CN1055298A - 可注射入活的生物体的稳定微泡 - Google Patents

可注射入活的生物体的稳定微泡 Download PDF

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CN1055298A
CN1055298A CN91102163A CN91102163A CN1055298A CN 1055298 A CN1055298 A CN 1055298A CN 91102163 A CN91102163 A CN 91102163A CN 91102163 A CN91102163 A CN 91102163A CN 1055298 A CN1055298 A CN 1055298A
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米切尔·施奈德
丹尼尔·比雄
菲利普·布塞
杰罗姆·皮杰尼尔
伊娃·海比
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    • A61K49/00—Preparations for testing in vivo
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Abstract

在水相中的气体或空气填装的微泡悬浮液，在超 声波回波描记术中用作成像对比剂。它们含有多层 状的表面活性剂及任意地亲水稳定剂。多层状的表 面活性剂可以是脂质体形式。悬浮液是通过在与水 相混合前或后使多层状的表面活性剂暴露于空气或 气体中而获得的。

Description

本发明涉及适用于注入活体的介质，如用于超声波回波描记的目的，更具体地讲涉及包含空气或生理学上可接受的气体的微泡作为在水质液体载体中的稳定分散液或悬浮液的可注射的液体组合物。这些组合物在超声波回波描记术中作为对比剂（contrast  agent）非常有用，以使活体如病人或动物的血管及其它腔内部成像。其它的作用如以下所示公开的也作了考虑。
本发明也涉及干燥的组合物，它与水质载体液体混合时，将产生上述微泡的无菌悬浮液，它可作为对比剂用于超声波回波描记术及其它目的。
已知象空气或气体的微小球或微颗粒的微体，如微泡或微气球，悬浮在液体中是在回波描记术中异常有效的超声波反射体。在此文本中，术语“微泡”特定地指一般以分离的形式导入空气或气体而产生的在液体悬浮液中的空气或气体小球，在液体中优先还含有表面活性剂以控制其表面性能及泡的稳定性。更特定地，可考虑到微泡的内体积系由气体/液体界面所限定，或者换一句话说，微泡仅由相当短暂的包复物限定，该包复物包含液体分子及松散连接在气体到液体接合界面的表面活性剂。
相反地，术语“微囊”或“微气球”系较佳指有物质界面或外壳包复的空气或气体，该物质界面或外壳由除悬浮液液体分子以外的物质构成，如聚合物膜壁。微泡和微气球均适于做超声波对比剂。例如，将在液体载体中的气体微泡或微小球（在0.5到10μm范围内）的悬浮液注入活体的血管流内将大大增强超声波回波描记术所成像，从而帮助显现内部器官的可见度。血管及内部器官的成像可以大大帮助医疗上的诊断，如用于检测心血管及其它疾病。
可根据各种方法制备适用于回波描记术的在可注射液体载体中的微泡悬浮液。例如在DE-A-3529195（Max-Planck  Gesell）中公开了一种产生0.5-50μm泡的技术，其中含有水溶性聚合物，一种油及无机盐的水质可乳化混合物与少量空气在一起，来回强迫从一个注射器通过一个小开口到另一个中去。在这里，机械力可使在液体中形成泡。
M.W.Keller  st  al.（J.ulfrasound  Med.5（1986），439-8）报道了使含高浓度溶质如葡萄糖，Renografin-76，Iopamidol（一种X-射线对比剂）的溶液在大气压力下经受超声波空化。通过空化的能量将空气驱动入溶液中。
其它技术依赖于震摇其中已掺入含微粒的空气的液体载体，所述液体载体通常包括有粘度增强剂作为稳定剂，如水溶性多肽类或碳水化合物和/或表面活性剂。已有效地确认通过液体载体的粘度和表面性质可以控制微泡的稳定性，以防止微泡的衰变或逃逸到大气中。在微粒中的空气或气体可包括粒子间的或晶体内所截留的气体，也可包括表面吸附气体，或由液体载体，通常是水质的，反应而产生的气体。所有这些在如EP-A-52，575（Ultra  Med.Inc）中得以充分描述，其中在1，2-乙二醇或聚乙二醇或其它水溶性聚合体的含水溶液中用了1-50μm微粒大小碳水化合物的聚集体（如半乳糖，麦芽糖，山梨醇，葡糖酸，蔗糖，葡萄糖及其类似物）。
