CN1306442A - 造影剂或与造影剂有关的改进 - Google Patents
造影剂或与造影剂有关的改进 Download PDFInfo
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- CN1306442A CN1306442A CN99807622A CN99807622A CN1306442A CN 1306442 A CN1306442 A CN 1306442A CN 99807622 A CN99807622 A CN 99807622A CN 99807622 A CN99807622 A CN 99807622A CN 1306442 A CN1306442 A CN 1306442A
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
Landscapes
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Abstract
使用新的含气体造影剂制剂对个体、特别是心肌和其它组织灌注进行超声显影,在施用后,所述制剂在体内促进气相可控和暂时地生长,因此可以用作沉积的灌注示踪剂。该制剂包括含有分散气体的可注射含水介质和可注射的水包油乳液,其中油相含有能够在体内扩散至分散气体内以促进其暂时生长的可扩散组分,从而使得在分散气相表面处存在的物质和在分散油相表面处存在的物质例如由于具有相反的电荷而具有相互亲和性。在心脏灌注成像中,可将该制剂有利地与血管舒张药如腺苷共同施用,以增强分别从正常的和灌注不足的心肌组织返回的信号强度之间的差异。
Description
本发明涉及超声波成像,更具体地讲,本发明涉及新的造影剂制剂及其在超声波成像例如显影组织灌注中的用途。
熟知利用微泡的低密度和易压缩性,含气体微泡分散液的造影剂是特别有效的超声反向散射剂。如果经适宜稳定化处理,所述微泡分散液常常可以较小的剂量进行高效的如血管系统和组织微血管系统的超声波显影。
测量血液灌注(即每单位组织量的血液流量)的超声检查法的使用在例如肿瘤检测(肿瘤组织通常与健康组织的血管供应不同)以及如用于检测心肌梗塞的心肌研究中是非常有价值的。用现有超声造影剂进行心脏灌注研究的问题是所得的图像信息量因心脏心室中造影剂引起的弱化而减少。
在我们的共同未决国际专利申请WO-A-9817324(其内容在本文引作参考)中,我们已经公开了对个体,特别是心肌和其它组织灌注的超声显影可以借助含气体的造影剂制剂而实现和/或增强,所述制剂在施用后在体内促进气相的可控和暂时生长。此类造影剂制剂可以用于促进例如微泡形式的气相在组织微血管系统内的可控和暂时的保留,因而提高所述气体在所述组织中的浓度并因此例如相对于血液提高了其产生回波性。
就可静脉内施用的微泡超声造影剂而言,这种气体作为沉积灌注示踪剂的使用显著不同于现有的提议。因此,通常认为需要避免微泡的生长,因为如果失控,就会导致很危险的组织栓塞。因此,需要限制施用的剂量和/或使用与选定组合物混合的气体混合物以便通过抑制血液气体向内扩散至微泡中而使气泡在体内的生长减至最小(参见例如WO-A-9503835和WO-A-9516467)。
根据WO-A-9817324,另一方面,将含有分散气相的组合物与含至少一种物质的组合物共同施用,所述物质具有或能够在体内产生气体或蒸气压,从而足以通过衍生于所述物质的气体或蒸气分子的向内扩散到气相中而促进所述分散气相的可控生长,为了简单起见,下文将所述物质称为“可扩散组分”,但应理解,如下文进一步详细讨论的,在本发明的实施中还额外或另外涉及扩散以外的运输机制。
就如在WO-A-9416739中所描述的单独施用挥发性物质(例如以相转变胶体的形式)而言,含分散气相的组合物和含具有适宜挥发度的可扩散组分的组合物的这一共同施用与以前的提议相反。因此,如下文详细描述的,通过选择共同施用组合物的适宜组分,WO-A-9817324的造影剂制剂可控制一些因素如分散气体生长的可能性和/或生长速率,而前述相转变胶体的单独施用可能会导致生长失控和不均匀的微泡产生,并且可能达到至少部分微泡可能引起例如心肌血管系统和脑的危险栓塞的程度(参见例如Schwarz,回波造影进展(Advancesin Echo-Contrast)[1994(3)],pp.48-49)。
已经发现单独施用相转变胶体不可能使分散相可靠或稳定地在体内挥发以产生气体或蒸气微泡。Grayburn等在美国胶体心脏病学杂志(J.Am.Coll.Cardiol.)26(5)[1995],pp.1340-1347中建议,需预活化全氟戊烷乳液以便在狗中以足以避免血液动力学副作用的低有效成像剂量达到心肌浑浊化。在WO-A-9640282中描述了用于所述胶体分散液的活化技术,涉及低压力的应用;通常这包括首先用所述乳液部分填充注射器,随后用力地拉回,然后释放注射器的活塞以产生瞬时压力改变,从而使乳液内形成气体微泡。这是一种本身有些麻烦的技术,这种技术可能不能使活化程度一致。
还是对于相转变胶体,在US-A-5536489中指出,不溶于水且可以形成气体的化学品如全氟戊烷的乳液可以用作位点特异性成像的造影剂,在超声能施用于身体需要成像的具体位置时,所述乳液仅产生显著量的提高成像的气体微泡。然而,我们自己的研究表明,当用WO-A-9817324的两组分造影剂以足以产生清楚的造影效果的能量水平超声时,挥发性化合物如2-甲基丁烷或全氟戊烷的乳液在体外或体内并未产生可检测的回波增加。
WO-A-9817324的组合制剂意欲在超声成像中作为造影剂同时、分开或依次使用,所述制剂包括:
ⅰ)其中分散有气体的可注射含水组合物;和
ⅱ)一种组合物,含有在体内能够扩散至所述分散气体内以便至少瞬时提高其尺寸的可扩散组分。
所述制剂可以有利地用于在个体中显影组织灌注,分散气体尺寸的增加可以用于使气体在该组织的微血管系统中富集或暂时滞留,从而增强其产生回波性。
该类制剂的一个特殊优点是分散气体的生长可以通过超声处理、通过施用适量其他形式的能量(包括频率低于或高于常用于医学超声成像中的频率的声能、摇动、振动、电场或辐射)、或通过例如用中性颗粒、离子或电子进行颗粒轰击而诱发或增强。这使得可以特别有效地控制诸如分散气体生长的开始和生长速率等因素并使得这种生长定位于个体体内的特定区域,从而例如使气体在靶器官的微血管系统中,例如在心肌中暂时滞留。
本发明基于WO-A-9817324中所公开的那类造影剂制剂的效力在两种组合物以如下方式配制时可以显著增强这一发现,即分散气体组分和可扩散的组分例如由于静电或其他物理吸引力或由于化学(包括生物)结合而具有相互亲和性。这可以通过将分散气体组分配制成稳定化的气体分散液并将可扩散的组分配制成稳定化的乳液以使分散气体表面处存在的物质对分散的可扩散组分表面处存在的物质具有亲和性而实现。相互具有亲和性的表面物质可以是例如用于稳定该气体和可扩散组分分散液的表面活性剂等物质。或者,具有合适的相互亲和性的表面物质可以与各分散液中的非亲和稳定化物质混合、化学连接或缔合。
尽管我们不希望受理论考虑的约束,但据信在分散气体和可扩散组分之间产生的亲和性将它们之间相互作用的可能性增加10-100倍或甚至更高,因而与其中组分缺乏这种相互亲和性的情形相比,对于给定剂量的两种组分引起更大数量的分散气体部分生长。当使用超声或类似活化来诱发分散气体的生长时尤其如此。这里,在组分之间没有显著的亲和性时,认为超声处理可以导致显著比例的分散气相崩解且仅仅导致与可扩散组分具有较低的相互作用水平。然而相互作用的水平可以通过使用具有相互亲和性的气体和可扩散组分而显著增加。
本发明的造影剂制剂因此可以比WO-A-9817324所建议的剂量明显更低的剂量使用,同时得到相同的造影效果。这对于产品安全性很有价值,因为它允许以低水平使用可扩散组分乳液,从而使得来自其挥发性内容物的栓塞的任何危险可以忽略不计,例如如J.Appl.Physiol.,40(5)[1976],第745至751页所述,甚至在用血液气体稀释之后。
或者或额外的是,气体分散液的剂量可以降低,从而可能就产品安全性和毒性产生益处。该剂量的降低也可通过允许分散气体从心室血液中较早清除并由此允许例如滞留于心肌组织中的气体更快速地显影而在诸如超声波心动描记法等应用中延长可用的成像时间范围。
此外,已经发现本发明的造影剂制剂易于允许使用常规的B模式扫描技术对组织如心肌进行有效的成像。由以B模式操作的扫瞄仪发射的超声能因此足以诱发分散气相的生长,然后滞留于微血管系统中并可产生诊断上有用的信息至少5至10分钟,而不发生超声诱发的劣化。该性能显著不同于现有含气体的造影剂所显示的性能,后者通常在超声处理过程中发生较快的降解且因此可能要求使用更复杂的技术,如涉及间歇成像,以进行令人满意的显影。
根据其一方面,本发明提供了一种在超声成像中作为造影剂同时、分别或依次使用的组合制剂,所述制剂包含:
ⅰ)第一组合物,其为含有分散气体和用于稳定所述气体的物质的可注射含水介质;和
ⅱ)第二组合物,其为可注射的水包油乳液,其中油相包含在体内能够扩散至所述分散气体内以便至少瞬时增加其尺寸的可扩散组分,所述组合物还含有用于稳定所述乳液的物质,
其特征在于存在于分散气相表面处的物质和存在于分散油相表面处的物质相互具有亲和性。
本发明还提供了在人或非人动物个体中产生改善的图像的方法,所述方法包括下列步骤:
ⅰ)将如上所定义的第一组合物注射至所述个体的血管系统内;
ⅱ)在注射所述第一组合物之前、过程中或之后,给所述个体注射如上所定义的第二组合物;和
ⅲ)在所述个体的至少部分区域产生超声图像。
在分别存在于第一和第二组合物中的表面物质之间的必要亲和性例如可以通过使用具有相反电荷的物质而达到,从而使它们相互作用并相互静电结合。因此,例如表面物质之一可以是阳离子表面活性剂且另一个是阴离子表面活性剂,例如如下面更详细讨论的。在表面物质之间的电荷差异也可通过根据需要将合适的阳离子和/或阴离子添加剂掺入存在于两个组合物的各分散相之一或二者的表面处的稳定化物质如表面活性剂中而达到。另外,各表面物质可以含有稳定剂或添加剂,所述稳定剂或添加剂含有能够通过化学结合相互作用如共价键合、氢键键合或离子键合而相互作用的特定的基团、分子、配体或载体。因此,表面物质可以例如分别包含抗原和抗体或其片段,凝集素和含碳水化合物的基团,抗生物素蛋白/链霉抗生物素蛋白和生物素或生物素基团,药物和受体,递质和受体,激素和受体,肽或蛋白质和互补肽或蛋白质,酶或无活性酶和基质类似物或抑制剂,核酸(DNA或RNA)序列和互补核酸序列,或螯合剂和配体;前面所列并不认为起限制作用。
