CN1069838C - 用作超声波回波检测术增强剂的稳定微泡悬浮液 - Google Patents
用作超声波回波检测术增强剂的稳定微泡悬浮液 Download PDFInfo
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- CN1069838C CN1069838C CN93114131A CN93114131A CN1069838C CN 1069838 C CN1069838 C CN 1069838C CN 93114131 A CN93114131 A CN 93114131A CN 93114131 A CN93114131 A CN 93114131A CN 1069838 C CN1069838 C CN 1069838C
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- phospholipid
- microvesicle
- suspension
- gas
- surfactant
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Abstract
本发明揭示在超声波回波检测术中可用作对比剂的充气微泡在水质液状载体中的可注射悬浮液。悬浮液含两亲化合物，其中至少一种可以是作微泡对抗时间和压力所致破灭的稳定剂的层状磷脂。磷脂在载体中的浓度低于0.01重量%，但等于或高于磷脂分子在气体微泡-液体界面单个存在的浓度。本发明还揭示了充空气或气体微泡稳定悬浮液的制备方法。
Description
本发明涉及在水液载体中的充气微泡可注射悬浮液，悬浮液含两亲化合物，其中至少有一种是用于防止由于时间和压力而导致的微泡破灭的磷脂稳定剂。该磷脂稳定剂可以是薄片状或层状的。本发明还涉及在超声波检测术中可用作对比剂的稳定微泡悬浮液的制备方法。
气体微泡在载体液中的悬浮液用作有效的超声反射体，这在现有技术中是众所周知的。早先观察到快速静脉注射可使溶解的气体从溶液中逸出成为气泡，随之发展了将微泡悬浮液作为回声药剂以增强超声波成像。由于声阻抗相对血液存在的实质差异，发现这些血管内气泡是极好的超声波反射体。将气体微泡在载体液中的悬浮液注射到活组织的血流内，显著地增强了超声波回波检测成像的能力，从而增强内部器官的显现。器官和深部组织成像在确定医学诊断上可能是决定性的，因此在发展高浓度气体微泡稳定悬浮液上投入了很大的努力，这种悬浮液同时又是易于制备和使用，含有最小限度非活性物质，能够长期贮存并易于分发。虽然针对能满足这些标准的溶液已作了大量努力，但迄今尚没有一种能提供完全满意的结果。
从EP-A-0077752(Schering)得知，通过将表面活性剂的水溶液和作为稳定剂的增粘剂溶液混合，可制得气体微泡悬浮液。使试剂混合物和空气通过一小孔，将气泡引入混合物。向得自含表面活性剂和碳酸氢钠的溶液和增粘剂溶液的混合物中加一种酸，可以得到CO2微泡悬浮液。但是，在临用前才将各成分混合，制备后立即将溶液用完/注射完。所公开的表面活性剂包括卵磷脂；脂肪酸和带聚氧乙烯的脂肪醇和聚氧乙烯化多元醇如山梨糖醇、乙二醇类和甘油、胆甾醇的酯类和醚类；及聚氧乙烯-聚氧丙烯聚合物类。所公开的表面活性剂在悬浮液中的浓度为0.01％-10％(重量)之间，要求保护的较佳范围为0.5％-5％之间。增粘剂和稳定剂化合物包括诸如单糖和多糖类(葡萄糖、乳糖、蔗糖、葡聚糖、山梨糖醇)；多元醇类，如甘油、聚乙二醇类；及多肽类，如蛋白质、明胶、氧化聚合明胶、血浆蛋白等。增粘剂的总量限定在0.5-50％。该专利文献也揭示了将聚氧丙烯-聚氧乙烯聚合物(如PluronicF-68)用作增粘剂。在优选的实施例中，将等量表面活性剂、0.5％(重量)PluronicF-68(一种聚氧丙烯-聚氧乙烯共聚物)的水溶液和增粘剂(10％乳糖溶液)在无菌条件下剧烈振摇以得到微泡悬浮液。所得的悬浮液维持2分钟，含近50％直径低于50μm的气泡。根据该文献，可以应用高达50％的表面活性剂和/或增粘剂，但具体实施例是使用1％-4％的PluronicF-68。
