CN1121314A - 造影剂或与其相关的改进 - Google Patents
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- A—HUMAN NECESSITIES
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- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
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Abstract
能在与适当载液如注射用水配制后和/或施用于受试者后如受血液或其他体液作用后能化学产生气体的微粒材料可在诊断成像,尤其在超声成像和磁共振成像中用作造影剂。
Description
本发明涉及新型造影剂,更具体地说是涉及到诊断成像中使用的微粒造影剂。
超声显像建立在超声波(例如1—10MHz频率范围)经由振子透过人或动物受试体的基础上,超声波与身体组织和体液的界面相互作用。
超声影像的反差来源于超声波在界面处不同的反射/吸收,其结果可用多普勒技术包括使用彩色多普勒技术来增强反射信号。以判断血液流动。
很早就认识到使用造影剂有利于加大不同的组织/体液的声学性质差别。自从1968年碘代花菁绿用作第一个超声造影剂以来,已经测试过其它许多潜在的造影剂,它们包括乳状液、固体微粒、水溶性化合物,无气泡的和各类包封的含气体系。大家普遍接受:易于压缩的低密度造影剂由于它们产生超声背景散射而尤其有效,于是含气和产生气体的体系倾向于表现出明显大于其它类型造影剂的功效。
现在,有三种超声造影剂在市场上可买到或不久将进行临床开发。它们是以含气半乳糖微晶为主要成分的EchovistR、以脂肪酸包壳的含气半乳糖微晶LevovistR和含有用部分变性人体血清蛋白包封的气泡构成的AlbunexR。
含气造影介质在磁共振(MR)成像中(例如作为会降低MR信号强度的敏感性造影剂)也被认为是有效的。含氧造影介质也表现为潜在有效的顺磁MR造影剂。
进一步来说,在X—射线成像领域已经观察到,如二氧化碳这样的气体可以用作成负像的口服造影剂。
最常见于含气和产生气体造影剂的一个共同缺点是它们在体内相对缺乏稳定性。这在如回声心动记描法等领域是个特殊的问题。在该领域需要改善造影剂使其具有产生微气泡的能力,微气泡需充分小至能通过肺的微血管床(即尺寸一般小于约10μm,最好小于约7μm),以便让左侧心脏显像,并且最好是足以能稳定进行数次循环流通。
还要求造影剂在相当长的时间内表现出良好的贮藏稳定性,例如直至一年以上,最好是2—3年或更长时间。
本发明以我们的发现为基础,即微粒材料作为诊断成像造影剂可能有用,该材料在与如注射用水这样的合适的载液配制后和/或在受试者服用后能够化学产生气体,例如,由于受血液或其它体液作用后能化学产生气体。
这些造影剂可以与现存的微粒造影剂(例如上述EchovistR和LevovistR)区别开。在EchovistR和LevovistR中,微气泡的产生基本上只是一种与气体带入微粒之上或之中有关的物理过程,例如作为包含物存在于其晶体结构的空穴中和/或粘附到它们的表面上。可以理解使用本发明的造影剂可以导致产生由这种物理吸附的气体以及化学产生的气体造成的微泡,这能提高造影效果的综合强度。
含有包封在脂质体中的化学产生气体的物质以前已有描述,例如在WO—A—9109629中。由于必要的稳定脂质体需要亲水中心,所以包封物质一般作为在水或另一相对亲水溶剂中的溶液存在。这些造影剂的造影效果将受可导入脂质体中心的溶液的产生气体的物质的最大负荷的限制,进一步说,由于诸如泡囊熔化和渗漏等因素的结果,这些脂质体产品倾向于表现出比根据本发明的干性微粒材料更低的长期贮存稳定性。
根据本发明的一个方面,提供了一种包含微粒物质的造影剂,在于载液中配制造影剂时和/或在将配制的造影剂给予人或动物受试体时,能够化学产生气体。
这些造影剂可用于许多显像诊断技术,包括超声、MR和X—射线成像,它们在超声成像和MR成像诊断(例如作为敏感性造影剂)中的应用构成了本发明的优选特征。