在用作本发明第一组合物的气体分散液中通常可含有任何生物相容性气体,本文所用术语“气体”包括在37℃的正常人体温度下至少部分,例如基本上或完全是气体或蒸气形式的任何物质(包括混合物)。因此,代表性气体可包括空气;氮气;氧气;二氧化碳;氢气;惰性气体如氦气、氙气、氩气或氪气;氟化硫如六氟化硫、十氟化二硫或三氟甲基硫五氟化物;六氟化硒;任选卤代的硅烷如甲基硅烷或二甲基硅烷;低分子量烃(例如含至多7个碳原子),例如链烷烃如甲烷、乙烷、丙烷、丁烷或戊烷,环烷烃如环丙烷、环丁烷或环戊烷,链烯烃如乙烯、丙烯、丙二烯或丁烯,或炔烃如乙炔或丙炔;醚如二甲醚;酮;酯;卤代低分子量烃(例如含至多7个碳原子);或前述任何物质的混合物。优选在卤代气体中的至少部分卤原子是氟原子;因此,生物相容性卤代烃气体可选自例如一溴一氯二氟甲烷,一氯二氟甲烷、二氯二氟甲烷,一溴三氟甲烷,一氯三氟甲烷,一氯五氟乙烷,二氯四氟乙烷,一氯三氟乙烯,氟乙烯,乙基氟化物,1,1-二氟乙烷和全氟化碳。代表性的全氟化碳包括全氟链烷烃如全氟甲烷,全氟乙烷,全氟丙烷,全氟丁烷(例如全氟正丁烷,任选地与其他异构体如全氟异丁烷混合),全氟戊烷,全氟己烷或全氟庚烷;全氟链烯烃如全氟丙烯,全氟丁烯(例如全氟丁-2-烯),全氟丁二烯,全氟戊烯(例如全氟戊-1-烯)或全氟-4-甲基戊-2-烯;全氟炔烃如全氟丁-2-炔;和全氟环烷烃如全氟环丁烷,全氟甲基环丁烷,全氟二甲基环丁烷,全氟三甲基环丁烷,全氟环戊烷,全氟甲基环戊烷,全氟二甲基环戊烷,全氟环己烷,全氟甲基环己烷或全氟环庚烷。其他卤代气体包括氯甲烷,氟化(例如全氟化的)酮如全氟丙酮和氟化(例如全氟化的)醚如全氟二乙醚。从含所述气体的微泡在血流中的公知高稳定性来看,使用全氟化气体例如六氟化硫和全氟化碳如全氟丙烷,全氟丁烷,全氟戊烷和全氟己烷是特别有利的。也可以使用其它有生理化学特征的气体,所述特征可使所述气体在血流中形成高度稳定的微泡。
例如气体可以至少部分由气体稳定化材料包封或稳定的微泡形式存在于第一组合物中。所述稳定化材料可以包括例如抗聚结表面膜(如明胶,如WO-A-8002365所述)、成膜(filmogenic)蛋白(例如白蛋白,如人血清白蛋白,如US-A-4718433,US-A-4774958,US-A-4844882,EP-A-0359246,WO-A-9112823,WO-A-9205806,WO-A-9217213,WO-A-9406477或WO-A-9501187所述)、聚合物材料(例如EP-A-0398935中所述的合成的生物可降解聚合物,EP-A-0458745中所述的弹性界面合成聚合物膜,EP-A-0441468中所述的微粒状生物可降解聚醛,EP-A-0458079中所述的微粒状聚氨基酸-聚环状酰亚胺的N-二羧酸衍生物,或者如WO-A-9317718或WO-A-9607434所述的生物可降解聚合物)、非聚合的和不可聚合的成壁材料(如WO-A-9521631中所述)或表面活性剂(例如聚氧乙烯-聚氧丙烯嵌段共聚物表面活性剂如Pluronic,在WO-A-9506518中描述的聚合物表面活性剂,或成膜表面活性剂如磷脂,例如在WO-A-9211873,WO-A-9217212,WO-A-9222247,WO-A-9428780,WO-A-9503835或WO-A-9729783中所述)。
第一组合物还可衍生于含气体的固体体系,例如其中含有气体或结合有气体(例如被吸附在其表面和/或被包含在空隙、洞或孔中,如EP-A-0122624,EP-A-0123235,EP-A-0365467,WO-A-9221382,WO-A-9300930,WO-A-9313802,WO-A-9313808或WO-A-9313809所述)的微粒(特别是微粒聚集体)。应理解,所述微粒状造影剂的产生回波性可直接来自于含有的/结合的气体和/或从固体材料中释放(如微粒状结构溶解后)的气体(例如微泡)。
与含气体制剂有关的上述所有文献的公开内容均引入本文作为参考。
气体微泡和其他含气体材料如微粒优选具有一初始平均尺寸,其不超过10微米(例如7微米或更小)以便使其在例如通过静脉内注射施用后自由通过肺系统。但是,若微泡例如含有一种或多种较具血溶性或扩散性气体如空气、氧气、氮气或二氧化碳与一种或多种基本上不溶的和不可扩散气体如全氟化碳的混合物时,可使用较大的微泡。施用后,所述可溶性/扩散性气体的向外扩散将会使所述微泡迅速收缩至由所含的不溶性/不可扩散性气体量所决定并可经选择以使所得微泡通过肺系统的肺毛细管的尺寸。
由于根据本发明施用的分散气体在体内通过与可扩散组分的相互作用而生长,所以所施用的微泡、与固体结合的气体等的最小尺寸可显著小于通常认为为提供与超声波具有显著相互作用所需的尺寸(在常规使用的成像频率下,通常约1-5微米);因此,分散的气体部分的尺寸可小至例如1nm或1nm以下。因此,本发明可以使用迄今为止由于分散气体部分的尺寸小,而未被提议用作超声造影剂的含气体组合物。
若根据本发明例如以磷脂-稳定化的气体微泡形式使用含磷脂的第一组合物,则有用磷脂的代表性例子包括卵磷脂(即磷脂酰胆碱),例如天然卵磷脂如蛋黄卵磷脂或大豆卵磷脂,半合成(如部分或全部氢化的)卵磷脂和合成的卵磷脂如二肉豆蔻酰磷脂酰胆碱,二棕榈酰磷脂酰胆碱或二硬脂酰磷脂酰胆碱;磷脂酸;磷脂酰乙醇胺;磷脂酰丝氨酸;磷脂酰甘油;磷脂酰肌醇;心肌磷脂;神经鞘磷脂;任何前述物质的氟化类似物;任何前述物质的混合物和与其他类脂如胆固醇的混合物。例如按WO-A-9729783所述,使用例如在天然(如大豆或蛋黄衍生的)、半合成(如部分或全部氢化的)以及合成的磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、磷脂酸和/或心肌磷脂中主要(例如至少75%)含各自带净总电荷如负电荷的分子的磷脂是特别有利的。
可在本发明的第一组合物中使用的含气体的微粒状材料的代表性例子包括碳水化合物(如己糖类如葡萄糖、果糖或半乳糖;二糖类如蔗糖,乳糖或麦芽糖;戊糖类如阿拉伯糖,木糖或核糖;α-、β-和γ-环糊精;多糖如淀粉、羟乙基淀粉,直链淀粉,支链淀粉,糖原,菊粉,短根霉多糖,葡聚糖,羧甲基葡聚糖,磷酸葡聚糖,酮基葡聚糖、氨乙基葡聚糖、藻酸盐、聚糖氨乙基几丁质,脱乙酰几丁质,透明质酸或肝素;和糖醇,包括醛醇如甘露糖醇或山梨糖醇),无机盐(如氯化钠),有机盐(如柠檬酸钠,醋酸钠或酒石酸钠),X-射线造影剂(如任何市售的羧酸和非离子酰胺造影剂,如在甲泛影酸,泛影酸,碘拉酸,碘克沙酸,碘海醇,碘喷托,碘帕醇,碘克沙醇,碘普罗胺,甲泛葡胺,胆影酸,胆影酸葡胺,醋碘苯酸葡胺,泛影葡胺中通常在3-和/或5-位含至少一个带取代基的2,4,6-三碘苯基,取代基如羧基,氨基甲酰基,N-烷基氨基甲酰基,N-羟基烷基氨基甲酰基,酰基氨基,N-烷基酰基氨基或酰基氨基甲基)以及多肽和蛋白质(如明胶或白蛋白如人血清白蛋白)。
可在本发明的第一组合物中使用的其它含气体材料包括通过金属稳定化的含气体材料(如在US-A-3674461或US-A-3528809中所述的),通过合成聚合物稳定化的含气体材料(如在US-A-3975194或Farnand在粉末技术(Powder Technology)22[1979],pp.11-16中描述的),Expancel型市售微球,如Expancel 551 DE(参见例如,欧洲塑料通讯(Eur.Plast.New)9(5)[1982],p.39,无纺织物工业(Nonwovens Industry)[1981],p.21和塑料及弹性体材料(Mat.Plast.Elast.)10[1980],p.468),Ropaque型市售微球(参见例如涂料技术杂志55(707)[1983],p.79),微米级和毫微米级的含气体结构如沸石,无机或有机气凝胶,毫微米级的含开口空隙的化学结构如富勒烯(fullerenes)、笼形包合物或nanotubes(如G.E.Gadd在科学277(5328)[1997],pp.933-936中描述的)和天然表面活性剂稳定化的微泡分散液(例如d’Arrigo在“稳定的液包气乳液,物理和理论化学研究”40-Elsevier,Amsterdam[1986]中描述的)。
在本发明制剂的第二组合物中的分散油相可以包含任何合适的可扩散组分,其至少部分不溶于水且与水不混溶。在该乳液中的可扩散组分有利的是在加工和储存温度下为液体,所述温度例如在水相含有合适的防冻物质时可以低至-10℃,同时在体温下为气体或具有显著的蒸气压。合适的化合物例如可选自前述WO-A-9416379中给出的可乳化低沸点液体的各种,该文献的内容引入本文作为参考。可乳化的可扩散组分的具体例子包括脂族醚如乙醚;多环油类或醇类如薄荷醇,樟脑,桉叶醇;杂环化合物如呋喃或二噁烷;脂族烃,可以是饱和的或不饱和的以及直链的或支链的,例如正丁烷,正戊烷,2-甲基丙烷,2-甲基丁烷,2,2-二甲基丙烷,2,2-二甲基丁烷,2,3-二甲基丁烷,1-丁烯,2-丁烯,2-甲基丙烯,1,2-丁二烯,1,3-丁二烯,2-甲基-1-丁烯,2-甲基-2-丁烯,异戊二烯,1-戊烯,1,3-戊二烯,1,4-戊二烯,丁烯炔,1-丁炔,2-丁炔或1,3-丁二炔;环脂族烃例如环丁烷,环丁烯,甲基环丙烷或环戊烷;以及卤代低分子量烃(例如含至多7个碳原子)。代表性的卤代烃包括二氯甲烷,溴甲烷,1,2-二氯乙烯,1,1-二氯乙烷,1-溴乙烯,1-氯乙烯,溴乙烷,氯乙烷,1-氯丙烯,3-氯丙烯,1-氯丙烷,2-氯丙烷和叔丁基氯。有利的是至少部分卤原子是氟原子,例如二氯一氟甲烷,三氯一氟甲烷,1,2-二氯-1,2-二氟乙烷,1,2-二氯-1,1,2,2-四氟乙烷,1,1,2-三氯-1,2,2-三氟乙烷,2-溴-2-氯-1,1,1-三氟乙烷,2-氯-1,1,2-三氟乙基二氟甲基醚,1-氯-2,2,2-三氟乙基二氟甲基醚,部分氟化的链烷烃(例如五氟丙烷如1H,1H,3H-五氟丙烷,六氟丁烷,九氟丁烷如2H-九氟-叔丁烷和十氟戊烷如2H,3H-十氟戊烷),部分氟化的链烯烃(如七氟戊烯如1H,1H,2H-七氟戊-1-烯和九氟己烯如1H,1H,2H-九氟己-1-烯),氟化的醚(如1,1,2,2-四氟乙基甲基醚,2,2,3,3,3-五氟丙基甲基醚,1,1,2,3,3,3-六氟丙基甲基醚或2,2,3,3,3-五氟丙基二氟甲基醚),更优选的是全氟化碳。全氟化碳的例子包括全氟链烷烃例如全氟丁烷,全氟戊烷,全氟己烷(如全氟-2-甲基戊烷),全氟庚烷,全氟辛烷,全氟壬烷和全氟癸烷;全氟环烷烃如全氟环丁烷,全氟二甲基-环丁烷,全氟环戊烷和全氟甲基环戊烷;全氟链烯烃如全氟丁烯(如全氟丁-2-烯或全氟丁-1,3-二烯),全氟戊烯(如全氟戊-1-烯)和全氟己烯(如全氟-2-甲基戊-2-烯或全氟-4-甲基戊-2-烯);全氟环烯烃例如全氟环戊烯或全氟环戊二烯;以及全氟化醇如全氟叔丁醇。
若需要,可扩散组分可以配制为专有注册药物乳液如Intralipid(Pharmacia)的一部分。