WO-91/15244(Schneider et.al)揭示了可用作超声波回声检测术成像剂的容易制备的水悬浮液。该悬浮液含薄片状和/或层状成膜表面活性剂，并可任意选择地含亲水性稳定剂。层状化的表面活性剂可以是脂质体的形式，即一般是球形的微细囊泡。这些囊泡通常由一种或几种紧密排列的两亲化合物(即兼有亲水性和疏水性基团的化合物)的双分子层组成。双层分子是这样编排的：疏水性基团头对头，亲水性基团指向水相。在和水相混合前或混合后，将层状化的表面活性剂与空气或一种气体接触，制得悬浮液。成膜表面活性剂向薄片状转化是按各种脂质体的形成技术来进行的，这些技术包括高压匀化或在声波或超声频率下进行声波处理。该文件所要求保护的磷脂的浓度为0.01％-20％之间，微泡浓度为108-109个气泡/ml。微泡悬浮液维持稳定可达数月。实施例1中磷脂浓度为0.5％。
WO-92/11873(Beller et.al.)公开了针对稳定回声源悬浮液的尝试。该文用聚氧乙烯/聚氧丙烯聚合物和带负电的磷脂如磷脂酰甘油、磷脂酰肌醇、磷脂酰乙醇胺、磷脂酰丝氨酸以及其可溶型(lysoform)，制备设计用来吸收和稳定微泡的用来作为回声检测对比剂的水质制剂。在制剂中磷脂的浓度范围可在0.01％-5％(体积或重量)之间，然而具体公开并要求保护的是含1％的二棕榈酰磷脂酰甘油(DPPG)的制剂。除了带负电的磷脂外，组合物还必须含有0.1％-10％的聚合物质(PluronicF-68)。制剂中溶质的总量为5.1％-10.4％之间。微泡的浓度未予报导，但根据所得的结果，可估计为约107个气泡/ml。据报告，悬浮液的稳定性比EP-A-0077 752中的好。
虽然现有技术组合物有其长处，但仍存在妨碍它们实际应用的种种弊端。首先，某些现有技术的组合物存在时间相当短，其次，起始气泡计数相当低，即在104-105个气泡/ml之间。这造成使用这些组合物进行的回声检测试验的再现性和分析相当困难。此外，某些技术产生的气泡直径范围宽(高至50μm)，这就使它们在某些应用中不能用作回声检测剂(如左心的回声检测术)。
由于某些现有技术组合物的稳定性差，因而对能抵抗血流中压力变化、贮存寿命长的稳定微泡配方的需求进一步增强。其分布和贮存不存在问题的微泡配方尤为重要。
另一个弊端是迄今已知的许多组合物含有大量不同种类的溶质，如聚合物类、磷脂类、电解质类及其他，这使得它们的实际应用越来越困难。例如，已知使用聚氧乙烯/聚氧丙烯聚合物类(Pluronic对某些特殊的病人会引起不良副反应(例如见G.M.Vercellotti et.al.Blood(1982)59,1299)。具有高磷脂含量的制剂在某些情况下也可能是不理想的。无论如何，具有高浓度各种溶质的组合物是不得已而投药的，它们的广泛使用正日益被认为是不理想的。事实上，制药工业的趋势是将各种医药配方中的活性和非活性成分浓度尽可能降低至最低水平，并从制剂中删除所有不必要的成分。发现替换方法和配制更有效的组合物仍然是重要的。对于用于回声检测术的微泡悬浮液尤为如此，因为这时各成分并无治疗作用，并应该使其可能引起的后效应为最小。但是，如前所述，典型浓度在1％-4％(重量)的本领域制剂的状况和现有技术的学说阻碍了磷脂和其他非磷脂添加剂的减量使用。阻碍的理由极可能是隐藏在这样的事实中，即在常规实验过程中，成分浓度的进一步降低就根本制不成足以稳定到有实际用途的或不能激励再进一步调整已知范围下限的悬浮液。
本发明是以如下出乎意料的发现为基础的，即使用磷脂作为稳定剂，那怕只使用很低的浓度，也能获得每毫升至少含107个微泡的非常稳定的充气微泡悬浮液。可用作超声回波检测对比剂的悬浮液是这样获得的：将为防止由于时间和压力而导致的微泡破灭而使用的稳定剂(至少一种磷脂)悬浮于水载体中，磷脂的浓度低于0.01％(重量)，但等于或高于磷脂分子在气体微泡-液体界面单个存在的浓度。
非常意料不到的是发现极小量的此处涉及的磷脂表面活性剂(单独使用或与相当小比例的其他两亲物一起使用)也可有效地稳定微泡。假定在有其他两亲化合物(如PluronicF-68)存在下，稳定剂分子之间的相互内聚力减小，单分子磷脂薄膜的形成受到抑制。但是，在不存在大量其他两亲试剂情况下，磷脂分子间的未受阻分子间结合力(静电相互作用或氢键)足以保证稳定的膜样结构的形成，使气泡能保持稳定，不破灭或聚结。
按照本发明，即使悬浮液中表面活性剂和其他添加剂的浓度保持在现有技术制剂所用的水平之下很多，仍能得到高微泡浓度、高稳定性、贮存时间长并且易于制备的悬浮液。在悬浮液中气泡的浓度维持在高于每毫升107个微泡的情况下，本发明组合物中所用的磷脂的量可以低到大约仅为在气体微泡周围形成单分子层表面活性剂所需的量。在本发明中，不象存在着也尚未观察到有脂质体状双层表面活性剂的微泡(充气脂质体)。
