CN1119831A - 用作超声造影剂的相转变胶体 - Google Patents
用作超声造影剂的相转变胶体 Download PDFInfo
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- CN1119831A CN1119831A CN94191564A CN94191564A CN1119831A CN 1119831 A CN1119831 A CN 1119831A CN 94191564 A CN94191564 A CN 94191564A CN 94191564 A CN94191564 A CN 94191564A CN 1119831 A CN1119831 A CN 1119831A
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Abstract
超声诊断过程中的造影增强剂,含有液体-液体型(即乳剂或微乳剂)的胶态分散体,其中分散的液体相是一种沸点低于被成像动物体温的液体,因此在给予动物后,分散的液体相从分散液体相转变为高度回声的分散气体泡或kugelschaum。液态的分散相使得能制成极稳定的、粒径通常低于1000nm的可药用乳剂。体温下的气体状态产生高回声的微泡,直径低于10000nm,可有效地作为超声造影剂。描述了静脉、动脉、口服、腹膜内和子宫内剂量形式、给药方法和成像技术。
Description
相关申请
本申请是199 3年11月8日提交的未决申请S.N.08/148,284的部分继续申请。而后者是1993年1月25日提交的未决申请S.N.08/008,172的部分继续申请。
发明领域
本发明涉及用于生物医学的含有水性胶态分散体的造影剂。更具体地来说,本发明涉及液-液型乳剂,其中分散的液体经温度和压力的激活使分散液相转变为分散的气体形式,它在诊断中对超声能的反射是有效的。
发明背景
已有人描述过在超声诊断,包括超声波心动描记术中使用的各种造影例。在Ophir和Parker,Ultrasound in Med.& Biol(1989),15:319-333中有这方面的评述。这些造影剂产生的声学反向散射(与造影效果相关的典型特性)可归因于它们作为固体、液体或气体所拥有的独特性能。然而,固体和液体对声的反射程度相似,已知气体是更有效的并且在超声造影剂的开发中是优选的介质。
已知的液体超声造影剂包括乳剂和水性溶液。关于这些情况,上述评述的作者描述,“Fink等(1985)试验了使用某些类脂的水性赋型剂的液体乳剂的思路。不幸的是,在这些试验中未能观察到反向散射的增强。”
已知的固体造影剂包括胶原微球。然而,固-液介面弱的声学反向散射影响了他们的使用范围。
已知的气体造影剂包括将各种两亲物质加到水性介质或加入增加粘度的材料来稳定的微泡和或固体颗粒或脂质体形式的气体前体物。然而,脂质体仅含有水溶性气体并因此而限制了由它们所能形成的微泡的稳定性,这是因为许多能形成特别稳定微泡的化学物质的物理特性之一是与水的不混溶特性。固体颗粒必须在使用前即行配制,需要稀释制剂且必须立即使用,这是因为颗粒完全溶解后微泡很快就消失。本申请人的在先美国专利申请S.N.07/761,311涉及确定作为超声造影剂的各种气体的相对有用性的方法,并确定特别适用于此的气体。
已确定了一种研究方法,它注射沸点低于被研究的有机体沸点的液体来增强超声多普勒信号(Ziskin MC,Bonakdarpour A,Weinstein DP,Lynch PR:
Contrast Agents For Diagnostic Ultrasound.Investigative Radiology 7:500-505,1972)。在该研究方法中,将多种溶液或液体注射到狗的动脉中并在低于注射部位5cm处检测多普勒信号。该研究报道“在我们试验的所有试剂中乙醚产生了最大对比效果,它是一种在体温下强力沸腾的液体,所以起到了产生非常活跃的气泡的作用。”该报告进一步阐明“然而大剂量注射的乙醚是一种毒性物质。在我们的实验中证明,注射20mL即致死。”在该报告中没有讨论稳定所有适于以后用作超声造影剂的材料的方法。在最需要存在造影剂的地方,静脉给予非胶态乙醚时,毒性太大。
包括碳氟化合物的乳剂的生物相容性关系到安全的问题。例如,Clark等(Clark LC,Becattini F,Kaplan S:Can fluorocarbonemulsions be used as artificial blood?Triangle 11:115-122,1972)关于碳氟化合物的选择方面时述及“它们的蒸汽压范围为0到约640毫米汞柱,当然不能使用蒸汽压超过400毫米汞柱的那些物质,因为输入血流时,他们会沸腾。”后来在相同的文章中,他们述及“如果静脉给予蒸汽压超过50毫米汞柱的碳氟化合物,在几小时内会导致死亡,而开胸时发现肺没有萎陷。”整整二十年后,同一作者L.C.Clark报道了类似的结果“如果不能发现预防或阻止HNCL(高充气的非萎陷性肺)的实用方法,并且如果HNCL发生在其它种类中,那么只有沸点在150℃以上的碳氟化合物才可认为是安全的,”Clark CL,Hoffmann RE,Davis SL:Response of the rabbitlung as a criterion of safety for fluorocarbon breathingand blood substitutes,Biomat.,Art.Cells & Immob.Biotech.,20:1085-1099,1992。
液-液乳剂的稳定性存在另一个问题。关于乳剂的稳定性和从溶解性预见稳定性人们有了相当的见解;该理论被称为奥福成熟理论(Ostwald ripening theory)(Kabalnov AS,Shchukin ED;Ostwald Ripenina Theory:Applications To Fluorocarbon Emulsion Stability,Advances in Colloid and InterfaceScience,38:69-97,1992)。该文简单地描述了乳剂分散相液体在连续相中溶解性越强,乳剂稳定性越差。这些作者在25℃下试验了十二氟代戊烷乳剂的稳定性(Kabalnov AS,Makarov KN,Shcher-bakova OV:Salubility of fluorocarbons in water as a keyparameter determining fluorocarbon emulsion stability.JFluorine chemistry 50:271-284,1990)。他们确定他们的乳剂具有1.4×10-18cm2/S的奥福成熟率。将这种速率常数转变为有用的术语表明起始大小211nm的Kabalnow等的十二氟代戊烷乳剂的平均粒径以11nm/秒或660nm/分钟的速率增长。在这种颗粒增长速度下,该乳剂的贮存期限低于1分钟,所以难以成为商业产品。
因此,需要一种具有长的贮存期限的有效的超声造影剂组合物,它比较容易制造,且生物相容性好,使用方便。
发明概述
为了符合这些需要,本发明涉及稳定的液-液型胶态分散体。该胶体由液体分散相组成,该液体分散相的沸点低于需进行超声造影研究的生物体体温,通常约37-40℃。这些乳剂优选由沸点在-20到37℃的分散相液体组成。
优选的液体分散相选自脂族碳氢化合物、有机卤化物或醚或其混合物等化学物质,这些化学物质具有6或更少的碳原子并具有上限约为300的分子量。其中有机卤化物优选含氟的化学物质,因为他们形成稳定的乳剂并且毒性较低。特别优选的是正戊烷、异戊烷、新戊烷、环戊烷、丁烷、环丁烷、十氟丁烷、十二氟戊烷、十二氟新戊烷、全氟环戊烷及其混合物。胶态分散体优选含有浓度为0.05到5.0%w/v(重量/体积)的分散相。该浓度的最适宜范围为0.5到3.5%w/v。
可通过加入各种两亲物质来稳定该胶态分散体,这些两亲物质包括阴离子、非离子、阳离子和两性离子表面活性剂,它通常使分散液和水之间的界面张力降到低于26达因/厘米(dynes/cm)。这些物质最合适的是含有含氟表面活性剂的非离子合成表面活性剂混合物,如Zonyk商标系列和聚氧丙烯-聚氧乙烯乙二醇非离子嵌段共聚物。
胶态分散体的液体连续相包含水介质。该介质可含有各种有助于稳定分散相或有助于使制剂生物相容的添加剂。可接受的添加剂包括酸化剂、碱化剂、抗微生物防腐剂、抗氧剂、缓冲剂、螯合剂、悬浮和/或粘度增强剂,包括triodobenzene衍生物,如碘海醇或碘帕醇以及张力剂。优选包括pH、张力控制剂和粘度增强剂。最适宜的是用一种也增强粘度的试剂来使张力至少为250mOsm,如山梨糖醇或蔗糖。
一般来说,通过使用机械、手工或声能来将分散相的混悬物分散在连续相中而形成胶态分散体。将分散相凝缩成连续相也可。优选的方式是使用高压分散。
发明的详细描述
本发明涉及增强所产生的用于医学和兽医诊断的超声图像对比的试剂。这些试剂由生物相容的胶态分散体组成,其中分散相在制造过程的条件下是液体,而在给予被研究生物体时或约在给药时进行相转变而成为分散的气体或kugelschaum。
为了清楚且一致地了解本发明和权利要求,包括所给出的术语的范围,下面提供了涉及本发明的意义:
胶态分散体:具有至少一种液体或气体形态的物质(分散相)的体系,该物质不能混溶,微细地分散且均匀分散在至少一种第二种物质中,所述第二种物质构成分散介质或连续的液相。
生物相容:能在活的生物体中以可接受的方式实现其功能而没有过分的毒性或不适当的生理或药理作用。
液体:物质的状况,在这种状态下物质显示易流动性,不易分散或不分散且具有较高的不易压缩性。
气体:物质的状态,在这种状态下物质以很低的密度和粘度、随温度和压力的变化而较强烈膨胀和收缩以及自动扩散而均匀地分散在任何容器中,这些性质与固体或液体状态不同。
相转变:因温度和/或压力的改变而引起的液体和气体之间的状态变化。
Kugelschaum:Manegold分类中两种形式气泡的一种(Manegold,E.“Schaum,Strassenbau,Chemie und technik.”Heidelberg,1953,引入本文供参考)。具体来说,kugelschaum或球状泡沫由广泛分离的球状气泡组成且区别于polyederschaum或多面泡沫,而多面泡沫由多面气泡组成,具有很低的分离分散相曲率的窄的层状膜。