在本发明的另一实施方案中,油相可以是两种流体的混合物,第一种例如为上述全氟化碳,如全氟二甲基环丁烷,而另一种为挥发性亲脂性“填充”物质,该物质具有稍高的水溶性,如卤代的吸入麻醉剂或烃。“填充”物质的目的是引起微泡尺寸的非特异性增加。在分散气相的生长开始后,由于“填充”物质通过向外扩散而损失导致微泡在其最初生长后迅速收缩。残留的微泡现在仅含有较低水溶性的第一挥发性化合物和血液气体,其具有降低的尺寸,该尺寸可以通过适当选择可扩散组分乳液中两种挥发性流体的起始比例而控制。这两种流体的代表性混合比为1∶9全氟化碳:“填充”物质。
乳液稳定化物质可以典型地包括一种或多种表面活性剂。应该理解这类表面活性剂的性质可以显著影响如分散气相的生长速率这样的因素。总之,许多表面活性剂都可以是有用的,例如选自EP-A-0727225给出的大量例子,该文献的内容引入本文作为参考。有用的表面活性剂的代表性例子包括脂肪酸(如含10-20个碳原子的直链饱和的或不饱和的脂肪酸)和碳水化合物和其甘油三酯,磷脂(如卵磷脂),含氟磷脂,蛋白质(如白蛋白如人血清白蛋白),聚乙二醇和嵌段共聚物表面活性剂(如聚氧乙烯-聚氧丙烯嵌段共聚物如Pluronics,增量聚合物如酰氧基酰基聚乙二醇,例如聚乙二醇甲基醚16-十六烷酰氧基-十六烷酸酯,例如其中聚乙二醇部分的分子量为2300,5000或10000),含氟的表面活性剂(以Zonyl和Fluorad商标销售的产品,或WO-A-9639197中描述的,该文献的内容引入本文作为参考),以及阳离子表面活性剂,例如包含一个或多个季铵基团和一个或多个类脂基团如长链(例如C10-30)烷基或链烷酰基的阳离子表面活性剂。
在本发明可扩散组分乳液中存在的表面物质中使用阳离子物质作为表面活性剂或其它稳定剂或作为稳定剂的添加剂与含阴离子表面物质如带负电的磷脂的气体分散液结合从这两种表面物质之间的静电相互作用来看是特别有用的,所述磷脂如天然的(如大豆或蛋黄衍生的),半合成的(如部分或全部氢化的)或合成的磷脂如磷脂酰丝氨酸,磷脂酰甘油,磷脂酰肌醇,磷脂酸和心肌磷脂。
通常可以使用宽范围的阳离子物质,例如具有碱性氮原子的至少稍微疏水和/或显著水不溶的化合物,如伯胺、仲胺、叔胺和生物碱,包括吡咯烷、哌啶、咪唑、吡啶、喹啉和烷基-和芳基鈲盐化合物。代表性阳离子物质的实例包括亲脂性季铵或吡啶鎓盐,如二-十二烷基二甲基溴化铵、十六烷基三甲基氯化铵、十六烷基吡啶鎓氯化物、十六烷基三甲基溴化铵、Quaternium-26、油基三甲基氯化铵、十六烷基乙基二甲基溴化铵、lapyrium氯化物、Halimide、cetalkonium氯化物、1,2-二硬脂酰基-3-三甲基铵丙烷、甜菜碱十六烷基酯或DC-胆固醇;亲脂性仲或叔胺,如二乙基硬脂基胺、甲基硬脂基胺、二甲基鞘氨醇、脂肪醇与二甲基甘氨酸的酯、脂肪酸与二甲基乙醇胺的酯、脂肪醇与肌氨酸的酯或脂肪醇与N(2)-或N(6)-二甲基赖氨酸的酯;脂肪酸与取代的二胺或三胺如N-硬脂酰基-N’-二甲氨基丙胺的酰胺;伯胺如硬脂基胺或十二烷基胺;脂肪醇与氨基酸如丙氨酸、赖氨酸、丝氨酸或苏氨酸的酯,如丙氨酸十六烷基酯或赖氨酸十六烷基酯;脂肪酸与二胺或三胺的酰胺,如单硬脂酰二氨基丙烷或单硬脂酰腐胺;或带正电的磷脂如二烷基-sn-甘油乙基磷脂酰胆碱或磷脂酸如二棕榈酰基磷脂酸或二硬脂酰基磷脂酸与氨基醇如赖氨酸羟乙基酰胺、羟基赖氨酸乙酯、1,3-二氨基-2-丙醇或2,4-二氨基苄醇的酯。含有氮以外的带正电原子如硫(例如锍化合物)、碘(例如碘鎓化合物)、硒或磷(例如鏻化合物)的亲脂性阳离子化合物以及合适的带正电金属配合物也是有用的。
优选的阳离子物质包括内源性化合物(如鞘氨醇、DL-二氢鞘氨醇、二甲基鞘氨醇、植物鞘氨醇或吐根素)或易于降解成内源性物质的化合物(如胆碱、乙醇胺、腐胺、赖氨酸、精酸、甘氨酸、肌氨酸、二甲基甘氨酸、肉碱、甜菜碱或亚精胺的酯或酰胺,如十六烷基甜菜碱酯,或通常为氨基酸的衍生物)。使用含氟阳离子表面活性剂,如氟化的带正电磷脂或氟化的阳离子表面活性剂(以商标名Zonyl市售)也是有利的。
第二组合物例如可以静脉内、肌内或皮下注射;当特别需要限制可扩散组分的作用于个体的特定靶区时,后一途径是有利的。皮下注射用组合物的一个例子包括毫微粒子如用于淋巴血管造影术的粒子。
意欲静脉内注射的乳液的液滴尺寸优选应小于10微米,如小于7微米,且大于0.1微米,以利于无障碍通过肺系统。有利的是使用分别包含具有基本相似的尺寸,如直径为1-7,如2-6微米的分散气体微泡和分散的可扩散液滴的第一和第二组合物。
若需要,可扩散组分也可配制成微乳液。该体系由于其热力学稳定性和可扩散组分实际上均匀分布在水相中的事实而是有利的;因此,微乳液具有溶液的外观,但就分散相的分压而言,却表现出乳液的特性。
如上所述,本发明允许使用比迄今认为必要的剂量明显更低的剂量的含可扩散组分的乳液。如WO-A-9416739所公开的相转变胶体造影剂通常以对应于约0.1ml分散相/kg体重的量约药。WO-A-9817324描述了当可扩散组分为配制成水包油乳液的全氟化碳时,其通常以对应于0.2-1.0μl全氟化碳/kg体重的剂量约药。但本发明允许使用剂量低至少20倍且可能的话低至多200倍的可扩散组分,例如1-100nl可扩散组分/kg体重,如20nl可扩散组分/kg体重,得到与WO-A-9817324所观察到的图像相当的图像。
尽管乳液的可扩散组分在蒸发时体积能增加至少100倍,但应理解在该剂量下可扩散组分的总给药量通常不足以引起栓塞危险。此外,该剂量可低于气泡能在循环(如腔静脉、右心室和肺动脉)的低压静脉腔隙中由于挥发性可扩散组分和血液气体使血液过饱和而自发产生的任何阈值。
为了确保施用后可扩散组分的最大挥发作用并提高分散气体的生长,这两者都是吸热过程,有利的是在施用前控制第一和/或第二组合物的温度和/或向其中掺入放热反应成分;使用在超声照射的影响下发生放热反应的所述成分是特别有利的。
分散气相在体内的生长例如可伴有任何包封稳定化材料(其具有足够的柔软性)的膨胀和/或从第二组合物中抽出过量的表面活性剂或其他稳定化材料至正在生长的气-液界面。但是,包封材料的拉伸和/或所述材料与超声波的相互作用也可能显著地增加其孔隙率。迄今为止,在许多情况下,已发现包封材料的所述破裂导致通过由此暴露的气体向外扩散和溶解而迅速损失产生回波性,但我们已发现,当用本发明的造影剂制剂时,暴露的气体基本上是稳定的。尽管不希望受理论计算的限制,但我们认为例如释放的微泡形式的暴露气体可以通过由可扩散组分产生的过饱和环境而被稳定化,从而例如避免微泡的破裂,所述可扩散组分提供向内的压力梯度,抵消了微泡气体向外的扩散趋势。由于基本上没有包封材料,所以暴露的气体表面可使造影剂制剂表现出异常好的声学特性,这可从高反向散射和低能量吸收(如由高反向散射:衰减比例表示)得到证实;这种产生回波的作用可持续相当长的时期,甚至在连续超声照射过程中。
因此,利用共同施用的可扩散组分的稳定化作用,可以大大提高现有含气体造影剂制剂的产生回波性的持续时间和强度,而当单独施用该造影剂组合物时,这些参数是不够的。因此,例如白蛋白基造影剂的作用时间常常受包封的白蛋白材料破裂的严重限制,或者是由于心脏或静脉系统中收缩压变化或者是由于超声照射,但通过与本发明可扩散组分的共同施用可使所述作用时间显著增加。
在本发明方法的代表性实施方案中,选择含分散气体组分的组合物和含乳化的可扩散组分的组合物,以便在静脉内注射这两种组合物后,至少部分分散的气相通过肺,然后,在通过肺后,通过可扩散组分的向内扩散而迅速生长,从而使所述气相暂时保留在心肌中,并由此可进行心肌灌注的超声显像。由于血流中挥发性可扩散组分的浓度降低,例如由于通过肺除去和由个体呼出,通过代谢或再分配至其它组织,所述组分被从血液中清除,所述可扩散组分通常将扩散出分散的气体,因此,分散的气体将收缩至其初始的较小尺寸,并最终又可以在血流中自由地流动,其通常由网状内皮系统从血流中除去。这种产生回波性的瞬时显著增加,接着造影效果的消失的模式明显不同于单独施用这两种组合物之一时所表现出的任何产生回波性能。因此,从前文可以理解,对所述分散气体的滞留时间的控制可通过适当调整可扩散组分的剂量和/或配方,特别是气体组分和可扩散组分之间的亲和性的性质和程度来达到。
其它毛细管系统,例如包括但不限于肾、肝、脾、甲状腺、骨骼肌、乳腺和前列腺同样可进行成像。
通过适当选择气体和气体稳定化材料,更具体地讲是乳化的可扩散组分的性质和配制可扩散组分的方式,包括乳液稳定化材料的性质和乳液液滴的尺寸,总的来说,就可控制分散气体的生长速率和/或生长程度。就后一点来说,对于给定量的乳化的可扩散组分,液滴尺寸的减小,相对于较大的液滴,可提高可扩散组分的转移速率,因为具有较大表面积:体积比的较小液滴可发生更迅速的释放。可以控制的其它参数包括施用的两种组合物的相对量,以及当所述组合物是分别施用时,施用的顺序、两次施用的时间间隔和两次施用的可能的空间间隔。就最后一点而言,应理解可扩散组分的内在扩散性可使其以各种方式例如皮下、静脉内或肌内应用到身体的不同部分。
就可扩散组分而言,特别重要的参数是其在水/血液中的溶解度和其扩散性(例如用其扩散常数表示),这些参数将决定其通过载体液体或血液的运输速率,以及其通过包封分散气体的任何稳定化材料膜的渗透性。可扩散组分在体内产生的压力也将影响其扩散至分散气体中的速率,其浓度也是一样。因此,根据Fick’s法则,相对于例如单个气体微泡与乳液液滴之间距离而言,可扩散组分的浓度梯度以及可扩散物质在周围液体介质中的扩散系数将决定通过简单扩散的转移速率;浓度梯度通过可扩散组分在周围介质中的溶解度和单个气体微泡和乳液液滴之间的距离来确定。类似地,可扩散组分的水溶性、蒸气压和分子尺寸将通过这些参数对可扩散组分扩散速度的影响而影响膨胀微泡的寿命。这相应地允许控制造影持续时间,该时间最佳为2-5分钟。
如果需要,例如通过调整分散气相组合物和/或可扩散组分组合物的粘度,例如通过将一种或多种生物相容性粘度增加剂如X-射线造影剂、聚乙二醇、碳水化合物、蛋白质、聚合物或醇掺入制剂中,可控制可扩散组分的有效运输速率。例如可有利地以较大体积的药团(在70kg人个体的情况下,有至少20ml的体积)共注射两种组合物,因为这样可延缓所述成分与血液的完全混合(且因此延缓分散气体生长的开始),直到其进入右心室和肺毛细管后再混合。分散气体的生长延缓可通过载体液体的使用达到最大程度,所述载体液体就前文所定义的气体和任何其他可扩散组分而言,例如由于被冷却而是欠饱和的。