例如,产生气体物质可以是在对受试者给药后发生化学反应产生气体的单一化合物(这里的术语化学反应包括酶促反应),例如由于热诱导的分解或pH的改变或酶降解的结果产生气体。于是象无毒无机和有机碳酸盐(如碱金属和碱土金属碳酸盐和碳酸氢盐)、碳酸精氨酸和分子式为RO·CO·OM的化合物(这里R是有机基团、M代表生理学可接受的阳离子)在血流正常pH条件下都将产生二氧化碳,正如氨基丙二酸盐等化合物的反应一样。
诸如丙二酸,α—氰基酸、α—硝基酸、α—芳基酸、α—酮酸、α,α,α—三卤代酸、β—酮酸和β,γ—不饱和酸等羧酸相对容易脱羧,在体内随着二氧化碳的产生也可自动脱羧。
亚甲基二酯(例如使用象在WO—A—9317718和WO—A—9318070中描述的技术所制备亚甲基二酯,这些内容引入本文供参考)用普通的酯酶裂解可导致二氧化碳放出,所以按照本发明,这些双酯衍生物(如葡聚糖等化合物的衍生物)可以提供有用的造影剂。
过氧化氢(可作为抗氧化剂—稳定化固体配制物或颗粒基质,作为一种聚乙烯基吡咯烷酮—过氧化氢络合物(例见WO—A—9107184)或其前体形式,例如四水合过硼酸钠(见EP—A—0253772)或过氧化脲(见WO—A—9011248)存在)随着放出二氧化碳而酶促降解。
可以理解,根据本发明的以上造影剂在按配方配制后保持稳定(例如在注射用水这样的可注射介质中的溶液),直至实际服用时才开始产生气体,这种配方构成了本发明另一特征。
其它类型的生成气体物质包括与水反应产生气体的化合物。应用这种化合物的造影剂在用注射用水配制时将立刻开始产生微泡。有代表性的这类化合物包括诸如硼氢化钠或氢化钙这样的氢化物;诸如乙炔钠等乙炔化物(acetylenides)、诸如碳化钙这样的碳化物、能反应生成氨基酸和二氧化碳的N—羧酸酐(见J.Am.Chem.Soc.112(1990)pp.7414—7416);和聚碳酸酯(见Pope等的Org.Synth.Coll.Vol.VI(1988)p.418),如分子式如下的化合物
(CH3)3C·O·(CO2)n·C(CH3)3
这里,n至少是2,这类化合物与水反应产生二氧化碳。
产生气体的物质还可以包含许多化合物,这些化合物既可以单独贮藏也可以一起贮藏,当它们例如与注射水配制时便相互作用。实例包括传统的泡腾系统,该系统一般含有碳酸盐或碳酸氢盐(例如无毒性碱金属或碱土金属盐)和有机酸,如酒石酸、琥珀酸或柠檬酸。其它具代表性的的混合配制物包括:过碳酸钙/碳酸氢钠/柠檬酸、5—硝基呋喃丙烯酸酯/乙二胺四乙酸/抗坏血酸/酒石酸/偏亚硫酸氢钠/碳酸氢钠和长链聚磷酸盐/碳酸氢钠。
如果期望的话,微粒材料可由下列方法稳定化,例如用合适的生物相容材料包壳或包封,该生物材料可选择那些例如可溶解的和/或可生物降解的材料。因此有代表性的材料包括:聚乙二醇、环氧乙烷—环氧丙烷嵌段共聚物(pluronics)、白蛋白、明胶、淀粉、胶原蛋白、葡聚糖、聚交酯/聚乙交酯、嵌段共聚物和可生物降解的聚合物,例如在WO—A—9204392、WO—A—9317718和WO—A—9318070中描述的那些材料。包壳/包封可以掺入离子载体(如尼日利亚菌素),以便当产生气体的物质由于pH的改变而活化时促进质子转移。
微粒材料可以以前脂质体的形式被有利地稳定化(例如Payne等人在J.Phorm.Sci.75(1986)pp.325—329中,Katare等人在J.Microencapsulation 7(1990),pp.455—462中和Ibid.8(1991)pp.1—7中所描述的,这些文章的内容在此引入供参考)。这些产品基本上包含用脂质体生成材料(例如卵磷脂,氢化卵磷脂或氢化磷脂酰丝氨酸这样的磷脂)以干燥形式包壳的微粒材料。这类产品一般含有干燥的、自由流动的粉末,特别是表现出良好的长期贮存稳定性。当产品用象注射水这样的水基载液配制时,形成脂质体常伴随有气体的产生。包壳材料还可以为这样的材料,即载液实际上是不可渗透的或是对其惰性的,但在服用时或服用前(例如由于pH的改变或酶活性的结果)被改性或活化(如表现出增强的渗透性),所以导致了服用后在体内脂质体的形成和气体的产生。后一类前脂质体的水基悬浮液和分散体可以显示出良好的贮存稳定性,并且构成了本发明另一个特征。如果希望,这种含水配制物的稳定性可以通过选择合适的条件(如pH值)来得到加强(例如用缓冲液将配制物调至微碱性),以确保服用前不出现气体的生成。