低沸点液体:液体的沸点在标准压力条件下低于40℃。本发明使用的低沸点液体包括(但不局限于)碳氢化合物、有机卤化物和醚,在任何情况下,其分子具有6个或少于6个碳原子。
脂肪族碳氢化合物:烷烃、烯烃、炔、环烷烃和环烯烃有机化合物。这些化合物中,仅使用沸点低于约40℃的化合物(如具有6个或6个以下碳原子的化合物)并因此而对本发明受体给药后能由液体转变为气体。本发明所用的脂肪族碳氢化合物包括但不局限于选自下列化学物质的那些化合物:异丁烷、异丁烯、1-丁烯、1,3-丁二烯、正-丁烷、2-丁烯(反式)、2-丁烯(顺式);乙烯基乙炔、1-丁炔新戊烷、丁二炔、1,2-丁二烯、环丁烷、3-甲基-1-丁烯、1,1-二甲基环丙烷、4-甲基-1,3-二氧戊环-2-酮、4-苯基-3-丁烯-2-酮(反式)、1,5-庚二炔、1,4-戊二烯、2-丁炔、2-甲基丁烷、1,2-二甲基环丙烷(反式,d1)、3-甲基-1-丁炔、1-戊烯、2-甲基-1-丁烯、2-甲基-1,3-丁二烯、2-甲基-2-丁烯-3-炔、异戊二烯、乙基环丙烷、正戊烷、甲基环丁烷、2-戊烯(反式)、2-戊烯(顺式)、1,2-二甲基环丙烷(顺)和1-壬烯-3-炔。
有机卤化物:含有至少一个碳原子或硫原子和至少一个卤原子即氯、溴、氟、碘的一类化合物。这些化合物中,仅使用沸点低于约40℃的那些化合物(如具有6个或6个以下碳原子的化合物),它们在给予体温低于40℃的本发明生物体后发生相转变。此类有机卤化物的例子包括:四氟甲烷、一氯三氟甲烷、六氟乙烷、全氟乙烷、一氟甲烷、四氟乙烯、六氟化硫、一溴三氟甲烷、二氟甲烷等化合物。
醚:一类两个烃基或其衍生物被氧原子连结的有机化合物。为本发明的目的,下列是可使用的(但不是全部)醚的例子:甲基醚、乙基甲基醚、甲基乙烯基醚、甲基异丙基醚、1,2-环氧丙基醚、乙醚、乙基乙烯基醚和乙烯基醚。
含氟化合物:至少含一个氟原子的化合物。作为有机卤化物上面列出了一些有用的含氟化合物。还可见下文的实施例。
本发明的胶态分散体可以是乳剂或微乳剂。
乳剂:一种不混溶的液体以液滴状形式分散在另一种液体中形成的胶态分散体,液滴的直径通常在100和3000nm之间且通常在光学上是不透明的,除非分散相和连续相的折射率是匹配的。该体系的稳定性有限,通常用所采用的体系或相关的参照体系来确定,可通过加入两亲物质或粘度增强剂来提高其稳定性。
微乳剂:一种用两亲物质稳定的由水和与水不混溶液体形成的稳定液态单相和光学各向同性胶态分散体,其中分散体具有适宜的光散射特性(意味着它们可以表现出光学透明或乳状但用透射光观察时,他们是红色或黄色)且颗粒直径通常在5和约140nm之间。
在本发明的优选实施例中,胶态分散体含有一种或多种两亲物质来提高制剂的稳定性。
两亲物质:一种在界面处被强力吸附且通常对界面张力产生戏剧性的减小作用而仅伴随很小的体相浓度变化的物质。例子包括合成的表面活性剂、天然物质如生物相容性蛋白质、类脂、甾醇、藻酸盐、纤维素衍生物和微细的有机或无机的固体颗粒。
有机固体颗粒:包括糖、蛋白质、氨基酸、类脂、核酸及其它。
无机固体颗粒:包括氧化铝、碳酸盐、碳酸氢盐、硅酸盐、硅铝酸盐、磷酸盐及其它。
界面:位于物质的两个截然不同的而又可分辨的相之间的物质世界的区域或边界,本文限定为液-液、液-固、固-气和液-气。
界面张力:单位长度的力,存在于物质的截然不同的而又可分辨的两个相的界面。
稳定性:从开始制备到包装的时间间隔,其间胶态分散体继续满足所有的化学和物理规格,例如均匀性、强度、质量及纯度,这些规格是按商品制造方法原则制订的,是由主管政府机构制订的。
表面活性剂:用化学方法制造的或从天然原料或用天然方法纯化的两亲物质。它们可以是本专业领域中公知的阴离子、阳离子、非离子和两性离子物质。在Emulsions:Theory and Praetice,Paul Becher,Robert E.Krieger Publishing,Malabar,Florida,1965中描述过这类物质,该文献引入本文供参考。
本发明胶态分散体的连续相是水性介质。
水性介质:含水的液体,它可含有可药用的添加物如酸化剂、碱化剂、抗微生物防腐剂、抗氧剂、缓冲剂、螯合剂、络合剂、增溶剂、湿润剂、溶剂、混悬和/或增粘剂、张力剂、浸润剂或其它生物相容物质。可在U.S.Pharmacopia National Formulary,1990,pp.1857-1859中查到上面各类组分,该文献引入本文供参考。
本发明优选的实施方案包括至少使用一种选自生物相容蛋白质、含氟表面活性剂、聚氧丙烯-聚氧乙烯乙二醇非离子嵌段共聚物及表面活性剂的两亲物质。
聚氧丙烯-聚氧乙烯乙二醇非离子嵌段共聚物:以Pluronic为商品名称而可从BASF Perfonmance Chemicals,Parsippany,NewJersey购得的表面活性剂,它由一组表面活性剂组成,CTFA名称为poloxamer 108、188、217、237、238、288、338、407、101、105、122、123、124、181、182、183、184、212、231、282、331、401、402、185、215、234、235、284、333、334、335和403。
含氟表面活性剂:含有一个或多个氟原子的表面活性剂。本发明可使用的某些但不是全部含氟表面活性剂可选自:含有氟化的表面活性剂的telomer B,购自Du Pont,Wilmington,DE,商品名称为Zonyl(包括Zonyl FSA,FSP,FSE,UR,FSJ,FSN,FSO,FSC,FSK和TBS),氟化学物质表面活性剂,购自3M IndustrialChemical Products Division,St.Paul,MN,商品名称为Fluor-ad(包括FC-95、FC-98、FC-143、FC-170C、FC-171、FC-430、FC-99、FC-100、FC-120、FC-129、FC-135、FC-431、FC-740),Mathis等人描述的全氟烷基聚氧乙烯表面活性剂(
J.Am.Chem.SOC.106,6161-6171(1984),引入本文供参考)、Serratrice等人描述的氟代烷硫基醚聚氧乙烯表面活性剂(
J.Chim Phys 87,1969-1980(1990),引入本文供参考)、Zarif等人的全氟烷基化多羟基化表面活性剂(
J.Am.Oil Chem SOC 66,1515-1523(1989),引入本文供参考),购自Atochem North America,Philadelphia,PA的氟代表面活性剂,商品名称为Forafac。
生物相容蛋白质:蛋白质,不管其来源也不管它是通过提取动物、植物或微生物组织获得的还是通过重组生物技术获得的,只要它能够以可接受的方式起稳定本发明胶态分散体的功能而不产生过度的毒性或不适当的生理或药理作用。某些可接受的生物相容性蛋白质可选自白蛋白、α-1-抗胰蛋白酶、α-胎儿球蛋白、氨基转移酶、淀粉酶、C-活性蛋白质、癌胚抗原、血浆铜蓝蛋白、补体、肌酸磷酸激酶、铁蛋白、血纤维蛋白原、血纤维蛋白、肽基转移酶、促胃液激素、血清球蛋白、血红蛋白、肌红蛋白、免疫球蛋白、乳酸脱氢酶、脂肪酶、脂蛋白、酸性磷酸酶、碱性磷酸酶、α-1-血清蛋白质部分、α-2-血清蛋白质部分、β-蛋白质部分、γ蛋白质部分、γ-谷氨酰转移酶及其它蛋白质。
制造本发明胶态分散体的优选方法是进行粉碎。另一种制造方法是进行凝缩。
粉碎:利用由手工、机械混合或超声作用所产生的机械能来将液体分散相和连续相混合在一起,然后使分散相颗粒大小由大颗粒减小到所要求的大小来制备胶态分散体的方法。适合的混合可在Microfluidic′s Model 110 Microfluidizer装置中,按美国专利4533254所述的方法来完成,此专利引入本文供参考。另一种可接受的方法是使用Rannie High Pressure Laboratory Homogeniser,Model Mini-Lab,8.30H型或相当型号进行。
凝缩:以气体为分散相,并与液体连续相接触,然后使分散相颗粒大小由分子系增加到所需大小来制备胶态分散体的方法,凝缩通常是经改变体系的温度和/或压力而诱导分散气体相变为液体。
通过以下实施例来更好地理解本发明:实施例1
通过测量两种状态的声学反散射来确定Ziskin等人所述的(参见上文)低沸点液体以微细分散体存在而不以纯液体存在的必要性。
制备两种溶液来模拟给予生物体低沸点胶态分散体或纯液体。用Hewlett Packard Model 77020超声扫描器在5.0MHz进行扫描并在Sony ES VHS胶带上记录所获得的图像。然后使用软件包GlobalLab Image Software(Data Translation,Marlboro,MA),将胶带上的模拟图像转变为数字形式。在注射实施例19胶态分散体或一定量的纯十二氟戊烷加到1000ml保持在37℃的烧杯前后,测定4900pixel(70×70pixel大小)感兴趣区域范围内的灰色标准强度(gray scale intensity)。
在2到254的灰色标度上进行测量。注射0.1mL实施例19乳剂的等分试样(含有3.4微摩尔十二氟戊烷)前的成像强度为4.27。注射该乳剂0.1mL后5秒钟,强度变为236,52秒后,强度变为182。
用0.2mL纯十二氟戊烷注射液进行相同的实验。它与1111微摩尔的十二氟戊烷相对应,其量超出以上实验的300倍。注射前成像强度为4.9;注射后5秒钟增加到7.7而注射后52秒钟为5.0。
这两个试验的比较(强度/数量)表明胶态分散体对超声波的散射比简单给予同样也能进行液相到气相转变的液体效力高27,000倍。实施例2
选择适于用作液体分散相的化学物质在某种程度上取决于所要进行超声研究的生物体的体温。例如,由于人的体温是37℃,进行液相到气相转变的温度,即沸点为37℃或更低的液体在本发明的胶态分散体中是特别有用的。类似地,下表可指导根据所研究生物体来选择液体分散相。生物体 直肠温度