如上所述,本发明的操作还涉及除扩散以外的运输机制。因此,通过周围液体介质中的流体动力学流动,也可进行运输;在可发生高剪切速率流动的血管和毛细管中,这是很重要的。可扩散组分向分散气体的运输也可能因例如气体微泡和乳液液滴之间的碰撞或近碰撞过程而发生,例如导致可扩散组分吸附在微泡表面和/或渗入微泡中,即呈融合形式。在这类情形中可扩散组分的扩散系数和溶解度对转移速率、可扩散组分的颗粒尺寸(例如配成乳液时的液滴尺寸)以及微泡与液滴之间的碰撞频率具有最小的影响,而后三者是控制微泡生长的速率和程度的主要因素。因此,例如对给定量的乳化的可扩散组分而言,液滴尺寸的减小将导致液滴总数增加且因而可以通过降低气体微泡与乳液液滴之间的平均粒间距离并因此增加碰撞和/或融合的可能性而增加转移速率。如上所述,若通过施加超声能量对气体微泡和可扩散组分的乳液液滴赋予额外的振动式运动,可以显著提高通过碰撞过程而进行的转移速率。由这种超声能量引起的碰撞过程的动力学不同于在载体液体和/或血液中运输可扩散组分的动力学,例如不同之处为必需要有特定的能量水平来引起碰撞的气体微泡和乳液液滴发生融合。因此有利的是选择乳液液滴的尺寸并因此选择其质量,以使其与振动的微泡产生足够的碰撞力而引起融合。
如上所述,任何包封分散气相的稳定化材料的渗透性是可能影响该气相的生长速率的参数,且因此理想的是选择易于渗透任何这类包封材料(例如可以是聚合物或表面活性剂膜,例如单层或一个或多个双层成膜表面活性剂如磷脂)的可扩散组分。但是,我们已发现也可以使用基本上不可渗透的包封材料,因为尽管在这种不可渗透材料,分散气体的声处理-或其他能量输入引发的生长仍可发生。
尽管我们不希望受理论的限制,但是超声处理至少瞬时改变了包封材料的渗透性、在周围液相中可扩散组分的可扩散性和/或乳液液滴与包封微泡间的碰撞频率。由于可用极短的超声脉冲(例如在B模式成像时持续约0.3μs或在Doppler或第二谐波成像(Second harmonicimaging)时为约2μs)观察到所述影响,因此它不可能是一种调整的(rectified)扩散,其中连续的超声照射使气泡的平衡半径稳定增加(参见Leighton,E.G.-“声学泡(The Acoustic Bubble)”,AcademicPress[1994],p.379),而且超声脉冲可能破坏包封膜,由此提高了分散气体通过可扩散组分向内扩散至因此暴露的气相中而生长。
如果需要,分散气体或可扩散组分可包括共沸混合物或者可加以选择以便共沸混合物在可扩散组分与分散气体混合时在体内形成。可有效地利用所述共沸物形成作用以提高在标准条件下在正常人体温度37℃时是液体的相对高分子量的化合物如卤代烃如碳氟化合物(包括全氟化碳)的挥发性,从而在该温度下可以气体形式施用所述化合物。就含所述共沸混合物的造影剂在体内的有效产生回波期而言,这是非常有益的,因为已知象化合物如碳氟化合物的水溶解性、脂肪溶解性、扩散性和耐压性等参数随分子量的增加而减小。含有在37℃下为气体的生物相容性共沸混合物的造影剂描述于WO-A-9847540中,其内容引入本文供参考。
总之,在制备、贮存和处理过程中以及施用后,共沸混合物对其成分分离作用的公认天然抗性将提高含所述混合物的造影剂组分的稳定性。
参考有关共沸物的文献、通过试验研究和/或通过理论预测,例如按Tanaka在流体相平衡(Fluid Phase Equilibria)24(1985),187-203页、Kittel,C.和Kroemer,H.在热物理(Thermal Physics)第10章(W.H.Freeman & Co.,New York,USA,1980)或Hemmer,P.C.在静态力学(Statistisk Mekanikk)第16-22章(Tapir,Trondheim,Norway,1970)中所述,选择可用于本发明的共沸混合物,所述文献的内容引入本文作为参考。
将较高分子量组分的沸点有效降至正常体温以下的共沸物的一个文献例子是在US-A-4055049中描述的1,1,2-三氯-1,2,2-三氟甲烷(b.p.47.6℃)和1,2-二氟甲烷(b.p.29.6℃)的57∶43w/w混合物,其共沸点为24.9℃。含卤代烃的共沸混合物的其它例子描述于EP-A-0783017、US-A-5599783、US-A-5605647、US-A-5605882、US-A-5607616、US-A-5607912、US-A-5611210、US-A-5614565和US-A-5616821,所述文献的内容引入本文作为参考。
Simons等在化学物理杂志,18(3)(1950),335-346页中报道全氟正戊烷(b.p.29℃)与正戊烷(b.p.36℃)的混合物与Raoult’s法则有较大的正偏差;约等摩尔混合物的效果最好。在实践中,发现共沸混合物的沸点是约22℃或更低。总之,全氟化碳和未取代烃的混合物具有有用的共沸特性;具有基本类似沸点的所述组分的混合物有强共沸作用。其它全氟化碳:烃共沸物的例子包括全氟正己烷(沸点59℃)和正戊烷的混合物,其中共沸物的沸点在室温和35℃之间,全氟-4-甲基戊-2-烯(沸点49℃)和正戊烷的混合物,所述共沸物的沸点为约25℃。
其它很有用的共沸混合物包括氟烷(halothane)与乙醚的混合物和两种或多种氟化气体的混合物,例如全氟丙烷与氟乙烷、全氟丙烷与1,1,1-三氟乙烷,或者全氟乙烷与二氟甲烷。
已知氟化气体如全氟乙烷可与二氧化碳形成共沸物(参见,例如WO-A-9502652)。因此,含所述气体的造影剂的施用可在体内与血液气体如二氧化碳形成三元或更高的共沸物,由此进一步提高了分散气体的稳定性。
若将本发明组合造影剂制剂的两组合物同时施用,则可用不同的注射器经适宜的联合装置注射或者优选在控制的条件下预混合以避免过早的分散气体生长。
将用于同时施用前混合的组合物有利的是贮存在适宜的双或多室装置中。因此,例如可将含分散气体的第一组合物或其干燥的前体[例如在含两亲材料的含水介质中包含气体微泡悬浮液的冻干残余物,特别是其中所述两亲材料主要由磷脂组成(例如至少75%,优选基本上完全是),所述磷脂含有各自带总净(如负)电荷的分子]放在第一室如小瓶中,含有含可扩散组分的第二组合物的注射器与其密封相连;用膜或塞将注射器出口密封以避免早期混合。注射器活塞的拔出使膜破裂并使第二组合物与第一组合物混合或者与其前体混合并重建其前体;然后,如果需要,可振荡和/或稀释,将混合物取出(例如通过注射器)并施用。
或者,将两种组合物贮存在一个密封的小瓶或注射器中,两种组合物可由例如膜或活塞分隔开;可将气体或蒸气超压应用至两组合物中之一或同时应用至其上。例如通过将皮下注射针插入小瓶中,使膜或活塞破裂而使所述组合物混合;如果需要,通过手振荡可提高混合程度,此后,取出混合物并施用。同样可使用其它实施方案,例如其中含第一组合物的干燥前体的小瓶装有含有所述前体再分散液的第一注射器和含第二组合物的第二注射器,或者其中含膜-分隔开的第二组合物和第一组合物的干燥前体的小瓶装有含用于后者的再分散液的注射器。
其中在施用前,在制造阶段或随后将两种组合物混合的本发明实施方案中,通常将所述混合物贮存在较高的压力或较低的温度下,以便可扩散组分的压力不足以使分散的气体生长。简单地通过释放过量压力或通过施用所述混合物后加热至体温可诱导分散气体生长的激活作用,或者如果需要,通过在施用前立即预热所述混合物来激活。
在两种组合物分别施用的本发明实施方案中,可利用两次施用之间的时间控制来影响分散气相主要生长的身体区。因此,例如,可先注射第二组合物,使其在肝中浓缩,由此提高在随后注射含分散气体的第一组合物时所述器官的成像。若气体分散液的稳定性允许,也可先注射所述气体分散液,使其在肝中浓缩,接着施用含可扩散组分的第二组合物以提高其产生回波性。
可在本发明中使用的代表性超声成像技术包括基础B模式成像;谐波B模式成像(包括次谐波和第二或高级谐波的接收);组织Doppler成像,任选包括基础、谐波或次谐波回波频率的选择性接收;彩色Doppler成像,任选包括基础、谐波或次谐波回波频率的选择性接收;功率Doppler成像,任选包括基础、谐波或次谐波回波频率的选择性接收;利用由造影剂微泡的声学性能变化引起的、例如可由自发或超声诱发的破坏、分裂、生长或融合引起的相关性损失或明显Doppler偏移的功率或彩色Doppler成像;脉冲转化成像,任选包括基础、谐波或次谐波回波频率的选择性接收,且还包括其中在各方向上发射的脉冲数超过2的技术;利用由造影剂微泡的声学性能变化引起的、例如可由自发或超声诱发的破坏、分裂、生长或融合引起的相关性损失的脉冲转化成像;脉冲扭曲成像,如1997 IEEE超声论文集第1567-1570页所述;以及基于为检测由气体微泡的存在引起的非线性作用而以不同发射输出幅度或波形获得的回波的比较的超声成像技术。
对于给定剂量的气体分散液和可扩散组分组合物,已发现在随后的B模式成像过程中,用彩色Doppler成像超声波诱导分散气体的生长可产生更强的造影效果,这可能是使用了较高的超声波强度造成的。为了减少运动的影响,借助适宜的同步技术(例如选通(gating to)个体的ECG或呼吸运动)可收集组织如心或肾的连续图像。测量伴随分散气体生长的共振频率或频率吸收的变化,也可用于检测造影剂。
应理解本发明组合造影剂制剂的分散气体含量以一定的浓度暂时保留在组织中,所述浓度与组织灌注的区域率成正比。因此,当使用图像直接来自返回信号强度的超声成像模式如常规的或谐波B模式成像时,可将所述组织的图像解释为灌注图,其中表现出的信号强度是局部灌注的函数。这与用自由流动的造影剂得到的图像相反,后者中造影剂的区域浓度和相应的返回信号强度取决于实际的血液含量而不是局部组织的灌注速率。
在心脏研究中,若根据本发明的该实施方案,灌注图来自返回信号强度,有利的是使患者经受物理或药理学压力(stress)以便提高正常灌注的心肌与窄动脉供应的心肌区之间的区别,由此提高图像强度方面的差异。正如从放射性核素心脏成像中已知的,所述压力可诱导血管舒张并增加健康心肌组织中的血流,而在由窄动脉供应的灌注不足的组织中的血流基本上无改变,因为小动脉血管舒张的能力已被内在的自我调节作用耗尽,这种内在的自我调节作用是寻求提高受限制的血流。
作为物理练习或通过施用肾上腺素能激动剂以药理学方式施加的压力可引起不适如可能患心脏病患者组中患者的胸痛,因此,优选通过施用血管舒张药物来提高健康组织的灌注。可用于本发明的代表性血管舒张药包括内源性/代谢性血管舒张药,如乳酸、三磷酸腺苷、二磷酸腺苷、单磷酸腺苷、腺苷、氧化氮和引起高碳酸血、缺氧/低氧血或充血的药物;磷酸二酯酶抑制剂如双嘧达莫和sildenafil;交感神经活性抑制剂如可乐定和甲基多巴;平滑肌松弛剂如帕帕菲林、肼屈嗪、双肼屈嗪和硝普钠;β受体激动剂如多巴胺、多巴酚丁胺、阿布他明、舒喘灵、沙美特罗和喘息定;α受体拮抗剂如多沙唑嗪、terazosin和哌唑嗪;有机硝酸酯如三硝酸甘油酯、二硝酸异山梨醇酯和单硝酸异山梨醇酯;血管紧张肽转化酶(ACE)抑制剂如苯骈普利、卡托普利、依那普利、福森曾利、赖诺普利、喹那普利和雷米普利;血管紧张肽Ⅱ拮抗剂(或AT1受体拮抗剂)如valsartane、losartan和candesartan;钙通道阻断剂如阿洛地平、尼卡地平、尼莫地平、费乐地平、伊拉地平、地尔硫、维拉帕和硝苯地平;前列腺素如前列地尔;以及内皮依赖性血管舒张药。