在EP-A-123，235和122，624（Schering，也参见EP-A-320，433）中也应用了吸收于固体中的空气。例如，122，624权利要求保护的一种用于超声波回波描记术的液体载体对比组合物，它含有固体表面活性剂的微粒，微粒任意地可与非表面活性剂的微粒结合。如在这个文本中所解释，在溶液中的空气泡是由于颗粒表面吸附的空气，或在颗粒晶格内吸收的空气，或捕获在单个颗粒间的空气的释放而形成的，当微粒与液体载体搅和时，就出现这样的情况。
EP-A-131，540（Schering）也公开了制备微泡悬浮液的方法，其中一种稳定的可注射的液体载体，如生理盐水溶液，或一种糖溶液如麦芽糖，葡萄糖，乳糖或半乳糖的溶液，没有粘度增强剂，与含有截留空气的同样糖的微粒（在0.1到1μm范围内）混合。为了使气泡的悬浮液能在液体载体中形成，上述文本建议在无菌条件下剧烈搅拌液体和固体组分，对两个组分的同时搅拌进行几秒钟，一旦完成后，须立即使用此悬浮液，即必须在5到10分钟内注射它后即进行回波描记术的测量，这表明悬浮液中的气泡寿命不长，因此微泡悬浮液注射的一个实际困难是缺少随时间的稳定性。本发明充分克服了此缺点。
在US-A-4，466，442（Schering）中，揭示了一系列生产在液体载体中气体微泡的悬浮液的不同技术，使用（a）一种在液体载体（水质）中的表面活性剂溶液，及（b）一种粘度增强剂作为稳定剂。为产生气泡，那儿使用的技术包括加力使（a），（b）和空气的混合物以高速通过一小的开口;或在使用生理学上合格的气体之前一点点时间，将（a）注入（b）中;或在（a）中加入一种酸，及在（b）中加入一种碳酸盐，就在使用前混合两组分，酸与碳酸盐反应产生CO2气泡;或将超增压的空气注入在储存中的（a）和（b）的混合物中，当使用混合物注射前，所述气体被释放成微泡。
在US-A-4，466，442的组分（a）中使用的表面活性剂包括卵磷脂;脂肪酸的酯和醚;以及具有聚氧乙烯和多氧乙基化多元醇的脂肪醇，如山梨醇，1，2-乙二醇及甘油，胆固醇;以及聚氧乙烯-聚氧丙烯聚合体。提高及稳定粘度的化合物包括例如单糖类或多糖类（葡萄糖，乳糖，蔗糖，右旋糖，山梨醇）;多元醇，例如甘油，聚乙二醇;及多肽如蛋白质，明胶，氧代聚合明胶，血浆蛋白质及其类似物。
在此文本中的一个典型较好的实施例中，等量体积的（a）0.5%重量的Pluronic
Figure 911021639_IMG1
F-68（一种聚氧丙烯-聚氧乙烯聚合体）及（b）10%的乳糖溶液在一起在无菌条件下剧烈震摇（封闭管形瓶），以提供微泡悬浮液，适于用作超声波对比剂，并可维持至少2分钟，约50%气泡的大小小于50μm。
虽然已有技术的实行具有优点，但是它们具有几个极大的局限它们被医生和医院实际应用的缺点，即它们比较短的生存时间（这使测试重演性困难），相当低的起始气泡浓度（泡数很少，少于104-105个/ml，此计数随时间快速下降），从测试到测试的起始气泡计数的重演性差（这也使得和对照难于比较）。也承认有效地使一些器官如左心脏造影，需要小于50μm，较佳在0.5到10μm范围的气泡;更长的气泡可能有凝块及连续性栓塞的危险。
另外，在液体载体中固体微粒或高浓度电解质及其它比较惰性的溶质的强迫性存在时，在有些情况下可能在生理学上是不需要的。最后，悬浮液在储存条件下是完全不稳定的，并且不能以此市售;因此就在使用前合适的时间需要制备微泡。
当然也存在微囊的稳定悬浮液，即具有固体，封存空气的坚固聚合物膜，它在悬浮液中完好地抵抗长时间的储存时间，已发展了它以克服此缺点（参见如K.J.Widder，EP-A-324，938）;但是，在其中气体封闭在固体膜囊中的微囊的性质与本发明的空气微泡有本质上的不同，并且属于不同领域;例如当在载体液中的稳定剂经排泄或代谢时，所讨论的气体微泡仅仅在血流中逃逸或溶解，形成上述微气球的壁的固体聚合物材料须最终由测试的生物体清除，这可能使之增加很重的后负担。另外，具有固体非弹性膜的囊可能在压力变化下不可逆地破裂。
本发明的如权利要求1限定的组合物完全克服了上述的缺点。
术语“多层片型”限定本发明组合物的至少一部分表面活性剂或表面活性剂的条件表明此表面活性剂，与已有技术的微粒强烈相反（例如EP-A-123，325），是薄膜型，它包括一种或多种分子层（以多层片型）。将形成膜的表面活性剂转变成多层型能够容易地做成的，例如通过高压均化或通过声波化在声学或超声波频率下进行。在此必须指出的是脂质体的存在是众所周知的及有用的描述，来描述其中表面活性剂，更特定地是脂质类，是多层片型的情况。
脂质体溶液是细小囊的水质悬浮液，通常是球形的，其中包裹了物质。这些囊通常由一或多种同心安排的分子层（薄层）的两亲性化合物形成，即兼具有憎脂亲水部分和亲脂疏水部分的化合物。例见“Liposome  Mcthodology”，Ed，L.D.Leserman  et  al  Inserm  136，2-8  May  1982）。许多表面活性剂，包括脂类，尤其是磷脂，可以层压至相应于此结构。在此发明中，人们优先使用通常用来制作脂质体的脂类，例如在其后公开的卵磷脂及其它表面活性剂，但这并不排除用其它表面活性剂，只要它们能形成多层或多层膜层。