即使磷脂表面活性剂的浓度保持在现有技术已知水平下很多，也可制备具有高微泡浓度如109-1010个微泡/毫升、相当高稳定性和贮存期长的悬浮液。只要所用的表面活性剂的量不低于在气体微泡周围形成单分子层脂类所需的量，只要按本文所揭示的方法之一进行制备就可制得低至每ml 1μg磷脂的悬浮液。
计算结果表明，对于108个气泡/ml的气泡浓度，根据微泡大小的分布，该浓度可低至1μg/ml或0.0001％，但磷脂浓度在0.0002％-0.01％之间较佳。更佳地是，本发明的稳定的微泡悬浮液中的磷脂浓度为在0.001％-0.009％之间。尽管进一步降低悬浮液中磷脂的量是可能的，但使用磷脂量低于0.0001％wt.制成的悬浮液是不稳定的，它们总的气泡计数低，注射时的回声检测反应不能令人满意。另一方面，用高于0.01％磷脂制成的悬浮液在注射时并不表现得更好，即它们的稳定性和回声检测反应并未随浓度的增高而进一步得以改善。因而，较高浓度只能增加不良副反应的可能性，如现有技术讨论中所述。暂时假设，只有薄片状或层状表面活性剂部分才能有效地释放排列恰当的分子以稳定气泡。这可解释为何表面活性剂的浓度可以如此低而不会削弱气泡的稳定性。
本发明的悬浮液提供的超过现有技术组合物的显著优点，不仅因为其磷脂含量低，而且因为注射的溶质即脂类和/或合成聚合物和其他添加剂的总量低于以前的1,000-50,000倍之间。能达到这样而无微泡浓度的损失即产品回声性或稳定性无损失。除了极低的溶质浓度之外，本发明提供的悬浮液可以只含有对回声检测信号贡献相当显著的微泡，即无任何不有效地参予成像过程的微泡。
无须说，在本发明可注射组合物中具有如此低浓度的溶质，使得不良副反应的可能性大大降低，注射剂的消除得到显著改善。
本发明的具有低磷脂含量的微泡悬浮液可从成膜磷脂来制备，该成膜磷脂的结构已用合适的方法加以修饰，例如将在合适溶剂中的粗磷脂的溶液进行冷冻干燥或喷雾干燥，在通过分散到水载体中形成悬浮液之前，将冷冻干燥或喷雾干燥而得的磷脂粉末与空气或其他气体接触。当与水载体接触时，其结构已碎裂的粉状磷脂会形成薄片状或层状部分，这会使分散于其中的空气微泡稳定。较方便地，本发明的低磷脂含量悬浮液也可用在与空气或其他气体接触前就已薄片化或层状化的磷脂来制备。因此，当磷脂以干粉形式或以层状化磷脂在水载体中的分散液的形式存在时，可进行膦脂和空气或其他气体的接触。
薄片状或层状这一术语是指表面活性剂以包含一层或几层分子的薄膜或薄片状形式存在。在这种形式中，表面活性剂分子以类似于脂质体囊泡上所存在的那样的结构排列。如WO-A-91/15244所述，成膜表面活性剂转化成薄片状可按任何脂质体形成方法容易地进行，例如高压匀化或在声波或超声频率下进行声波处理。通过用磷脂包覆水溶性固体载体(NaCl、蔗糖、乳糖或其他碳水化合物)的微粒(10μm或更小)，随后被包覆的载体溶解于水相，也可完成向薄片状的转化。同样，通过用在有机溶剂中的磷脂溶液湿润，然后蒸发溶剂，可以包覆不溶性颗粒，如玻璃或树脂微珠。然后将脂类包覆的微珠与水载体相接触，藉此在载体相中会形成脂质体囊泡。通过加热略高于临界温度(Tc)并温和的搅拌，也可使磷脂层状化。临界温度是磷脂从凝胶向液态过渡的温度。
实际上，为制备按本发明所述的低磷脂含量微泡悬浮液，可以从用任何已知技术制备的脂质体悬浮液或溶液着手，只要脂质体囊泡是“空载的”，即它们并未包裹任何外来物质于其中，而只是溶液本身的水相。
用通常的方法注入即使空气或气体通过小孔进入脂质体溶液，或通过加压使空气溶解在溶液中然后突然撤去压力，均能有效地将空气或气体引入脂质体溶液。另一种方法是在空气或另一种生理学上可接受的气体的存在下搅拌或声处理脂质体溶液。人们也可在脂质体溶液自身中引起气体的形成，例如通过释放气体的化学反应，如用酸分解溶解的碳酸盐或碳酸氢盐。
据认为，当将已层状化的表面活性剂悬浮在水质液体载体中并通入空气或其他气体以产生微泡的情况下，象在脂质体囊泡的情况一样，微泡单层表面活性剂分子而不是双层所逐渐包围并稳定化。表面活性剂分子的这种结构性重排可用机械的(搅拌)或用加热的方法而加以激活。在有内聚力释放剂如(PluronicF-68存在下，所需能量较低。另一方面，在微泡配方中内聚力释放剂的存在降低了磷脂分子间的自然亲和力，其直接结果是微泡对外压(如20-30乇以上)的稳定性降低。
