CN1121315A - 造影剂及其改进 - Google Patents
造影剂及其改进 Download PDFInfo
- Publication number
- CN1121315A CN1121315A CN94191801A CN94191801A CN1121315A CN 1121315 A CN1121315 A CN 1121315A CN 94191801 A CN94191801 A CN 94191801A CN 94191801 A CN94191801 A CN 94191801A CN 1121315 A CN1121315 A CN 1121315A
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Abstract
用作超声造影剂的水包油型乳状液,其油相含有凝聚的或溶解的油溶性气体/流体或气体前体。这类产品在储存形态含极其微量的游离气泡或微泡,并有良好的储存稳定性,但可预期在给药前或给药时使其立即迅速地产生微泡。
Description
本发明涉及新型的造影剂,更具体地说涉及用于超声影象诊断的新造影剂。
超声显象是根据超声波(如频率范围为1—10MHz)经由振子透入人体或动物体内,超声波与人体组织和体液的界面发生的相互作用为基础。超声影象的反差来自超声波在上述界面上不同的反射/吸收;采用多普勒技术可以增强反射信号,也可采用彩色多普勒技术来判断血液流动。
早已认识到采用造影剂有利于增强不同组织/体液的声学性质的差异。并从1968年碘代花菁绿作为首先试用的超声造影剂以来,已对许多其它可能的造影剂进行了试验。其中包括乳状液、固体微粒、水溶性化合物、无气泡的和各类包封着的含气体系。通常认为,可压缩的低密度造影剂由于其产生超声背景散射,所以是特别有效的;因此含气体的和产生气体的体系比其它类型造影剂具有更好的效果。
目前在市场上可购得的或近来临床开发的超声造影剂有三种:它们是以含气体的半乳糖微晶为主要成分的EchovistR;含气体的以脂肪酸包壳的半乳糖微晶的LevovistR;及由部分变性的人体血清蛋白包封的气泡构成的AlbunexR。这些造影剂由于它们造影半衰期较短(即它们在体内缺少稳定性)和有限的储存期,因而在临床应用上受到限制。因此继续需要兼有良好的储存稳定性与体内稳定性的超声造影剂,特别是用于心脏和非心脏灌注的研究时,最好是在心脏内注射情况下可供至少几个循环流通的超声造影剂。
微细粒子超声造影剂如Echovist和Levovist的另一个缺点是必须在给药前配制,如添加适当的载持液体并用摇动方法拌和。由此不可避免地会引起某些延误,因此需要改进超声造影剂,使其能以“随时可用”的形态储存相当长的时间(如至少12个月,最好2—3年)。
本发明是以我们研究结果为基础的,通过采用在分散的油相中含凝聚态或溶解态的油溶性气体/流体或气体前体的水包油型乳状液造影剂,可以实现本发明的目的。
因此,根据本发明的一个方面是提供一种与生物相容的水包油型乳状液超声造影剂,其中油相含油溶性气体/流体或气体前体。
本发明造影剂的特征是它们在给药前的储存状态实际上完全没有气泡/微泡,但在给药后,如通过静脉或动脉内注射可随之迅速产生微气泡,或者在给药前如按下文更详细叙述的方法直接诱导产生微气泡。在这方面,本发明的产品可以与现有的超声造影剂作一对比,现有的造影剂通常在储存状态含游离气体,该游离气体可存在于晶体结构的空穴中和/或粘附在细微粒材料的表面(如Echovist和Levovist)或以被包封的形态存在于材料中(如Albunex)。本发明造影剂采用的气体,优选具有较低水溶性,以保证它们在乳状液亲油相中有更好的溶解度,并提高在静脉或动脉内注射造影剂后在血流的含水环境中所产生的微泡的稳定性。但是,显而易见,气体在油相中的溶解度,优选不应高到给药后会抑制微泡产生的程度。虽然,在这种情况下,如果必要,仍可通过如给药前预热乳状液的方法来增加微泡的形成,如在后面所更详细叙述的。因此,适用的气体包括例如惰性气体(如氦、氖、氩、氪或氙)、烃类(如甲烷、乙炔或3—甲基—1—丁烯)、卤代烃(包括卤代链烷烃如溴代甲烷、C1—4氢氟代链烷烃如六氟丙烷以及更优选全氟代链烷烃如全氟甲烷或全氟丁烷)及硫的卤化物(如六氟化硫)等。
本文所用的术语“气体”,包括在正常人体温度37℃下的任何气态物质,因此包括在环境温度如20—25℃下为液体的各种油溶性物质。可适用的、被认为能与乳状液油相相混合、在本文中是溶于油相的物质的实例包括必要时卤化和/或其它取代的烃类、脂族和环醚类、硅烷类、胂及硫的卤化物,实例如下:
物质 沸点(℃)4—甲基—1,3—二氧戊环—2—酮 24.2二溴二氟甲烷 24.51—硝基七氟戊烷 25.0四甲基硅烷 26.52—丁炔 27.02—甲基丁烷 27.8十氟化二硫 29.0全氟—1—戊烯 29—301—戊烯 30.01,2—二氟乙烷 30.72—甲基—1—丁烯 31.2呋喃 31.4正丁基氟化物 32.5甲基异丙基醚 32.5三个三氟甲基胂 33.32—甲基丁—1,3—二烯 34.1氧化丙烷 34.2二*** 34.5异丙基氯 35—36戊烷 36.12—戊烯(反式、顺式) 36.3—36.9
本文中所采用的术语“流体”表示挥发性有机物质,优选是沸点不超过60℃的有机物质。显而易见,上述的低水溶性并最好是(但要求不过度)油溶性的要求,对于这类流体应是指其具有溶混性,而能溶解于乳状液的油相中,应是指其可与油相相混合的。
这类流体的实例包括1,1—二氯乙烯、2—甲基—2—丁烯、3,3—二甲基—1—丁炔、二甲氨基丙酮、全氟戊烷、环戊烷、环戊烯及2,3—戊二烯。显而易见,这类沸点超过37℃的流体在给药后一般不产生气体微泡。然而,它们会产生流体微泡,流体微泡会因流体密度较低而产生超声造影作用。
油溶性气体前体的实例包括有机碳酸盐类,如下式的化合物
RO·CO·OM其中R是亲油有机基团、M是生理上可接受的阳离子。这类物质在pH约7或低于7时,如在静脉或动脉内给药后在血流中含量较高的条件下会产生二氧化碳。采用依赖于pH活化的这类前体有利于离子载体(如尼日利亚菌素)混入乳状液中以促进通过油相的质子转移。
其它的气体前体包括能产生氮的物质,如吡唑啉、吡唑、***啉、重氮酮、重氮盐、四唑、叠氮化物及叠氮化物/碳酸盐混合物,它们可用辐射进行活化,如在给药前直接用紫外光活化。在光解时会产生二氧化碳的物质(如某类环酮、内酯及碳酸盐)同样也可采用。
产生氧的气体前体包括过酸类如过苯甲酸。
在给药后靠人体热量来活化的可热降解的气体前体,也可被采用。这类物质的实例是可热降解的羧酸如2—甲基乳酸。
还有一类气体前体包括在体内可被酶降解并伴随产生气体的物质。其实例包括可为普通酯酶裂解而能放出二氧化碳的亚甲基二酯(如采用WO—A—9317718和WO—A—9318070中所述技术制备的,该两篇文献的内容在此列入本文作为公开内容的一部分)。另一种可用的物质是过氧化氢,过氧化氢可溶于亲油介质(如醚)中并在体内可被酶降解而放出氧气。如果采用过氧化氢,添加一种抗氧化稳定剂也是有利的。
在气体或流体本身能够形成稳定的乳状液情况下,乳状液的油相主要可以包括气体/流体以及任何必须的生物相容的乳化剂;在这种情况下,一个关键性的要求是气体或流体应是凝聚态而不是气态,如果必要可施加压力使其成为凝聚态。
更为通常的是,油相主要由气体/流体或溶解于至少一种亲油溶剂组分的气体前体以及任何必须的、生物相容的包括表面活性剂和其它稳定剂的乳化剂所组成。显而易见,根据特定的乳状液体系的要求,这类乳化剂可以优先或在油相中或在水相中溶解或分散。
适用于根据本发明乳状液油相的一类亲油溶剂组分包括高度氟化的有机化合物(如已经被提议作为“人造血液”的组分—见EP—A—0231091和WO—A—8910118,其内容在此列入本文作为公开内容的一部分)。应该注意到,当这些氟化的化合物用于人造血液时,可认为氟化化合物是与氧分子复合而实现氧的输送的。本发明与此不同,氟化的化合物在本发明中有效提供了一种脂溶性气体/流体的溶剂介质。
依据本发明可以采用的高度氟化有机化合物包括如至多含20个碳原子的脂族和脂环族全氟碳化合物(如全氟—2,2,4,4—四甲基戊烷、全氟辛烷、全氟癸烷、全氟三甲基环己烷、全氟异丙基环己烷、全氟萘烷、全氟二氢化茚、全氟三甲基二环〔3.3.1〕壬烷、全氟二环〔5.3.0〕癸烷、全氟甲基金刚烷及全氟二甲基金刚烷);上述这类化合物的溴代类似物(如全氟溴代辛烷);至多含20个碳原子的脂族和脂环族全氟代胺(如全氟代三丙基胺、全氟三丁基胺、全氟代—N—甲基十氢喹啉、全氟—4—甲基八氢喹诺里西啶和全氟—1—氮杂三环胺);全氟醚及任何上述化合物的混合物。其中优选的化合物包括全氟溴代辛烷和全氟萘烷,后者可与全氟三丙基胺组合使用如在Fluosol DA产品中。
表面活性剂可用作乳化剂以稳定乳状液或其本身作为溶解气体/流体或气体前体的亲油溶剂组分。适用的、生物相容的表面活性剂包括阴离子表面活性剂如脂肪酸碱金属盐(如十二烷酸钠盐)、烷基硫酸碱金属盐(如月桂基硫酸钠)和磺化酯碱金属盐(如磺基丁二酸二辛酯钠盐(docusate)),更优选的是非离子或两性离子表面活性剂。后两类表面活性剂的实例包括脂肪醇(如正十二烷醇)、聚氧乙烯—聚氧丙烯共聚物(Poloxamers如PluronicRF68)、脱水山梨醇脂肪酸酯如斯盘(Span)类表面活性剂及其聚氧乙基化的类似物如吐温(Tween)类表面活性剂、磷脂类(如磷脂酰胆碱(即卵磷脂)或二油酰磷脂酰二乙醇胺)以及脂肪酸聚乙二醇酯(如CremaphorR产品)。