重要的是需注意不应在本发明和Ryan（US-A-4，900，540）文本之间有任何混淆，后者报告用于回波描记术的空气或气体填充脂质体。在此方法中Ryan在脂质体小囊中包裹了空气或气体;在本发明的实施例中，在脂质体悬浮液中形成了本发明的空气或气体微泡（即装有液体的脂质体），以及脂质体能明显地稳定微泡。在Ryan中，空气在脂质体内，它意味着在现今用的命名的范围内，Ryan的装有空气的脂质体属于微气球属，而不属于本发明的微泡。
实践上，为了得到本发明的微泡悬浮液，可以从用已有技术报道过的任何技术制备的脂质体悬浮液或溶液开始，明显的区别是在现在情况下，脂质体囊优先是“未装载”的，即他们不需要在其中包入任何除悬浮液外的外来物质，而传统脂质体一般装有此类目标。因此优先地，本发明的脂质体含有同溶液本身的含水相相同的或相似的水相。然后将空气或气体引入脂质体溶液中，这样将形成微泡悬浮液，所述悬浮液由以多层形的表面活性剂稳定。尽管如此，形成脂质体壁的材料可以在本发明范围内加以修饰，例如在其上面用共价键嫁接这些外来分子，这些外来分子将解释为特定目的而设计，的，以后将作说明。
在许多出版物，如US-A-4，224，179和Wo-A-88/09165及所有其中提到的引证中已充分描述了脂质体溶液的制备。这个已有技术在这里作为举例说明各种适于将形成膜的表面活性剂转变成多层型的参考材料。另一个基础参考例可在M.C.Woodle和D.Papahadjopoulos，“Methods  in  Enzymology”171（1989）193中发现。
例如，在D.A.Tyrrell et al，Biochimica & Biophysica Aota 457（1976），259，302中公开的方法中，剧烈搅拌脂类和水质液体载体的混合物，然后在室温或提升温度下声学或超声波频率下使用声波处理它。在本发明中，已证实不用搅拌的声波处理是可行的。另一方面，可使用做脂质体的设备，例如MicofluidizerR的高压均化器，它可从Microfluidics Corp.，Newton，MA 02164 USA购得。在可达600-1200巴的压力下用此设备可制得大量脂质体溶液。
在另一个方法中，根据GB-A-2，134，869（Squibb）所指导的，水溶性固体载体微粒（10μm或更小）（NaCl，蔗糖、乳糖及其它碳水化合物）用两亲试剂包衣;包衣载体在水相中溶解而产生脂质囊。在GB-A-2，135，647中，不溶性颗粒如玻璃或树脂微珠通过在有机溶剂中的脂类溶液中使它潮湿而包衣，接着蒸发去除溶剂。脂类包衣的微珠接着与水质载体相接触，其中在载体相中形成脂质囊。
将空气或气体引入脂质体溶液以形成微泡悬浮液可通过一般方法进行，特别是注射，即加力迫使所述空气或气体通过小孔进入脂质体溶液，或通过使用压力单纯使气体溶解在溶液中，然后突然释放去该压力。另一种方法是在空气或可截留在内的气体存在下搅拌或声波化此脂质体溶液，另一方面也可在脂质体溶液本身中产生形成气体，例如通过气体释放的化学反应，如用酸分解可溶解碳酸盐或碳酸氢盐。同样的作用也可通过在压力下在水相中溶解低沸点液体，例如丁烷，然后通过立即降去压力使所述液体沸腾。
尽管这样，一种优越的方法是在多层型或薄膜形的干燥表面活性剂引入到液体载体相前，使之与空气或可吸收的或可截留的空气接触。在此方面，可用GB-A-2，135，647中揭述的技术所衍生的方法，即将固体微粒或珠浸在挥发性溶剂中的成膜表面活性剂（或表面活性剂混合物）溶液中，随后将溶剂蒸发掉，将珠留下与空气（或可吸收气体）接触足够长的时间使空气表面上与表面活性剂层的表面结合。然后，将装有表面活性剂并有空气包裹的珠放入液体载体中，通常是有或没有添加剂的水中，其中通过温和搅拌在液体中形成空气泡，根本不需要剧烈搅拌。然后可通过例如过滤将固体珠从微泡悬浮液中分离出来，该微泡悬浮液随时间非常稳定。
不用说，除用不溶珠或小球外，可以使用支持颗粒水溶性材料如GB-A-2，134，869中所描述（碳水化合物或亲水聚合体），其中所述支持颗粒最终将溶解，固体的最后分离将变得不必要。另外在此案中，颗粒材料需要的话时可被选来最终作为稳定剂或粘度增强剂。
