CN1079266C - 造影剂及其改进 - Google Patents
造影剂及其改进 Download PDFInfo
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- CN1079266C CN1079266C CN95194934A CN95194934A CN1079266C CN 1079266 C CN1079266 C CN 1079266C CN 95194934 A CN95194934 A CN 95194934A CN 95194934 A CN95194934 A CN 95194934A CN 1079266 C CN1079266 C CN 1079266C
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Abstract
含有含气体的聚合物微粒和/或微球的造影剂,其中,聚合物是含通式(II)的重复单元(式中a是9-19中的一个整数,b是1-8中的一个整数)的生物降解聚合物。此聚合物可用在诸如超声和磁共振成象等的诊断应用。此聚合物是新的,其本身也是权利要求所保护的。
Description
本发明涉及新的造影剂,更具体地说,涉及用于诊断成象的以新的含气体聚合物为基础的造影剂,以及涉及其新的聚合物成分。
公开的国际专利申请WO93/17718公开了包含有含气体或产生气体的聚合物微粒和/或微球的造影剂,这篇专利的内容在此作为参考。这种造影剂的特征在于该聚合物是含有下式单元的生物降解聚合物
-(O)m-CO-O-C(R1R2)-O-CO-(O)n- (I)(其中,R1和R2每个表示一氢原子或一与碳连结的一价有机基团或R1和R2共同形成一与碳连结的二价有机基团,m和n各是0或1)。这些造影剂可以用于诊断用途,如超声和磁共振成象,显示出良好的贮存稳定性以及服药后在体内的稳定性和造影效果,常常可经过几次循环。但是由于此后通式(I)的单元对普通酯酶造成的降解的敏感性,造影剂在体内很容易生物降解。
本发明涉及属于上述的讨论的WO93/17718的范围内的造影剂,但是这些造影剂设有专门公开。这种新型造影剂是特别有利的,因为这种造影剂具有卓越的稳定性和在体内的造影效应,以及造影剂在体内降解成可以允许的产物,并且在大多数情况下是内生的。
本发明一个方面是提供了含有包含气体的聚合物微粒和/或微球的造影剂,其特征在于,此聚合物是由通式(II)(II)的重复单元组成的生物降解聚合物(式中,a表示9-19中的一个整数,例如13-17,b表示1-8中的一个整数,例如3-6)。已经发现,这些造影剂在动物试验中显示出非常敏锐超声造影效果,例如,既提供了在狗的心室壁所有部分的心肌造影增强,也提供肾的卓越的造影增强。在造影剂为网状内皮系统吸收后,还可以保留产生回声,可用作巨噬细胞成象剂。
本发明的造影剂显示出卓越的贮存稳定性,例如,在25℃在水悬浮液保持产生回声达8周。然而,在服药后造影剂很快降解井从身体清除,例如,在肝中有1-2天的半寿期。
将会知道,含通式(II)重复单元的聚合物在体内的主要降解产物是通式HO·(CH2)aCOOH(式中a如前所定义的)的ω-羟基酸,通式HOOC·(CH2)bCOOH(式中b如前所定义的)的二元酸和乙醛。乙醛是一种内生物质,在体内将被氧化成醋酸,如在乙醇代谢中那样。整数a和b可以有利地选择,以产生内生的ω-羟基酸和二元酸;例如,a=15和b=4的聚合物将降解生成16-羟基棕榈酸和己二酸,后两者都是内生的。
本发明的造影剂可以用于各种诊断显影方法,包括超声、磁共振和x-射线成像。将它们用于超声诊断成象和磁共振成象,例如,作为敏感造影剂,构成本发明的优选特征。
任何生物相容气体可以用在本发明的造影剂中,例如,空气、氮气、氧气、氢气、一氧化二氮、二氧化碳、氦气、氢气、六氟化硫、低分子量任选氟代烃,如甲烷、乙炔、四氟化碳和其它的全氟烷烃,如全氟丙烷、全氟丁烷和全氟戊烷,以及上述化合物任何混合物。在微球内的气体可以是游离的,或被所含有的物质吸收或吸附。这里所用的“气体”一词包括在37℃里气态的任何物体(包括蒸汽)。
对于诸如回声心电术的超声应用,为了能够自由通过肺系统和同优选的约0.1-15兆赫芝的显影频率达到共振,可以方便地利用平均尺寸0.1-10微米,例如1-7微米的微球。但是,平均尺寸达500微米的大球可以用于其它用途,例如肠胃显影或子宫或输卵管的研究。
本发明的造影剂可以加入各种添加剂,如乳化剂、涂层剂、增塑剂、填充剂、低温防护剂和/或抗氧剂,例如以改进其稳定性、分散性、聚集倾向、生物性能等,或改进膜的柔韧性和/或极性。
代表性的乳化剂包括脂肪酸(例如直链饱和或不饱和脂肪酸,如含10-20个碳原子)和碳水化合物和它们的三甘油酯;蛋白质,如明胶或更优选地人血清蛋白;磷脂,如卵磷脂;多糖类,如淀粉、改性的(如亲脂化的)淀粉或阿拉伯树胶;和表面活性聚合物,如聚乙烯醇、聚乙二醇和嵌段共聚物(包括增量聚合物),例如聚(氧亚乙基)-聚(氧亚丙基)-聚(氧亚乙基)嵌段共聚物,如普卢兰尼克(Pluronics)。
当利用嵌段共聚物(包括增量聚合物)表面活性剂时,这些共聚物可含如上述定义的通式(I)的生物降解的键,如在通式中,R1和R2(当不是氢时)每个可表示与碳连接的烃基或杂环基,例如至多20个碳原子,如烷基或链烯基(优选至多10个碳原子)的脂肪基团,环烷基(优选至多10个碳原子),如芳烷基(优选至多20个碳原子)的芳脂基,芳基(优选至多20个碳原子)或具有至多20个碳原子和一个或多个选自O、S和N的杂原子的杂环基。这样一种烃基或杂环基可带一个或多个诸如卤素原子或通式为-NR3R4、-CONR3R4、-OR5、-SR5和-COOR6基团的官能团,式中R3和R4每个为氢原子、酰基或如对R1和R2定义的烃基;R5是氢原子、酰基或如对R1和R2定义的基团;R6是氢原子或如对R1和R2定义的基团。其中R1和R2表示二价基团,例如可以是亚烷基(烷叉)、亚链烯基(烯叉)、亚烷基或亚链烯基(优选具有至多10个碳原子),它们可含一个或多个如上述定义的官能团。
在这些嵌段共聚物中存在通式(I)的单元是有好处的,在通式(I)中,R1和R2可以是氢和甲基,例如,在其中R1表示氢原子,R2表示甲基;选择m和n是零的单元也是有利的。