腺苷的使用是特别优选的,因为其为内源性物质且具有迅速但短效的血管舒张作用。后一性能由如下事实证实:血液半衰期仅为几秒钟;因此将血管舒张过程中对患者造成的可能不适降至最小。由腺苷诱发的血管舒张在心脏中最为强烈,因为该药物倾向于在低于药理活性浓度下达到更远端组织;因此其为本发明方法的心动描记应用中选定的血管舒张药。
除动脉狭窄外,影响局部血管调节的其他组织/灌注异常可通过血管改性的诱发而按本发明检测。因此,例如具有恶性损伤的血管已知很难区分且因此与正常组织相比对血管收缩药的响应受损;血管收缩响应的类似缺乏可发生于严重发炎的组织。因此就成像过程中信号强度的变化而言观察对血管收缩药刺激的响应可给出有用的诊断信息。可用于这类实施方案的血管收缩药的代表性实例包括喘息定、肾上腺素、去甲肾上腺素、多巴胺、间羟胺、对羟苯心安、麦角胺、二氢麦角胺、二甲麦角新碱以及硝酸生产的抑制剂例如L-精氨酸类似物;例如该类药物可以局部或全身给药。
对于某些目的,有利的是一起或依次给予两种或更多种血管活性物质。当施用两种血管活性物质时,二者可以均为血管舒张药,二者可以均为血管收缩药,或者一种可为血管舒张药而另一种可为血管收缩药。当使用两种血管舒张药或两种血管收缩药时,它们至少应有一种性能不同,如组织特异性或作用机理,从而在单次检测中可确定出信号强度的局部差异。当单独给药时,可以首先给予血管收缩药,然后给予血管舒张药,或可以使用相反顺序。
在腺苷的情况下,这会使健康心肌组织的冠状动脉中的血流增加4倍,大大提高本发明造影剂的摄入和暂时滞留,并因此显著提高正常与灌注不足的心肌组织之间的返回信号强度差别。由于涉及必需的物理截留过程,因此,本发明造影剂的滞留是非常有效的;这可以与放射性核素示踪剂如铊201和锝sestamibi的摄入相比拟,所述示踪剂的摄入受示踪剂和组织之间接触时间短的限制,并因此在示踪剂分布于血液池的整个过程(铊闪烁法为4-6分钟)中,均需保持血管舒张以确保效果最佳。另一方面,本发明的造影剂没有这种扩散或运输限制,且因为例如通过停止产生生长的超声波照射也可以迅速终止其在心肌组织中的滞留,因此,达到本发明本实施方案的心脏灌注成像所需的血管舒张期是很短的,例如不到1分钟。这将减少因施用血管舒张药物给患者引起的任何可能不适的时间。
应该理解的是,由于上述腺苷的半衰期短,其重复注射或输注在根据本发明的实施方案进行的心脏成像过程中可能是必要的;例如开始施用150μg/kg腺苷,基本上同时施用造影剂组合物,10秒钟后,例如在20秒钟内缓慢再注射150μg/kg腺苷。也可以在覆盖造影剂注射和在心肌中沉积的时间间隔过程中以稳定速率输注腺苷。
有利的是可将本发明的造影剂制剂用作生物活性部分如治疗药物的传递剂(即对活人或非人动物的具体疾病有有益作用的试剂),特别是传递至靶位点。因此,例如可将治疗化合物放在第一组合物中,例如在分散气体中,可例如通过共价键或离子键,如果需要,通过间隔臂与稳定化材料的部分相连,或者物理混合至该稳定化材料中;如果治疗化合物和稳定化材料具有类似的极性或溶解度,则所述最后一种方案是特别适宜的。
可以利用分散气体的可控生长特性,使其暂时滞留在所需靶区的微血管系统中;用超声波照射来诱导生长并因此使气体和结合的治疗化合物滞留在靶结构中是特别有利的。还可利用本文上述含气体的第一组合物或更优选含可扩散组分的第二组合物的定位注射来集中分散气体在靶区的生长。
如果需要可与对特异性细胞、结构或病理学位点具有亲和性的位点-特异性载体相连的治疗化合物可因例如分散气体生长引起的气体稳定化材料的拉伸或破裂、稳定化材料的加溶或者气体微泡或含气体微粒的崩解(例如通过超声处理或通过在靶区可扩散组分浓度梯度的逆转而引起)而释放。若治疗药物与气体稳定化物质化学相连,则该键或与其相连的间隔臂有利的是含有一个或多个可裂解以释放所述药物的不稳定基团。代表性的可裂解基团包括在体内例如通过水解和/或酶催作用可生物降解的酰胺、酰亚胺、亚胺、酯、酸酐、缩醛、氨基甲酸酯、碳酸盐、碳酸酯和二硫化物基团。
用于本发明实施方案的代表性和非限制性药物实例包括抗肿瘤药物如长春新碱、长春碱、长春地辛、白消安、苯丁酸氮芥、螺铂、顺铂、卡铂、甲氨蝶呤、阿霉素、丝裂霉素、博来霉素、阿糖胞苷、阿糖腺苷、巯嘌呤、米托坦、丙卡巴肼、放线菌素D(antinomycin D)、柔红霉素、盐酸阿霉素、紫杉酚、普卡霉素、氨鲁米特、雌莫司汀、氟他胺、亮丙瑞林(leuprolide)、醋酸甲地孕酮、他莫昔芬、睾内酯、曲洛司坦、安吖啶(m-AMSA)、天冬酰胺酶(L-天冬酰胺酶)、依托泊苷、干扰素a-2a和2b、血液产品如血卟啉或前述药物的衍生物;生物反应改性剂如胞壁酰肽(muramylpeptides);抗真菌剂如酮康唑、制真菌素(nystatin)、灰黄霉素、氟胞嘧啶、咪康唑或两性霉素B;激素或激素类似物如生长激素、促黑素细胞激素、雌二醇、二丙酸倍氯米松、倍他米松、醋酸可的松、地塞米松、氟尼缩松、氢化可的松、甲泼尼龙、醋酸帕拉米松、泼尼松龙、泼尼松、曲安西龙或乙酸氟氢可的松;维生素如维生素B12或类维生素A;酶如碱性磷酸酶或超氧化锰歧化酶;抗过敏药如amelexanox;抗凝剂如苄丙酮香豆素、苯丙香豆素或肝素;抗血栓形成药物;促进循环的药物如普萘洛尔;代谢增效剂如谷胱甘肽;抗结核药如对氨基水杨酸、异烟肼、硫酸卷曲霉素、cyclosexine、乙胺丁醇、乙硫异烟胺、吡嗪酰胺、利福平或硫酸链霉素;抗病毒剂如阿昔洛韦、金刚烷胺、叠氮胸苷、利巴韦林或阿糖腺苷;血管舒张剂如地尔硫、硝苯地平、维拉帕米、四硝赤醇、硝酸异山梨酯、硝酸甘油或戊四硝酯;抗生素如氨苯砜、氯霉素、新霉素、头孢克洛、头孢羟氨苄、头孢氨苄、头孢拉定、红霉素、克林霉素、林可霉素、阿莫西林、氨苄西林、巴氨西林、羧苄青霉素、双氯青霉素、环青霉素、picloxacillin、海他西林、甲氧西林、萘夫西林、青霉素或四环素;抗炎剂如二氟尼柳、布洛芬、吲哚美辛、meclefenamate、甲芬那酸、萘普生、保泰松、吡罗昔康、托美丁、阿司匹林或水杨酸盐;抗原生动物剂如氯喹、甲硝唑、奎宁、锑酸葡胺;抗风湿剂如青霉胺;麻醉剂如阿片樟脑酊;阿片制剂如可待因、吗啡、鸦片;强心苷如脱乙酰毛花甙、洋地黄毒甙、地高辛、洋地黄甙或洋地黄;神经肌肉阻断剂如阿曲库铵甲磺酸盐、加拉碘铵、溴己氨胆碱、碘甲筒箭毒、泮库溴铵、氯化琥珀胆碱、氯化筒箭毒碱或维库溴铵;镇静剂如异戊巴比妥、异戊巴比妥钠、阿普比妥、仲丁巴比妥钠、水合氯醛、乙氯维诺、己炔蚁胺、盐酸氟安定、格鲁米特、盐酸甲氧异丁嗪、甲乙呱酮、盐酸咪达唑仑、副醛(paraldehyde)、戊巴比妥、司可巴比妥钠、他布比妥、替马西泮或三唑仑;局部麻醉剂如布比卡因、氯普鲁卡因、依替卡因、利多卡因、甲哌卡因、普鲁卡因或丁卡因;全身性麻醉剂如氟哌利多、依托咪酯、枸橼酸芬太尼与氟哌利多、盐酸氯胺酮、美索比妥钠或硫喷妥和可药用盐(如酸加成盐如盐酸盐或氢溴酸盐,或者碱盐如钠、钙或镁盐)或其衍生物(如乙酸盐);和放射性化学物质,如含β发射体的化学物质。特别重要的是抗血栓形成药如维生素K拮抗剂、肝素和具有肝素样活性的药物如抗凝血酶Ⅲ,dalteparin和依诺肝素;血小板凝集抑制剂如噻氯匹定、阿司匹林、双嘧达莫、伊洛前列素和abciximab;和溶栓酶如链激酶和纤溶酶原激活物。治疗药物的其它例子包括遗传物质例如核酸、天然或合成的RNA和DNA,包括重组RNA和DNA。将编码特定蛋白质的DNA用于治疗许多不同的疾病。例如肿瘤坏死因子或白细胞介素-2可治疗晚期癌症;胸苷激酶可治疗卵巢癌或脑肿瘤;白细胞介素-2可治疗成神经细胞瘤、恶性黑素瘤或肾癌;白细胞介素-4可治疗癌症。
本发明的造影剂制剂可用作载体,用于除超声波以外的成像模式如X射线、光成像、磁共振,更优选闪烁成像剂的造影增强部分。可利用分散气相的可控生长将所述造影剂定位在个体体内的所需区域,例如,利用超声照射靶器官或组织以诱导所述造影剂的所需的可控生长和暂时滞留,然后用适宜的非超声成像形式成像。
本发明造影剂制剂还可用作治疗活性物质的载体,所述治疗活性物质不需从所述制剂中释放即可表现出其治疗效果。所述制剂例如可掺入放射性原子或离子如β-发射体,所述放射性原子或离子在分散气相生长以及所述造影剂暂时滞留在靶位点后,表现出定位发射辐射的作用。应理解,优选应将所述造影剂设计成在所需的治疗辐射剂量被施用前,不会发生分散气体的随后收缩以及分散气体停止滞留。
另外,本发明的造影剂制剂本身还可有治疗特性。因此,例如可通过静脉注射高剂量的药物、然后暴露具有肿瘤的动脉于局部超声照射而在治疗上使用该制剂。因此,可以通过应用定位的超声波能来获得可控的和定位栓塞;这本身或与其它治疗方法结合都是很重要的。在高温治疗中,分散气体在毛细管中的浓度还可以增加超声波能的吸收;这可用于例如治疗肝肿瘤。可用该方法治疗的其他组织包括乳房、甲状腺和前列腺。在所述应用中,用相对高能量(例如5W)聚焦的超声波束(如1.5MHz)照射是适宜的。
下列非限制性实施例用来说明本发明。
制备1
具有带负电的表面物质的全氟丁烷气体分散液
将氢化磷脂酰丝氨酸(5mg/ml,在丙二醇的1%w/w提纯水溶液中)和全氟丁烷气体在7800rpm和约40℃下在线均化得到乳状白色微泡分散液。该分散液被分级以基本除去筛下的微泡(<2微米)且通过加入蔗糖水溶液将分散液的体积调节到所需的微泡浓度以使蔗糖浓度为92mg/ml。将2ml的所得分散液填充到特别设计用于冻干的10ml平底小瓶中,并将内容物冻干以得到白色多孔饼。然后将冻干室用全氟丁烷填充并密封该小瓶。在使用前,将水加入小瓶中并用手将内容物温和振摇几秒钟以得到全氟丁烷微泡分散液;微泡在该分散液中的浓度为1.1%v/v,且平均微泡尺寸为2.7微米。
制备2
具有带正电的表面物质的全氟丁烷气体分散液
将1ml 1,2-二硬脂酰基-3-三甲基铵丙烷(1mg/ml)和二硬脂酰基磷脂酰胆碱(4mg/ml)在2%w/v丙二醇的提纯水溶液中的分散液置于2ml的小瓶中。液面上空间用全氟丁烷气体冲洗,然后将小瓶密封并使用牙科材料所用的Espe CapMix混合器振摇45秒。所得乳状白色微泡分散液通过离心和除去次层清液(infranatant)而洗涤3次,然后加入等体积的提纯水。微泡在所得分散液中的浓度为4.9%v/v且平均微泡尺寸为3.2微米。
制备3
具有生物素化表面物质的全氟丁烷气体分散液
将二硬脂酰基磷脂酰丝氨酸(4.5mg)和生物素-二棕榈酰基磷脂酰乙醇胺(0.5mg)称入清洁小瓶中并加入1.0ml 1.4%丙二醇/2.4%甘油的溶液。加热到78℃后,将混合物冷却至室温,并用全氟丁烷气体冲洗液面上空间。密封该小瓶,使用Espe CapMix混合器振摇45秒,然后放置在辊压台上16小时。将所得微泡分散液用去离子水充分洗涤。
制备4
具有带正电表面物质的全氟二甲基环丁烷乳液