在此方法的一个变种中也可从脱水脂质体开始，即通过常规技术制备的水溶液形式的脂质体，随后通过普通方法脱水，如在US-A-4，229，360中公开的也在此结合作为参考。在此参考材料中推荐的脱水脂质体的一个方法是冻干（冷冻干燥），即在减压下冷冻脂质体溶液并蒸发干燥（升华）。在进行冻干前，将亲水性稳定剂化合物溶解在溶液中，例如如乳糖或蔗糖的碳水化合物，或像右旋糖酐，淀粉，PVP（聚乙烯吡咯烷），PVA（聚乙烯醇）及其类似物的亲水聚合物。在本发明中这很有用，因为这种亲水化合物也帮助均化微泡的大小分布及增强储存下的稳定性。实际上做成极稀的冻干脂质体的水溶液（0.1-10重量百分数），用例如5∶1到10∶1的乳糖对脂类的重量比稳定，可产生达108-109微泡/毫升（大小分布主要是0.5-10μm）的含水微泡悬浮液，它们能稳定至少一个月（可能更长）而无显著的可观察到的变化。通过将存储有空气的干燥脂质体简单溶解而不震摇或任何剧烈搅拌可获得它。另外，在减压下的冻干技术很有用，因为它允许在干燥后，在干燥脂质体上用任何可截留的气体以重建压力，即氮气，CO2，氩，甲烷，氟利昂等，在此条件下处理过的脂质体溶解后，获得含上述气体的微泡悬浮液。
通过在水中的多层脂类稀释溶液（0.1-10重量百分数）上加气体压力，然后突然释放压力形成微泡悬浮液，具有甚至更高的气泡浓度，如在级数1010-1011泡数/毫升。但是，平均汽泡大小一般在10μm以上，如在10-50μm范围内。在此情况下，气泡大小分布辐度可通过离心和层倾析而减小。
适于在本发明中使用的表面活性剂可选自在水和气体存在下能形成稳定膜的所有两亲性化合物。较佳可成多层的表面活性剂包括卵磷脂（磷脂酰化-胆碱）及其它磷脂，特别是磷脂酸（PA），磷脂酰-肌醇，磷脂酰-乙醇胺（PE），磷脂酰-丝氨酸（PS），磷脂酰-丙三醇（PG），心脂（CL），神经鞘磷脂，原浆，脑苷脂类等。合适脂类的例子总体上说是磷脂，如天然卵磷脂，如鸡蛋卵磷脂或大豆卵磷脂，或合成卵磷脂如饱和合成卵磷脂，例如二一十四酰磷脂酰胆碱，二一十六酰磷脂酰胆碱或二一十八酰磷脂酰胆碱或不饱和合成卵磷脂，如二油酰磷脂酰胆碱或二亚油酰磷脂酰胆碱，较佳为鸡蛋或大豆卵磷脂。象胆固醇及其它物质（见以下）的添加剂可以从0到50重量百分比的范围的比例加入一种或多种上述脂类中。
这些添加剂可包括其它可与成膜表面剂混合的表面活性剂，它们中的大多数已在本说明书介绍中讨论的已有技术中得以描述。例如，可用游离脂肪酸，脂肪酸与聚氧化烯化合物的酯，如聚氧丙烯乙二醇和聚氧乙烯乙二醇的醚;脂肪醇与聚氧化烯乙二醇的醚;脂肪酸与聚氧烷化脱水山梨醇的酯;肥皂;丙三醇-聚链烯基硬脂酸脂，丙三醇-聚氧乙烯蓖麻醇酸酯;聚氧化烯乙二醇的齐聚物或共聚物;聚乙氧化大豆油及蓖麻油及其氢化衍生物，蔗糖或其它碳水化合物与脂肪酸，脂肪醇的酯及醚，这些可任意地是聚氧烷化的，不饱和或饱和脂肪酸的单，二及三甘油酯;大豆油及蔗糖的甘油酯。非膜形成表面活性剂的量可达组合物中表面活性剂总量的50重量百分比，但较佳在0和30之间。
相对于水液体载体的表面活性剂的总量在0.01到25重量百分数之间，但在0.5到5范围内的量是较佳的，因为人们总是尽其可能将在可注射溶液中的活性物质的量压低，这是为了减少向活体输入外来物质，即使当它们是无害或生理学上可配伍时。
在表面活性剂中进一步任意的添加剂包括：
（a）已知能在脂质体上提供负电荷的物质，例如磷脂酸，磷脂酰-丙三醇或二一十六烷基磷酸酯;
（b）已知能提供正电荷的物质，例如十八烷胺或十八烷胺乙酸酯;
（c）已知能以更需要的形式影响脂类膜的物理性质的物质;例如己内酰胺和/或甾醇如胆固醇，麦角甾醇，植物甾醇，谷甾醇，谷甾醇焦谷氨酸脂，7-脱氢-胆固醇或羊毛甾醇，可以影响脂类膜的刚性;
（d）已知具有抗氧化性质，能促进悬浮液中组分化学稳定性的物质，如维生素E，棓酸丙酯，抗坏血酸棕榈酸酯，或丁基羟基甲苯。
本发明中的水载体大部分是水，可能具有少量生理学上可相容的液体，如异丙醇，甘油，己醇及其类似物（例见EP-A-52，575）。总体上说，有机水可溶性液体的量不超过5到10重量百分比。
本发明组合物也可能含溶解的或悬浮在内的一般称为粘度增强剂或稳定剂的亲水化合物及聚合物。虽然这些化合物的存在并不是强迫的，以保证空气或气体在本分散液中随时间的稳定性，但它们是优越的，能给溶液一些“稠度”。当需要时，当完全无毒时这些添加剂的上限浓度可以很高，例如对Iopamol和其它碘化X射线对比剂可高达溶液的80到90重量百分比。但是对其它粘度增强剂例如糖类，如乳糖，蔗糖，麦芽糖，半乳糖，葡萄糖等，或亲水聚合物如淀粉，葡聚糖，糊精，黄原胶或部分水解纤维素寡聚体，以及蛋白质和多肽，浓度最佳在1到40重量百分数之间，较佳在约5-20范围内。
如已有技术中，本发明的可注射组合物也可含生理学上合格的电解质;一种例子是等渗盐溶液。
本发明自然也包括干燥的可储存的粉状掺合物，当它与水或含水载体相简单混合时，能产生本发明的含微泡分散液。较佳地这些干燥掺合物或制剂将含有所需所有的当仅加入水时会提供所需微泡悬浮液的固体组分，即实质上多层型其中截留的或吸附了的微泡形成所需空气或气体的表面活性剂，以及需要地其它非形成膜的表面活性剂，粘度增强剂及稳定剂以及可能地其它任意添加剂。如前所述，由多层型表面活性剂截留空气或气体可通过简单地使所述表面活性剂在室压或超大气压力下暴露在空气（或气体）中足够长的时间，引起所述空气或气体截留在表面活性剂中而发生。这段时间可以非常短即几秒钟到几分钟，虽然过度暴露即在空气或气体环境下储存也无害。重要的是空气可以尽其可能很好地与层压的表面活性剂的可能表面接触，即干燥材料须较佳是处于“松软的”轻度流动状态。这状态精确地如此，是由于冻干脂质体的水溶液和亲水试剂的水溶液而形成的，如US-A-4，229，360中所描述。