嵌段共聚物表面活性剂可含两个或多个不同亲液性的嵌段,例如在直链的二嵌段、三嵌段或嵌段排列中,如A-B、A-B-A、B-A-B或A-B-A-B-A中,A和B是不同亲液性的聚合物嵌段,优选各为亲水和疏水嵌段。支链结构,如
型和大环结构,如型也可以利用。
在这些嵌段共聚物表面活性剂中的亲水嵌段可以是,如来自诸如聚糖、聚醇(如聚乙烯醇)、聚乙烯基吡咯烷酮、聚乙二醇和聚氨基酸。诸如聚原酸酯、聚缩醛、聚酐、聚乙醇酸、聚(甲基)丙烯酸和其酯等衍生物等聚合物当需要时由亲水基取代后也可以利用。亲水嵌段主要由聚乙二醇单元组成是有利的。
在这些嵌段共聚物表面活性剂中的疏水嵌段可来自,例如油溶性缩合、离子和自由基产生聚合物,例如聚(甲基)丙烯酸酯、聚原酸酯、乙烯基和苯乙烯聚个物、聚缩醛、聚酐、聚乙醇酸及其醚和酯,和聚乳酸/聚乙醇酸共聚物;这些聚合物可以,例如,嵌入或用诸如烷基、芳烷基或芳基等疏水基团取代以增加其疏水性。疏水嵌段可有利地包含有含由和/或嵌入通式(I)单元连接的一个或多个长链脂族基团(如C10-20聚亚甲基)的聚酯链。这些疏水嵌段可以是低聚的或准聚合的,如在增量聚合物中,并且本身可以包括单体基团,这可以,例如显示出聚合物特性(例如由于存在长链单元),同时又不严格具有确定的重复单元。
一类优选的嵌段共聚物表面表活性剂中,其聚合物含有聚乙二醇单元作为亲水嵌段,在疏水部分含有通式为
-Ra-(CH2)a-CO-O-CH(CH3)-O-CO-(CH2)a-Rb- (III)单元(式中a如前述定义的,Ra和Rb每个表示价键或连接基团,如通式-O-CO-(CH2)b-CO-O的羰基或二酸残基,式中b如前述定义的),作为增量部分或作为低聚或聚合嵌段中一部分。
其它优选的表面活性剂包括脂肪酸酰化的聚乙二醇,如MYRJ和含有用疏水部分酰化的甲氧基封端的聚乙二醇亲水嵌段增量聚合物,此疏水部分含有两个或多个脂肪酸链,例如酰氧酰基,如16-十六酰氧十六酰基。
代表性的填充剂和低温防护剂包括醇,例如脂肪醇,如叔-丁醇,多元醇,如甘油,糖,如蔗糖、甘露糖醇、海藻糖或环糊精,以及聚二醇,如聚乙二醇。
代表性的保存剂包括抗氧剂。
本发明的造影剂可用许多方法制备,例如在WO93/17718中讨论过的,如通过将一种气体加入含通式(II)重复单元的生物降解聚合物中,使形成聚合物微粒和/或微球。
一种有效的方法符合EP-A-0398935和EP-A-458745中讨论的界面沉积方法。此法包括将聚合物溶于或悬浮在水-不混溶的有机溶剂中,乳化(例如通过高速搅拌或高切变混合)在水溶液相中所得到的溶液或悬浮液,优选是在表面活性剂存在下以稳定所得到的油在水中的乳液,随后,除去有机溶剂,优选是两相(例如,通过蒸发或亲液化,优选是在要被加入的气体中,例如在减压下),这样,聚合物在水溶液相和有机相的界面形成膜。
用在这些方法中的有机溶剂包括如含至多10个碳原子的脂族、脂环和芳脂族烃,例如,正辛烷、环辛烷、环己烷、二甲基环己烷、乙基环己烷、甲基庚烷、乙基己烷、甲苯、二甲苯或萜烯、萜类化合物或类异戊二烯,如莰烯或苎烯;卤代烃,如二氯甲烷、氯仿、四氯化碳溴代甲烷或氟利昂;酯类,如醋酸乙酯或丙酯、甲酸丁酯、丁酸或异丁酸丙酯或异丙酯;以及适当的醚和其它亲油溶剂。象莰烯这样的溶剂的优点是,它们是生物允许的,所以在服药前不需要从造影剂除去残余溶剂。这些高溶点的溶剂在乳液冷冻和亲油化的过程中也具有优点,因为在这些条件下这些溶剂会快速固化,所以可以增强所得到的微粒造影剂的结构完整性。
如上指出的,乳化优选在表面活性剂存在下进行。这些乳化剂和/或任何其它添加剂,例如前面讨论过的,可方便地预先溶于水溶液相。
在相除去之前,可以将乳液过滤和/或挤压,例如通过适宜大小的孔的喷咀或一或多种膜,以增加最终获得的微粒和/或微球的大小分布的均匀性。
本发明的造影剂可以干的形式贮存和运输,在这种条件下它们通常可长期稳定,在服用前同适宜的液体载体(例如注射用消毒水、生理盐水或磷酸盐缓冲液)混合。根据应用的精确性质,用这种方法,可任意改变注射或服用造影剂的浓度。也可以将造影剂贮存在这些载体的悬浮液中,只要没有酯酶存在,在水溶液介质中它们是非常稳定的。
含有如前面所讨论的通式(II)重复单元的聚合物本身也是新的产品,构成本发明的又一个特点。除可以用作制备本发明的造影剂的原料外这些聚合物还可用作或用于,例如外科植入,如缝线、软组织修复、海绵、薄膜(例如人造皮)、伤口敷料(例如水凝胶片)、柔软的板材和制品,如由其形成的容器、药物和农用化学品缓释制剂。
这些新聚合物可通过任何方便的方法制备。例如,在适宜的有机溶剂中通过活性衍生物,如通式HOOC·(CH2)bCOOH的二元酸的二酰卤(式中b如前述定义的)同通式
HO.(CH2)a.CO.O.CH(CH3).O.CO.(CH2)a.OH的二醇(式中a如在前面定义的)进行反应。二醇本身可以通过偏卤乙烯,如偏碘乙烯同两摩尔的ω-羟基酸HO·(CH2)a·COOH在碱存在下进行反应制得。
下面非限制性的实施例用于说明本发明。
实施例1-中间体的制备
a)双(16-羟基十六酸)亚乙基酯
在溶于二甲基甲酰胺(150毫升)的16-羟基十六酸(4.90克,0.018摩尔)中加入1,8-重氮二环[5.4.0]十一烯-7(1,5-5)(DBU)(2.74克,0.018摩尔)。搅拌5分钟后,加入偏碘乙烯(2.54克,0.009摩尔),此混合物在搅拌下在40℃留置3天。将反应混合物冷至20℃,当沉淀完全(2小时)后,过滤分离沉淀的单体,此单体用活性碳处理,从二氯甲烷中重结晶两次,得到1.03克(20%)标题化合物。差示扫描量热法(SDC)指出,开始熔点为88.93℃。
1H NMR(200MHz,CDCl3):δ1.25(s,44H,CH2),1.45(d,3H,CH3CH),1.56(m,8H,CH2),2.30(t,4H,CH2CO),3.63(t,4H,2×CH2O),6.86(q,1H,CHCH3).13C NMR(50MHz,CDCl3):δ20.86,25.91,26.98,30.22,30.44,30.67,30.84,34.00,35.30,64.00,89.00,171.77(C=O).