可聚合的两亲物质如在WO—A—9217212中所述的(其内容在此列入本文作为公开内容的一部分),也可用作表面活性剂;这类两亲物质可通过紫外辐射或其它适当的引发方式,根据需要可在乳化后进行聚合。
也可采用多间隔泡囊状表面活性剂(如由Kim等在Biochem.Biophys.Acta728(1983)P.339和EP—A—0280503中所述的)。这类表面活性剂可被认为具有双层脂膜包裹的非同轴芯结构,即具有半蜂窝结构。可以方便地采用许多两亲的脂质化合物,这类化合物的优点之一是具有净负电荷,也可存在一种或一种以上中性脂质类化合物。代表性化合物包括磷脂酰丝氨酸、磷脂酰甘油(如二肉豆蔻酰磷脂酰甘油)、磷脂酸(如二肉豆蔻酰磷脂酸)、磷脂酰胆碱(如二油酰磷脂酰胆碱或二棕榈酰磷脂酰胆碱)、碱脂酰乙醇胺、二油酰卵磷脂、胆甾醇、三油酸甘油酯、三辛酸甘油酯及其它的油类/甘油三酯类和它们的衍生物。
可以用在乳状液中的其它亲油物质(如作为稳定的组分)包括抗氧化剂(如生育酚或硫辛酸)、可溶解并可稳定脂溶性气体或气体前体的全氟化表面活性剂、液晶、供制备Langmuir—Blodget膜的化合物以及亲油的生物可降解聚合物,如嵌段共聚物(如在WO—A—9204392或WO—A—9317718中所述的)。也可使用气体/流体的油溶性载体分子,卟啉是适用于此目的的载体。
也可使用象表面活性剂助剂那样的添加剂如糖类增粘剂,如蔗糖。
一类特别适用的乳状液包括以脂肪为基本成分的乳状液(如市场上可购得的静脉给药乳状液LiposynR(Abbot Laboratories)、IntralipidR(Kabi Vitrum)及SoyacalR(Alpha Therapeutic))。这类乳状液通常是以大豆油、蛋黄磷脂、甘油和注射用水为主要成分的,并且乳状液微粒直径小于0.5μm,其大小与天然存在的乳糜粒相似。这类乳状液在使用方面的优点包括长的储存期限、改善的血管造影半衰期和能持续地释放气体。
如果需要,根据本发明的造影剂油相可额外含有一种或多种生物相容的、粒子小于1μm,优选小于0.2μm的无机物悬浮固体微粒。包括如二氧化硅或氧化铁的这种微粒可起成核点作用以促进造影剂在给药后,在固体/液体界面上产生气体。
根据本发明造影剂的确切组成可依据诸如如所采用的各具体组分、面对的特殊用途、以及给药后预期的微泡大小等诸因素作很大的改变。
因此,给药后所形成的微泡体积一般随气体/流体的浓度增加而增加,也受构成油相材料性质的影响。在造影剂含有溶解气体的场合,通常气体含量可达到任何需要的程度,直到饱和或甚至过饱和(如造影剂在压力下储存)。
在增压造影剂情况下,微泡是在造影剂给药前,如小瓶子或其它形状容器一打开就开始形成的,并且给药后在体内继续形成。对于非增压造影剂,由于在体内造影剂被温热到体温,血液成分扩散进入稳定化的乳状液中和/或乳状液逐渐破乳而产生微泡。另一种方法,可在给药前如通过预热(微波加热)乳状液来诱导产生微泡。
如上所述,优选的油溶性气体是那些在水中溶解度低的气体。由此能促进气体与乳状液中亲油组分结合,因而进一步增强了微泡的稳定性,并可导致产生柔性的微泡/亲油的结合体,如被包壳的微泡形态。在技术上可以认为,这种柔性的结构与较刚性包封的微泡体系在增强超声造影效应方面相比较是特别有利的。
可以用任何方便的方法制备根据本发明的造影剂。因此,可采用常规技术(如均质化或超声均质)将含气体/流体或含气体前体的油相(如含凝聚的油溶性气体/流体或油溶性气体/流体或气体前体在至少一种亲油溶剂介质中的溶液)在水相中乳化而形成水包油型乳状液,或者将所需的气体/流体或气体前体掺混到已经预先形成的水包油乳状液的油相中。
采用油溶性气体时,气体如在加压下溶入所选定的亲油溶剂介质中,按下文方法使油相顺利地乳化。即在过量气体自身的压力下并根据需要或要求,在一种或多种生物相容的乳化剂存在下进行乳化。当采用油溶性流体或气体前体时,也可用这类技术。可选择的另一方法是将气体混入到已经预先形成的乳状液中,如将气体通入乳状液中和/或使乳状液保持在较高的气体压力之下。
本发明的超声造影剂可以肠道给药或非肠道给药,虽然在具体应用中直接向体腔如输卵管给药是有利的。但是,为了增强血管影象,通常最可能采用血管内给药(最常用的为静脉注射)包括心脏和心脏外灌注。
显而易见,供静脉给药的造影剂所产生的微泡应当小到足以透过肺系的毛细管床。因此,最好是能产生直径小于10μm、优选0.2—8μm范围(如0.3—7μ)微泡的造影剂。
下列非限制性实施例用于说明本发明。
实施例1
将0.1021g Span20溶解在10ml正戊烷中,加入溶解有0.5466g Tween60的40ml水溶液,采用Ystral均质器在0℃下将混合物乳化,得到稳定的细乳状液。将2ml乳状液注加到5ml 37℃(高于正戊烷沸点)蒸馏水中,测量其超声波衰减。得到的超声波衰减信号在20分钟内是稳定的。
实施例2