(华氏度)猪(Sus scrofa) 101.5-102.5羊(Ovis sp.) 101-103兔(Oryctolaqus cuniculus) 102-103.5鼠(Tattus morvegicus) 99.5-100.6猴(Macaca mulatta) 101-102小鼠(Mus musculus) 98-101山羊(Capra hircus) 101-103豚鼠(Cavia porcellus) 102-104大田鼠(Mesocricetus sp.) 101-103人(Homo sapiens) 98.6-100.4马(Equus sp.) 101-102.5狗(Canin familiars) 101-102狒狒(Papio) 98-100猫(Felis catus) 101-102牛(Bos taurus) 101.5-102.5黑猩猩(Pan) 96-100实施例3
使用实施例45的方法和标准,粉碎有机卤化物,制备胶态分散体。
具体来说,制备100mL制剂,它含有:poloxamer 488,2.5%v/v;含氟表面活性剂Zonyl FSN 2.5%v/v;全氟辛酸钠(Sodiumperfluorooctanoate),pH7.0,0.1% w/v;氯化钠,0.9% w/v;和十二氟戊烷,2.0%,v/v。低剪切混合后,在4℃温度下于Micr-ofluidizer Model 110Y中粉碎8次。将该奶状乳剂等分在血清小瓶中并密封。
在19℃温度下,使用Nicomp Model 370(Nicomp ParticleSizing,Santa Barbara,CA)来确定72小时内的颗粒大小及大小的分布情况。乳剂高斯分析的平均直径为90.1nm(数加权,numberweighted),其标准偏差为48%。体积加权平均直径为316nm。实施例4
制备乳剂期间,在各个步骤或在不同条件下测定颗粒大小和大小的分布情况。
配制20mL乳剂,它含有全氟辛酸钠,pH7.2,2.5% w/v,以及十二氟戊烷,2% w/v。将这些组分加到水中并将混悬液冷却到4℃。在最后粉碎前,用Emulsiflex-1000(Avestin,Inc.,Otta-wa,Canada)来“预混和”该溶液。
在两个10mL注射器之间使溶液通过20次后,将白色、奶状混悬液放在Nicomp 370中确定颗粒大小。该预混的混悬液的平均颗粒径为452nm(数加权)和2398nm(体积加权)。
在最高为7MPa压力下手工操作通过8次Emulsiflex-1000(Avestin,Inc.,Ottawa,Canada)进行粉碎来制备最终乳剂。该乳剂颗粒小得多,数加权平均直径为201nm和体积加权平均直径为434nm。
将该物质通过0.45微米无菌滤器(Gelman Acrodisc,Ann Arb-or,MI)来无菌填充该物质。最终无菌胶态分散体的数加权平均直径为160nm。实施例5
粉碎后立即测量乳剂的平均颗粒径是一个估计制剂稳定性的有效试验。下列乳剂说明这一点:
按实施例19的方法配制2% v/v的十二氟戊烷乳剂,它含有2%Pluronic P-123和2.6% Zonyl FSO。平均颗粒径为151nm,标准偏差为35%。根据物理现象和颗粒大小来判断,该乳剂可至少稳定6周。
向同一制剂中加入0.25%全氟辛酸钠。尽管推测可因加入该化合物而降低界面张力使制剂进一步稳定,但该表面活性剂在乳剂界面上所产生的高密度阴离子电荷实际上可阻碍小颗粒的产生。事实上,立即测量颗粒大小的结果表明平均颗粒大小为1060nm,其标准偏差为106%。若干天中,该乳剂劣化。实施例6
经离心分离可测量乳剂颗粒大小的分布情况。将实施例19的乳剂样品放置在Horiba CAPA-700颗粒分析器(Horiba Instruments,Irvine,CA)中。假定颗粒密度为1.66g/cm3来进行计算,颗粒大小分布情况如下:
颗粒大小范围 体积百分数
微米
0.0-0.5 12
0.5-1.0 26
1.0-1.5 22
1.5-2.0 15
2.0-2.5 7
2.5-3.0 0实施例7
确定本发明乳剂的长期稳定。将实施例19所述的乳剂放置在19℃温度下,并使用Nicomp 370空一时间间隔测定颗粒的大小。所得结果列于下表中:
时间(天) 平均颗粒径(nm)
5 194
13 216
19 245
27 258
33 289
41 283
47 306
61 335
89 305
在第一个月内,该乳剂开始迅速地从194增长到289nm。然而,此后增长基本上停止。由直径对时间的曲线推知该乳剂至少稳定一年。实施例8
使用实施例42的乳剂来试验经各种途径给予这些胶态分散体时的成像能力。用巴比妥酸钠麻醉约20kg的杂种狗,并按实施例38所述的方法来进行超声检查。
以0.2mL/kg剂量进行静脉注射,注射后1分钟内,在心脏的右心室和左心室产生强的造影信号。在0.5mL/kg剂量时,所有检查的器官都产生强的多普勒信号,这些器官包括:血管系统、肝、肾、心脏和中枢神经系统。
经真皮内、皮内或肌内途径注射0.5mL产生局部造影,可检查肌骨胳系统。
口服1000mL通过将50mL实施例42乳剂稀释到550mL盐水中制备的溶液,有效地给予胃内和十二指肠内管腔内。增强胃肠系统的流明,产生更好的肝、脾和内部再生器官的造影。
囊内给予10mL体积的实施例42乳剂,提供增强的膀胱造影。
可采用上述实施例,通过另外途径给药,用本发明的胶态分散体提供有用的超声造影作用。具体来说,可通过下列任何途径给予乳剂:腹内、动脉内、关节内、囊内、子宫颈管内、颅内、管内、硬膜内、损害部内、小房内、腰内、器官壁内、肺内、手术期中、脑顶区内、腹膜内、胸膜内、肺内、脊柱内、胸内、气管内、鼓室内、子宫内和心室内。在经典的放射学教课书中可以找到通过这些途径给药的方法,如由DP Swanson,HM Chilton,JH Thrall编辑的“Pharmaceuticals in Medical Imaging’,MacMillianPublishing Co.,Inc.,1990,将该教课书引入本文供参考。
除上文所述的研究器官或器官系统外,通过已知方法来研究的还有肺、胸、前列腺及内分泌系统。可用本发明的造影剂来研究的医学疾病种类很多。他们包括代谢、创伤、先天性、肿瘤或感染疾病。 在教材“Diagnostic Ultrasound’中可找到有关在这些疾病中进行超声成像的描述,该书由CM Rumack,SR Wilson,JW Char-bonean编辑,Mosby Year Book,Boston,1991,引入本文供参考。实施例9
在0.00001% w/v到166% w/v浓度范围时,本发明的胶态分散体可对超声信号产生造影效果。
如果将1%乳剂(如实施例42的乳剂)稀释10倍(将1mL乳剂加到9mL缓冲液中)并将0.1mL等分试样加到1000mL 37℃温度的水中并测量超声强度,反散射有大幅度的增加。具体来说,在加入上述的乳剂后1分钟内,用实施例1所述的系统测量的信号强度从2.7增加到9.8。极大地稀释时,反散射不能与背景区分。因此,分散相材料的低限浓度为0.00001%。
如果将5mL十二氟戊烷加到5mL含有实施例25所述表面活性剂混合物的水中,并用实施例4的方法将混悬液粉碎5分钟,制成166%w/v的乳剂可将此乳剂立即给予(如口服)生物体而产生极好的超声造影作用。该量代表分散相材料的高限浓度,因为浓度更高产生趋于不稳定的制剂。实施例10
可使用蛋白质来稳定本发明的胶态分散体。因为使用高强度超声,可合成由非水性液体充填的蛋白质微球的水性混悬液(即,微囊)。他们不同于美国专利4,718,433和4,774,958的超声造影剂,所述美国专利的造影剂仅含有气体,并仿效Suslick和Grinstaff所述的方法(Suslick KS,Grinstaff MW:Protein microencapsula-tion of nonaqueous liquids.
J Amer Chem Soc 112:7807-7809,1990)。该文献仅描述使用高沸点非水性液体(它不适于用作超声造影剂)且未公开使用一般性的低沸点液体或有机卤化物,特别是非水性液体。
可由人血清白蛋白或血红蛋白合成具有高强度超声探针(HeatSystem,W375,20kHz,0,5 in.Ti horn)的蛋白质微球。通常,将5%戊烷或乙醚和5%白蛋白在约150 W/sq cm声能,23℃和pH7.0下照射3分钟。所得分散体具有高斯分布且平均颗粒径约为2.3微米。在4℃温度下,它们可保持其颗粒大小长达2个月。
除白蛋白或血红蛋白之外,可使用下列蛋白质:α-1-抗胰蛋白酶、α-胎儿球蛋白、氨基转移酶、淀粉酶、C-活性蛋白质、癌胚抗原、血浆铜蓝蛋白、补体、肌酸磷酸激酶、铁蛋白、血纤维蛋白原、血纤维蛋白、肽基转移酶、促胃液激素、血清球蛋白、肌红蛋白、免疫球蛋白、乳酸脱氢酶、脂肪酶、脂蛋白、酸性磷酸酶、碱性磷酸酶、α-1-血清蛋白质部分、α-2-血清蛋白质部分、β-蛋白质部分、γ-蛋白质部分、γ-谷氨酰转移酶。
除戊烷或乙醚之外,可使用其它脂肪族碳氢化物、有机卤化物及醚代替上述的戊烷。实施例11
可确定作为乳剂或微乳剂的胶态分散体颗粒的大小与经相转变所形成的微泡大小之间的关系。
将实施例27的乳剂的等分试样放在Nicomp 370中,在19℃温度下运行并确定液体乳剂的平均颗粒大小为231.7nm。将仪器温度调到37℃并在温度平衡后(约需5分钟),再确定颗粒大小。所形成的微泡分散体的平均颗粒大小为1701.5nm,大小增加7.34倍。
如果知道分散液体的气体形式和液体形式的相对密度,也可以计算分散系大小所要发生的变化。例如,在W Braker和A Mossman,Matheson的Gas Data Book中包含了这些数据。检查八氟环丁烷,发现在760mm Hg压力和15℃温度下1L的液体产生188L的气体。因为球体体积的立方根与球体直径相关,因此八氟丁烷乳剂颗粒的相转变会使直径增加5.7倍。实施例12
在小猪上显著地证明了本发明乳剂的安全性。Albunex标记的超声造影剂(正在开发,也是美国专利4,718,433和4,774,958的主题)在猪中显示严重的血液运力学作用(Ostensen J,Hede R,Myreng Y,Ege T,Holtz E.),静脉注射Albunex微球在猪中使血栓素成为引起肺部高血压的介质,但在猴或兔中不是如此(ActaPhysiol Scand 144:307-315,1992)。在0.001-0.05mL/kg的低剂量时,导致低血压。缓慢输入0.05mL/kg时,一头猪死亡。