b)双[16-(5-氯代羰基戊酰氧)-十六酸]亚乙基酯
在装有迴流冷凝器、玻璃的气体导入管和均压化滴液漏斗的三颈圆底烧瓶中加入溶于无水氯仿(15毫升)中的新蒸馏的己二酰氯(2.60毫升,17.50毫摩尔)中。将温度升至约50℃,在温和的氮气流通过溶液下,滴加溶于无水氯仿(30毫升)的双(16-羟基十六酸)亚乙基酯(1.0克,1.75毫摩尔)的溶液,加入后再保持此温度3小时。然后将混合物冷至室温并迅速转移到装有减压蒸馏装置的50毫升的圆底烧瓶中。在常温下首先蒸馏出氯仿,然后建立油泵真空,在约75℃,5毫巴压力下蒸出过量的己二酰氯,留下的是标题化合物(1.56克)。
c)16-十六酰氧十六酸
将16-羟基十六酸(5.43克19.9毫摩尔)溶于四氢呋喃(190毫升)中,加入吡啶(2.36克,29.9毫摩尔)。将棕榈酰氯(5.48克,19.9毫摩尔)溶于四氢呋喃(10毫升)中并在室温下滴加。在室温下搅拌16小时后,将混合物过滤,在减压下蒸发滤液。将残留物溶于氯仿中,用水洗(3×50毫升),干燥有机相(用MgSO4)。经减压蒸发后,在硅胶柱上将残留物纯化,用渐增甲醇浓度的氯仿(氯仿中的甲醇由1%-2%)洗脱,得到8.41克(83%)的标题化合物。
1H NMR(300MHz,CDCl3):δ0.85(t,3H,CH3),1.20-1.35(s,46H,-CH2-),1.55-1.70(m,6H,-CH2-),2.25(t,2H,-CH2-C(O)-O),2.45(t,2H,-CH2-COOH),4.05(t,2H,-O-CH2).13C NMR(75MHz,CDCl3):δ14.01,22.57.,24.10,24.91,25.82,28.53,28.75,28.94,29.08,29.15,29.25,29.36,29.54,31.81,34.29,35.16,64.27,76.48,76.90,77.10,77.32,169.50,173.91.
d)16-十六酰氧十六酰氯
将在上面(c)中制备的16-十六酰氧十六酸(7.73克15.13毫摩尔)溶于四氢呋喃(140毫升)中,并逐滴加入草酰氯(4.80克,37.83毫摩尔)。在室温下将混合物搅拌3天。然后在减压下蒸发溶剂和未反应的草酰氯,得到8.0克(100%)的标题化合物。
e)16-羟基十六酸1-[16-(16-十六酰氧十六酰氧)-十六酰氧]乙酯
将双(16-羟基十六酸)亚乙基酯(4.38克,7.67毫摩尔)溶于四氢呋喃(80毫升)中,加入吡啶(0.61克,7.71毫摩尔)。将16-十六酰氧十六酰氯(4.18克,7.90毫摩尔)溶于四氢呋喃(20毫升)中并逐滴加入。在室温3天后,过滤混合物,将滤液置于-20℃2小时。将沉淀的产品滤出,用急骤色谱纯化(硅胶,氯仿),得到2.4克(29%)的标题化合物。 1H NMR(300MHz,CDCl3):δ0.85(t,3H,CH3),1.2-1.4(s,90H,-CH2-),1.45(d,3H,-O-CH(CH3)-O-),1.5-1.7(m,14H,-CH2-),2.25(m,8H,-CH2-C(O)-O-),3.60(t,2H,-CH2-OH),4.05(t,4H,-C(O)-O-CH2-),6.85(q,1H,-O-CH(CH3)-O-).13C NMR(75MHz,CDCl3):δ13.7,19.1,22.2,24.2,24.6,25.2,25.5,28.2,28.5,28.7,28.8,29.0,29.2,31.5,32.3,33.7,34.0,62.5,64.0,88.0,171.5,173.5.
f)甲氧基封端的聚乙二醇(PEGS)的制备,典型聚合物(MeO-PEG2000)的制备
在惰性气氛下,将金属钾(0.400克,10.23毫摩尔)小心加到甲醇(1.300克,40.57毫摩尔)中以制备引发剂溶液。将这种引发剂溶液的一部分(0.220克,1.32毫摩尔甲醇钾)注入含环氧乙烷(10,000克,227.0毫摩尔)的安瓿中。将封好的安瓿在室温下静置过夜。然后将温度升至60℃,使反应进行72小时。除去未反应的单体后,将安瓿中的内容物溶于二氯甲烷,用稀的盐酸水溶液中和此溶液。用蒸馏水将聚合物溶液洗3次,经旋转蒸发,然后真空干燥。MeO-PEG聚合物的说明。1H-核磁共振:δ2.7(OH),3.2(OCH3),3.5(-CH2-主链),3.4(-CH2OCH3)。13C-核磁共振:δ58.5(-O-CH3),61.2(-CH2OH),70.5(-CH2-主链),71.3(-CH2OCH3),72.2(-CH2CH2OH)。在四氢呋喃记录了GPC(凝胶透过色谱),通过PEG标准校准了分子量分布。典型试样的GPC数据:MP:2679,Mn:2012,Mw:2283。多分散性:1.135。
g)甲氧基PEG氯代甲酸酯的一般制法
将PEG2000单甲基醚(6.00克,3.00毫升)溶于甲苯(50毫升)中,在迪安斯塔克(Dean Stavk)装置中通过回流进行干燥。在室温下加入吡啶(0.24克,3.00毫摩尔)。将氯代甲酸三氯甲基酯(“diphosgene”)(0.60克,3.00毫摩尔)溶于甲苯(10毫升)中,并逐滴加入。将混合物在室温下搅拌12小时并过滤。在减压下蒸发溶剂,得到定量产率的标题化合物。实施例2-聚合物和乳化剂的制备
a)由双(16-羟基十六酸)亚乙基酯和己二酰氯制备的聚合物
将己二酰氯(0.48克,2.6毫摩尔)在二甲苯/三氯乙烯(80∶20V/V,5毫升)的溶液在60℃加到上面实施例1(a)得到的双(16-羟基十六酸)亚乙基酯(1.48克,2.6毫摩尔)在二甲苯/三氯乙烯(80∶20V/V,100毫升)的溶液中。在60℃减压(147毫巴)2天后,将反应混合物冷却到20℃。在减压下蒸去溶剂,将得到的聚合物溶于氯仿中,在己烷中重新沉淀并过滤,得到1.05克(60%)的白色粉状的标题化合物。大小排除色谱(SEC):Mn=39068,Mn=9442,Mg=48536,Mw/Mn=4.138(用苯乙烯作标准)。差示扫描量热法(DSC)指出,开始熔点为48.61℃, 1H NMR(200MHz,CDCl3):δ1.28(s,44H,CH2),1.45(d,3H,CH3CH),1.62(m,12H,CH2),2.32(m,8H,CH2CO),4.02(t,4H,2×CH2O),6.88(q,1H,CHCH3)13C NMR(50MHz,CDCl3):δ 20.85,25.64,25.68,25.89,27.16,29.84,30.15,30.21,30.44,30.81,35.08,35.12,35.27,65.45,88.98,171.77(C=O),173.41(C=O).
