或其较高级同系物。
6.如权利要求1所述的衬比剂，其中膜的聚合物选自聚乳酸或聚乙醇酸及其共聚物、网状血清白蛋白、网状血红蛋白、聚苯乙烯，及聚谷氨酸和聚天冬氨酸的酯。
7.如权利要求6所述的衬比剂，其中微囊充填SF6。
8.如权利要求1所述的衬比剂，其中微囊中的气体选自CF4、CBrF3、C4F8、CClF3、C2F6、C2ClF5、CBrClF2、C2Cl2F4或C4F10。
9.制备权利要求1所述包含充气微囊在水质液状载体相中的悬浮液的衬比剂的方法，其特征在于：在包含至少一种生理上可接受的卤代烃气体或氟化硫属元素化物的气体混合物氛围下形成微囊，所述气体混合物的至少一部分在标准条件下以升气体/升水计的水中溶解度与分子量道尔顿的平方根之比低于0.003。
10.制备权利要求1所述包含充气微囊在水质液状载体相中的悬浮液的衬比剂的方法，其特征在于：用包含至少一种生理上可接受的卤代烃气体或氟化硫属元素化物的气体混合物充填已形成的微泡，所述气体混合物的至少一部分在标准条件下以升气体/升水计的水中溶解度与分子量道尔顿的平方根之比低于0.003。
11.如权利要求9或10所述的方法，其中水质载体包含溶解的层状磷脂和稳定微泡的稳定剂。
12.如权利要求10所述的方法，其中用两步形成微泡，第一步在第一种气体的氛围下先形成微囊或其干燥前体，然后在第二步中，第一种气体至少部分被生理上可接受的卤代烃或氟化硫属元素化物替代。
13.如权利要求12所述的方法，其中含有所述气体混合物微囊的形成按如下进行：交替地使其干燥前体受到减压和用所述气体混合物恢复压力，最后将前体分散在液状载体中。
14.如权利要求12所述的方法，其中第一种气体是空气、氮气或CO2。
15.如权利要求9-13之一所述的方法，其中卤代烃气体或氟化硫属元素化物是SF6或选自CF4、CBrF3、C4F8、CClF3、C2F6、C2ClF5、CBrClF2、C2Cl2F4或C4F10的氟利昂。
16.如权利要求12所述的方法，其中第一种气体完全被选自CF4、CBrF3、C4F8、CClF3、C2F6、C2ClF5、CBrClF2、C2Cl2F4或C4F10的第二种生理上可接受的卤代烃气体取代。
17.如权利要求10所述的方法，其中用气体混合物充填微囊是将微囊悬浮液用气体进行吹扫。
18.衬比剂前体，由包含冻干脂质体和稳定剂的干燥粉末组成，所述粉末可分散在水质液状载体中，形成权利要求1所述的充气微囊回波检测悬浮液，其中所述粉末储存于包含至少一种生理上可接受的卤代烃气体或氟化硫属元素化物的气体混合物氛围下，气体混合物中至少一部分在标准条件下以升气体/升水计的水中溶解度与分子量道尔顿的平方根之比低于0.003。
19.衬比剂前体，由包含冻干脂质体和稳定剂的干燥粉末组成，所述粉末可分散在水质液状载体中，形成权利要求1所述的充气微囊回波检测悬浮液，其中所述粉末储存于生理上可接受的卤代烃气体或氟化硫属元素化物的氛围下，其在标准条件下以升气体/升水计的水中溶解度与分子量道尔顿的平方根之比低于0.003。
20.如权利要求18或19所述的衬比剂前体，其中脂质体包括磷脂，其脂肪酸残基具有16个或更多碳原子。
21.如权利要求18或19所述的衬比剂前体，其中卤代烃气体或氟化硫属元素化物是SF6或选自CF4、CBrF3、C4F8、CClF3、C2F6、C2ClF5、CBrClF2、C2Cl2F4或C4F10的氟利昂。
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IS1621B (is) 1996-10-18
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US6881397B2 (en) 2005-04-19
NO930041L (no) 1993-07-26
IL104084A (en) 1996-09-12
DE69307351D1 (de) 1997-02-27
EP0554213A1 (en) 1993-08-04
DE69307351T2 (de) 1997-08-07
HU219340B (en) 2001-03-28
GR3022461T3 (en) 1997-04-30
NO305385B1 (no) 1999-05-25
US20050058605A1 (en) 2005-03-17
HU9300179D0 (en) 1993-04-28
KR100221950B1 (ko) 1999-09-15
EP0554213B2 (en) 2004-08-18
FI930258A (fi) 1993-07-25
ZA9210127B (en) 1994-04-12
HUT65225A (en) 1994-05-02
EP0554213B1 (en) 1997-01-15
JP3136016B2 (ja) 2001-02-19
ES2098015T3 (es) 1997-04-16
FI119973B (fi) 2009-05-29
US5413774A (en) 1995-05-09
IL104084A0 (en) 1993-05-13
ES2098015T5 (es) 2005-04-01
DK0554213T4 (da) 2004-12-13
DE69307351T3 (de) 2005-05-04
US20010001657A1 (en) 2001-05-24
CA2085525A1 (en) 1993-07-25
CN1074619A (zh) 1993-07-28
CA2085525C (en) 2003-02-25
JPH05255127A (ja) 1993-10-05
NO930041D0 (no) 1993-01-07
KR930016105A (ko) 1993-08-26
US20020150538A1 (en) 2002-10-17
AU3186093A (en) 1993-07-29
ATE147636T1 (de) 1997-02-15
DK0554213T3 (da) 1997-02-03
FI930258A0 (fi) 1993-01-22

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