总体上说，在干燥制剂中表面活性剂对亲水粘度增强剂的重量比率在0.1∶10到10∶1级，如有进一步任意组分，存在比率相对于表面活性剂加粘度增强剂的总量不超过50%。
本发明的干燥掺合制剂可由很简单的方法制备。如前所见，一个较佳的方法是先制备其中膜成形脂类是多层形的水溶液，例如通过声波化，或用脂质体领域中常用的任何常规技术，该溶液也可含其它所需添加剂，即粘度增强剂，非成膜表面活性剂，电解质等，然后冻干成自由流动的粉末，然后将它储存在具有空气或可截留气体环境下。
干燥混合物可以干燥状态保有任何长短时间，并且这样售出。将它投入使用时，即制备超声波成像气体或空气微泡悬浮液时，仅需将已知重量的干燥粉状制剂溶解于无菌水相，如水或生理学上可接受的介质中。粉末依赖于在可注射产品中气泡所需浓度，约108-109汽泡/毫升一般需5-20重量百分比粉末在水中的溶液。但是自然地这数字仅是表示性的，气泡量主要依赖于在制作干燥粉末时截留的空气或气体量。当生产步骤处于控制下时，干燥制剂的溶解可以提供具有很好重复计数的微泡悬浮液。
所得微泡悬浮液（气泡在0.5-10μm范围内）随时间特别稳定，在起始原测量的计数可在几周甚至几月内维持不变或只有少量变化，仅能观察到的变化是分离现象，较大的气泡（约10μm）倾向于比小的升得快。
还发现本发明的微泡悬浮液稀释时微泡数由于稀释的损失非常小，即在高比率稀释的情况下，即1/102到1/104，微泡计数的减少准确地与稀释比率相符。这表明气泡的稳定性更依赖于多层型的表面活性剂，而不是如已有技术中稳定剂或粘度增强剂的存在。考虑到成像测试重复性，这性质是有利的，因为在注射入病人时，气泡并不受血液稀释的影响。
与已有技术由具有刚性但可破的膜所包围的在应力下不可逆地破损的微囊相比，本发明的气泡的另一个优点是当本发明悬浮液经受突然压力变化时，本发明气泡暂时性弹性收缩，当压力释放时恢复原来的形状。在临床应用上时这很重要，当微泡泵出心脏，并且随后暴露于可选择压力搏动。
本发明中微泡如此稳定的原因尚未彻底弄懂。因为防止气泡逃逸，浮力应该与摩擦力即粘度引起的维持力平衡，推理气泡可能被多层状的表面活性剂所围绕。这多层片状的表面活性剂是否是连续的或不连续的膜，或者是否可能是作为封闭球体与微泡相连，目前还未知但正在研究中。但是对目前涉及的情况缺乏详细的知识并不排除对本发明的完全工业上可操作性。
本发明的气泡悬浮液在其它医学/诊断应用中也有用，在那些中在注射后需将稳定微泡瞄准体内的特定位点，例如导向血管中的血栓，导向动脉中的动脉粥样硬化损害处（空斑），导向肿瘤细胞，以及用于诊断体腔的改变的表面积，如在胃中的溃疡位点或膀胱中的肿瘤。为达到这目的，将通过基因工程得到的单克隆抗体，设计成模拟抗体的抗体片段或多肽，生物粘附性聚合体，卵磷脂和其它位点识别性分子与稳定微泡的表面活性剂层结合。这样通过由L.D.Leserman，P.Machy及J.Barbet描述的方法（“Lipsome  Technology  Vol.Ⅲ”p.29ed  by  G.Gregoriadis，CRC  Press  1984），单克隆抗体可与磷脂双分子层结合。在另一个方法中，先合成十六烷酰基抗体，然后根据L.Huang，A.Huang及Kennel（“Liposome  Technology  Vol.Ⅲ”p51  ed.by  Gregoriadis，CRC  1984）与磷脂双分子层结合。可选择地，可仔细选择一些本发明中用的某些磷脂以获得在器官或组织中较佳的吸收，或在血中增加的半衰期。因此，含GM1神经节苷脂或磷脂酰肌醇的脂质体，优先除胆固醇外，在静脉内给药后将导致在血中增加半衰期，类似于A.Gabizon，D，Papahadjopoulos，Proc.Natl.Acad.Sci.USA  85（1988）6949。
在本发明中微泡中的气体可包括，除现在的无害生理学上合格的气体如CO2，氮气，N2O，甲烷，丁烷，氟利昂及其混合物外，在核医学中尤感兴趣的放射性气体如133Xe或81Kr，用于血液循环测量，肺闪烁法等。
以下的实施例从实践角度出发进一步说明本发明。
回波测量
回波测量在脉冲-回声系统上进行，该系统包括有胶质玻璃样品架（直径30mm），及浸在恒温水浴中的传感器，在接收部分有脉冲接收器（Accutron  M  30105），用于接收部分外部预放大器具有固定的放大系数为40dB，内部放大器具有可调节的从-40到+40dB的放大系数。在接收部分中安插入一个10MHz的低通滤波器以使信号增强到噪音比率。在IBM  PC中的A/D板是Sonotek  STR  832。在2.25，3.5，5和7.5MHz进行测量。