b)PEG1500,己二酰氯和双(16-羟基十六酸)亚乙基酯(6.37∶1.85∶1.75)多嵌段随机链增量聚合物
在室温下,将新蒸馏的己二酰氯(270微升,1.85毫摩尔)加到双(16-羟基十六酸)亚乙基酯(1.0克,1.75毫摩尔)在二甲氧基乙烷(10毫升)的悬浮液中。将混合物的温度逐渐升至60℃,得到无色的溶液。在此温度5小时后,加入PEG1500(0.55克,0.37毫摩尔)。在混合物冷到室温之前,再继续加热17小时。蒸去溶剂,固体残余物在石油醚(沸点40-60℃)中搅拌15分钟,过滤后得到白色固体的标题化合物(1.30克)。
c)由PEG1500和双[16-(5-氯代羰基戊酰氧)-十六酸]亚乙基酯制备,增量聚合物(A-B-A)
在装有玻璃气体导入管和回流冷凝器的100毫升3颈圆底烧瓶中,将在实施例1(b)制备的双[16-(5-氯代羰基戊酰氧)-十六酸]亚乙基酯(0.88克,1.02毫摩尔)溶于甲苯(15毫升)中。加入PEG1500(3.06克,2.04毫摩尔),将混合物在60℃加热22小时,冷至室温,减压除去溶剂,得到白色蜡状标题化合物(4.12克)。
d)由PEG1500和双[16-(5-氯代羰基戊酰氧)十六酸]亚乙基酯制备增量聚合物(多嵌段)
如在实施例2(c)进行反应,但用溶于甲苯(20毫升)的双[16-(5-氯代羰基戊酰氧)-十六酸]亚乙基酯(1.02克,1.18毫摩尔)和PEG1500(1.77克,1.18毫摩尔),得到白色蜡状的标题化合物(2.29克)。
e-h)PEG、己二酸和双(16-羟基十六酸)亚乙基酯制备的增量聚合物(随机多嵌段)
在氮气下,用注射器将适当分子量的PEG(A)(2.07毫摩尔)在所述的溶剂(26毫升)中的溶液加到含双(16-羟基十六酸)亚乙基酯(B)(118毫克,0.207毫摩尔)的圆底烧瓶中。将所得到的混合物加热到60℃。当得到清亮的溶液后,用注射器加入己二酰氯(c)(417毫克,2.277毫摩尔)。减压到250毫巴,将溶液在60℃搅拌所述时间。在减压下和60℃在旋转蒸发器进行蒸馏3小时,然后在真空(<0.1毫米汞柱)和60℃下再蒸馏24小时,以除去剩下的在反应中放出的氯化氢和溶剂。最后,通过加入石油醚,并在冰浴中冷却2小时,聚合物从丙酮溶液中沉淀出来。经过滤后得3.5克白色蜡状固体聚合物。
在用这种方法制备的差别在于原料PEG的分子量不同的全部四种不同的嵌段聚合物中,每种聚合所用的专利条件在下面表1中列出。这些聚合物的13C NMR-和1H NMR谱与所期望的产品是相符合的。
表I
项目 | 原料PEG的分子量 | 摩尔比A∶B∶C | 溶剂 | 反应时间(小时) |
e | 400 | 10∶1∶11 | 二甘醇二甲醚-二甲苯 | 21 |
f | 600 | 10∶1∶11 | 二甘醇二甲醚 | 24 |
g | 1500 | 10∶1∶11 | 二甲氧基乙烷 | 21 |
h | 2000 | 10∶1∶11 | 1,1,2-三氯乙烯 | 92 |
1)字母是指在上面正文中规定的反应物
i)PEG 2300甲基醚16-十六酰氧十六酸酯
将PEG2300甲基醚(10.000克,4.35毫摩尔)溶于四氢呋喃(90毫升)中,加入吡啶(0.413克,5.22毫摩尔)。将16-十六酰氧十六酰氯(2.301克,4.35毫摩尔)溶于四氢呋喃(10毫升)中井逐滴加入。在室温下搅拌3天后,将混合物过滤,减压蒸去溶剂。残留物(12.08克)在硅胶柱上纯化,用甲醇浓度渐增的氯仿(甲醇在氯仿中的浓度由1%到3%)洗脱,得到5.20克(43%)的标题化合物。
1H NMR(300MHz,CDCl3):δ0.80-0.87(m,CH3),1.21(s,(br),CH2),1.53-1.62(m,CH2),2.20-2.35(m,CH2CO),3.34(s,CH3O),3.6l(s,OCH2CH2O),4.02(t,COOCH2CH2O),4.19(t,COOCH2CH2O).13C NMR(75MHz,CDCl3):δ13.95,22.49,24.71,24.83,25.74,28.45,28.95,29.07,29.16,29.28,29.34,29.40,29.46,31.72,34.05,34.21,58.85,63.15,64.19,69.01,70.37,71.73,173.64,173.82.