可以理解,由造影剂以前脂质体形式产生的脂质体可以帮助稳定微泡,这是借助其在诸如脉管系统中较长的停留时间而产生的。
根据本发明,如果希望的话,造影剂中的微粒材料可以掺入一种对产生渗透梯度有用的溶质来加强流体通过任何包壳层进入材料的扩散作用。
微泡的稳定性通常可以通过作为凝聚核的产生气体物质的微粒本身来加强,微粒也可以有多孔的或海绵状结构,例如在该结构的孔或网络中含有产生气体的物质,或具有是在颗粒表面形成的气袋或空穴。这种结构上的挠曲性相对于较刚性的含气体系来说将提高它们的回波性能。
本发明的造影剂可用任何方便的方法制备,例如通过使产生气体物质微粉化的方法制备。在此微粉化之前或之后,可以应用任何期望的包壳或包封材料。这样,例如优选的亲水性微粉化产生气体物质可以分散于挥发性亲油溶剂中,而在分散步骤之前、之中或之后,期望的包壳材料已溶于此溶剂中,此后,除去溶剂(如在减压下),得到根据本发明的包壳的微粒产品。
一般来说,可以使用诸如研磨或碾磨等常规微粉化技术,球磨也许特别方便。
包壳/包封使用常规方法(例如流化床,喷涂模制、浸渍、凝聚—相分离、多孔板离心和溶剂蒸发技术)可以同样有效包壳/包封,得到具有合适的组成、厚度和渗透性的一层或多层的包衣层。
本发明的造影剂可以例如经肠道或非肠道服用,尽管在特殊的应用中直接给入象输卵管这样的体腔也许更有利。然而一般来说,为了增强血管成像,包括心脏和心脏外灌注,血管内给予,最常见的是静脉注射是最可能使用的方法。
可以理解,对于静脉给予的造影剂产生的微泡应当足够小以通过肺系统的毛细血管床。所以应当优选诸如产生直径小于10μm的微泡的造影剂,最好在0.2—8μm范围内(比如0.3—7μm),例如微颗粒可以便利地具有1—7μm(如1—4μm)的平均尺寸。实际上,较大的微粒和微泡尺寸(例如直径高至500μm)的在象胃肠成像这样的应用中可能是有用的。
以下非限定性实施例对于阐述本发明很有用。实施例1
卵磷脂(2.5g)加入于氯仿(30ml)中的无水碳酸氢钠(10g)的悬浮液中,使其溶解,然后在40℃减压除去溶剂,得到固体产品。
该产品(100mg)溶于水基葡萄糖(5ml 50mg/ml溶液),溶液用盐酸酸化至pH为2,加热至50℃,形成混浊的悬浮液,其中存在的颗粒倾向于浮于顶部,光学显微镜显示出脂质体的形成和泡中含有气体。实施例2
于氯仿中(20ml)的磨细的无水碳酸钠(1.6g)的悬浮液超声化处理几分钟以破坏其结块。加入氢化卵磷脂(280mg),搅拌使其溶于悬浮液,于40℃减压除去溶剂,得到固体粉末。
该产品(100mg)加入含水抗坏血酸(2ml 25mg/ml溶液)导致混浊悬浮液生成,存在于其中的颗粒倾向于浮上顶部,光学显微镜证实脂质体已形成,且泡中含气体。实施例3
于氯仿(20ml)中的磨细的无水碳酸钠(1.6g)悬浮液超声化处理几分钟破坏其结块,加入氢化磷脂酰丝氨酸(280mg),搅拌使其溶于悬浮液,加入甘油(4ml),然后于40℃减压除去溶剂,得到无水浓缩物。
该产品(200mg)加入水基葡萄糖(4ml 50mg/ml溶液),于是通过碳酸钠形成气体,这一过程被磷脂的丝氨酸部分的质子诱发,导致形成混浊的悬浮体,存在于其中的颗粒倾向于浮于顶部,光学显微镜证实脂质体已形成,并且泡中含气体。实施例4
由实施例1—3配制的产品的声学效果通过以下方法测定:将产品用IsotonII(Coulter Electronics Limited,Luton England)再稀释十倍,将此稀释样品放入池中,该池于37℃水浴中保温,用3.5MHz单电池转换器以脉冲—反射技术测定声学反散射,在所有情况下都获得了来自池内部强的声学反散射,而在仅含有Isoton II的池上进行的参比测定没有表现出声学反散射。实施例5
将磨细的碳酸钠和碳酸氢钠粉末(1∶1w/w,1.36g)分散于含Aerosol OT(1.75g)的己烷(20ml)中,加入溶于水(50ml)的吐温60(1.0g),得到的混合物用Ystral均化器乳化,得到精细的乳液。
将该产品(2ml)注入磷酸缓冲液(5ml),观察得到的混合物在试管内表现出回波效果,此信号可稳定20分钟。
Claims (15)
1.一种造影剂,包括在配制造影剂和/或在将配制的造影剂用于人或动物受试体时能化学产生气体的微粒材料。