使用以上参考文献的实施方案,在卤代烷麻醉下,在30kg小猪上进行实验。所得结果列于下表中:剂量,mL/kg 累积剂量,mL/kg 血液动力学作用0.01 0.01 无0.02 0.03 无0.05 0.08 无0.10 0.18 无0.20 0.38 无0.30 0.68 无0.40 1.08 无0.50 1.58 无0.60 2.18 无0.60 2.78 无0.80 3.58 无0.30 3.88 无2.00 5.88 呼吸困难
所有剂量都产生好的心脏造影效果。剂量超过0.4mL/kg也增强肝的多普勒效果。
其结论是:以40倍于白蛋白微球致死剂量在小猪中注射本发明的乳剂具有最低限度的瞬时效果。Albunex有效阈剂量为0.001mL/kg白蛋白微球,低于本发明胶态分散体阈剂量的2000倍。实施例13
选择具有合适的亲水亲油平衡(HLB)值的两亲物质用于选定的分散相对稳定胶态分散体十分重要。确定HLB值的一种方法是测量各种表面活性混合物的界面张力。(下列文献对评价HLB的方法作了很好的综述:Emulsions:Theory and Practise,Paul Becher,参见上文,pp.232-252)。
制备Pluronic P-123和Pluronic F-127混合物,生成1%溶液(v/v),使用Kruss Drop Volume Tensiometer DVY-10,Kruss USA,Charlotte,NC,确定在4℃下该溶液相对于十二氟戊烷的HLB值和界面张力(IFT),HLB和IFT值均呈梯度分布。所得结果列于下表中:
HLB和界面张力之间的关系P-123 F-127 HLB IFT(达因/cm)1.00 0.00 8 27.070.86 0.14 10 23.940.75 0.25 12 23.580.60 0.40 14 22.480.50 0.50 15 23.800.40 0.60 16 23.160.25 0.75 19 23.610.00 1.00 22 26.36
当绘图时,上述数据表示十二氟戊烷约14的HLB。使用具有HLB值为14的两亲物质,如阴离子、阳离子、阳离子或两性离子表面活性剂对以上液体分散相的乳剂产生最大的稳定性。实施例14
由于液体分散相和液体连续相之间界面张力显著影响胶态分散体的稳定性,因此可利用这一性质来开发制剂。
奥福成熟理论预示颗粒大小的稳定性与界面张力密切相关(Kabalnov AS,Shchukin ED奥福成熟理论:Application to flu-orocarbon emulsion stability,Advances in colloid and In-terface Science,38:69-97,1992,引入本文供参考)。该理论预示稳定性与界面张力之间成反比。例如,如果加入两亲性物质使界面张力降低五倍,那么稳定性会增加五倍。
在4℃下测定各种两亲物质在水溶液中(全部以v/v溶液表示)相对于十二氟戊烷的界面张力,并按实施例13所述方法,用各配方制备乳剂。
Pluronic P-123,1%,和十二氟戊烷的界面张力为27.1达因/cm且不能形成稳定的乳剂。
Pluronic F-127,1%,和十二氟戊烷的界面张力为26.4达因/cm且不能形成稳定的乳剂。
Zonyl FSO,1%,和十二氟戊烷的界面张力为5.8达因/cm且形成稳定的乳剂。
Pluronic P-123,0.33%,Pluronic F-127,0.33%,和ZonylFSN,0.33%,和十二氟戊烷的界面张力为14.1达因/cm并可形成稳定的乳剂。
Pluronic P-123,1%,Zonyl FSO,1.0%,氯化钠,1%,和全氟辛酸钠,0.5%,和十二氟戊烷的界面张力为2.71达因/cm且形成稳定的乳剂。
因此,要求具有低于26达因/cm界面张力的两亲物质以形成稳定的乳剂。用其它有机卤化物或脂肪族碳氢化合物或醚会获得相关的结果。实施例15
可使用液体连续相的粘性来开发制剂,因为该特性显著影响胶态分散体的稳定性。
奥福成熟理论预示颗粒大小稳定性强烈地依赖于粘度(参见实施例14中的Kabalnov AS等人的评述)。该理论预示稳定性与粘度之间成正比。例如,如果加入生粘剂(viscogens)(粘度增强剂)使粘度增加五倍,那么通常稳定性也增加五倍。
胶粘剂的例子包括但不局限于,羟甲基纤维素、山梨醇、碘海醇、其它碘化的X-线造影物质、葡萄糖、聚乙二醇。加或不加5%聚乙二醇(PEG)200来制备实施例38的乳剂,它的粘度为1.1CP,且明显稳定。含5%PEG 200的乳剂稳定性更高。实施例16
用Hewlett Packard Model 77020超声扫描仪测量实施例44和18乳剂混悬液所产生的超声反散射来确定本发明相转变胶体的相对效力,它们在室温下为液-液乳剂分散体,但在按Long等(US4,767,610、4,987,154及JP 2196730)、Davis等(EP 245019、及JP专利1609986和JP 63060943)所描述的方法给予稳定乳剂,或按EP467031、EP 458745、WO 9115244、US 5088499、5123414、US4844882、US 4832941、US 4466442和US 4276885中所述的方法给予真正的气体微泡后,均变成气泡。这些文献均引入本文供参考。
通过下列过程产生气体微泡。将0.5mL空气吸入10mL注射器中并将10mL 1.0%(v/v)的Pluronic F-68溶液吸入另一个10mL注射器中,用一个三通活塞将两个注射器连结。液体和气体在两根注射器之间快速地前后通过。约通过5次后,空气和液体混合且溶液呈乳状、白色外观。继续混合使通过总次数达20次。加到250mL水中的1mL气体分散体样品给出具有与肝组织强度相似的超声图像(4+强度)。出人意料的是,由空气微泡产生的超声反散射的强度迅速减小,在5分钟内反散射恢复到基线。这种缺乏持久性的现象限制了空气微泡的诊断使用。
另一方面,在37℃温度下,在250mL水中的1.0到10.0mL的全氟己烷乳剂产生类似于血流的超声图像(0-1+强度),表明这些制剂仅在极高剂量下才产生超声造影作用,这样限制了它们的总的用途。
稀释在250mL 37℃水中的1.0mL十二氟戊烷乳剂样品产生具有微泡溶液强度的超声图像(4+强度),它持续10分钟以上,足以诊断使用。
附带说明的是:所有三个实验溶液肉眼观察均为近乎外观混浊的混浊液。这些实验表明本发明的超声造影剂比现有技术中诊断所用的超声造影剂更加持久和/或有效。实施例17
用装有21号针的1.0mL注射器从小瓶中抽取1.0mL的实施例19的造影剂样品并将约0.2mL放置在载玻片上。将盖玻片放置在液体上并将该样品放置在装有目测微尺、温度控制室、35-mm照相机和松下摄相机的光学显微镜的镜台上。
在20℃的油浸下检测乳剂。在该温度下,乳剂由0.2-0.3微米的颗粒组成,它们正进行快速的布朗运动。
将温度控制器调到37℃并观察乳剂、记录图像。当温度升高时,颗粒会分别地突然长大,直至达到37℃,该乳剂变为聚集的1-3微米泡。泡与液体乳剂不同,易于变形。然而,它们不结合。实验40分钟后,全部微泡保持完整稳定。实施例18
通过液体分散相均不同的乳剂在37℃下进行超声成像来试验在用超声造影剂成像的生物体体温下(在这种情况下使用37℃温度)液体分散相的某些部分进行液相到气相转变的关键性。
配制或由原料获得下列乳剂并将1.0mL等分试样放在1000mL37℃的水中。按Long等公开方法(US 4,767,610,4,987,154和JP2196730)配制由1-碘全氟辛烷形成的乳剂。按JP专利1609986和JP63060943公开的方法配制具有全氟萘烷的乳剂。按Davis等公开的方法(EP 245019)配制具有triolean的乳剂。各专利的成分均引入本文供参考。获得加入溶液前后的超声图像,所得结果以所观察到增强倍数乘以观察到增强的时间表示。分散相 两亲物质/D.P.类 沸点 分钟×增强情况百分数
(℃) ×1000十氟丁烷 十八烷基胺HCl/ -5.8 625
阳离子十二氟戊烷 Poloxamer-Zonyl 29 740
/非离子全氟己烷 十二烷基硫酸盐/ 59 178
阴离子全氟辛烷 Poloxamer-Zonyl 98 24
/非离子全氟萘烷 Poloxamer-磷脂- 141 8
油酸盐/混合的1-碘全氟辛烷 磷脂/两性离子 160 6Triolean 磷脂/两性离子 235 0.2盐水 不能使用 摇动 0.006
如上所示,在37℃或低于37℃温度下完全进行相转变的乳剂是优选的制剂。当与室温下蒸汽压低于20毫米汞柱的搅拌的盐水或全氟萘烷相比较时,室温下蒸汽压在20毫米汞柱以上的高蒸汽压全氟己烷和全氟辛烷具有某些区别。这可表明关于使用这些化合物作为超声造影剂的某些优点,然而,这些物质增强的机制还不十分清楚,而且事实上也考虑被认为对沸点约为40℃或低于40℃的那些物质适用。实施例19
可使用下列设备和步骤来制备本发明的超声造影剂:微流体化器(Microfluidizer),110Y型,互通压力室14,000 PSI;压力容器,316号钢,5L和12L;滤布,醋酸纤维素,0.22微米;滤斗,142mm。制备下列溶液:25%(w/v)山梨醇,12L;2.5% w/v全氟辛酸钠(PCR,Inc.,Gainsville,FL);60g Plurinic P-123;60gZonyl FSO,7mL 2.5%全氟辛酸钠溶液,1L,声作用助溶(贮备的表面活性剂溶液)。用山梨醇将微流体化器打底。在粉碎过程中用碎冰将互通室、管道和冷却盘管覆盖。搅拌下,在冰浴的5L压力容器中顺序加入:500mL山梨醇溶液;500mL贮备的表面活性剂溶液;800mL水;200g十二氟戊烷。用氮使容器加压至10PSI,维持45分钟。在14,000PSI下使混悬液通过微流体化器45分钟。在4℃下,将乳剂转移到含8L 25%山梨醇的容器中并混合均匀。使用正压,将乳剂转移到100mL瓶中,在此过程中,物质通过0.22微米的滤布。加盖封瓶。本实施例的两亲物质包括含氟表面活性剂和聚氧丙烯-聚氧乙烯乙二醇非离子嵌段共聚物,它产生具有可接受的稳定性的制剂。实施例20