将1ml二-十二烷基二甲基溴化铵(5mg/ml,在提纯水中)的分散液置入2ml小瓶中,向其中加入100微升全氟二甲基环丁烷(沸点45℃)。将小瓶密封,然后使用Espe CapMix振摇75秒,得到可扩散组分的乳液,将其在不用时储存在0℃。该乳液通过离心和除去次层清液,然后加入等体积的提纯水而洗涤三次。乳液中液滴的浓度为6.2%v/v且平均液滴尺寸为2.3微米。
制备5
具有带正电的表面物质的全氟己烷乳液
将1ml1,2-二硬脂酰基-3-三甲基铵丙烷(1mg/ml)和二硬脂酰基磷脂酰胆碱(4mg/ml)在提纯水中的分散液置入2ml的小瓶中,向其中加入100微升全氟己烷(沸点57℃)。将小瓶密封,然后使用Espe CapMix振摇75秒,得到可扩散组分的乳液,将其在不用时储存在0℃。该乳液通过离心和除去次层清液,然后加入等体积的提纯水而洗涤三次。乳液中液滴的浓度为2.9%v/v且平均液滴尺寸为2.9微米。
制备6
具有带负电的表面物质的全氟二甲基环丁烷乳液
将1ml氢化磷脂酰丝氨酸(5mg/ml,在提纯水中)的分散液置入2ml的小瓶中,向其中加入100微升全氟二甲基环丁烷(沸点45℃)。将小瓶密封,然后使用Espe CapMix振摇75秒,得到可扩散组分的乳液,将其在不用时储存在0℃。该乳液通过离心和除去次层清液,然后加入等体积的提纯水而洗涤三次。乳液中液滴的浓度为6.9%v/v且平均液滴尺寸为2.7微米。
制备7
具有抗生物素蛋白化表面物质的全氟二甲基环丁烷乳液
将二硬脂酰基磷脂酰丝氨酸(4.5mg)和生物素-二棕榈酰基磷脂酰乙醇胺(0.5mg)称入清洁小瓶中并加入1.0ml 2%丙二醇的溶液。加热到80℃后,将混合物冷却至室温。加入100微升全氟二甲基环丁烷并密封该小瓶,使用Espe CapMix振摇75秒,得到可扩散组分的乳液。将该乳液的稀释样品(100微升乳液在1ml水中)用过量的抗生物素蛋白培养并置于辊压台上。然后用水充分洗涤该稀释的乳液并通过离心浓缩。
制备8
具有带正电的表面物质的全氟二甲基环丁烷乳液
将1,2-二硬脂酰基-3-三甲基铵丙烷(73mg)和二硬脂酰基磷脂酰胆碱(641mg)置入250ml的圆底烧瓶中并加入氯仿(100ml)。将该烧瓶在热自来水下加热直到得到透明的溶液,然后将烧瓶置于旋转蒸发器上并通过使用45℃的浴温在350毫巴下蒸发而除去氯仿。为了除去残留的痕量溶剂,将样品暴露于约20毫巴的真空下过夜。然后加入MilliQ水(143ml)并将烧瓶再次置于旋转蒸发器上并全速旋转,同时浸入80℃的水浴中。在约25分钟之后,将样品转移到合适的小瓶中并置于冰箱中以冷却过夜。
将1ml该样品转移到2ml色谱分离瓶中并将100微升全氟二甲基环丁烷(沸点45℃)加入各小瓶中。将小瓶在Espe CapMix上振摇75秒并立即在冰上冷却样品。在较大的小瓶中收集各瓶中的内容物,并将乳液用Coulter计数器以尺寸分布和总颗粒体积浓度表征。平均液滴尺寸为2.67微米,证实该乳液可用于注射。颗粒体积浓度的测量用于使用MilliQ水将浓度调节为约1%v/v分散相。该乳液在使用前储存在冰箱中。
制备9
具有带正电的表面物质的全氟甲基环戊烷乳液
重复制备8的过程,但使用全氟甲基环戊烷(沸点48℃)代替全氟二甲基环丁烷。Coulter计数器分析显示该乳液的平均液滴尺寸为2.63微米。
制备10
具有带正电的表面物质的全氟-2-甲基戊烷乳液
重复制备8的过程,但使用全氟-2-甲基戊烷(沸点50-57℃)代替全氟二甲基环丁烷。Coulter计数器分析显示该乳液的平均液滴尺寸为2.72微米。
制备11
具有带正电的表面物质的全氟己烷乳液
重复制备8的过程,但使用全氟己烷(沸点58-60℃)代替全氟二甲基环丁烷。Coulter计数器分析显示该乳液的平均液滴尺寸为2.54微米。
制备12
该脂肽在ABI 433A肽自动合成仪上合成,由Rink酰胺树脂以0.25mmol规模开始,使用1mmol氨基酸药筒。所有氨基酸和棕榈酸在偶合前使用O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(HBTU)预活化。在含有5%苯酚、5%三异丙基硅烷和5%水的三氟乙酸(TFA)中进行肽和侧链保护基团从树脂上的同时除去2小时,得到150mg产量的粗产物。通过制备型HPLC(Vydac218TP1022柱)提纯30mg等分样的粗材料,使用70-100%B的梯度以9ml/min的流速进行40分钟(A=0.1%TFA/水且B=乙腈)。冻干后,得到19mg纯物质(分析HPLC:70-100%梯度的B,其中B=乙腈,A=0.01%TFA/水;柱-Vydac218TP54:检测-UV214纳米;产物停留时间=11分钟)。其它产物表征使用MALDI质谱进行;预期的M+H为1845,实测值为1850。
制备13
带正电的脂肽的合成:棕榈酰基-Dpr(棕榈酰基)-Arg-Arg-Lys-NH2(其中Dpr=二氨基丙酸)
该脂肽在ABI 433A肽自动合成仪上合成,由Rink酰胺树脂以0.25mmol规模开始,使用1mmol氨基酸药筒。所有氨基酸和棕榈酸在偶合前使用HBTU预活化。在含有5%苯酚、5%三异丙基硅烷和5%水的TFA中进行肽和侧链保护基团从树脂上的同时除去2小时,得到50mg产量的粗产物。通过制备型HPLC(Vydac218TP1022柱)提纯粗材料,使用90-100%B的梯度以9ml/min的流速进行40分钟(A=0.1%TFA/水且B=0.1%TFA/乙腈)。冻干后,得到5mg纯物质(分析HPLC:80-100%梯度的B,其中A=0.1%TFA/水且B=0.1%TFA/乙腈;柱-Vydac218TP54;检测-UV214纳米;产物停留时间=15分钟)。其它产物表征使用MALDI质谱进行;预期的M+H为1021,实测值为1022。
制备14
a)十六烷酸2-叔丁氧基羰基氨基乙基酯
将N-Boc-乙醇胺(1.6g,10mmol)和棕榈酰氯(3.28g,12mmol)溶于二氯甲烷(25ml)中并在搅拌下加入三乙胺(1.68ml,12mmol)。反应混合物室温搅拌过夜。将反应混合物用二氯甲烷稀释至100ml,转移至萃取容器中,用1×10ml1M碳酸氢钠和2×25ml水洗涤并干燥,然后真空除去溶剂。粗产物通过在二氧化硅上的柱色谱提纯。鉴定:TLC(一点)和MALDI(M+1)。
b)十六烷酸2-氨基乙基酯盐酸盐
将来自上面(a)的十六烷酸2-叔丁氧基羰基氨基乙基酯(1.1g,2.7mmol)在搅拌下溶于4M氯化氢/二噁烷(10ml)中。几分钟后白色沉淀开始形成。TLC显示30分钟后原料全部转化。通过过滤收集白色沉淀,用二噁烷在过滤器上洗涤并真空干燥。鉴定:TLC(一点)和MALDI(M+1)。
制备15
a)4-十六烷酰基氨基丁基氨基甲酸叔丁酯
将Boc-1,4-二氨基丁烷(1g,5.3mmol)和棕榈酰氯(1.64g,6mmol)溶于二氯甲烷(25ml)中。加入三乙胺(0.64ml,6mmol)并搅拌反应混合物过夜,然后用二氯甲烷稀释至150ml,转移至萃取漏斗中,用1×10ml1M碳酸氢钠和2×25ml水洗涤并干燥,然后真空除去溶剂。粗产物溶于氯仿(25ml)中并在冰箱中放置过夜。纯产物以粘性结晶分离。鉴定:TLC(一点)和MALDI(M+1)。
b)十六烷酸4-氨基丁基酰胺盐酸盐
将来自上面(a)的4-十六烷酰基氨基丁基氨基甲酸叔丁酯(1g,2.3mmol)在搅拌下溶于4M氯化氢/二噁烷(10ml)中。几分钟后白色结晶开始沉淀。将反应混合物用二噁烷(10ml)稀释并继续搅拌4小时,此时TLC显示原料全部转化。通过过滤收集白色沉淀,用二噁烷在过滤器上洗涤并真空干燥。鉴定:TLC(一点)和MALDI(M+1)。
制备16
a)叔丁氧基羰基氨基乙酸十六烷基酯
将Boc-Gly-OH(1.74g,10mmol)和1-十六烷醇(2.5g,10mmol)溶于二氯甲烷(30ml)中并加入二甲氨基吡啶(30mg,催化量)。在搅拌下于10分钟内滴加溶于二氯甲烷(10ml)中的二环己基碳化二亚胺(2.1g,10mmol)并室温搅拌反应混合物过夜。通过过滤除去沉淀的二环己基脲并用二氯甲烷将有机相稀释至150ml。将有机相用1×5ml 1M碳酸氢钠和2×10ml水萃取并干燥,然后真空除去溶剂。粗产物无需提纯而直接用于下一步中。鉴定:TLC(一点)和MALDI(M+1)。
b)氨基乙酸十六烷基酯盐酸盐
将从上面(a)得到的叔丁氧基羰基氨基乙酸十六烷基酯(2g,5mmol)溶于二噁烷(20ml)中。加入4M氯化氢/二噁烷(10ml)并室温搅拌反应混合物。30分钟后开始形成白色沉淀。加入乙醚(50ml)并将反应混合物搅拌过夜,然后通过过滤收集沉淀并用乙醚洗涤。TLC显示原料完全转化,但产物被少量1-十六烷醇污染。纯产物通过在二氧化硅上的柱色谱提纯。鉴定:TLC(一点)和MALDI(M+1)。
制备17
甲基氨基乙酸十六烷基酯盐酸盐
将4M氯化氢/二噁烷(10ml)加入含有N-甲基甘氨酸(100mg,1.1mmol)和1-十六烷醇(1g,4.1mmol)的反应容器中。淤浆在室温下搅拌几天。4天后反应混合物呈均相,且TLC显示氨基酸全部转化。真空除去溶剂并将粗产物通过在二氧化硅上的柱色谱提纯。鉴定:TLC(一点)和MALDI(M+1)。
制备18
二甲基氨基乙酸十六烷基酯盐酸盐
将4M氯化氢/二噁烷(10ml)加入含有N,N-二甲基甘氨酸盐酸盐(150mg,1.1mmol)和1-十六烷醇(1.33g,5.5mmol)的反应容器中。淤浆在室温下搅拌。3周后反应混合物呈均相,且TLC显示氨基酸全部转化。真空除去溶剂并将粗产物通过在二氧化硅上的柱色谱提纯。鉴定:TLC(一点)和MALDI(M+1)。
制备19-36
具有带正电的表面物质的乳液
将二硬脂酰基磷脂酰胆碱(90mg)和下表1所示的阳离子添加剂(10mg)置于50ml圆底烧瓶中并加入氯仿(10ml)。[在制备31中,将甲醇(10ml)加入氯仿中以溶解各组分]。将烧瓶在热自来水下加热直到得到透明溶液,然后将烧瓶置于旋转蒸发器上并通过使用45℃的浴温在350毫巴下蒸发而除去氯仿。为了除去残留的痕量溶剂,将样品暴露于约20毫巴的真空下过夜。然后加入MilliQ水(20ml)并将烧瓶再次置于旋转蒸发器上并全速旋转,同时浸入80℃的水浴中。在约10分钟之后,将样品转移到合适的小瓶中并置于冰箱中以冷却过夜。
将1ml各样品转移到2ml色谱分离瓶中并将全氟二甲基环丁烷(100微升)加入各小瓶中。在Espe CapMix上振摇75秒并立即在冰上冷却样品。在较大的小瓶中收集乳液,并将乳液用Coulter计数器以尺寸分布和总颗粒体积浓度表征。平均液滴尺寸给于下表1中。颗粒体积浓度的测量用于使用MilliQ水将浓度调节为约1%v/v分散相。该乳液在使用前储存在冰箱中。
表1
制备号 | 阳离子添加剂 | 平均液滴尺寸(微米) |
19 | DC-胆固醇 | 3 |
20 | 1,2-二硬脂酰基乙基胆碱磷酸 | 2.4 |