将0.1193g Span20溶解在10ml四甲基硅烷(TMS)中,加入溶解有0.9535g Tween60的40ml水溶液,采用Ystral均质器在0℃下将该混合物乳化,得到稳定的细乳状液。将2ml乳状液注加到5ml 37℃(高于TMS的沸点)蒸馏水中,测量其超声波衰减。得到强的超声波衰减并且信号在20分钟内是稳定的。
实施例3
将0.35ml上述实施例2的乳状液注加到6.65ml 37℃(高于TMS的沸点)的蒸馏水中。获得的超声回声效应在4分钟后显示最大,且信号在20分钟内是稳定的。
实施例4
将2ml上述实施例2的乳状液注加到5ml 0℃蒸馏水中,并将该稀释后的乳状液缓慢加热到37℃。在加热过程中测量其超声波衰减,发现在20分钟内造影效果缓慢地提高,说明气体随时间释放的。
实施例5
将0.0987g Span20加到10ml呋喃中,加入溶有1.0098gTween60的40ml水溶液,并用Ystral均质器在0℃下乳化,得到稳定的细乳状液。取2ml乳状液注加到5ml 37℃(高于呋喃沸点)蒸馏水中。测量其超声波衰减。得到回声效应,信号在20分钟内是稳定的。
实施例6
将5ml戊烷加到含0.68g二—十二烷基二—甲基溴化铵的40ml水溶液中,并用Ystral均质器在0℃下乳化该混合物,由于形成层状液晶相而得到稳定的细乳状液。取2ml该乳状液注加到5ml37℃蒸馏水中,测量其超声波衰减。得到回声效应,信号在20分钟内稳定。
实施例7
将5ml戊烷加到含0.56g十二烷基硫酸钠和0.60g 1—癸醇的40ml水溶液中,并用Ystral均质器在0℃下将混合物乳化,得到由于形成层状液晶而稳定的细乳状液。取2ml该乳状液注加到5ml37℃蒸馏水中,并测量其超声波衰减。得到回声效应,信号在20分钟内是稳定的。
实施例8
将0.10g Span20分散在4ml全氟萘烷中,然后在4℃下用六氟化硫饱和。将0.45g Tween60溶于36ml水中,冷却至4℃,然后采用Ystral均质器在4℃下以20000rpm将该两溶液乳化30秒钟。取2ml该乳状液注加到6ml 4℃蒸馏水中并缓慢加热到37℃,测量其超声波衰减。观察到2dB/cm或更高的衰减持续约120秒。
实施例9
将0.5ml正癸醇和0.50g十二酸钠分散在36ml水中,将4ml全氟萘烷冷却到4℃并用六氟化硫饱和。采用Ystral均质器在4℃下以20000rpm将该两溶液乳化30秒钟。将2ml该乳状液与6ml37℃蒸馏水混合,测量其超声波衰减。观察到强衰减(>2dB/cm)持续约30秒。
实施例10
取实施例9的乳状液2ml与6ml 4℃蒸馏水混合,并将稀释的乳状液缓慢加热到37℃。测量其超声波衰减,约30秒后观察到最大衰减为2.7dB/cm。
实施例11
将0.5ml正癸醇和0.5g十二酸钠分散在36ml水中,将4ml全氟萘烷冷却至4℃并用氙气饱和。采用Ystral均质器在4℃下以20000rpm将该两溶液乳化30秒钟。取2ml该乳状液与6ml 37℃蒸馏水混合,测量其超声波衰减。在5分钟内超声波衰减从1dB/cm增加到约3dB/cm。
实施例12
将0.5ml正癸醇和0.5g十二酸钠分散在36ml水中,将4ml全氟溴辛烷冷却到4℃并用氙气饱和。采用Ystral均质器在4℃下以20000rpm将该两溶液乳化30秒钟。取2ml该乳状液与6ml 37℃蒸馏水混合,测量其超声波衰减。
实施例13
在高压釜中将Intralipid(Kabi Vitrum,Stockholm,Sweden)或Fluosol(Alpha Therapeutic Ltd,UK)或10ml全氟溴辛烷冷却到4℃。在用氙气加压(20atm)下搅拌乳状液16小时。然后停止搅拌、缓慢地释放压力。分别取每种乳状液2ml与6ml37℃蒸馏水混合,测量其超声波衰减。
实施例14
将1.6g 2.5大气压力的全氟正丁烷加到已冷却到—5℃(低于全氟正丁烷的沸点(约—2℃))的0.4g全氟萘烷中。得到的油相组分与含Pluronic F68(1%W/W)和蔗糖(30%W/W)的40ml水溶液,在冷却的密闭塑料容器中超声乳化20分钟。用显微镜观察所制得的水包油乳状液微滴的直径大约是1微米;储存一星期后无显著变化。取部分乳状液(5ml)置于15ml容器中,在800W微波炉中加热至80℃(通常加热时间为8—10秒),冷却并过滤(Millipore,10μm)。显微镜观察证实形成了具有全氟萘烷稳定包壳的全氟正丁烷微泡。稀释到总油含量为0.2%W/W的微泡分散体,其容器内的超声波衰减,在1—6MHz频率范围内为大于10dB/cm,可稳定10分钟以上。准备一个相同的试样,只是乳状液不预先加热,在37℃下进行容器内超声衰减试验,在微泡自发地产生的7分钟内超声衰减从2dB/cm增至6dB/cm。
Claims (15)