在4℃温度下,将0.4mL的正戊烷(Aldrich Chemical,Milwa-ukee,WI)加到2.0mL的水中。得到两个清楚分离的相。加入氯化钠(0.4mL的10% w/v溶液)使总量为2.8mL。搅拌下加入约135mg的磷脂酰卵磷脂(Sigma Chemical,St.Louis,MO)并用剧烈的涡流搅拌使所得的淤浆混合。放置5分钟内,乳剂白色溶液分为两相。以0.1mL的增量混入乙醇使总量达1.74mL。两相混合物的外观没有改变。本实施例的制剂在体外显示好的超声反散射特性且说明使用具有6个或低于6个碳原子和17个总原子的脂肪族碳氢化合物的情况。实施例21
通过将1.80mL水、0.2mL 10% NaCl、0.1mL乙醇和100mg卵磷脂混合在一起来制备混悬液。加入0.1mL的十二氟戊烷(PCR,Gainsville,FL),然后获得两相混合物。加入0.1mL的正戊烷,再加入0.1mL的十二氟戊烷等分试样而使十二氟戊烷的总量达20%v/v。混合所得混悬液,获得三相混合物,两个乳状相和一个小的透明相。另加NaCl使溶液到7%且加入1mL乙醇等分试样,混悬液的特性没有变化。该实施例的制剂在体外显示好的超声反散射特性且说明使用碳氢化物和碳氟化物的混合物的情况。实施例22
将330mg的卵磷脂加到2.0mL的十二氟戊烷中。混合物,加入1.0mL水并进一步混合混悬液。形成乳状胶态分散体。在使用天然两性离子表面活性剂的情况下形成乳状胶态分散体,表明可使用单一的表面活性剂作为两亲物质。用醚来代替制剂中的十二氟戊烷部分也会形成有用的造影剂,特别是发现乙醚产生有用的造影信号。相关的化合物,如甲基醚和乙烯基醚也会是有用的。实施例23
将0.46g的十二烷基硫酸钠(SDS)加到0.72mL水和8.00mL十二烷中。缓慢加入1.47mL的戊醇等分试样。起初混悬液在透明的液体中含有白色、“纤细的”SDS。再加1.0mL戊醇并轻轻混合使SDS基本上溶解。再加0.5mL戊醇混合并在室温下过10-15分钟而获得透明、单相的微乳剂。该制剂确实产生弱的声学反散射,表明含有沸点高于40℃液体分散相(这里以十二烷为例(b.p.216℃))的胶态分散体不适合作为本发明方法中的超声造影剂。实施例24
改变实施例23的水、戊醇、十二烷、十二烷基硫酸钠微乳剂组成来确定微乳剂的组成范围。室温下制备下列混合物并在搅拌30分钟后观察其外观:
加入的体积(ml)实施例号 水 戊醇 十二烷 SDS 外观5-1 1.00 1.00 1.00 372mg 透明5-2 1.10 1.00 1.00 372mg 透明5-3 1.20 1.00 1.00 372mg 透明5-4 1.30 1.00 1.00 372mg 透明5-5 1.50 1.00 1.00 372mg 乳状5-6 1.50 1.10 1.00 372mg 乳状5-7 1.50 1.30 1.00 372mg 乳状5-8 1.50 1.50 1.00 372mg 略显乳状5-9 1.50 1.60 1.00 372mg 透明,蓝色
加热(超过约45℃)时5-9的微乳剂变为乳状而再冷却到室温时,变为蓝色透明状。这种外观的可逆变化至少可重复6个温度变化循环。实施例25
将0.51mL的辛酸(Sigma Chemical Corp.St.Louis,MO)加到1.0mL水中,形成透明溶液。加入1.0mL辛烷,透明溶液变为乳状。加入0.49mL的辛酸,溶液变为胶体。将3.6M KOH溶液的0.17mL等分试样溶于胶体而产生透明的微乳。以0.1mL等分试样加入5次水并混合,仍产生透明微乳剂。第六次加入使透明乳剂变为乳状胶态分散体。该实施例说明具有含有阳离子表面活性剂的两亲物质的含脂肪族碳氢化合物乳剂的制剂的情况。实施例26
将1.0mL的十二氟庚醇(PCR)加到1.0mL的十二氟戊烷中,形成透明均匀的溶液。等量的八氟戊醇与十二氟戊烷产生两个透明的、不混合相。将2.0到4.0mL水加到十二氟庚醇-十二氟戊烷中产生两个不混合相。冷却到4℃,两个透明相变为三个透明相。实施例27
室温下,将10mL FC-430加到100mL水中并混合制备10%Fluorad FC-430(3M Chemical,St.Paul,MN)的水溶液。在5mL该溶液中加入1.0mL十二氟戊烷和1.0mL八氟戊醇,产生乳剂。实施例28
将2.0mL 10% v/v FC-430溶液加到2.0mL十二氟戊烷中,形成两相。再加入0.3mL十二氟戊醇产生乳状、白色乳液。实施例29
将1mL 1.26M的2-氨基-2-甲基-1-丙醇(AMP)全氟辛酸盐加到1.0mL的十二氟戊烷和1mL 25% Pluronic F68中,产生两相乳状液体。再加入0.05mL十二氟戊醇产生单相胶态分散体。实施例30
在冰上,将20mL 15%(v/v)的Pluronic F68溶液依次加到2.0mL十二氟戊烷和0.2mL十二氟庚醇中。将混合物吸入连有三通活塞和另一个5mL玻璃注射器的5mL玻璃注射器中并在注射器间用力使之前后通过来产生粘稠的白色乳剂。实施例31
在4℃温度下,依次添加形成下列混合物:2.0mL 15% Plur-onic F68,2.0mL十二氟戊烷,2.0mL 0.2M AMP全氟辛酸盐,0.1mL十二氟庚醇。将混合物吸入连有三通活塞和另一个5mL玻璃注射器的5mL玻璃注射器中并在注射器间用力使之前后通过来产生粘稠的白色乳剂。实施例32
在4℃温度下,依次添加形成下列混合物:2.0mL 15% Plur-onic F68,溶于0.5mL H2O的0.42g D-山梨醇(Sigma),0.2mL十二氟庚醇和2.0mL十二氟戊烷。将混合物吸入连有三通活塞和另一个5mL玻璃注射器的5mL玻璃注射器中并在注射器之间用力使之前后通过以产生粘稠白色乳剂。实施例33
在4℃温度下,依次添加制备下列混合物:2.0mL 15%(v/v)的Pluronic F-68,0.40mL 0.1M Tris(羟甲基)氨基甲烷(Tris)全氟辛酸盐,pH7.2,2.0mL十二氟戊烷。将混合物吸入连有三通活塞和另一个5mL玻璃注射器的5mL玻璃注射器中并在注射器之间用力使之前后通过以产生白色胶态分散体。实施例34
在4℃温度下,依次添加制备下列混合物:60mL 25%的Plur-onic F68,24mL 1,1,7-H-十二氟庚醇,75.8g十二氟戊烷。使用30cc注射器、三通活塞和40次手工操作,将混合物分批混合而粉碎。使用由8.0mL 25% Pluronic F68,2.0mL 50%D-山梨醇,1.0mL pH7.2,0.1M Tris全氟辛酸盐组成的溶液按1∶10,将混合物依次稀释两次,并进一步经注射器挤压进行粉碎。将该制剂经尾静脉注射给予体重为20-30g的小鼠并观察7天。所得结果列于下表中:
剂量(mL/kg) 观察情况
20 存活
25 病态但存活
30 病态但存活
40 未存活
配制后,该生物相容的胶态分散体至少稳定两周。实施例35
制备下列制剂:1.0mL 25%聚乙二醇3550,1.0mL 50%山梨醇,3.0mL 15%(w/v)Pluronic F-68,3.0mL 20%(w/v)Fluorosurfactant FC 430,0.4mL 0.1M Tris全氟辛酸盐和1.0%(v/v)十二氟戊烷。在4℃温度下,用声能在水浴声波器中粉碎混合物10分钟以产生乳状胶态分散体。实施例36
制备各自含有不同配比两亲物质的一系列水溶液,并以此为制剂进行试验。
溶液A:含有6.0mL 25%的Pluronic F-68溶液、6.0mL 50%的PEG3350溶液,0.60mL 0.1M Tris全氟辛酸盐和2.4mL水的透明溶液。
溶液B:含有1.18mL 25%的Pluronic F68溶液,6.0mL 50%的PEG 3350溶液,0.12mL Tris全氟辛酸盐和7.7mL水的透明溶液。
溶液C:含有混合6.0mL 50% PEG 3350,0.75mL Tris全氟辛酸盐和1.5mL H2O而获得的胶化沉淀物的混浊液。静脉给药时,该混浊液与生物体是不容的但口服、腹膜内、直肠或子宫内给药是生物相容的。
溶液D:混合6.0mL 25%(w/v)的Pluronic F-68,6.0mL50%(w/v)PEG 3350,0.6mL 0.1M Tris全氟辛酸盐和2.4mLH2O获得的透明溶液。
溶液E:混合6.0mL 50%(w/v)PEG 3350,7.5mL 20%(w/v)的FC-430,0.75mL Tris全氟辛酸盐和0.75ml H2O获得透明溶液。
溶液F:混合1.8mL 25%(w/v)Pluronic F-68,6.0mL 50%(w/v)PEG 3350,0.12mL 0.1M Tris全氟辛酸盐和7.7mL H2O获得透明溶液。
溶液G:含有经混合3.0mL Pluronic F-68,3.75mL(w/v)FC-430,6.0mL PEG 3350,0.68ml Tris全氟辛酸盐和1.57mLH2O形成的微小沉淀物的透明溶液。
在4℃温度下,将0.14mL的十二氟戊烷加到7.0mL A-G溶液中。经40次通过用三通活塞相连的两个注射器来产生胶态分散体。
经尾静脉注射给予制剂D,LD50为20ml/kg。制剂F和G的毒性剂量为10ml/kg。实施例37
经混合45mL 20% EPG 3350,237mg Pluronic F68,0.225mL Fluorad FC-171,2.25mL 0.1M Tris全氟辛酸盐和10%(v/v)十二氟戊烷来配制乳剂。在两个注射器、三通活塞装置中混合粉碎乳剂。
在溶血试验中,该制剂是生物相容的。经心脏内穿刺收集大鼠全血(2mL),置于含EDTA清除的收集管中。将0.10mL的血液等分试样加到0.20mL的上述制剂的等分试样中来模拟静脉给予100mL/kg剂量后所获得的血液峰值水平。将血液与制剂混合2分钟并将样品离心分离。上清液透明,片状沉淀红色,表明甚至在极高的剂量时没有溶血。
通过以20mL/kg的剂量静脉给予小鼠仅引起较小的呼吸困难,该急性毒性试验也说明制剂是生物相容的。实施例38