2.如权利要求1的造影剂,其中,能够化学产生气体的物质选自碱金属和碱土金属碳酸盐和碳酸氢盐、碳酸精氨酸、分子式为RO·CO·OM的化合物,(这里R代表有机基团,M代表生理学可接受的阳离子,在体内自动脱羧的羧酸、酶可降解的亚甲基二酯、过氧化氢或其前体的固体组分、氢化物、乙炔化物、碳化物、N—羧基酸酐、聚碳酸酯和包含至少一种碳酸盐或碳酸氢盐和至少一种有机酸的泡腾配制物。
3.如权利要求2的造影剂,其中,能化学产生气体的物质选自碳酸钠、碳酸氢钠和其混合物。
4.如上述权利要求任一项所述的造影剂,其中微粒物质用生物相容性材料包壳或包封。
5.如权利要求4的造影剂,其中,微粒物质用脂质体产生材料以干燥形式包壳。
6.如权利要求5的造影剂,其中,脂质体产生材料选自卵磷脂、氢化卵磷脂和氢化磷脂酰丝氨酸。
7.如权利要求5或6的造影剂,其中脂质体产生材料当贮存于含水配制介质中时是不反应的,但是在服用造影剂时或之前调整了组分时,它能在体内促进脂质体的产生。
8.含有前述任何权利要求所述的造影剂的无水悬浮液和浓缩物。
9.如前述权利要求任一项所述的造影剂的配制形式,包括仅在服用时活化的能化学产生气体的物质。
10.如权利要求9的配制形式,包括权利要求7所述的造影剂的水悬浮液和水分散体。
11.制备如权利要求1所述的造影剂的方法,该方法包括微粉化能化学产生气体的物质和/或在此微粉化之前或之后,将包壳或包封材料加于该物质上。
12.如权利要求1—10中任一项所述的造影剂在诊断成像中的应用。
13.如权利要求1—10中任一项所述的造影剂在超声成像中的应用。
14.如权利要求1—10中任一项所述的造影剂在磁共振成像中的应用。
15.产生人或非人动物体的增强的成像的方法,该方法包括给予该人或非人动物体如权利要求1—10任一项所述的造影剂,该人或非人动物体的至少一部分产生超声或磁共振成像。
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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 |
JPH0678247B2 (ja) * | 1988-10-04 | 1994-10-05 | 大塚製薬株式会社 | Nmr造影用鉄含有製剤 |
US5147631A (en) * | 1991-04-30 | 1992-09-15 | Du Pont Merck Pharmaceutical Company | Porous inorganic ultrasound contrast agents |
US5795562A (en) * | 1992-03-06 | 1998-08-18 | Nycomed Imaging As | Contrast agents comprising gas-containing or gas-generating microparticles or microballoons |
-
1993
- 1993-03-16 GB GB939305351A patent/GB9305351D0/en active Pending
-
1994
- 1994-03-16 WO PCT/GB1994/000522 patent/WO1994021302A1/en not_active Application Discontinuation
- 1994-03-16 BR BR9406199A patent/BR9406199A/pt not_active Application Discontinuation
- 1994-03-16 JP JP6520776A patent/JPH08507781A/ja active Pending
- 1994-03-16 KR KR1019950703924A patent/KR960700760A/ko not_active Application Discontinuation
- 1994-03-16 CN CN94191800A patent/CN1121314A/zh active Pending
- 1994-03-16 CA CA002158359A patent/CA2158359A1/en not_active Abandoned