1.由生物相容的水包油型乳状液构成的超声造影剂,其中油相包括油溶性气体/流体或气体前体。、
2.根据权利要求1的造影剂,其中气体/流体是惰性气体,必要时卤化的或其它取代的烃,脂族或环醚、硅烷、胂或硫的卤化物。
3.根据权利要求2的造影剂,其中气体/流体是全氟烷烃。
4.根据权利要求2的造影剂,其中气体/流体选自氙、正戊烷、呋喃、四甲基硅烷、六氟化硫及全氟正丁烷。
5.根据权利要求1的造影剂,其中气体前体是有机碳酸盐;吡唑啉、吡唑、***啉、重氮酮、重氮盐、四唑、叠氮化物或叠氮化物/碳酸盐混合物;可光解的环酮、内酯或碳酸盐;过酸;可热降解的羧酸;酶可降解的亚甲基二酯或过氧化氢。
6.根据权利要求1至4任何一项的造影剂,其中乳状液的油相主要包括凝聚的气体/流体与任何必须的生物相容的乳化剂。
7.根据权利要求1至5任何一项的造影剂,其中乳化剂的油相主要包括溶解在至少一种亲油溶剂组分中的气体/流体或气体前体与任何必须的生物相容的乳化剂。
8.根据权利要求7的造影剂,其中亲油溶剂组分选自脂族和脂环族全氟碳及其溴取代类似物,脂族和脂环族全氟胺、全氟醚及任何上述化合物的混合物。
9.根据权利要求8的造影剂,其中亲油溶剂组分是全氟溴代辛烷、全氟萘烷或全氟萘烷与全氟三丙基胺的混合物。
10.根据权利要求6至9任何一项的造影剂,含一种或多于一种选自脂肪酸碱金属盐、烷基硫酸碱金属盐和磺化酯、聚氧乙烯—聚氧丙烯共聚物、脱水山梨醇脂肪酸酯及其聚氧乙基化类似物、磷脂、脂肪酸聚乙二醇酯、可聚合的两亲化合物以及多间隔泡囊状表面活性剂***的表面活性剂作为乳化剂。
11.根据权利要求7至10任一项的造影剂,其中乳化剂也作为亲油溶剂组分。
12.根据权利要求1至5任一项的造影剂,其中乳状液的油相含大豆油和蛋黄磷脂,水相含甘油和注射用水。
13.根据上述权利要求中任一项造影剂,其中一种或多于一种生物相容的无机物微粒是悬浮在油相中的。
14.制备权利要求1所述超声造影剂的方法,包括(i)将含凝聚的油溶性气体/流体或溶于至少一种亲油溶剂组分的油溶性气体/流体或气体前体的溶液在水相中乳化而形成水包油型乳状液;或(ii)将所需的油溶性气体/流体或气体前体混合到已预先形成的水包油乳状液的油相中。
15.增强人体或动物躯体影象的方法,包括向所述躯体给予根据权利要求1至13任一项的造影剂并使至少部分所述躯体产生超声影象。
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JP (1) | JP3787639B2 (zh) |
KR (1) | KR960700759A (zh) |
CN (1) | CN1066963C (zh) |
AT (1) | ATE194292T1 (zh) |
AU (1) | AU696091B2 (zh) |
BG (2) | BG62084B1 (zh) |
BR (1) | BR9406228A (zh) |
CA (1) | CA2158365A1 (zh) |
CZ (1) | CZ237095A3 (zh) |
DE (1) | DE69425136T2 (zh) |
ES (1) | ES2147784T3 (zh) |
FI (1) | FI954325A (zh) |
GB (1) | GB9305349D0 (zh) |
HK (1) | HK1004981A1 (zh) |
HU (1) | HUT72982A (zh) |
NO (1) | NO953637D0 (zh) |
PL (1) | PL175128B1 (zh) |
RU (1) | RU2128520C1 (zh) |
SK (1) | SK113895A3 (zh) |
WO (1) | WO1994021301A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1087954C (zh) * | 1995-06-07 | 2002-07-24 | 联合药品公司 | 利用具有低奥斯特瓦尔德系数的氟代醚稳定的气乳液 |
Families Citing this family (20)
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US5874062A (en) * | 1991-04-05 | 1999-02-23 | Imarx Pharmaceutical Corp. | Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents |
US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