j)PEG5000甲基醚16-十六酰氧十六酸酯
将PEG5000甲醚(7.500克,1.50毫摩尔)溶于甲苯(90毫升)中并在迪安斯塔克装置中回流干燥.加入吡啶(0.143克,1.80毫摩尔),随后加入(逐滴)溶于甲苯(10毫升)的16-十六酰氧十六酰氧(1.191克,2.25毫摩尔)。将混合物加热到回流,在回流下搅拌3天后,将混合物冷至室温:在己烷中沉淀。过滤后,用己烷洗沉淀,并干燥(MgSO4)。减压蒸发后,将残留物在硅胶上纯化,用甲醇浓度渐增的氯仿溶液(甲醇在氯仿中的浓度由1%到3%)洗脱,得到5.93克(72%)的标题化合物。 1H NMR(300MHz,CDCl3):δ0.82-0.86(m,CH3),1.22(s,(br),CH2),1.53-1.62(m,CH2),2.20-2.35(m,CH2CO),3.34(s,CH3O),3.61(s,OCH2CH2O),4.01(t,COOCH2CH2O),4.18(t,COOCH2O).13C NMR(75MHz,CDCl3):δ13.66,22.21,24.43,24.54,25.46,28.17,28.67,28.79,28.87,28.99,29.06,29.11,29.17,31.44,33.73,33.93,58.57,62.87,63.90,68.72,69.62,69.86,70.09,71.45,76.85,173.35,173.53.
k)PEG10000甲基醚16-十六酰氧十六酸酯
将PEG10000甲基醚(7.500克,0.75毫摩尔)溶于甲苯(140毫升),并加入吡啶(0.107克,1.35毫摩尔)。将溶液加热到60℃,将溶于甲苯(10毫升)的16-十六酰氧十六酰氯(0.595克,1.12毫摩尔)逐滴加入。加热混合物到回流,并在回流下搅拌3天后,将混合物冷至室温,在己烷中沉淀。过滤后,用己烷洗沉淀,并干燥。用急骤色谱法在硅胶柱上纯化,用5%甲醇的氯仿溶液洗脱,得到5.39克(68%)的标题化合物。 1H NMR(300MHz,CDCl3):δ0.84(t,CH3),1.21(s,(br),CH2),1.55-1.60(m,CH2),2.20-2.35(m,CH2CO),3.34(s,CH3O),3.61(s,OCH2CH2O),4.01(t,COOCH2CH2O),4.18(t,COOCH2CH2O).13C NMR(75MHz,CDCl3):δ13.94,22.48,24.70,24.82,25.73,28.94,29.05,29.14,29.26,29.33,29.39,29.45,31.71,34.00,58.84,63.14,68.99,69.36,69.86,69.97,70.01,70.36,70.74,70.82,70.86,71.72,77.10,173.62,173.80.
l)16-[ω-甲氧基-PEG2000-羰氧基]十六酸1-[16-(16-十六酰氧十六酰氧)-十六酰氧]乙基酯
将甲氧基PEG2000氯代甲酸酯(1.90克,0.95毫摩尔)溶于甲苯(90毫升)中,加入吡啶(0.09克,1.13毫摩尔)。将16-羟基十六酸1[[16-(16-十六酰氧-十六酰氧)十六酰氧]乙酯(1.00克,0.95毫摩尔)溶于甲苯(10毫升)中并逐滴加入。将混合物加热到回流。在回流下搅拌10小时后,冷却混合物到室温并过滤。在减压下将溶剂蒸发,残留物在硅胶柱上用含2%甲醇的氯仿纯化,得到1.00克(35%)的标题化合物。
1H-NMR(300MHz,CDCl3):δ0.85(t,CH3),1.20-1.33(m,CH2),1.45(d,-O-CH(CH3)-O),1.5-1.7(m,CH2),2.0(H2O),2.2-2.3(m,-CH2-C(O)-O),3.35(s,CH3-O-),3.5-3.7(s,-OCH2CH2O-),4.03(t,-C(O)-O-CH2-),4.10(t,-CH2-O-C(O)-O-),4.26(m,-O-C(O)-O-CH2-CH2-O-)6.8-6.9(q,-O-CH(CH3)-O).13C-NMR(75MHz,CDCl3):δ13.7,19.2,22.1,24.2,24.6,25.2,25.5,28.2-29.2,31.5,33.9,34.0,58.7,64.0,66.3,67.9,68.5,70.0,71.5,87.9,171.5,173.7.
m)16[a-甲氧基PEG5000羰氧基]-六酸1-[16-(16-十六酰氧十六酰氧)-十六酰氧]乙酯
将甲氧基PEG5000氯代甲酸酯(8.50克,1.70毫摩尔)溶于甲苯(90毫升)中并加入吡啶(0.146克,1.85毫摩尔)。将16-羟基十六酸1-[16-(16-十六酰氧十六酰氧)十六酰氧]乙酯(1.79克,1.70毫摩尔)溶于甲苯(10毫升)中,并逐滴加入。将混合物加热至回流,在回流下搅拌3天后,混合物冷至室温并过滤。减压蒸去溶剂,残留物在硅胶柱上纯化,用含渐增浓度甲醇的氯仿溶液(甲醇在氯仿中的溶度由3%到5%)洗脱,得到3.90克(38%)的标题化合物,
1H-NMR(300MHz,CDCl3):δ0.85(t,CH3),1.20-1.33(m,CH2),1.45(d,-O-CH(CH3)-O),1.5-1.7(m,CH2),1.8(H2O),2.2-2.3(m,-CH2-C(O)-O),3.35(s,CH3-O-),3.5-3.7(s,-OCH2CH2O-),4.03(t,-C(O)-O-CH2-),4.10(t,-CH2-O-C(O)-O-),4.26(m,-O-C(O)-O-CH2-CH2-O-),6.8-6.9(q,-O-CH(CH3)-O).