如早已提到的那样，为制备本发明的低磷脂浓度悬浮液取代磷脂溶液，可从干的磷脂类着手，这些磷脂可以是层状化的也可以不是层状化的。当为层状化时，可通过诸如脂质体脱水获得这样的磷脂类，即用常规技术将脂质体制成水溶液形式，然后用通常方法脱水。脂质体脱水的一个方法是冷冻干燥(低压冻干法)，即将脂质体溶液(最好含亲水性化合物)冷冻，并在减压下蒸发(升华)干燥。
在另一种方法中，将磷脂溶解于有机溶剂并不经脂质体形成过程而干燥该溶液可得到非薄片状化或非层状化的磷脂类。换言之，可以这样做：将磷脂类与一种亲水性稳定剂物质如像PVP、PVA、PEG等一类聚合物或者是既溶于有剂溶剂也溶于水的化合物一起溶解在合适的有机溶剂中，再将溶液冷冻干燥或喷雾干燥。既溶于水也溶于有机溶剂的亲水性稳定剂化合物的例子还有苹果酸、乙醇酸、麦芽酚等一类。任何合适的有机溶剂均可使用，只要其沸点足够低，熔点足够高，以利于随后的干燥。典型的有机溶剂为诸如二噁烷、环己醇、叔丁醇、四氯二氟乙烯(C2Cl4F2)或2-甲基-2-丁醇，而以叔丁醇、2-甲基-2-丁醇和C2Cl4F2为佳。在这一变化中，用于选择亲水性稳定剂的标准是它在所选择的有机溶剂中的溶解度。采用与用层状化磷脂类粉末同样的步骤，从这类粉末可制备得微泡悬浮液。
同样，在进行经预薄片化的或经预层状化的磷脂溶液冷冻干燥之前，将亲水性稳定剂化合物溶于溶液中。但此处亲水性稳定剂的选择余地大得多，因为碳水化合物如乳糖或蔗糖以及亲水性聚合物如葡聚糖、淀粉、PVP、PVA、PEG等均可使用。在本发明中这是有益的，因为这类亲水性化合物也有助于微泡大小分布的均匀化并增加贮存时的稳定性。实际上，利用例如聚乙二醇∶脂类重量比为10∶1-1000∶1来稳定的冻干磷脂类制成很稀的水溶液(0.0001-0.01重量％)，可得到计数为109-1010个气泡/ml(大小分布大体上为0.5-10μm)的微泡水悬浮液，这种悬浮液是稳定的，即使长期贮存也无明显可见的变化。只要通过简单地溶解贮于空气中的干燥的层状磷脂类就可制得这种悬浮液而无需振摇或剧烈搅拌。在减压下冷冻干燥的技术是很有用的，因为可用任何生理学上可接受的气体即氮气、CO2、氩气、甲烷、氟利昂、SF6、CF4等恢复在已经过干燥的粉上的压力，籍此将在这样条件下处理的磷脂类重新分散后，就能得到含上述气体的微泡悬浮液。
业已发现，适合本发明的表面活性剂可选自在水和气体存在下能形成稳定薄膜的两亲化合物。优选的表面活性剂包括卵磷脂(磷脂酰胆碱)和其他磷脂类，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)、磷脂酰甘油(PG)、心磷脂(CL)、神经鞘磷酯类。合适的磷脂类的例子为天然或合成的卵磷脂类，如鸡蛋或大豆卵磷脂；或饱和的合成卵磷脂类，如二肉豆蔻酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱或二花生酰磷脂酰胆碱或不饱和的合成卵磷脂类，如二油酰磷酯酰胆碱或二亚油酰磷脂酰胆碱，而以饱和的卵磷脂类为佳。
添加剂类如胆甾醇和其也物质可以0-50重量％范围的比例加到一种或多种上述脂类中。此类添加剂可包括其他非磷脂表面活性剂，它们可用在和成膜表面活性剂组成的混合物中，它们大多数是已知的，例如，聚氧丙二醇、聚氧乙二醇这样的化合物及其各种共聚物，磷脂酰甘油、磷脂酸、联十六烷基磷酸酯、脂肪酸类、麦角甾醇、植物甾醇、谷甾醇、羊毛甾烯醇、生育酚、棓酸丙酯、棕榈酸抗坏血酯和2,6-二叔丁基对苯酚。这些非成膜表面活性剂的量通常可达表面活性剂总量的50重量％，而较佳地为0-30％之间。而本发明的低磷脂含量悬浮液中各种添加剂的浓度在0-0.05％范围内，这表明比迄今已知的组合物中浓度低100倍以上。
还应提到的是，本发明悬浮液的另一个特征是其相当“高”的微泡截留气体量，即在表面活性剂的量和截留的气体总量之间的高比例。因此，用微泡大小在1-5μm范围内的悬浮液，推算性地估侧出存在于气泡-液体界面的磷脂类和截留气体量的重量比在标准条件下为0.1mg/ml和100mg/ml之间。
实际上，所有可注射的组合物应当尽可能与血液等渗。因此，在注射前也可将少量等渗试剂加到本发明的悬浮液中。等渗试剂是医药中通常使用的生理溶液，其组成中含盐水溶液(0.9％NaCl)、2.6％甘油溶液、5％葡萄糖溶液等。