CA2148372A1 (en) * | 1992-11-02 | 1994-05-11 | Margaret A. Wheatley | Surfactant-stabilized microbubble mixtures, process for preparing and methods of using the same |
US5716597A (en) * | 1993-06-04 | 1998-02-10 | Molecular Biosystems, Inc. | Emulsions as contrast agents and method of use |
US5736121A (en) * | 1994-05-23 | 1998-04-07 | Imarx Pharmaceutical Corp. | Stabilized homogenous suspensions as computed tomography contrast agents |
US5897851A (en) * | 1995-06-07 | 1999-04-27 | Sonus Pharmaceuticals, Inc. | Nucleation and activation of a liquid-in-liquid emulsion for use in ultrasound imaging |
US5834519A (en) * | 1996-10-11 | 1998-11-10 | Wayne State University | Stabilized gas-supersaturated emulsions and suspensions |
US6548047B1 (en) * | 1997-09-15 | 2003-04-15 | Bristol-Myers Squibb Medical Imaging, Inc. | Thermal preactivation of gaseous precursor filled compositions |
US20010003580A1 (en) | 1998-01-14 | 2001-06-14 | Poh K. Hui | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
GB9808581D0 (en) * | 1998-04-22 | 1998-06-24 | Nycomed Imaging As | Improvements in or relating to contrast agents |
US6514209B1 (en) | 1999-06-07 | 2003-02-04 | Drexel University | Method of enhancing ultrasonic techniques via measurement of ultraharmonic signals |
WO2002034297A2 (en) * | 2000-10-24 | 2002-05-02 | Visys Ag | Endoscopic vascular visualisation, diagnostic and/or surgical procedure |
WO2006043359A1 (ja) * | 2004-10-22 | 2006-04-27 | Hitachi Medical Corporation | 超音波造影剤 |
US9220709B2 (en) | 2006-05-19 | 2015-12-29 | Drexel University | Drug loaded contrast agents: combining diagnosis and therapy |
JP4800862B2 (ja) * | 2006-06-21 | 2011-10-26 | 株式会社日立製作所 | ファントム |
JP5124185B2 (ja) * | 2007-07-02 | 2013-01-23 | 株式会社日立製作所 | 診断又は治療用薬剤の調製方法及び装置 |
CA2872142C (en) | 2012-05-09 | 2021-01-05 | Sinvent As | Ultrasound contact fluid |
BR112017013787A2 (pt) | 2014-12-31 | 2018-03-13 | Lantheus Medical Imaging, Inc. | Composições de microesfera de gás lipídio- encapsulado e métodos relacionados |