21 | 苄基十六烷基二甲基氯化铵 | 2.4 |
22 | 十六烷基三甲基溴化铵 | 2.6 |
23 | 十六烷基吡啶鎓氯化物 | 2.5 |
24 | 棕榈酰基-Dpr(棕榈酰基)-Arg-Arg-Lys-NH2(制备13) | 3.6 |
25 | 肉豆蔻酰基胆碱氯化物 | 2.9 |
26 | 十六烷酸2-氨基乙基酯(制备14) | 2.5 |
27 | 十六烷酸4-氨基丁基酰胺(制备15) | 2.3 |
28 | 氨基乙酸十六烷基酯(制备16) | 2.4 |
29 | 十六烷基肉碱酯 | 2.4 |
30 | 吐根素 | 2.5 |
31 | D-鞘氨醇硫酸酯 | 2.7 |
32 | 植物鞘氨醇 | 2.4 |
33 | DL-二氢鞘氨醇 | 2.9 |
34 | 二-十二烷基二甲基溴化铵 | 2.4 |
35 | 甲基氨基乙酸十六烷基酯(制备17) | 3.1 |
36 | 二甲基氨基乙酸十六烷基酯(制备18) | 3.5 |
制备37
含有带正电的脂肽棕榈酰基-Lys(棕榈酰基)-Lys-Lys-Ahx-Lys-Arg-Lys-Arg-Lys-Arg-NH2(其中Ahx=氨基己酸)的全氟二甲基环丁烷乳液
将二硬脂酰基磷脂酰胆碱(90mg)和来自制备12的带正电的脂肽棕榈酰基-Lys(棕榈酰基)-Lys-Lys-Ahx-Lys-Arg-Lys-Arg-Lys-Arg-NH2(10mg)置于50ml圆底烧瓶中并加入氯仿(10ml)。将烧瓶在热自来水下加热直到得到透明溶液,然后将烧瓶置于旋转蒸发器上并通过蒸发除去氯仿。为了除去残留的痕量溶剂,将样品暴露于真空下过夜。然后加入MilliQ水(20ml)并将烧瓶再次置于旋转蒸发器上并全速旋转,同时浸入80℃的水浴中。在约10分钟之后,将样品转移到合适的小瓶中并置于冰箱中以冷却过夜。
将1ml该样品转移到2ml色谱分离瓶中并将100微升全氟二甲基环丁烷加入各小瓶中。将小瓶在Espe CapMix上振摇75秒并立即在冰上冷却样品。在较大的小瓶中收集各小瓶的内容物,并将乳液用Coulter计数器以尺寸分布和总颗粒体积浓度表征。颗粒体积浓度的测量用于使用MilliQ水将浓度调节为约1%v/v分散相。该乳液在使用前储存在冰箱中。
实施例1
狗心脏的体内成像
将20kg的mongrel狗麻醉,进行中线胸骨切开术,并除去前心包。通过低衰减的30mm聚硅氧烷橡胶间隔臂进行心脏的中线短轴B模式成像,使用装有P3-2转导器的ATL HDI-3000扫描仪。支架速率(framerate)为40Hz且机械指数为1.1。
a)(对比)使用带负电的全氟丁烷气体分散液和带负电的全氟二甲基环丁烷乳液进行成像
将一定量的来自制备1的全氟丁烷气体分散液(对应于0.2微升气体/kg体重)和一定量的来自制备6的全氟二甲基环丁烷乳液(对应于0.4微升全氟二甲基环丁烷/kg体重)同时静脉内注射到狗中。观察到来自心肌的回波强度明显升高,在注射20秒后开始且持续10分钟。造影剂效果从血液中的清除早于心肌造影效果的消失发生。
b)使用带负电的全氟丁烷气体分散液和带正电的全氟二甲基环丁烷乳液进行成像(高剂量)
将一定量的来自制备1的全氟丁烷气体分散液(对应于0.2微升气体/kg体重)和一定量的来自制备4的全氟二甲基环丁烷乳液(对应于0.1微升全氟二甲基环丁烷/kg体重)同时静脉内注射到狗中。所得心肌造影效果远比在上面(a)中观察到的强且持续20分钟。
c)使用带负电的全氟丁烷气体分散液和带正电的全氟二甲基环丁烷乳液进行成像(低剂量)
重复实施例1(b)所述的程序,不同的是将全氟二甲基环丁烷乳液的剂量降低为0.02微升全氟二甲基环丁烷/kg体重。所得心肌造影效果与在实施例1(a)中观察到的相当。
实施例2
狗心脏的体内成像(低造影剂剂量)
a)使用带负电的全氟丁烷气体分散液和带正电的全氟己烷乳液进行成像
重复实施例1(b)所述的程序,不同的是将全氟甲基环丁烷乳液用一定量的来自制备5的全氟己烷乳液(对应于0.02微升全氟己烷/kg体重)代替。所得心肌造影效果与在实施例1(a)中观察到的相当。
b)(对比)使用带负电的全氟丁烷气体分散液和带负电的全氟二甲基环丁烷乳液进行成像
重复实施例1(a)所述的程序,不同的是将全氟二甲基环丁烷乳液的剂量降低为0.02微升全氟二甲基环丁烷/kg体重。仅能看到微弱的心肌造影效果。
c)(对比)使用带正电的全氟丁烷气体分散液和带正电的全氟己烷乳液进行成像
将一定量的来自制备2的全氟丁烷气体分散液(对应于0.2微升气体/kg体重)和一定量的来自制备5的全氟己烷乳液(对应于0.02微升全氟己烷/kg体重)同时静脉内注射到狗中,如实施例1所述进行成像。仅能看到微弱的心肌造影效果。
d)使用带正电的全氟丁烷气体分散液和带负电的全氟二甲基环丁烷乳液进行成像
将一定量的来自制备2的全氟丁烷气体分散液(对应于0.2微升气体/kg体重)和一定量的来自制备6的全氟二甲基环丁烷乳液(对应于0.02微升全氟己烷/kg体重)同时静脉内注射到狗中,如实施例1所述进行成像。所得心肌造影效果与在实施例1(a)中观察到的相当。
实施例3(对比)
仅使用带正电的全氟己烷乳液对狗的心脏进行成像
将一定量的来自制备5的全氟己烷乳液(对应于0.02微升全氟己烷/kg体重)静脉内注射到狗中,如实施例1所述进行成像。不能观察到血液或心肌造影效果。
实施例4(对比)
无预先超声处理而对狗的心脏进行成像
重复实施例1(c)的程序,不同的是在注射后的最先2分钟关闭超声扫描仪。再次开启扫描仪后心肌中的造影效果非常短暂,与在单独注射全氟丁烷气体分散液之后在相同的时间和相同的成像模式下看到的相当。
实施例5
使用生物素化的全氟丁烷气体分散液和抗生物素蛋白化的全氟二甲基环丁烷乳液对狗心脏进行成像
将一定量的来自制备3的全氟丁烷气体分散液(对应于0.02微升气体/kg体重)和一定量的来自制备7的全氟二甲基环丁烷乳液(对应于0.02微升全氟二甲基环丁烷/kg体重)同时静脉内注射到狗中。
使用中线短轴投影由Vingmed CFM-750扫描仪进行心脏的成像。调节该扫描仪以通过使用连续的高支架速率成像和最高的输出能(0-7级中的7级)的组合而使成像组织区域的超声暴露最大。注射之后,在心脏的心室中均看到起始的造影增强。在心肌的所有区域看到造影增强的稳定上升,直到增强强度接近屏幕的最大白色水平。组织造影的持续时间大约为30分钟,而血液中的造影效果在注射的5分钟内降低到接近基线,从而留下几乎没有血液衰减的图象,且留下完全和极亮的心肌周缘造影增强。在靠近转导器的心肌中的造影效果似乎不会衰退,尽管进行连续的高强度超声暴露。
实施例6-9
使用带负电的全氟丁烷气体分散液和来自制备8-11的带正电的乳液进行狗心脏的成像
将19kg的mongrel狗麻醉,进行中线胸骨切开术,并除去前心包。通过低衰减的30mm聚硅氧烷橡胶间隔臂进行心脏的中线短轴B模式成像,使用装有P3-2转导器的ATL HDI-3000扫描仪。支架速率为40Hz且机械指数为1.1。将一定量的来自制备1的全氟丁烷气体分散液(对应于0.2微升气体/kg体重)和一定量的来自上述制备8-11的乳液(对应于0.02微升挥发性油/kg体重)同时静脉内注射到狗中。在每种情况下观察到来自心肌的回波强度明显升高,在注射20分钟后开始;峰值强度高于在实施例1(a)中所观察到的。
注射90秒钟后在心肌中的超声强度对基线进行校正且所得心肌造影增强(MCE)给于下表2中。
表2
实施例号 | 可扩散组分 | 基线校正的MCE(dB) |
6 | 全氟二甲基环丁烷 | 7.9 |
7 | 全氟甲基环戊烷 | 4.8 |
8 | 全氟-2-甲基戊烷 | 6.6 |
9 | 全氟己烷 | 7.5 |
当心室几乎不含造影剂时,看到心肌浊化的显著增加,这表明观察到的造影增强是由于微泡滞留于心肌中。造影效果的持续时间从约5分钟变化至约20分钟,且取决于诸如挥发性油的水溶性和蒸气压等因素。下表3显示各试验的MCE半衰期。
表3
*-来自分别为2.4和3.4分钟的两次测量的平均
实施例号 | 可扩散组分 | MCE半衰期(分钟) |
6 | 全氟二甲基环丁烷 | 2.9* |
7 | 全氟甲基环戊烷 | 1.9 |
8 | 全氟-2-甲基戊烷 | 6.9 |
9 | 全氟己烷 | 7.4 |
实施例10-27
用带负电的全氟丁烷气体微泡和来自制备19-36的带正电的乳液进行狗心脏的成像
将24kg的mongrel狗麻醉,进行中线胸骨切开术,并除去前心包。通过低衰减的30mm聚硅氧烷橡胶间隔臂进行心脏的中线短轴B模式成像,使用装有P3-2转导器的ATL HDI-3000扫描仪。支架速率为40Hz且机械指数为1.1。在检测包含根据制备19-28的乳液的造影剂时,将一定量的来自制备1的全氟丁烷气体分散液(对应于0.2微升气体/kg体重)和一定量的全氟二甲基环丁烷乳液(对应于0.02微升全氟二甲基环丁烷/kg体重)同时静脉内注射到狗中。对于包含来自制备29-36的乳液的造影剂,对应的剂量分别为0.35和0.04微升/毫升气体和全氟二甲基环丁烷。观察到来自心肌的回波强度明显升高,在注射20秒后开始且持续10分钟;在每种情况下峰值强度高于在实施例1(a)中所观察到的。
注射约2分钟后对基线校正心肌中的超声浊化且所得心肌造影增强(MCE)给于下表4中。在心室几乎不含造影剂时观察到心肌浊化显著增加,表明观察到的造影增强是由于滞留在心肌中的微泡引起的。
表4
实施例号 | 阳离子添加剂 | 基线校正的MCE(dB) |
10 | DC-胆固醇 | 11.78 |
11 | 1,2-二硬脂酰基乙基胆碱磷酸 | 17.03 |
12 | 苄基十六烷基二甲基氯化铵 | 10.43 |
13 | 十六烷基三甲基溴化铵 | 11.46 |
14 | 十六烷基吡啶鎓氯化物 | 11.16 |
15 | 棕榈酰基-Dpr(棕榈酰基)-Arg-Arg-Lys-NH2 | 10.64 |
16 | 肉豆蔻酰基胆碱氯化物 | 10.29 |
17 | 十六烷酸2-氨基乙基酯 | 14.41 |
18 | 十六烷酸4-氨基丁基酯 | 12.74 |
19 | 氨基乙酸十六烷基酯 | 16.14 |
20 | 十六烷基肉碱酯 | 12.11 |
21 | 吐根素 | 13.56 |
22 | D-鞘氨醇硫酸酯 | 13.44 |
23 | 植物鞘氨醇 | 13.56 |
24 | DL-二氢鞘氨醇 | 17.05 |
25 | 二-十二烷基二甲基溴化铵 | 9.54 |
26 | 甲基氨基乙酸十六烷基酯 | 15.50 |
27 | 二甲基氨基乙酸十六烷基酯 | 15.33 |
实施例28-用带负电的全氟丁烷气体分散液和来自制备37的带正电乳液进行狗心脏的成像