试验含有十二氟戊烷和两亲物质在水介质中的制剂作为超声造影剂的生物相容性和实用性。将90mL 20% PEG 3350的贮备液,474mg的Pluronic F-68,0.45mL Flurorad FC-171和4.5mL 0.1M Tris全氟辛酸盐混合而产生透明溶液。在9.0mL的上述溶液中加入0.18mL的十二氟戊烷。经在两个5mL注射器间粉碎形成胶态分散体。
按Keller MW,Feinstein SB,Watson DD:Successful leftventricular opacification following peripheral venousinjection of sonicated contrast:An experimental evaluati-on.Am Heart J 114:570d(1987)所述的模型在32kg狗上进行心回波学研究。该文献引入本文供参考。以0.05到0.75mL/kg剂量静脉十一次给予上述制剂。注射后,0.05mL/kg剂量仅产生轻微的左右心室对比增强作用。0.10和0.75mL/kg之间的所有剂量都获得诊断有用的心室增加作用。注射对血液动力学参数影响最小。
在上述配制的水介质中制备10%十二氟戊烷乳剂并将所产生的对比增强作用与2%制剂相比较。以最小影响血液动力学的静脉给药方式给予0.20和0.25mL/kg的制剂后产生强烈的心室浑浊。实施例39
按配方配制含高密度、高粘度生物相容的水性溶媒作为连续相的乳剂。该乳剂含0.06mL 15%的Pluronic F68,0.06mL ZonylFSO-100,0.12mL 5% Zonyl FSN-100,0.146mL 0.1M Tris全氟辛酸盐,pH7.2,4.47mL 76% w/v碘海醇(Omnipaque 350,Sterling Winthrop,New York),和0.6mL十二氟戊烷。通过双注射器混合粉碎形成稳定的制剂。其它高密度碘化X-线造影剂如碘帕醇、碘佛醇、碘喷托、iodiximol和其它相关化合物都可代替碘海醇。单纯以水作连续相溶媒,在瓶中配制后产生快速沉降的造影剂。本实施例证明了高密度、高粘度生物相容的水性溶媒作为连续相的效用。实施例40
测定一系列聚氧丙烯-聚氧乙烯乙二醇非离子嵌段共聚物在稳定十二氟戊烷液-液乳剂配方中作为两亲物质发挥作用的能力。配制下述溶液:
A-1.9mL 25% Pluronic F-68和0.04mL十二氟戊烷。
B-1.9mL Pluronic L-121和0.04mL十二氟戊烷。
C-1.9mL Pluronic L-122和0.04mL十二氟戊烷。
D-1.9mL Pluronic L-121和0.04mL十二氟戊烷。
E-1.9mL Pluronic L-101和0.04mL十二氟戊烷。
F-1.9mL Pluronic L-92和0.04mL十二氟戊烷。
G-1.9mL Pluronic L-81和0.04mL十二氟戊烷。
H-1.9mL Pluronic P-123和0.04mL十二氟戊烷。
将上述溶液放入密封的玻璃管中并且在4℃下旋涡混合10分钟。可以看见,被分散的十二氟戊烷相的颗粒大小和数量增加。溶液H产生最小的颗粒。实施例41
相对亲水-亲油平衡(HLB)是使非离子表面活化剂溶液尽可能完善来获得最大稳定性的手段。详见
Emulsions:Theory and Prac tice,Paul Becher,1965,Robert E.Krieger Publishing Comp-any Malabar,FL,及其中的参考文献,引入本文供参考。混合Pluronic L61(HLB 3.0)和F68(HLB 29)而后的溶液得到按下式计算的中等HLB值:
HLB=fL61{L61的HLB}+ff68{F68的HLB}下表包含实际溶液,计算的HLB值和最终配制液(2% v/v十二氟代戊烷乳剂)的稳定性:
PLURONIC L61 PLURONIC F68 相对HLB 稳定性
9.6mL 0.4mL 4 0
8.8 1.2 6 +++
8.1 1.9 8 +++
7.3 2.7 10 +
6/5 3.5 12 0
5.8 4.2 14 0
5.0 5.0 16 0
4.2 5.8 18 00=不稳定;+=有些稳定;+++=最稳定
通过本方法确定的全氟己烷的相对HLB为6-8。使用相对HLB值为6-8的两亲物质(不必考虑它们的化学结构)将得到最稳定的全氟己烷乳剂。实施例42
本发明超声造影剂的大规模配制涉及到下列设备和步骤:微流体化器,(Microfluidizer),型号110Y,相互作用室的压力为14,000PSI;高压容器,316号钢,5L和12L大小;滤布,醋酸纤维素,0.22微米;滤架,142mm。制备下列溶液:2.5%(w/v)山梨醇12L;60g Pluronic P-123,60g Zonyl FSO,1L,声处理助溶(表面活化剂储备溶液)。把山梨醇溶液装入微流体化器中。在粉碎期间,用碎冰覆盖相互作用室、管子和冷却盘管。在冰浴下,向装有搅拌棒的5 L高压容器中相继加入:500mL山梨醇溶液;500mL表面活化剂储备溶液;800mL水;200g十二氟代戊烷。用氮气将容器加压到10PSI并维持45分钟。在14,000PSI压力下,将悬浮液通过微流体化器45分钟。在4℃下,将乳剂转移到含8L 25%山梨醇的容器中并充分混合。用正压将乳剂通过0.22微米的滤器转移到100mL药瓶中,盖塞并封口。实施例43
本发明的制剂涉及下列设备和步骤:微流体化器,型号110Y,相互作用室压力14,000PSI;高压容器,316号钢,5L和12L大小;滤布,醋酸纤维素,0.22微米;滤架,142mm。制备下列溶液:62.5%(w/v)山梨醇10L;41.75g Pluronic P-123,41.75gZonyl FSO,2.5L,声处理助溶(表面活化剂储备溶液)。将山梨醇溶液装入微流体化器中。在粉碎过程中,用碎冰覆盖相互作用室、管子和冷却盘管。在冰浴下,向装有搅拌棒的5L的高压容器中相继加入:1800mL表面活化剂储备溶液;200g十二氟代戊烷。用氮气将容器加压到10PSI 45分钟同时搅拌。在5,000PSI压力下将悬浮液通过微流体化器30分钟,在14,000PSI压力下通过60分钟。将乳剂转移到含8L 62.5%山梨醇的4℃的容器中并充分混合。用正压将乳剂通过0.22微米的滤器转移到100mL药瓶中,盖塞并封口。实施例44
本发明的配制涉及下列设备和步骤:微流体化器,型号110Y,相互作用室压力14,000PSI;高压容器,316号钢,5L和12L大小;滤布,醋酸纤维素,0.22微米;滤架,142mm。制备下列溶液:33%(w/v)蔗糖20L;150.0g Pluronic P-123,150.0g ZonylFSO,2.5L,声处理助溶(表面活化剂储备溶液)。将蔗糖溶液装入微流体化器中。在粉碎过程中,用碎冰覆盖相互作用室、管子和冷却盘管。在冰浴下,向装有搅拌棒的5L高压容器中相继加入:1800mL表面活化剂储备溶液;333g十二氟代戊烷。用氮气将容器加压到10PSI同时搅拌。在14,000PSI下,将悬浮液通过微流体化器160分钟并用循环水浴冷却相互作用室至-3.0℃。将乳剂转移到含8L 33.3%(w/v)蔗糖的4℃下的容器中并混合45分钟。用正压将乳剂通过0.22微米的滤器转移到20mL预冷药瓶中,盖塞并封口。实施例45
本发明分散相应该由任何生物相容的化学物质组成,该化学物质的沸点等于或低于服用制剂的并且在给药后用超声的方法测定生物体的体温,这样在检查期间足够量的化学物质变成气态分散相,给测得的超声数据方面提供诊断上有用的改变。实施例2的表中包含多物种的体温,该表可用于选择本文公布的制剂的量恰当的分散相。
在某些情况下,例如,发热情况下的生物体或在空气压力降低的高空诊室进行研究,沸点超过生物体正常体温18℃的化学物质可用作此超声造影剂的分散相。
已确定选择用作低沸液体分散相的温度的上限,下限取决于生产方法。如果可用的设备仅包含封闭的容器并且是一种在配制胶体分散液期间不能加压的反应容器,那么只能使用沸点等于或高于连续相冰点温度的分散相。例如,含大约25% w/v碘海醇的连续相冰点接近-6℃。使用这种连续相时,任何沸点超过-6℃的低沸点液体都可能仅仅因为冷却而被液化。
然而,如果某设备是能加压的反应容器,例如在30PSI压力下用氮气罐操作,那么低沸点液体能处于液化潜伏状态并因此得到分散,甚至这些沸点可低于连续相的冰点。
实施例44描述了用沸点超过连续相冰点的分散相液体来制备乳剂的方法,同时实施例48描述了通过加压并致冷而用沸点低于连续相冰点的分散相液体制备乳剂的方法。显然,用正压降低高蒸汽压的即沸点低的那些物质的汽化作用将会使任何化学物质更有效地分散。