CA3022698A1 (en) | 2016-05-04 | 2017-11-09 | Lantheus Medical Imaging, Inc. | Methods and devices for preparation of ultrasound contrast agents |
US9789210B1 (en) | 2016-07-06 | 2017-10-17 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
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US4900540A (en) * | 1983-06-20 | 1990-02-13 | Trustees Of The University Of Massachusetts | Lipisomes containing gas for ultrasound detection |
US4684479A (en) * | 1985-08-14 | 1987-08-04 | Arrigo Joseph S D | Surfactant mixtures, stable gas-in-liquid emulsions, and methods for the production of such emulsions from said mixtures |
EP0245019A3 (en) * | 1986-04-30 | 1989-05-10 | Michael A. Davis | Low density contrast medium for diagnosis of pathologic conditions |
AU635200B2 (en) * | 1988-02-05 | 1993-03-18 | Schering Aktiengesellschaft Berlin Und Bergkamen | Ultrasonic contrast agents, process for producing them and their use as diagnostic and therapeutic agents |
US5088499A (en) * | 1989-12-22 | 1992-02-18 | Unger Evan C | Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same |
DK0605477T4 (da) * | 1991-09-17 | 2007-10-01 | Ge Healthcare As | Gasformige ultralydskontrastmidler |
IL104084A (en) * | 1992-01-24 | 1996-09-12 | Bracco Int Bv | Sustainable aqueous suspensions of pressure-resistant and gas-filled blisters, their preparation, and contrast agents containing them |
-
1993
- 1993-03-16 GB GB939305349A patent/GB9305349D0/en active Pending
-
1994
- 1994-03-16 JP JP52077594A patent/JP3787639B2/ja not_active Expired - Fee Related
- 1994-03-16 CN CN94191801A patent/CN1066963C/zh not_active Expired - Fee Related
- 1994-03-16 HU HU9502694A patent/HUT72982A/hu unknown
- 1994-03-16 DE DE69425136T patent/DE69425136T2/de not_active Expired - Fee Related
- 1994-03-16 PL PL94310656A patent/PL175128B1/pl unknown
- 1994-03-16 CA CA002158365A patent/CA2158365A1/en not_active Abandoned
- 1994-03-16 KR KR1019950703923A patent/KR960700759A/ko not_active Application Discontinuation
- 1994-03-16 EP EP94909226A patent/EP0689461B1/en not_active Expired - Lifetime