本发明还涉及可用作超声波回声检测对比剂的按权利要求1所述制备稳定的微泡悬浮液的方法。该方法基本上包括将用所述磷脂类稳定的微泡悬浮液中磷脂类的浓度调节到权利要求中所述范围内的选定值。通常可从含高于所需值的磷脂的微泡悬浮液着手，然后在基本上不减少产生回声的气泡的计数情况下，可减少相应于微泡中截留的气体或空气量的所述磷脂类的量。例如可以这样做，通过去掉部分不涉及气/液界面的含有磷脂类的载体液，并用更多的新鲜载体液稀释悬浮液。为做到这点，可在悬浮液中建立区域(a)其中聚集了产生回声的气泡，及区域(b)其中所述气泡被高度稀释。然后，用通常的分离方法(倾析、虹吸等)可除去区域(b)的液体，添加相应量的新鲜载体液以补足悬浮液。这一操作可重复一次或多次，从而逐渐减少不直接涉及稳定气泡的磷脂含量。
完全除去不存在于气泡的气/液界面上的磷脂分子通常是不值得的，因为这会使平衡产生一定程度的不平衡，即如这种去除进行得过度，则会使气/液界面的一些表面活性剂分子释放出来，结果造成气泡不稳定。实验表明，载体液中磷脂类的浓度可降低到权利要求书中所述下限的邻近而不会引起性质明显的改变和不良的效果。这实际上意味着最适磷脂浓度(在给定限度内)更受应用类型的支配，即如果可采纳相对高的磷脂浓度，则理想的浓度值将接近范围的上限。另一方面，如果根据所诊断患者的情况，而必须进一步减少磷脂类的绝对值，这可以做到，而无需考虑对微泡计数和回声源效率的不良影响。
方法实施例包括选择成膜表面活性剂，可任选地用现有技术已知的或上文公开的一种方法将其转化为层状。然后在密闭容器内将表面活性剂与空气或其他气体接触，并与水质液状载体混合，从而形成微泡悬浮液。将悬浮液静置片刻，所形成的充气微泡层分出，并升到容器的顶部。除去下部母液，用饱和了微泡制备中所用气体的水溶液洗涤微泡上清层。如此洗涤可重复数次直至将所有未使用的或游离的表面活性剂分子除去。未使用的或游离的分子是指未参与形成气体微泡周围稳定的单分子层的所有表面活性剂分子。
除了提供低磷脂含量悬浮液外，洗涤技术还提供了另一个优点，可将本发明的悬浮液进一步纯化，即除去全部或几乎全部对注入的悬浮液的回声检测响应作用极小的微泡。因而这样的纯化提供的悬浮液只含正向选择的微泡，即微泡在注入时会同等地参与回声检测信号的反射。这使悬浮液不只是含有极低浓度磷脂和其他添加剂，而且不含任何不积极参与成像过程的微泡。
在方法的变动中，在与空气或另一种气体接触前，将可选择地为层状的表面活性剂与水质液状载体混合。
图1是按本发明新鲜制备的悬浮液其回声检测响应作为微泡浓度函数的图示。
本发明的悬浮液和制备低磷脂含量悬浮液的方法将以下面的实施例加以进一步阐明。
实施例1
将240mg二花生酰磷脂酰胆碱(DAPC，得自Avanti PolarLipids)和10mg二棕榈酰磷脂酸(DPPA酸型，得自Avanti PolarLipids)溶解在50ml己烷/乙醇(8/2,V/V)中，然后用旋转式蒸发器在园底烧瓶中蒸发溶剂至干，制得多层囊泡(MLVs)。残留的脂类薄膜在真空干燥器中干燥。加水5ml后，将悬浮液在搅拌下90℃培养30分钟。将得到的MLVs于80℃下挤压通过0.8μm聚碳酸酯滤器(NuclePore)。将所得的2.6ml MLV制剂加到47.4ml的浓度为167mg/ml葡聚糖10’000MW(Fluka)的水溶液中。将所得的溶液充分混合，转入500ml园底烧瓶中，于-45℃冷冻并在0.1乇下冻干。过夜以使冰完全升华。此后，将已抽真空的容器中恢复空气压力。将各种量的所生成的粉末引入玻璃管形瓶中(见表)，用橡皮塞塞紧瓶口。用针头通过橡皮塞抽真空，从瓶中抽除空气。抽空空气后，使粉末与六氟化硫气体SF6相接触。
在每瓶中(经过塞子)注入3％甘油水溶液10ml，接着轻轻混合，得到气泡悬浮液。用血球计数器对所生成的微泡悬浮液进行计数。平均气泡大小(体积)为2.2μm。
干重 磷脂浓度 浓度
(mg/ml) (μg/ml) 气泡数/ml
0.5 8 9.0×106
1 16 1.3×107
5 81 7.0×107
10 161 1.4×108
以1ml/5kg的剂量将制剂注入家兔(经颈静脉)及小猪(经耳静脉)。用Acuson XP 128超声波系统(Acuson Corp.USA)和7MHz扇形传感器进行体内回声检测。将动物麻醉，放置传感器，并固定在胸腔左侧处，在家兔，提供左右心室图，在小猪，提供纵向四室图。在家兔和小猪，含0.5mg/ml干重的制剂使右心室和左心室均轻度不透明。但用1、5和10mg/ml的制剂，不透明度就较高。