n)16-[ω-甲氧基PEG10000羰氧]十六酸1-[16-(16-十六酰氧十六酰氧)十六酰氧]乙酯
将甲氧基PEG10000氯代甲酸酯(7.50克,0.75毫摩尔)溶于甲苯(90毫升)中,并加入吡啶(0.063克,0.80毫摩尔)。将16-羟基十六酸1-[16-(16-十六酰氧十六酰氧)十六酰氧]乙酯(0.79克,0.75毫摩尔)溶于甲苯(10毫升)中并逐滴加入。将混合物加热至回流,在回流下搅拌3天后,将混合物冷至室温,并过滤。在减压下蒸去溶剂,残留物在硅胶柱上提纯化,用渐增浓度的甲醇在氯仿中的溶液(甲醇在氯仿中的浓度由3%到5%)洗脱,得到1.60克(19%)的标题化合物。
1H-NMR(300MHz,CDCl3):δ0.85(t,CH3),1.20-1.33(m,CH2),1.45(d,-O-CH(CH3)-O),1.5-1.7(m,CH2),2.2-2.3(m,-CH2-C(O)-O),3.35(s,CH3-O-),3.5-3.7(s,-OCH2CH2O-),4.03(t,-C(O)-O-CH2),4.10(t,-CH2-O-C(O)-O-),4.26(m,-O-C(O)-O-CH2-CH2-O-),6.8-6.9(q,-O-CH(CH3)-O).实施例3-聚合物颗粒的制备
a)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物的颗粒
在30毫升人血清白蛋白溶于水中的5%重量的溶液中,加入10毫升的实施例2(a)中的聚合物在甲苯中的5%重量/体积(W/V)溶液。用Ultra TuraxT25混合器在20,000转/分钟速度下将两相混合1分钟,在干水/甲醇浴上冷冻并亲液化18小时,得到微黄色粉末。光学显微镜指出生成微粒。
b)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物的颗粒
在30毫升的人血清白蛋白在水中的5%重量溶液中,加入10毫升的实施例2(a)的聚合物在对-二甲苯中的10%(重量/体积)溶液。将混合物用Ultra TuraxT25混合器在20,000转/分钟速度下混合1分钟30秒,在干冰/甲醇浴上冷冻并亲液化18小时,得到白色粉末。光学显微镜证明生成微粒。
c)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物的颗粒
在30毫升的改性淀粉(Lyckeby,瑞典,PU-24,000)在水中的5%重量溶液中,加入10毫升的实施例2(a)的聚合物在对-二甲苯中的5%(重量/体积)溶液。用Ultra TuraxT25混合器在20,000转/分钟速度下将混合物混合1分30秒,在干冰/甲醇浴上冷冻,亲液化18小时,得到白色粉末。光学显微镜证明生成微粒。
d)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物的颗粒
在30毫升的聚乙烯醇在水中的0.8%重量的溶液中,加入10毫升实施例2(a)的聚合物在对-二甲苯中的5%(重量/体积)溶液。用Ultra TuraxT25混合器在20,000转/分钟速度将混合物混合1分钟,在干冰/甲醇浴上冷冻,亲液化18小时,得到白色粉末。光学显微镜证明生成微粒。
e)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物的颗粒
在30毫升的明胶在水中的1%重量溶液中,加入10毫升的实施例2(a)的聚合物在对-二甲苯的5%(重量/体积)溶液。用Ultra TuraxT25混合器在20,000转/分钟速度下将混合物混合1分钟,在于冰/甲醇浴上冷冻,亲液化18小时,得到白色粉末。光学显微镜证明生成微粒。
f)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物的颗粒
保持在60℃下的15毫升的人血清白蛋白在水中的5%重量的溶液中,在加入相同温度下的5毫升的由实施例2(a)的聚合物在(-)莰烯中的5%(重量/体积)的溶液。用-Ultra TuraxT25混合器在20,000转/分钟速度下将混合物热混合1分钟,在干冰/甲醇浴上冷冻,亲液化48小时,得到白色粉末。光学显微镜证明生成微粒。
g-n)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的用嵌段共聚物稳定在分散液中的聚合物的颗粒
一般描述
将保持在60℃的10毫升的由实施例2(a)的聚合物在(-)-莰烯中的5%(重量/体积)溶液,加入到在相同温度下的30毫升的上面实施例2的嵌段共聚物(表2)的水溶液中,嵌段共聚物的浓度列于表2中。用转子/定子混合器(Ultra TuraxT25)以慢速将混合物混合几分钟,在于冰/甲醇上冷冻,并亲液化48小时,得到白色粉末。
表2
实施例3 | 实施例2的嵌段共聚物 | 浓度[%重量/重量] |
g | 2d | 1 |
h | 2d | 2 |
i | 2h | 1 |
j | 2h | 2 |
k | 2j | 1 |
l | 2k | 1 |
m | 2l | 2 |
n | 2n | 2 |
o)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物的颗粒
将保持在70℃的16毫升的实施例2(a)的聚合物在(-)-莰烯中的3%(重量/体积)溶液加入到相同温度下的64毫升的含1%(重量/体积)的实施例2(k)的嵌段共聚物和5%(重量/体积)的PEG3000的水溶液中。用转子/定子混合器将混合物以中速混合达5分钟,在干冰/甲醇浴上冷冻,并亲液化48小时,得到白色粉末。在实验室摇动器上将干产品以10毫克干物质/毫升的浓度分散在盐水溶液中。
p)双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物颗粒
重复实施例3(o)的方法,但用环辛烷代替(-)-莰烯作有机溶剂。
q)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物的颗粒
重复实施例3(o)的方法,但用环己烷代替(-)-莰烯作有机溶剂。
r)由双(16-羟基十六酸)亚乙基酯和己二酰氯制得的聚合物的颗粒
重复实施例3(o)的方法,但是,乳化的实施是在60℃,用28毫升的实施例2(a)的聚合物在(-)-莰烯中的7.5%(重量/体积)溶液和62毫升的含2%(重量/体积)的实施例2(k)的聚合物的水溶液进行的。
实施例4-声学特性
一般方法
通过在一实验室摇动器上振动12-16小时,将按照上述实施例3制备的聚合物颗粒的干粉重新分散成10毫克/毫升的干物质在Milliq水中。用光学显微镜的检验证明,生成颗粒的分散液。这些颗粒极易漂浮,如对含气体颗粒所预期的。
在试管内的声学效应
在脉冲反射方法中,用3.5兆赫芝宽谱带能量转换器通过测量在水溶液载液的不同浓度溶液中超声传输可得到上述制备的悬浮淮的声学效应。水溶液载液用作参考,对用载液一系列稀释液进行,上到信号降低到约3-5分贝/厘米。给出了需要得到衰减8分贝/厘米的浓度(表3);因此,低值表示良好的造影效应。所得到的声学效应在指明,产品可以预期用作超声造影剂。按照理论考虑,相同大小和在相同稀释度的固体(相对于含气体的)颗粒应给出小于0.1分贝/厘米的声学衰减。
表3
上述实施例3颗粒的声学测量。
在表3第3列给出了声学测量中得到8分贝/厘米的造影效应的浓度,即饱和信号的半值。在高浓度,信号强度增加直到观测到饱和。
表3
实施例4 | 实施例的颗粒 | 在8分贝/厘米的颗粒浓度[毫克/毫升] |
a | 3a | 1.0 |
b | 3b | 0.12 |
c | 3c | 0.03 |
d | 3d | 0.16 |
e | 3e | 0.35 |
f | 3f | 0.15 |
g | 3g | 0.04 |
h | 3h | 0.02 |
I | 3I | 0.02 |
j | 3j | 0.02 |
k | 3k | 0.03 |
l | 3l | 0.01 |
m | 3m | 0.09 |
n | 3n | 0.08 |
实施例5-在活体中的特性
如上面实施例3(a)-(f)讨论的而制备的聚合物颗粒粉末通过一实验室摇动器摇动12-16小时重新分散在无菌的0.9%(重量/体积)NaCl(水)溶液中,将此分散液注入狗的腿部静脉中,使用Vingmed SoundCFM750超声扫描器在5MH3得到短的坐标经胸廓的心回声成象。成象片断贮存在视频仪上。颗粒的分散在两心室都引起很清楚的造影增强,也引起了相当的心肌造影增强(MCE),在活的视频结果上可见到。在前和后壁部显示了MCE。造影效应的延续说明,在注射后颗粒分散液在活体循环达几分钟,心肌造影的存在和造影持续时间长说明,在活体的稳定性是很好的。
Claims (23)
2.权利要求1的造影剂,其中,a表示13-17中的一整数,b表示3-6中的一个整数。
3.权利要求1的造影剂,其中,a是15,b是4。
4.权利要求1-3中任一项的造影剂,加入一种或多种添加剂,这些添加剂选自乳化剂,涂料,增塑剂,填充剂,低温防护剂和抗氧剂。
5.权利要求4的造影剂,加入一种选自脂肪酸、脂肪酸的碳水化合物酯、脂肪酸三甘油酯,蛋白质、磷脂、聚糖和表面活性聚合物作为乳化剂。
6.权利要求5的造影剂,其中,乳化剂是人血清白蛋白,改性淀粉或明胶。
7.权利要求5的造影剂,其中,乳化剂是聚乙烯醇或嵌段共聚物/增量聚合物。