实施例1
通过REV方法（见F.Szoka Jr.及D.Papahadjopoulos，Proc.Natl.Acad，Sci USA 75（1987）4194）用氢化大豆卵磷脂（NC 95H，Naffermann Chemie，K ln，W.Germany）及二一十六烷（三十二烷）磷酸酯，摩尔比为9/1在蒸馏水中制备脂质体溶液（50毫克脂类每升）。在65℃脂质体制剂挤压（以较准囊的大小）通过1μm聚碳酸酯滤器（Nucleopore）。2毫升该溶液与5毫升75%在水中的Ipamidol溶液及0.4毫升空气混合，加力该混合物来回通过一个二注射器系统，如DE-A-3529195中所描述，同时连续维持略微的过压。这结果是在液体中形成空气微泡的悬浮液（每毫升105-106气泡，如光学显微镜检查估计气泡大小为1-20μm），在室温稳定几小时。在7.5，5，3.5和2.25MHz用超声波回波描记术测试时，此悬浮液给出强回声信号。
实施例2
含2%（重量）氢化大豆磷脂及二一十六烷磷酸脂摩尔比为9/1的蒸馏水溶液（100毫升）在60-65℃用Bransom探针声波器（250型）声波化15分钟。
冷却后，在10，000g将溶液离心15分钟，回收上清液，加入乳糖使成7.5%b.w的溶液。溶液置于紧闭密的容器中，其中震摇容器时在几分钟内使压力为4巴的氮气压。接着，突然释放压力，这样获得高浓度的气泡悬浮液（1010-1011气泡/毫升）。气泡大小分布比实施例1中的大，即约1到50μm。溶液很稳定，但几天后，在固定相中发生分离现象，较大的气泡趋向于在悬浮液的上层浓集。
实施例3
将20克玻璃珠（直径约1毫米）浸在含100毫克二一十六酰磷脂酰胆碱（Fluka A.G.Buchs）的10毫升氯仿溶液中。珠在减压情况下在旋转蒸发器中旋转蒸发，直到所有CHCl3逃逸掉。然后将珠在大气压下进一步旋转几分钟，加入10毫升蒸馏水。移去珠子，获得空气微泡的悬浮液，在显微镜下检查后发现含106气泡/毫升。气泡的平均大小约3-5μm。悬浮液至少几天内稳定。
实施例4
用如实施例1中所描述的REV技术使在水中的氢化大豆卵磷脂二一十六烷磷酸脂悬浮液成多层状。将2毫升脂质体制剂加入含15%麦芽糖的蒸馏水溶液8ml中。所得溶液在-30℃冰冻，然后在0.1托下冷冻干燥。在几小时后冰完全升华。然后，在抽空容器中恢复空气压力，这样几分钟后，冻干粉末使空气饱和。
然后在温和搅拌下，使干燥粉末溶解于10毫升无菌水中，获得微泡悬浮液（108-109微泡每毫升，动态粘度＜20mpa.s）。这悬浮液含多数气泡在1-5μm范围之内，在很长时间内稳定，因为在置放2个月后仍可测到无数的气泡。此微泡悬浮液在超声波回波描记术中给出很强的应答。如果在此实施例中溶液通过在空气中在-30℃到-70℃喷射以获得冰冻雪花而不是整块，并且雪花在真空中蒸发，这样获得卓越的结果。
实施例5
如实施例4中所述获得的脂质体溶液取2毫升样品与10毫升5%明胶水溶液（样品5A），人白蛋白（样品5B），葡聚糖（样品5C）及Iopamidol（样品5D）的含水溶液混合。所有样品均经冷冻干燥。在冷冻干燥和引入空气后，各种样品与20毫升无菌水温和混合。在所有情况下，气泡浓度在108气泡每毫升以上，几乎所有气泡小于10μm。前面实施例的步骤用9毫升脂质体制剂（450毫克脂类）及仅1毫升5%人白蛋白溶液重复。在冷冻干燥后，暴露于空气，及加入无菌水（20毫升）后，所得溶液含2×108气泡每毫升，它们中的大多数小于10μm。
实施例6
乳糖（500毫克）精细地研磨到颗粒大小为1-3μm，用含100毫克二一十四酰磷脂酰胆碱/胆固醇/二一十六酰磷脂酸（来自Fluka），摩尔比为4∶1∶1的氯仿溶液（5毫升）湿润，然后在旋转蒸发器中在真空下蒸发。所得自由流动性白色粉末在氮气下常压下旋转几分钟，然后溶解于20毫升无菌水中。获得约105-106微泡每毫升，微泡在1-10μm大小范围内，如在显微镜下观察到。在此实施例中，包覆了的表面活性剂对水溶性载体的重量比为1∶5。当将此比率降到较低值如1∶20时，也获得卓越的结果（107-108微泡/毫升），这实际上增加了表面活性摄取空气的效率，即这钭减少产生同样气泡计数的需要的表面活性剂重量。
实施例7
含2%氢化大豆卵磷脂和0.4%PluronicRF68（一种非离子型聚氯乙烯一聚氧丙烯共聚物表面活性剂）如实施例2所述声波化。冷却和离心后，将5毫升此溶液加入到5毫升含15%麦芽糖的水中。所得溶液在-30℃冰冻，在0.1托蒸发。然后在含干燥粉末的容器中恢复空气压力。它在空气中置放几秒钟，然后它被用来制做10重量百分比的水溶液，在显微镜下检查表现出是微小气泡（小于10μm）的悬浮液;气泡浓度在107气泡每毫升范围内。这制剂在2.25，3.5，5和7MHz下在超声波回波描记术中给出很强应答。