实施例2
按实施例1所述，用气相空气(代替SF6)制备冷冻品。然后将冷冻品悬浮于0.9％盐水(代替3％甘油溶液)。得到同样的气泡浓度。但是，给家兔和小猪注射后，效应持续时间缩短，例如10-20秒，而不是120秒。而且，在小猪，即使用10mg/ml制剂，左心室的不透明度也差。
实施例3
如实施例1所述，用240mg DAPC和10mg DPPA(摩尔比95∶5)制备MLV脂质体。将2ml这种制剂加到20ml聚乙二醇(PEG2’000)溶液(82.5mg/ml)中。室温下混合10分钟后，将所得溶液于-45℃下冷冻5分钟，于0.2毫巴下冻干5小时。所得粉末(1.6g)转入带有橡皮塞的玻璃管形瓶中。将粉末暴露于SF6中(如实施例1中所述)，然后溶于20ml蒸馏水中。所得悬浮液气泡浓度为5×109个气泡/ml，气泡平均直径按体积计为5.5μm。将悬浮液吸入20ml注射器中，封闭注射器，水平放置24小时。在注射器中的溶液顶部可见一层白色气泡。将大部分液相(约16-18ml)抽出，而注射器保持在水平位置，引入等体积饱和了SF6的新鲜水。然后将注射器振摇片刻，以使气泡在水相中均匀分布。8小时后在同样条件下进行第二次洗涤，按每隔4小时再进行3次洗涤。将最终气泡相(批号P145)悬浮在3ml蒸馏水中，它含1.8×109气泡/ml，气泡平均直径按体积计为6.2μm。将一份这样的悬浮液(2ml)于0.2毫巴下冷冻干燥6小时。将所得粉末溶于0.2ml四氢呋喃/水(9/1 V/V)，通过高压液相色谱法(HPLC)，用光散射检测器分析存在于溶液中的磷脂。该溶液含DAPC 0.7mg/ml，相当于每108个气泡有3.9μg磷脂。批号P145中实际气泡大小分布的Coulter计数分析表明每108个气泡的总表面积为4.6×107μm2。假定一个DAPC分子会占据502表面，可以计算出形成围绕每个气泡的单层磷脂，每108个气泡需1.3μg DAPC。然后将悬浮液P145置于4℃，按正常的基础上测量气泡浓度。10天后，产品看起来和制备后一样好，每毫升仍含1-1.2×109个气泡。考虑到悬浮液中极低含量的磷脂，其超凡的稳定性是很令人吃惊的。
上述实验在第二批微泡上进行重复，为了收集较理想的较大气泡，使用了较短的洗涤时间(批号P132)。获得的气泡平均直径(按体积计)为8.8μm，用Coulter计数器测得总表面积为22×108μm2/108个气泡。计算表明，用单层DAPC复盖气泡群，每108个气泡就需要6μg DAPC。用HPLC测得的DAPC实际含量为每108个气泡20μg。将取得气泡群总表面积精确估测的困难性考虑进去，此结果看来是在实验误差范围内，所得结果符合于用一层磷脂复盖微泡。
用不同洗涤的气泡制剂进行的回声检测表明，在分离后较低部位的相与较高部位的相或新鲜制备的样品相比，只给出弱得多的回声检测信号。乍看起来，这似乎是正常的，因为注射器顶部的白色层无论如何都含有气体微泡的大部分。然而，如图1所示，气泡计数显示在下层也有高得惊人的微泡量。只是在Coulter测量时，显示微泡大小在0.5μm以下，这表明小气泡即使在高浓度时也无合适的超声信号反射。将制剂P132在3％甘油溶液中的四倍稀释液注入小猪(0.2ml/kg)。含气泡2.5×107个/ml和含磷脂类5μg/ml的经洗涤过的气泡制剂提供左右心室极佳的不透明度，具有明显的心内膜边缘轮廓。给小猪注入相当于0.2μg磷脂/kg的一份P145制剂(稀释到含3％甘油)，也得到好的不透明度。注射0.02μg/kg后，甚至可在左心室检出对比剂。此外，在磷脂剂量低至0.005μg/kg时，利用脉冲多普勒(Doppler)可在肾动脉检出对比剂效应的存在。
因此，只要层状磷脂类排列成围绕气体微泡的单分子层，所产生的悬浮液就有适当的稳定性。从而为出乎意料的本发现提供了解释，并证明磷脂的量不是必须大于存在于悬浮液中的微泡周围单分子层形成所需的量。
实施例4
按实施例1所述，制得了含48mg DAPC和2mg DPPA的己烷/乙醇8/2(V/V)溶液，将溶剂蒸干。在60℃下，将5mg所得粉末和375mg聚乙二醇在60℃溶于5g叔丁醇中。然后将清液迅速冷至-45℃并冻干。将80mg冻干品装入玻璃管形瓶，使粉末与SF6接触(见实施例1)。然后加3％甘油溶液(10ml)到管形瓶中，缓缓旋动使冻干品溶解。形成的悬浮液有气泡1.5×108个/ml，平均直径按体积计为9.5μm。将溶液注入家兔，提供极好的右心室和左心室图像。此悬浮液即使十倍稀释也仍显示强烈的对比剂增强作用。