- 1994-03-16 WO PCT/GB1994/000521 patent/WO1994021301A1/en not_active Application Discontinuation
- 1994-03-16 RU RU95121645A patent/RU2128520C1/ru active
- 1994-03-16 ES ES94909226T patent/ES2147784T3/es not_active Expired - Lifetime
- 1994-03-16 SK SK1138-95A patent/SK113895A3/sk unknown
- 1994-03-16 BR BR9406228A patent/BR9406228A/pt not_active Application Discontinuation
- 1994-03-16 AT AT94909226T patent/ATE194292T1/de active
- 1994-03-16 CZ CZ952370A patent/CZ237095A3/cs unknown
- 1994-03-16 AU AU62152/94A patent/AU696091B2/en not_active Ceased
-
1995
- 1995-09-12 BG BG99998A patent/BG62084B1/bg unknown
- 1995-09-12 BG BG100272A patent/BG100272A/xx unknown
- 1995-09-14 FI FI954325A patent/FI954325A/fi unknown
- 1995-09-15 NO NO953637A patent/NO953637D0/no not_active Application Discontinuation
-
1998
- 1998-05-13 HK HK98104117A patent/HK1004981A1/xx not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1087954C (zh) * | 1995-06-07 | 2002-07-24 | 联合药品公司 | 利用具有低奥斯特瓦尔德系数的氟代醚稳定的气乳液 |
Also Published As
Publication number | Publication date |
---|---|
BG100272A (en) | 1996-05-31 |
RU2128520C1 (ru) | 1999-04-10 |
BG62084B1 (bg) | 1999-02-26 |
WO1994021301A1 (en) | 1994-09-29 |
EP0689461A1 (en) | 1996-01-03 |
NO953637L (no) | 1995-09-15 |
KR960700759A (ko) | 1996-02-24 |
JPH08509706A (ja) | 1996-10-15 |
EP0689461B1 (en) | 2000-07-05 |
CN1066963C (zh) | 2001-06-13 |
PL310656A1 (en) | 1995-12-27 |
GB9305349D0 (en) | 1993-05-05 |
SK113895A3 (en) | 1997-02-05 |
PL175128B1 (pl) | 1998-11-30 |
CA2158365A1 (en) | 1994-09-29 |
HUT72982A (en) | 1996-06-28 |
DE69425136T2 (de) | 2001-03-22 |
BR9406228A (pt) | 1995-12-12 |
ATE194292T1 (de) | 2000-07-15 |
AU6215294A (en) | 1994-10-11 |
FI954325A0 (fi) | 1995-09-14 |
HK1004981A1 (en) | 1998-12-18 |
NO953637D0 (no) | 1995-09-15 |
CZ237095A3 (en) | 1996-03-13 |
FI954325A (fi) | 1995-10-11 |
ES2147784T3 (es) | 2000-10-01 |
HU9502694D0 (en) | 1995-11-28 |
JP3787639B2 (ja) | 2006-06-21 |
AU696091B2 (en) | 1998-09-03 |
DE69425136D1 (de) | 2000-08-10 |
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