实施例8
在实验狗上往外周静脉内注入0.1到2毫升实施例4中获得的制剂后，进行二维心回波描记术测量。看到左心浑浊化，具有清楚的心内膜轮廓，这样确定了微泡（或至少它们的显著部分）能通过肺毛细管循环。
实施例9
如实施例4所述制备磷脂/麦芽糖冻干粉末。但是，在冻干步骤的末期，将含133Xe的气体混合物代替空气引入抽空容器中。几分钟后，引入无菌水，温和搅拌后，产生在气相中含133Xe的微泡悬浮液。将此微泡悬浮液注入活体以进行需要用133Xe作为追踪剂的研究。获得卓越的结果。
实施例10（对照）
在US-A-4，900，540中，Ryan等人描述用装有气体的脂质体进行超声波测试，根据文献，脂质体是通过常规方法制备的，但在水质组合物中加入气体或气体前体以形成脂质核芯（卷2，15-27行）。
在参考文献中的实施例1和2中详细描述了使用气体前体（碳酸氢盐）。用加入气体的水载体将气体包裹在脂质体中（未被Ryan等人举例描述过）需要该气体是很小的气泡形式，即相似或小于脂质体囊的大小。
在M.W.Keller等人，J.Ultrasound  Med，5（1986），413-498中揭示了其中空气能以很小的气泡（2.5-5μm）被截留的水介质。
在20毫升圆底烧瓶中，将126毫克卵磷脂和27毫克胆固醇溶解在9毫升氯仿中。脂类溶液在Rotavapor上蒸发到干燥，这样在烧瓶壁上形成脂类膜。根据M.W.Keller等人（ibid）将10毫升50重量百分数葡萄糖溶液声波化5分钟以在其中产生空气微泡，然后将声波化溶液倒入含脂类膜的烧瓶中，这样通过手工摇动容器，结果在含气泡的载体液体中磷脂发生水合作用，形成多层的脂质体。
置放一会儿后，所得脂质体悬浮液在5000g离心15分钟以从载体中去除未封存入囊中的空气。在离心中，也可见装有空气的脂质体由于浮力而分离到表面上。
离心后检查试管，显示在底部残余物包括附聚葡萄糖填装的脂质体，上清液中基本上已无剩下的气泡，由浮力上升的装有空气的脂质体的数量小得可以忽略，不能被观察到。
实施例11（对照）
根据Ryan（US-A-4，900，540，col.3，Example  1）制备注射对照组合物。将126毫克蛋卵磷脂和27毫克胆固醇溶解在9毫升二乙醚中。在溶液中加入3毫升0.2摩尔含水碳酸氢盐，使所得两相系统声波化直至均匀。混合物在Rotavapor  Apparatus中蒸发并加入3毫升0.2摩尔含水碳酸氢盐。
将1毫升脂质体悬浮液部分注入实验兔的颈静脉中，该动物处于用Acuson 125-XP5超声波成像机（7.5传感器探针以使心脏成像）进行心脏超声波成像情况下。探针提供左右心室的截面像（乳头中间肌）。注射后，可观察到右心室轮廓的光度和瞬间增加（几秒钟）。这效果与用实施例4的制剂观察到的效果相比要差很多。未观察到左心室成像的改进现象，很可能表明装有CO2的脂质体不能越过肺毛细管屏障。

Claims (27)

1、一种适用于注射进活体血管和体腔内的组合物，如用于超声波回波描记术的目的，包括在生理学上可接受的水质载体相中的空气或气体微泡悬浮液，含有约0.01到20百分重量的一种或多种溶解的或分散的表面活性剂，其特征在于至少一种在组合物中的膜形成表面活性剂至少部分是薄片状的或多层形。
2、根据权利要求1所述的组合物，其特征在于多层状的表面活性剂是单或多分子膜层形式。
3、根据权利要求1所述的组合物，其特征在于多层状表面活性剂是脂质体囊形式。
4、根据权利要求1所述的组合物，其特征在于它主要包括其中形成空气或气体微泡的脂质体溶液。
5、根据权利要求4所述的组合物，其特征在于多数脂质体和微泡的大小小于50μm，较佳小于10μm。
6、根据权利要求1所述的组合物，含约108-109的0.5-10μm大小/毫升的气泡，所述浓度在储存下至少一个月只有很少或基本无变化。
7、根据权利要求1所述的组合物，其特征在于表面活性剂选自包括卵磷脂的磷脂，如磷脂酸，磷脂酰-胆碱，磷脂酰-乙醇胺，磷脂酰-丝氨酸，磷脂酰甘油磷脂酰肌醇，心脂及神经鞘磷脂。
8、根据权利要求7所述的组合物，其特征在于其进一步含影响脂质体性质的物质，选自磷脂酰-甘油，二-十六烷-磷酸酯，胆固醇，麦角甾醇，植物甾醇，谷甾醇，羊毛甾醇，维生素E，棓酸丙酯，抗坏血酸酰棕榈酸酯及丁化羟基甲苯。
9、根据权利要求1所述的组合物，进一步包含溶解的粘度增强剂或稳定剂，选自线性的或交联的聚或寡多糖，糖，亲水聚合物及如Iopamidol的碘化化合物，含量与表面活性剂比重量比率在1∶5到100∶1之间。
10、根据权利要求1所述的组合物，其中表面活性剂含高达50百分重量的非多层型表面活性剂，选自脂肪酸，脂肪酸的酯和醚，以及具有多元醇的醇，如聚链烯乙二醇，聚链烯化糖及其它碳氢化合物，以及聚链烯化乙二醇。
11、制备权利要求1所述的悬浮液的方法，其特征在于下列步骤：