实施例5
除了省去开始的将磷脂溶于己烷/乙醇溶液之外，重复实施例4的过程。换言之，将粗磷脂与聚乙二醇一起溶于叔丁醇，将溶液冻干；此后，将残渣悬浮在水中。在这些实验中研究了不同的磷脂及磷脂与其他脂类合用。下表所示结果中，磷脂溶于含100mg/mlPEG 2’000的叔丁醇溶液中。将冷冻干燥后所得残渣用SF6饱和(见实施例1)，然后以100mg干重/ml浓度溶于水。脂类混合物 在叔丁醇 气泡浓度 平均直径(重量比) 中的浓度 (X109/ml) (μm)
(mg/mlDSPC 2 1.3 10DAPC/DPPG(100/4) 2 3.8 7DSPC/Chol(2/1) 6 0.1 40DAPC/Plur F68(2/1) 6 0.9 15DAPC/Palm.ac.(60/1) 2 0.6 11DAPC/DPPA(100/4) 1 2.6 8DAPC/Chol/DPPA(8/ 8 1.2 191/1)DAPC/DPPA(100/4)* 5 2.4 18
DAPC=二花生酰磷脂酰胆碱
DSPC=二硬脂酰磷脂酰胆碱
DPPG=二棕榈酰磷脂酰甘油(酸型)
DPPA=二棕榈酰磷脂酸
Chol=胆碱
Palm.ac.=棕榈酸
Plur F68=Pluronic F-68
*在本实验中，CF4用作气体代替SF6
在各种情况下，所得的悬浮液均显示高的微泡浓度，磷脂无须先转为脂质体。如实施例3所述，将这些悬浮液用0.15M NaCl稀释，并注入小猪。各种制剂在剂量为10-50μg脂类/kg体重或更低时均得到极好的右心室和左心室不透明度以及良好的心内膜边缘轮廓。
实施例6
将PEG-2000(2g)、DAPC(9.6mg)和DPPA(0.4μg)溶于20ml叔丁醇，在0.2毫巴下将溶液冷冻干燥过夜。所得粉末与SF6接触，然后溶于20ml蒸馏水中。将含气泡1.4×109/ml(用血球计数器测得)的悬浮液吸入20ml注射器，密闭，水平位置放置16小时。在溶液顶部可见一层气泡白层。去除下层相(16-18ml)，同时将注射器保持水平位。在注射器中吸入等量SF6饱和的新鲜蒸馏水，通过搅动使水相中的气泡均匀化。通过经短时间反复洗涤，得到两类不同的微泡，即大体积和中等体积的微泡，大气泡在洗涤仅10-15分钟后收集到，中等大小的气泡在30-45分钟后收集到。这样的洗涤重复10次，以便两类气泡得到狭窄的气泡大小分布，并消除不与微泡结合的全部磷脂。合并含大气泡的各相(“大体积气泡”)。同样合并含中等体积气泡的各部分(“中等体积气泡”)。将两类气泡的等分试样冷冻干燥，然后用HPLC分析，以测定存在于每一部分的磷脂量。大体积气泡部分含气泡2.5×107个/ml，平均直径为11.3μm，每107个气泡有13.7μg磷脂。这一结果与假定单层磷脂围绕气泡和每个磷脂分子表面积为50所计算得到的理论数，每107个气泡11.5μg，非常一致。中等体积气泡部分含气泡8.8×108个/ml，平均直长为3.1μm，每107个气泡有1.6μg磷脂，后一个值也和理论数每107个气泡1.35μg非常一致。这些结果进一步表明，本说明书所揭示的微泡悬浮液的稳定性最可能就是由于在微泡周围形成磷脂单分子层所致。
Claims (18)
1．可用作超声波回波检测对比剂的充气微泡在水质载体液中的可注射悬浮液，含有至少107个微泡/ml和两亲化合物，其中至少一种是微泡抗破灭的磷脂稳定剂，其特征在于：载体液中磷脂浓度低于0.01重量％，而高于0.00013重量％。
2．按权利要求1所述的可注射悬浮液，其中每毫升微泡的浓度为108-1010之间。
3．按权利要求1所述的可注射的悬浮液，其中磷脂浓度在0.001％-0.009％之间。
4．按上述任一权利要求所述的可注射悬浮液，其中水质载体还含有水溶性多糖类和寡糖类、糖类和亲水性聚合物如聚乙二醇作为稳定剂。
5．按上述任一权利要求所述的可注射悬浮液，其中磷脂类至少部分是薄片状或层状的，并选自卵磷脂类如磷脂酸、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、心磷脂和神经鞘磷脂。