- 1994-03-16 SK SK1137-95A patent/SK113795A3/sk unknown
- 1994-03-16 EP EP94909227A patent/EP0689462A1/en not_active Withdrawn
- 1994-03-16 CZ CZ952371A patent/CZ237195A3/cs unknown
- 1994-03-16 HU HU9502693A patent/HUT72984A/hu unknown
- 1994-03-16 AU AU62153/94A patent/AU695529B2/en not_active Ceased
- 1994-03-16 PL PL94310657A patent/PL310657A1/xx unknown
-
1995
- 1995-09-14 FI FI954326A patent/FI954326A/fi unknown
- 1995-09-15 NO NO953638A patent/NO953638L/no unknown
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100347562C (zh) * | 1998-01-05 | 2007-11-07 | Ge健康公司 | 磁共振研究方法 |
WO2007012962A2 (en) * | 2005-07-29 | 2007-02-01 | Yuhong Xu | Sono-active liposomes and lipid particles and use thereof as contrast agents and active-agent delivery systems |
WO2007012962A3 (en) * | 2005-07-29 | 2007-06-14 | Yuhong Xu | Sono-active liposomes and lipid particles and use thereof as contrast agents and active-agent delivery systems |
CN113423437A (zh) * | 2018-12-21 | 2021-09-21 | 通用电气医疗集团股份有限公司 | 超声造影剂及其使用方法 |
CN113423437B (zh) * | 2018-12-21 | 2024-03-08 | 通用电气医疗集团股份有限公司 | 超声造影剂及其使用方法 |
Also Published As
Publication number | Publication date |
---|---|
SK113795A3 (en) | 1997-02-05 |
FI954326A (fi) | 1995-10-11 |
CZ237195A3 (en) | 1996-05-15 |
HUT72984A (en) | 1996-06-28 |
BR9406199A (pt) | 1995-12-12 |
PL310657A1 (en) | 1995-12-27 |
HU9502693D0 (en) | 1995-11-28 |
NO953638D0 (no) | 1995-09-15 |
KR960700760A (ko) | 1996-02-24 |
EP0689462A1 (en) | 1996-01-03 |
AU6215394A (en) | 1994-10-11 |
JPH08507781A (ja) | 1996-08-20 |
CA2158359A1 (en) | 1994-09-29 |
GB9305351D0 (en) | 1993-05-05 |
AU695529B2 (en) | 1998-08-13 |
NO953638L (no) | 1995-09-15 |
WO1994021302A1 (en) | 1994-09-29 |
FI954326A0 (fi) | 1995-09-14 |
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