（a）选择至少一种能形成膜的表面活性剂并将它转变成多层型;
（b）使多层型表面活性剂与空气或可吸收或可截留气体接触足够长的时间，使该空气或气体被所述表面活性剂结合;及
（c）将多层型表面活性剂与水质载体混合，这样将得到在所述液体载体中空气或气体微泡的稳定分布。
12、根据权利要求11所述的方法，其中步骤（c）系置于步骤（b）前，后者是通过向液体载体引入加压空气或气体，然后释放压力而形成的。
13、根据权利要求11所述的方法，其中步骤（c）是通过温和混合组分而完成的，不需要震摇，这样在步骤（b）中与多层状表面活性剂结合的空气或气体在悬浮液中形成稳定微泡。
14、根据权利要求11或12所述的方法，其中液体载体含有溶解在其中的稳定剂化合物，选自水溶性蛋白质，多肽，糖，多糖类或寡糖类及亲水性聚合体。
15、根据权利要求11所述的方法，其中步骤（a）中的转变是通过将表面活性剂包覆在可溶性或不溶性材料颗粒上完成的;步骤（b）是通过使包覆了的颗粒在空气或气体下置放一会儿而完成的;及步骤（c）是通过混合包覆了的颗粒与含水液体载体。
16、根据权利要求11所述的方法，其中步骤（a）中的转变是通过在高压下使膜形成脂类的含水溶液声波化或均化，这个方法至少部分导致形成脂质体。
17、根据权利要求16所述的方法，其中步骤（b）是通过冷冻干燥含脂质体的溶液并使所述冷冻干燥产物与空气或气体接触一段时间而进行的，所述溶液含亲水稳定剂。
18、根据权利要求16和17所述的方法，其中膜形成脂类的水溶液还含粘度增强剂或稳定剂，它们选自亲水聚合物及碳水化合物，其重量比相对于脂类在1∶5到100∶1之间。
19、一种干燥粉状制剂，当溶解于水中时，将形成水质微泡悬浮液用于超声波回波描记术，其特征在于含一种或多种多层形的膜形成表面活性剂及水溶性稳定剂。
20、根据权利要求19的干燥制剂，其中多层形的表面活性剂是细小层形沉积在可溶性或不溶性固体颗粒材料的表面。
21、根据权利要求20所述的干燥制剂，其中不溶性固体颗粒是玻璃或聚合物珠。
22、根据权利要求20所述的干燥制剂，其中可溶性颗粒包括水溶性碳水化合物，多糖，合成聚合物，白蛋白，明胶或Iopamidol。
23、根据权利要求19的干燥制剂，它包括冷冻干燥的脂质体。
24、根据权利要求1的可注射组合物用于超声波回波描记术。
25、根据权利要求1-10的可注射的组合物的应用，用于在血液或体腔中运送治疗上或诊断上有活性的外来气体的气泡。
26、根据权利要求4所述的组合物，其中表面活性剂包含与此结合的生物活性品种，它们是为特定定向目的，如在循环系统，或在器官中或在组织中在特定位置固定化气泡而设计的。
27、根据权利要求4所述的组合物，其中表面活性剂包含与此结合的生物活性品种，这些生物活性品种选自单克隆抗体，抗体片段或多肽设计成模拟抗体，生物粘着性聚合体，卵磷脂及其它受体识别分子。
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CN1079678C (zh) * 1992-01-24 2002-02-27 勃勒柯国际有限公司 耐压充气微泡的长效水质分散液及其备方法
CN1069838C (zh) * 1992-11-02 2001-08-22 勃勒柯国际有限公司 用作超声波回波检测术增强剂的稳定微泡悬浮液
CN1066965C (zh) * 1994-12-16 2001-06-13 勃勒柯研究有限公司 超声用气体悬浮体及其贮存方法
CN104337766A (zh) * 2014-10-09 2015-02-11 唐春林 一种地高辛脂质微泡及其制备方法
CN111467266A (zh) * 2020-05-14 2020-07-31 深圳市陆讯纳米科技有限公司 一种臭氧纳米气泡漱口液及制备方法
CN111569683A (zh) * 2020-05-14 2020-08-25 深圳市陆讯纳米科技有限公司 一种高浓度长效臭氧纳米气泡水溶液及制备方法
CN111467266B (zh) * 2020-05-14 2022-10-28 深圳市陆讯纳米科技有限公司 一种臭氧纳米气泡漱口液及制备方法

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US5271928A (en) 1993-12-21
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US7033574B1 (en) 2006-04-25
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US5380519A (en) 1995-01-10
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