6．按权利要求4或5所述的可注射悬浮液，还进一步含有影响磷脂性质的物质，它们是选自磷脂酰甘油、磷脂酸、联十六烷基磷酸酯、胆甾醇、麦角甾醇、植物甾醇、谷甾醇、羊毛甾烯醇、生育酚、酸丙酯、棕榈酸抗坏血酯和2,6-二叔丁基对苯酚。
7．按权利要求1、2或3所述的可注射悬浮液，其中磷脂类是通过冷冻干燥或喷雾干燥所得的粉末形式。
8．按权利要求1所述的可注射悬浮液，每毫升含约108-109个微泡，微泡大小在0.5-10μm之间，贮存中只表现出极少或没有变化。
9．按权利要求1所述的可注射悬浮液，其中水质载体还含有0-50重量％的非成膜表面活性剂，它们选自脂肪酸、脂肪酸的酯类和醚类和带多羟基的醇类如聚亚烷基二醇类、多烷基化糖类和其它糖类及多烷基化甘油。
10．按上述任一权利要求所述的可注射悬浮液，其中微泡充有SF6、CF4、氟利昂或空气。
11．制备权利要求1所述充气微泡可注射悬浮液的方法，包括选择至少一种成膜表面活性剂，将表面活性剂转化为粉状，将粉末与空气或另一种气体接触，将粉状表面活性剂和水质液状载体混合形成所述悬浮液，其特征在于：将悬浮液引入一容器，在容器上部形成一层充气微泡，分离所形成的微泡层，用饱和了微泡气体的水溶液洗涤微泡。
12．按权利要求11所述的方法，其中成膜表面活性剂在转化为粉状之前至少部份层状化。
13．按权利要求12所述的方法，其中经部分层状化表面活性剂在与空气或另一种气体接触之前，先与水质液状载体混合。
14．按权利要求12或13所述的方法，其中水质液状载体还包含选自水溶性蛋白质类、多肽类糖类、多糖类和寡糖类及亲水性聚合物的稳定剂化合物。
15．按权利要求12所述的方法，其中转化是这样进行的：将表面活性剂包覆到可溶性或不溶性物质颗粒上，使包覆后的颗粒在空气或气体中静置片刻，将包覆后的颗粒与水质液状载体相混合。
16．按权利要求12所述的方法，其中转化是这样进行的：在高压下将成膜磷脂的水溶液进行声处理或匀化，这一操作至少部分导致脂质体的形成。
17．按权权利要求16所述的方法，其中至少部分层状化的表面活性剂在与空气或另一种气体接触之前，将含脂质体溶液冷冻干燥。
18．按权利要求16或17所述的方法，其中成膜脂类的水溶液还包含增粘剂或稳定剂，它们是选自亲水性聚合物和糖类、其与所含脂类重量的比为10∶1和1000∶1之间。
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- 1993-10-21 HU HU9401409A patent/HU227043B1/hu active Protection Beyond IP Right Term
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- 1993-10-21 WO PCT/EP1993/002915 patent/WO1994009829A1/en active IP Right Grant
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- 1993-10-28 IS IS4089A patent/IS1625B/is unknown
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- 1994-07-01 FI FI943167A patent/FI115953B/fi not_active IP Right Cessation
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- 1995-10-17 AU AU34317/95A patent/AU681812B2/en not_active Expired
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1997
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1998
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2000
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2001
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