将20kg的mongrel狗麻醉,进行中线胸骨切开术,并除去前心包。通过低衰减的30mm聚硅氧烷橡胶间隔臂进行心脏的中线短轴B模式成像,使用装有P3-2转导器的ATL HDI-3000扫描仪。支架速率为40Hz且机械指数为1.1。将一定量的来自制备1的全氟丁烷气体分散液(对应于0.1微升气体/kg体重)和一定量的来自制备37的全氟二甲基环丁烷乳液(对应于0.04微升全氟二甲基环丁烷/kg体重)同时静脉内注射到狗中。测量来自心肌的回波强度的升高和持续时间。
Claims (27)
1.一种在超声成像中作为造影剂同时、分别或依次使用的组合制剂,所述制剂含有:
ⅰ)第一组合物,其为含有分散气体和用于稳定所述气体的物质的可注射含水介质;和
ⅱ)第二组合物,其为可注射的水包油乳液,其中油相含有在体内能够扩散至所述分散气体内以便至少瞬时增加其尺寸的可扩散组分,所述组合物还含有用于稳定所述乳液的物质,
其特征在于存在于分散气相表面处的物质和存在于分散油相表面处的物质相互具有亲和性。
2.权利要求1的组合制剂,其中所述分散气体包括空气、氮气、氧气、二氧化碳、氢气、惰性气体、氟化硫、六氟化硒、任选卤代的硅烷、任选卤代的低分子量烃、酮、酯或者前述任何物质的混合物。
3.权利要求2的组合制剂,其中所述气体包括六氟化硫或全氟化碳。
4.权利要求3的组合制剂,其中所述全氟化碳为全氟丙烷、全氟丁烷或全氟戊烷。
5.前述任一权利要求的组合制剂,其中通过抗融合的表面膜、成膜蛋白质、聚合物材料、非聚合和不可聚合的成壁材料或表面活性剂来稳定所述分散气体。
6.权利要求5的组合制剂,其中所述表面活性剂至少包括一种磷脂。
7.权利要求6的组合制剂,其中至少75%的所述表面活性剂包括各自携带净总电荷的磷脂分子。
8.权利要求7的组合制剂,其中至少75%的表面活性剂包括选自磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、磷脂酸和心肌磷脂的一种或多种磷脂。
9.权利要求8的组合制剂,其中至少80%的所述磷脂包括磷脂酰丝氨酸。
10.前述任一权利要求的组合制剂,其中可扩散组分包括脂族醚、多环油、多环醇、杂环化合物、脂族烃、环脂族烃或卤代低分子量烃,或前述任何物质的混合物。
11.权利要求10的组合制剂,其中所述可扩散组分包括一种或多种全氟化碳。
12.权利要求11的组合制剂,其中所述全氟化碳包括一种或多种全氟链烷烃、全氟链烯烃、全氟环烷烃、全氟环烯烃和/或全氟化醇。
13.权利要求12的组合制剂,其中所述可扩散组分包括一种或多种全氟戊烷、全氟己烷、全氟二甲基环丁烷和/或全氟甲基环戊烷。
14.前述任一权利要求的组合制剂,其中所述可扩散组分乳液通过磷脂或脂肽表面活性剂稳定化。
15.前述任一权利要求的组合制剂,其中第一和第二组合物分别含带有相反电荷的表面物质。
16.权利要求15的组合制剂,其中第一组合物含有阴离子表面物质和第二组合物含有阳离子表面物质。
17.权利要求16的组合制剂,其中所述阴离子物质为带负电的磷脂且所述阳离子物质为亲脂性季铵盐、亲脂性吡啶鎓盐、亲脂性伯、仲或叔胺、任选取代的二-或三-胺的脂肪酸酰胺、氨基酸的脂肪醇酯或带正电的磷脂或脂肽。
18.权利要求17的组合制剂,其中所述阳离子物质以第二组合物的稳定化物质的添加剂存在。
19.前述任一权利要求的组合制剂,还包括血管舒张药物和/或血管收缩药物。
20.权利要求19的组合制剂,其中所述血管舒张药物是腺苷。
21.权利要求1-18任一项的组合制剂,还含有治疗药物。
22.权利要求1-18任一项的组合制剂,还包括用于除超声波外的成像方式的提高反差的部分。
23.一种在人或非人动物个体中产生增强的图像的方法,所述方法包括如下步骤:
ⅰ)将如权利要求1所定义的第一组合物注射至所述个体的血管系统;
ⅱ)在注射所述第一组合物之前、过程中或之后,给所述个体注射如权利要求1所定义的第二组合物;和
ⅲ)在所述个体的至少部分区域产生超声波图像。
24.权利要求23的方法,其中来自造影剂的微泡生长通过施用外部活化而在所述个体内活化。
25.权利要求24的方法,其中所述外部活化包括超声波照射。
26.权利要求23-25任一项的方法,其中将血管舒张药物或血管收缩药物共同施用给个体。
27.权利要求26的方法,其中所述血管舒张药物是腺苷。
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WO1998018495A2 (en) * | 1996-10-28 | 1998-05-07 | Marsden, John, Christopher | Improvements in or relating to diagnostic/therapeutic agents |
EP0963209A2 (en) * | 1996-10-28 | 1999-12-15 | Marsden, John Christopher | Improvements in or relating to diagnostic/therapeutic agents |
ES2206689T3 (es) * | 1996-10-28 | 2004-05-16 | Amersham Health As | Agentes de contraste. |
-
1998
- 1998-04-22 GB GBGB9808599.6A patent/GB9808599D0/en not_active Ceased
-
1999
- 1999-04-22 HU HU0102878A patent/HUP0102878A3/hu unknown
- 1999-04-22 JP JP2000544366A patent/JP2002512206A/ja not_active Abandoned
- 1999-04-22 DE DE69937341T patent/DE69937341D1/de not_active Expired - Lifetime
- 1999-04-22 CN CN99807622A patent/CN1306442A/zh active Pending
- 1999-04-22 IL IL13914799A patent/IL139147A0/xx unknown
- 1999-04-22 CA CA002329175A patent/CA2329175A1/en not_active Abandoned
- 1999-04-22 KR KR1020007011727A patent/KR20010042915A/ko not_active Application Discontinuation
- 1999-04-22 WO PCT/GB1999/001221 patent/WO1999053963A1/en active IP Right Grant
- 1999-04-22 AU AU36172/99A patent/AU3617299A/en not_active Abandoned
- 1999-04-22 PL PL99343464A patent/PL343464A1/xx unknown
- 1999-04-22 AT AT99918133T patent/ATE375806T1/de not_active IP Right Cessation
- 1999-04-22 EP EP99918133A patent/EP1073473B1/en not_active Expired - Lifetime
- 1999-04-22 BR BR9909822-9A patent/BR9909822A/pt not_active IP Right Cessation
-
2000
- 2000-10-18 ZA ZA200005789A patent/ZA200005789B/xx unknown
- 2000-10-19 NO NO20005250A patent/NO20005250L/no not_active Application Discontinuation
-
2003
- 2003-11-19 US US10/717,196 patent/US20040146462A1/en not_active Abandoned
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100453050C (zh) * | 2005-09-21 | 2009-01-21 | 北京市肿瘤防治研究所 | 提高超声造影图像分辨力的方法和超声造影成像仪 |
CN108586300A (zh) * | 2018-03-28 | 2018-09-28 | 成都福柯斯医药技术有限公司 | 一种s-碘化丁酰硫代胆碱的合成方法 |
CN108586300B (zh) * | 2018-03-28 | 2020-03-17 | 成都福柯斯医药技术有限公司 | 一种s-碘化丁酰硫代胆碱的合成方法 |
CN113769154A (zh) * | 2021-03-04 | 2021-12-10 | 艾柯医疗器械(北京)有限公司 | 改进的液体栓塞组合物和相关方法 |
Also Published As
Publication number | Publication date |
---|---|
DE69937341D1 (de) | 2007-11-29 |
US20040146462A1 (en) | 2004-07-29 |
HUP0102878A2 (hu) | 2002-03-28 |
HUP0102878A3 (en) | 2002-12-28 |
IL139147A0 (en) | 2001-11-25 |
CA2329175A1 (en) | 1999-10-28 |
ZA200005789B (en) | 2001-07-30 |
KR20010042915A (ko) | 2001-05-25 |
EP1073473A1 (en) | 2001-02-07 |
JP2002512206A (ja) | 2002-04-23 |
GB9808599D0 (en) | 1998-06-24 |
EP1073473B1 (en) | 2007-10-17 |
NO20005250D0 (no) | 2000-10-19 |
NO20005250L (no) | 2000-12-18 |
PL343464A1 (en) | 2001-08-13 |
AU3617299A (en) | 1999-11-08 |
WO1999053963A1 (en) | 1999-10-28 |
ATE375806T1 (de) | 2007-11-15 |
BR9909822A (pt) | 2000-12-19 |
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