8.权利要求7的造影剂,其中,嵌段共聚物/增量聚合物含有聚乙二醇单元作为亲水嵌段,在疏水部分含有通式(III):
-Ra-(CH2)a-CO-O-CH(CH3)-O-CO-(CH2)a-Rb (III)的单元作为增量部分或作为低聚或聚合嵌段,式中a如权利要求1中所定义的,Ra和Rb每个选自羰基和通式-O-CO-(CH2)b-CO-O-基团,式中b如权利要求1所定义的。
9.权利要求7的造影剂,其中,乳化剂是含有用含两个或多个脂肪酸链的疏水部分酰化的甲氧基封端的聚乙二醇亲水嵌段的增量聚合物。
10.权利要求9的造影剂,其中,疏水部分是酰氧酰基。
11.权利要求10的造影剂,其中,疏水部分是16-十六酰氧十六酰基。
12.制备权利要求1的造影剂的方法,此法包含在含权利要求1所定义的通式(II)重复单元的生物降解聚合物中加入一种气体,以形成聚合物微粒和/或微球。
13.权利要求12的方法,此方法包括在水溶液相中乳化聚合物在水-不混溶有机溶剂中的溶液,此后在要加入的气体中除去有机溶剂。
14.权利要求12的方法,此方法包括在水溶液相中乳化聚合物在水-不混溶有机溶剂中的溶液,此后在要加入的气体中除去有机溶剂和水溶液相。
15.权利要求13或14的方法,其中,水溶液相含有权利要求5-11中任何一项定义的乳化剂。
16.权利要求13或14定义的方法,其中,在除去溶剂之前,将乳液过滤和/或挤压。
17.由权利要求1定义的通式(II)重复单元组成的生物降解聚合物。
18.权利要求17的生物降解聚合物,其中,a表示13-17中的一个整数,b表示3-6中的一个整数。
19.权利要求17的生物降解聚合物,其中,a是15,b是4。
20.含有权利要求17-19中任何一项的聚合物的外科植入物、软组织修复、海绵、薄膜、伤口敷料、柔软板、容器、医学或农业用延迟释放配剂、颗粒显影剂或增塑剂。
21.权利要求17-19中任一项的聚合物在制备用于诊断成像的造影剂中的用途。
22.权利要求21的用途,用于制备超声或核磁共振成像的造影剂。
23.制备权利要求17的聚合物的方法,此方法包含使以下通式的二元酸的活性衍生物,
HOOC·(CH2)b·COOH式中b是权利要求1所定义的,同通式为
HO·(CH2)a·CO·O·CH(CH3)·O·CO·(CH2)a·OH的二元醇进行反应,式中a如权利要求1所定义的。
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CN95194934A Expired - Fee Related CN1079266C (zh) | 1994-09-06 | 1995-09-06 | 造影剂及其改进 |
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US (1) | US5990263A (zh) |
EP (1) | EP0779821B1 (zh) |
JP (1) | JP3843327B2 (zh) |
CN (1) | CN1079266C (zh) |
AT (1) | ATE214948T1 (zh) |
AU (1) | AU701907B2 (zh) |
BR (1) | BR9508888A (zh) |
CA (1) | CA2199047A1 (zh) |
CZ (1) | CZ69497A3 (zh) |
DE (1) | DE69526093T2 (zh) |
ES (1) | ES2174958T3 (zh) |
GB (1) | GB9417941D0 (zh) |
HU (1) | HUT77368A (zh) |
IL (1) | IL115181A (zh) |
NO (1) | NO313270B1 (zh) |
WO (1) | WO1996007434A1 (zh) |
ZA (1) | ZA957471B (zh) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
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GB9624548D0 (en) * | 1996-11-25 | 1997-01-15 | Nycomed Imaging As | Improvements in or relating to surfactants |
GB9701237D0 (en) * | 1997-01-22 | 1997-03-12 | Nycomed Imaging As | Improvements in or relating to contrast agents |
US6054118A (en) * | 1997-01-22 | 2000-04-25 | Nycomed Imaging As | Contrast agents comprising two types of gas-containing microparticles |
IT1298269B1 (it) * | 1998-02-18 | 1999-12-20 | Promefarm S R L | Uso di un polietilenglicole come mezzo di contrasto in ecografia |
WO1999052564A1 (en) * | 1998-04-09 | 1999-10-21 | Nycomed Imaging A.S | Method |
GB9822158D0 (en) * | 1998-10-09 | 1998-12-02 | Nycomed Imaging As | Compositions |
EP1289565B1 (en) | 2000-06-02 | 2015-04-22 | Bracco Suisse SA | Compounds for targeting endothelial cells |
US6962071B2 (en) * | 2001-04-06 | 2005-11-08 | Bracco Research S.A. | Method for improved measurement of local physical parameters in a fluid-filled cavity |
CA2513044A1 (en) | 2002-03-01 | 2004-08-05 | Dyax Corp. | Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy |
US8623822B2 (en) | 2002-03-01 | 2014-01-07 | Bracco Suisse Sa | KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy |
US7261876B2 (en) | 2002-03-01 | 2007-08-28 | Bracco International Bv | Multivalent constructs for therapeutic and diagnostic applications |
US7211240B2 (en) | 2002-03-01 | 2007-05-01 | Bracco International B.V. | Multivalent constructs for therapeutic and diagnostic applications |
US7794693B2 (en) | 2002-03-01 | 2010-09-14 | Bracco International B.V. | Targeting vector-phospholipid conjugates |
CA2477836A1 (en) | 2002-03-01 | 2003-09-12 | Dyax Corp. | Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy |
CN100374165C (zh) | 2003-02-04 | 2008-03-12 | 伯拉考国际股份公司 | 超声造影剂及其制备方法 |
CA2517939C (en) | 2003-03-03 | 2015-11-24 | Dyax Corp. | Peptides that specifically bind hgf receptor (cmet) and uses thereof |
WO2004097017A2 (en) | 2003-04-29 | 2004-11-11 | Avi Biopharma, Inc. | Compositions for enhancing transport and antisense efficacy of nucleic acid analog into cells |
JP5513708B2 (ja) | 2003-12-22 | 2014-06-04 | ブラッコ・シュイス・ソシエテ・アノニム | 造影イメージング用の気体封入マイクロベシクル・アセンブリー |
US7025726B2 (en) | 2004-01-22 | 2006-04-11 | The Regents Of The University Of Nebraska | Detection of endothelial dysfunction by ultrasonic imaging |
WO2006018433A1 (en) * | 2004-08-18 | 2006-02-23 | Bracco Research Sa | Gas-filled microvesicles composition for contrast imaging |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1993017718A1 (en) * | 1992-03-06 | 1993-09-16 | Nycomed Imaging A/S | Improvements in or relating to contrast agents |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4004430A1 (de) * | 1990-02-09 | 1991-08-14 | Schering Ag | Aus polyaldehyden aufgebaute kontrastmittel |
AU636481B2 (en) * | 1990-05-18 | 1993-04-29 | Bracco International B.V. | Polymeric gas or air filled microballoons usable as suspensions in liquid carriers for ultrasonic echography |
PH31064A (en) * | 1990-09-07 | 1998-02-05 | Nycomed As Of Nycoveten | Polymers containing diester units. |
DE4100470A1 (de) * | 1991-01-09 | 1992-07-16 | Byk Gulden Lomberg Chem Fab | Echokontrastmittel |
GB9106673D0 (en) * | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
GB9106686D0 (en) * | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
CA2078388A1 (en) * | 1991-10-02 | 1993-04-03 | Mridula Nair | Biocompatible emulsion particles |
US5674468A (en) * | 1992-03-06 | 1997-10-07 | Nycomed Imaging As | Contrast agents comprising gas-containing or gas-generating polymer microparticles or microballoons |
GB9204918D0 (en) * | 1992-03-06 | 1992-04-22 | Nycomed As | Chemical compounds |
DE4219723A1 (de) * | 1992-06-13 | 1993-12-16 | Schering Ag | Mikropartikel, Verfahren zu deren Herstellung, sowie die Verwendung dieser in der Diagnostik |
GB9318288D0 (en) * | 1993-09-03 | 1993-10-20 | Nycomed Imaging As | Improvements in or relating to contrast agents |
GB9402867D0 (en) * | 1994-02-15 | 1994-04-06 | Nycomed Imaging As | Improvements in or relating to contrast agents |
-
1994
- 1994-09-06 GB GB9417941A patent/GB9417941D0/en active Pending
-
1995
- 1995-09-06 HU HU9702178A patent/HUT77368A/hu unknown
- 1995-09-06 IL IL11518195A patent/IL115181A/xx not_active IP Right Cessation
- 1995-09-06 CA CA002199047A patent/CA2199047A1/en not_active Abandoned
- 1995-09-06 WO PCT/GB1995/002109 patent/WO1996007434A1/en active IP Right Grant
- 1995-09-06 ES ES95930653T patent/ES2174958T3/es not_active Expired - Lifetime
- 1995-09-06 ZA ZA957471A patent/ZA957471B/xx unknown
- 1995-09-06 CZ CZ97694A patent/CZ69497A3/cs unknown
- 1995-09-06 DE DE69526093T patent/DE69526093T2/de not_active Expired - Fee Related
- 1995-09-06 AU AU33966/95A patent/AU701907B2/en not_active Ceased
- 1995-09-06 CN CN95194934A patent/CN1079266C/zh not_active Expired - Fee Related
- 1995-09-06 AT AT95930653T patent/ATE214948T1/de not_active IP Right Cessation
- 1995-09-06 EP EP95930653A patent/EP0779821B1/en not_active Expired - Lifetime
- 1995-09-06 BR BR9508888A patent/BR9508888A/pt not_active Application Discontinuation
- 1995-09-06 JP JP50931296A patent/JP3843327B2/ja not_active Expired - Fee Related
-
1996
- 1996-03-04 US US08/610,257 patent/US5990263A/en not_active Expired - Fee Related
-
1997
- 1997-03-04 NO NO19970995A patent/NO313270B1/no unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993017718A1 (en) * | 1992-03-06 | 1993-09-16 | Nycomed Imaging A/S | Improvements in or relating to contrast agents |
Also Published As
Publication number | Publication date |
---|---|
DE69526093D1 (de) | 2002-05-02 |
US5990263A (en) | 1999-11-23 |
ATE214948T1 (de) | 2002-04-15 |
IL115181A0 (en) | 1995-12-31 |
BR9508888A (pt) | 1997-12-30 |
NO970995L (no) | 1997-05-06 |
IL115181A (en) | 1999-11-30 |
NO970995D0 (no) | 1997-03-04 |
CN1157573A (zh) | 1997-08-20 |
NO313270B1 (no) | 2002-09-09 |
JPH10505082A (ja) | 1998-05-19 |
EP0779821B1 (en) | 2002-03-27 |
AU701907B2 (en) | 1999-02-11 |
HUT77368A (hu) | 1998-03-30 |
DE69526093T2 (de) | 2002-11-28 |
GB9417941D0 (en) | 1994-10-26 |
ES2174958T3 (es) | 2002-11-16 |
AU3396695A (en) | 1996-03-27 |
CA2199047A1 (en) | 1996-03-14 |
JP3843327B2 (ja) | 2006-11-08 |
EP0779821A1 (en) | 1997-06-25 |
ZA957471B (en) | 1996-07-08 |
WO1996007434A1 (en) | 1996-03-14 |
CZ69497A3 (en) | 1997-10-15 |
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