确定了分散相液体的合适沸点,就可参考经典教材,如CRC或类似的概要,快速确定可用的实际化学物质。以沸点为序,下表列出了某些低沸点液体,但不是全部:化学物质表:沸点以摄氏度表示化学物质名称 分子量 沸点 化学物质类别氖 20.18 -246.0 11氮(N2) 28.01 -196.0 11氩 39.98 -189.4 10氧(O2) 32 -183.0 11甲烷 16.04 -164.0 1氪 83.8 -153.0 11氧化氮 30.01 -151.6 11四氟甲烷 88 -129.0 3氙 131.29 -108.0 11乙烯 28.05 -103.7 1乙烷 30.07 -88.6 1氧化亚氮 44.01 -88.5 11乙炔 26.04 -84.0 1亚硝基三氟甲烷 99.01 -84.0 3三氟甲烷 70.02 -84.0 3碳酰氟化物 66.01 -83.0 91,2-二氟乙烯 64 -83.0 31,1-二氟乙烯 64.04 -83.0 3三氟甲烷 70.01 -82.2 3一氯三氟甲烷 104.46 -81.4 3六氟乙烷 138.01 -79.0 3全氟乙烷 138.01 -79.0 3氟代甲烷 34.03 -79.0 3二氧化碳 44.01 -78.6 11氟代甲烷 34.03 -78.4 3亚硝酸丁酯 103.12 -77.8 11四氟乙烯 100.02 -76.3 3六氟化硫 146.05 -64.0 11三氟乙腈 95.02 -64.0 10一溴三氟甲烷 148.91 -57.9 3二氟甲烷 52.02 -51.6 3三氟乙烯 82.03 -51.0 3硫化羰 60.08 -50.0 113,3,3-三氟丙炔 94.04 -48.3 3五氟乙烷 120 -48.0 3丙烯 42.08 -47.4 11,1,1-三氟乙烷 84.04 -47.3 3丙烷 44.1 -42.1 1亚硝基五氟乙烷 149.02 -42.0 3一氯二氟甲烷 86.47 -40.8 31,1,1,2,3,3-六氟-2,3-二 221 -39.03 3氟丙烷四氟丙二烯 112.03 -38.0 31-氯-1,1,2,2,2-五氟乙烷 154.47 -38.0 3一氯五氟乙烷 154.47 -38.0 3氟代乙烷 48.06 -37.7 3全氟二甲胺 171.02 -37.0 10全氟丙烷 188.02 -36.0 3全氟乙胺 171.02 -35.0 10丙二烯 40.06 -34.5 1环丙烷 42.08 -32.7 1三氟甲基过氧化物 170.01 -32.0 11六氟偶氮甲烷 166.03 -31.6 11硝基三氟甲烷 115.01 -31.1 3氯代乙炔 60.48 -30.0 3二氯二氟甲烷 120.91 -29.8 3全氟丙烯 150.02 -29.4 3六氟代丙酮 166.02 -28.0 31,1,2,2-四氟乙烷 102.03 -27.0 31,1,1,2-四氟乙烷 102.03 -26.5 31-氯-1,2,2-三氟乙烯 116.47 -26.2 3一氯三氟乙烯 116.47 -26.2 3甲醚 46.07 -25.0 61,1-二氟乙烷 66.05 -24.7 3全氟2-丁炔 162.03 -24.6 31-氯-1-氟乙烯 80.5 -24.0 3丙炔 40.06 -23.2 1一碘三氟甲烷 195.91 -22.5 3三氟甲基硫化物 170.07 -22.2 11三氟甲磺酰氟化物 152.06 -21.7 33,3,3-三氟丙烯 96.05 -21.0 31,1,1,3,3-五氟丙烯 132.04 -21.0 3(五氟硫代)三氟甲烷 196.06 -20.0 31,1,2,2-四氟乙烷 102.04 -19.7 32-氯-1,1-二氟乙烯 98.5 -17.7 32-H-七氟丙烯 170.03 -15.0 31,1,1-三氟丙烷 98.07 -13.0 3一溴二氟一亚硝基甲烷 159.92 -12.0 3亚硝酸甲酯 61.04 -12.0 11七氟-1-亚硝基丙烷 199.03 -12.0 32-氯-1,1,1,2-四氟乙烷 136.48 -12.0 3异丁烷 58.12 -11.6 11-氯-1,1,2,2-四氟乙烷 136.48 -10.0 32-氟丙烷 62.09 -10.0 3一氯一氟甲烷 68.48 -9.1 3异丁烯 56.11 -6.9 1六氟二甲胺 153.03 -6.7 101-丁烯 56.11 -6.3 1亚硝酰氯 65.47 -5.5 111,3-丁二烯 54.09 -4.4 1八氟环丁烷 200.03 -4.0 33-氟丙烯 60.07 -3.0 3氯化二甲基氧 82.53 -2.0 32-氯七氟丙烷 204.47 -2.0 31,1,1,2,2,3-六氟丙烷 152.04 -1.4 31,1,1,3,3,3-六氟丙烷 152.05 -1.1 3三氟甲亚磺酰氯 136.52 -0.7 3正丁烷 58.12 -0.5 12,2-二氟丙烷 80.08 -0.4 32-氯-1,1-二氟乙烷 100 -0.1 3硝基-五氟乙烷 165.02 0.0 3全氟2-丁烯 200.03 0.0 3异丙基乙炔 68 0.0 12-丁烯{反式} 56.11 0.9 14-甲基-1,2-苯并蒽 242.32 1.0 21,1,1,2,2,3-六氟丙烷 152.04 1.2 3八氟-2-丁烯 200.04 1.2 3偶氮甲烷 58.08 1.5 11四氯苯二甲酸 303.91 2.0 3三甲胺 59.11 2.9 10全氟环丁烯 162.03 3.0 33,3,4,4,4-五氟-1-丁烯 146 3.0 31,1,2,2-四氟-1,2-二氯乙烷 170.92 3.0 31,2,2,2-四氟-1,1-二氯乙烷 170.92 3.6 32-丁烯{顺式} 56.11 3.7 11,2-二氯四氟乙烷 170.92 3.8 3十氟丁烷 238.03 4.0 3甲基环丙烷 56.11 4.0 1二氯三氟乙烷 152 4.0 3溴代乙炔 104.93 4.7 3全氟1-丁烯 200.03 4.8 3五氯苯甲酰氯 312.79 5.0 31,1,2-三氟乙烷 84.04 5.0 3乙烯基乙炔 52.08 5.1 1六氟1,3-丁二烯 162.03 6.0 32-三氟甲基丙烯 110.08 6.0 3甲硫醇 48.1 6.2 111,1,1,2,3,3-六氟丙烷 152.04 6.5 3二氧化三碳 68.03 6.8 112-氯-1,1,1-三氟乙烷 118.49 6.9 3亚甲基环戊二烯 78.11 7.0 11二甲基胺 45.08 7.4 102-氯-1,3-二氟丙烷 114.51 8.0 31-丁炔 54.09 8.1 1二氯一氟甲烷 102.92 9.0 3新戊烷 72.15 9.5 11-氯-2-氟乙烯 80.5 10.0 3丁二炔 50.06 10.3 11,2-丁二烯 54.09 10.8 1甲乙醚 60.1 10.8 62-氟-1,3-丁二烯 72.08 12.0 3丁烯腈 67.09 12.0 11环丁烷 56.11 12.0 11,2-环氧-3-氯-异丁烷 106.55 12.0 3甲基乙烯基醚 58.08 12.0 61-溴七氟丙烷 248.9 12.0 3一碘五氟乙烷 245.9 12.0 32-(三氟甲基-1,1,1,3,3,3- 211 12.03六氟丙烷)氯化乙烷 64.51 12.3 31,1,1-三氟重氮乙烷 110.04 13.0 33-甲基-2-丁烯 68 14.0 1二硅烷醇甲烷 76.25 14.7 11亚硝酸乙酯 75.07 16.0 11乙胺 45.08 16.6 10六氟化钨 298 17.5 112,2-二甲基-2-降冰片烷醇 140.23 19.0 111,1-二氯-2,2-二氟乙烯 133 19.0 3-溴-氟甲烷 112.93 19.0 33-甲基-1-丁烯 70.13 20.0 1三甲基硼 55.91 20.0 11Fluorinert,FC-87(3M Unknown 20.0 3Trade Mark)1,1-二甲基环丙烷 70.13 20.6 1乙醛 44.05 20.8 7乙酰氟 62.04 20.8 9二甲基甲氧基硼 71.19 21.0 111,2-二氯-1,2-二氟乙烯 132.92 21.1 3二氯二氟乙烯 1132.92 21.1 3二氟一碘甲烷 177.92 21.6 3二乙炔 50.08 22.0 12-氯丙烯 76.53 22.6 3d-香芹酮 150.22 23.0 11三氯一氟甲烷 137.37 23.7 34-甲基-1,3-二氧戊环-2-酮 102.09 24.2 1二溴二氟甲烷 209.82 24.5 34-氨基-4-甲基-2-戊酮 115.18 25.0 10一氯二氟-硝基甲烷 131.47 25.0 3七氟-1-硝基丙烷 215.03 25.0 33-氯环戊烯 102.56 25.0 31,4-戊二烯 68.12 26.0 11,5-庚二炔 92.14 26.0 14-苯基-3-丁烯-2-酮{反式} 146.19 26.0 21,1,2,2,3-五氟丙烷 134.06 26.0 32-丁炔 54.09 27.0 12,2-二氯-1,1,1-三氟乙烷 152.9 27.0 3八氟环戊烯 211.05 27.0 31-壬烯-3-炔 122.21 27.0 12-甲基丁烷 72.15 27.8 12-甲基丁烷 72.15 27.8 11,2-二氯三氟乙烷 152.9 28.0 3二氟甲基2,2,2-三氟乙基醚 150.05 28.0 31,2-二甲环丙烷{反式,左旋} 70.13 28.0 1乙烯醚 70 28.0 61,2-二甲环丙烷{反式,右旋} 70.13 29.0 12,4-二氨基甲苯 122.17 29.0 2全氟-1-戊烯 250.04 29.0 33-甲基-1-丁炔 68.12 29.5 11-戊烯 70.13 30.0 13,3,4,4,5,5,5-七氟-1-戊烯 196 30.0 3一碘三氟乙烯 207.9 30.0 33-氟苯乙烯 122.14 30.0 113-溴-1-戊烯 149.03 30.5 3全氟戊烷 288.04 30.5 31,2-二氟乙烷 66.05 30.7 33-甲基-1,1,1-三氟丁烷 126.12 31.0 32-甲基-1-丁烯 70.13 31.2 1甲酸甲酯 60.05 31.5 9三氟甲磺酰氯 168.52 31.6 31,1-二氯-1-氟乙烷 116.95 32.0 31-氟戊烷 90.14 32.0 3二碘乙炔 277.83 32.0 32-氨苛丙烷 59.11 32.4 101-氟丁烷 76.11 32.5 3甲基异丙醚 74.12 32.5 61-氯丙烯 76.53 32.8 32-溴-丁醛 151 33.0 32-氯-1,1,1,4,4,4-六氟-2-丁烯 198.5 33.0 31,2,3-三氯-1,3-丁二烯 157.43 33.0 32-氯-1,1,1,4,4,4-六氟丁烯 199 33.0 3双-(二甲基膦基)胺 137.1 33.5 102-甲基-1,3-丁二烯 68.12 34.0 12-甲基-1-丁烯-3-炔 66.1 34.0 1异戊二烯 68.12 34.0 1-氯-二硝基甲烷 140.48 34.0 31,2-环氧丙烷 58.08 34.3 6乙基-环丙烷 70.13 34.5 1乙醚 74.12 34.5 6六氟二甲基二硫化物 202.13 34.6 111,2-二氯-1-氟乙烯 115 35.0 31,2-二氯六氟丙烷 220.93 35.0 3乙基乙烯基醚 72.11 35.0 62-氯丙烷 78.54 35.7 3-溴-氯-氟甲烷 147.37 36.0 32,3,6-三甲基-哌啶 127.23 36.0 112-羟基-1,2,3-十九烷三羧酸 500.72 36.0 9三甲酯二甲基乙基胺 73.14 36.0 10正戊烷 72.15 36.1 12-戊烯{反} 70.13 36.3 1甲基环丁烷 70.13 36.3 1乙基甲基胺 59.11 36.7 102-戊烯{顺} 70.13 37.9 11,2-二甲基环丙烷{顺} 70.13 37.0 11,1-二氯乙烯 96.94 37.0 31-氯丙烯{反} 76.53 37.4 31,1-二氯-2-氟-乙烯 114.93 37.5 3二氟甲烷 84.93 40.0 3碘甲烷 141.94 42.4 31,1-二氯乙烷 98 57.3 3化学物质类别说明:
1、脂肪族碳氢化合物和/或衍生物
2、芳香族碳氢化合物和/或衍生物
3、有机卤化物和/或衍生物
6、醚和/或衍生物
7、醛和/或衍生物
9、羧酸和/或衍生物
10、胺和/或衍生物
11、其他实施例46
根据实施例45所制定的规则和标准,分散相也可选自共沸混合物。下面列出了某些,但不是全部二元共沸混合物的沸点:
丙酮(21%)-戊烷(79%)32℃;乙醚(48%)-异戊二烯(52%)33℃;乙醚(44%)-甲酸甲酯(56%)28℃;乙醚(98.8%)-水(1.2%)34℃;异戊二烯(86%)-2-甲基-2-丁烷(14%)34℃;2-氯丙烷(99%)-水(1%)35℃;甲基乙烯基氯化物(99.1%)-水(0.9%)33℃;戊烷(98.6%)-水(1.4%)34℃;乙烯基乙基醚(98.5%)-水(1.5%)34℃。
下面列出某些,但不是全部三元共沸混合物的沸点:
丙酮(7.6%)-异戊二烯(92%)-水(0.4%)32℃,二硫化碳-甲醇-乙酸甲酯37℃;二硫化碳(55%)-甲醇(7%)-甲缩醛(38%)35℃。实施例47
给予有机体后,本发明胶态分散体的至少一部分分散相渗出或蒸发,这有别于现有技术的乳剂。独特的液-气界面物质的存在产生强力的声束反散射。
分散气相乳剂存在的一个试验是由压力的改变所引起的混悬液的超声反散射应答。真正的液体分散体对压力是极不敏感的,而当加压时,由于气体的压缩和有效反散射横截面的减小,气体胶态分散体会显示声学反散射的减小。
按实施例1的试验体系,通过声窗来试验封密的烧杯中的声学反散射。然后对体系加压并重新记录声学反散射。因为加压后声学反散射有显著不同,断定分散相中含有某些气态部分。实施例48
通过由气态分散相的缩合而不是通过由液态分散相的粉碎来制备本发明的制剂且包含下列设备和步骤:微流体化器,110Y型,相互作用室压力14,000PSI;压力容器,316号钢,5L和12L尺寸;滤布,醋酸纤维素,0.22微米;滤架,142mm。制备下列溶液:36%碘海醇,10L;41.75g Pluronic P-123,41.75g Zonyl FSO,2.5L,超声助溶(表面活化剂储备溶液)。缩合期间,用碎冰包覆相互作用室、导管和冷却管。将1800mL表面活性剂储备溶液加到装有搅棒的放在冰浴中的5L压力容器中。用气体密封装置,将丙烷罐(沸点-42℃)装在相互作用室上并使相互作用室装上200g的丙烷。搅拌下,用氮气将整个容器加压到10PSI,保持45分钟。将混悬液在5,000PSI下通过微流体化器30分钟,在14,000PSI下通过微流体化器60分钟。在4℃下,将乳剂转移到含8L水的容器中并混合均匀,用正压将物质压过0.22微米微布而转移到100ml的瓶中。加盖并密封小瓶。
通过改变分散相,可以类似的方法制备含有实施例45的其它低沸点物质的乳剂,压力和温度足以使分散相物质液化。实施例49
分散相可以由在标准压力条件下沸点低于被给予制剂的生物体的体温并且在给药后可通过超声来检测的任何化学物质组成。实施例45讨论如何基于所选择的化学物质的沸点和制备方法参数所获得的温度范围来选择合适的分散相化学物质。
已经确定,标准压力条件下的沸点优选地低于约37℃,已发现通过所存在的原子总数来选择化学物质是另一种选择适于作为超声造影剂物质的方法。以所存在的原子总数为序,列出了合适的化学物质,显示所有优选的化学物质都含有4到17个原子。化学物质表:沸点为℃名称 原子数 分子式 分子量 沸点溴代甲烷 4 CH3Br 94.94 3.2一溴二氟甲烷 5 CHBrF2 130.92 -14.15氯氟甲烷 5 CH2ClF 68.48 -9.15一溴三氘甲烷 5 CD3Br 12 2.8丙二烯二酮 5 C3O2 68.03 6.8二氯-氟甲烷 5 CHCl2F 102.92 8.9甲基硒醇 5 CH4Se 95 12二氟-碘甲烷 5 CHF21 177.92 21.6二溴二氟甲烷 5 CBr2F2 209.82 22.79三氯一氟甲烷 5 CC13F 137.7 23.65溴氯氟甲烷 5 CHBrClF 147.37 36.112-氯-1,1-二氟乙烯 6 C2HClF2 98.48 -18.6三氟甲基硒醇 6 CHF3Se 148.97 -14.5氯代乙烯 6 C2H3Cl 62.5 -13.9草酰氟 6 C2F2O2 94.02 -2.7甲酰胺 6 CH3NO 45.04 2.182-溴-1,1-二氟乙烯 6 C2HBrF2 142.93 5.7甲硫醇 6 CH4S 48.1 5.9丁二炔 6 C4H2 50.06 9溴代乙烯 6 C2H3Br 106.95 15.61,1-二氯-2,2-二氟乙烯 6 C2Cl2F2 132.92 18.9反式-1-溴-2-氟乙烯 6 C2H2BrF 124.94 19.8溴代甲烷 4 CH3Br 94.94 3.21,1-二氯-2,2-二乙烯 6 C2Cl2F2 132.92 201,1-二氯乙烯 6 C2H2Cl2 96.94 31.8反式-1,2-二氯一氟乙烯 6 C2HCl2F 114.93 37顺式二氯-氟乙烯 6 C2HCl2F 114.93 371,1-二氯-2-氟乙烯 6 C2HCl2F 114.93 37甲基二氟胺 7 CH3F2N 67.02 -16二氟苯磷酸甲酯 7 CH3F2OP 100 -15.5甲胺 7 CH5N 31.06 -6.5二氯甲基甲硼烷 7 CH3BCl2 96.75 11.5四氯-1,2-二氟-乙烷 8 C2Cl4F2 203.83 -37.51,1,2-三氯乙烷 8 C2H3Cl3 133.4 -241,1,1,2-四氯乙烷 8 C2H2Cl4 167.85 -16.31-氯-1,1-二氟-乙烷 8 C2H3ClF2 100.5 -9.81,2-二溴-1,1-二氯乙烷 8 C2H2BrCl2 256.75 1.781,1-二氯-四氟乙烷 8 C2Cl2F4 170.92 31,1,2-三氟乙烷 8 C2H3F3 84.04 31,2-二氯-四氟乙烷 8 C2Cl2F4 170.92 3.5四氟(甲基-甲胺) 8 C2HF4N 115.03 5丁烯炔 8 C4H4 52.08 5.112-氯-1,1,1-三氟乙烷 8 C2H2ClF3 118.49 6氟羰基-三氟甲基硫烷 8 C2F4OS 148.08 8氯甲基硅烷 8 CH5ClSi 80.59 81,2-二氟乙烷 8 C2H4F2 66.05 10氯代乙烷 8 C2D5Cl 64.51 12五氟-碘乙烷 8 C2F5I 245.92 12.52-重氮基-1,1,1-三氟 8 C2HF3N2 110.04 13乙烷1-氯-1-氟乙烷 8 C2H4ClF 82.31 161,1,2-四氯乙烷 8 C2H2Cl4 167.85 16.31,1,2-三氯乙烷 8 C2H3Cl3 133.4 242-溴-1,1,1-三氟乙烷 8 C2H2BrF3 162.94 26氯甲基-三氟硅烷 8 CH2ClF3Si 134.56 261,2-二氟乙烷 8 C2H4F2 66.05 30.72-氯-1,1-二氟乙烷 8 C2H3ClF2 100.05 35.1四氯-1,2-二氟乙烷 8 C2Cl4F2 203.83 37.5溴代-五氘乙烷 8 C2BrD5 114 38二甲基硅烷 9 C2H8Si 60.1 -20五氟环丙烷 9 C3HF5 132.03 -9二氟甲基-三氟甲基硫化 9 C2HF5S 152.08 0.8物1,1,2,3,3-五氟丙烯 9 C3HF5 132.03 1.8一氯五氟环丙烷 9 C3ClF5 166.48 3甲锗烷基乙炔 9 C2H4Ge 100.64 3.85反式-1,1,2,3-四氟环丙 9 C3H2F4 114.04 6烷2-氯-五氟丙烯 9 C3ClF5 166.48 6.73-氯-五氟丙烯 9 C3ClF5 166.48 7.31-氯-五氟丙烯 9 C3ClF5 166.48 8氟甲基甲基醚 9 C2H5FO 64.06 19一溴五氟环丙烷 9 C3BrF5 210.93 20.5乙烯氧基乙炔 9 C4H4O 68.08 222-氯丙烯 9 C3H5Cl 76.53 22.6顺-反-1-氯-1,2,2,3-四 9 C3HClF4 148.49 24.5氟环丙烷3-溴-五氟-丙烯 9 C3BrF5 210.93 26.52,2-二氯-1,1,1-三氟乙 9 C2HCl3F3 152.93 27烷呋喃 9 C4H4O 68.08 311-氯丙烯 9 C3H5Cl 76.53 32.12-氯-乙烯基-三氟硅烷 9 C2H2ClF3Si 146.57 33顺式-1,1,2,3-四氟环丙 9 C3H2F4 114.04 34烷3-溴-1,1,3-四氟丙烯 9 C3HBrF4 192.94 34乙硫醇 9 C2H6Si 62.13 35二甲基硫化物 9 C2H6S 62.13 36(氯-氟-甲基)-三氟甲基 9 C2HClF4S 168.54 37硫化物1-三氯丙烷 9 C3H5Cl 76.53 37.21,3-丁二烯 10 C4H6 54.09 -4.61,5-Dicarbaclosotri- 10 C2H5B3 61.49 -3.7boraneω-亚硝基全氟丙腈 10 C3F4N2O 156.04 2五氟丙醛 10 C3HF5O 148.03 21,1-二氟-1,3-丁二烯 10 C4H4F2 90.07 3.5甲基乙烯基醚 10 C3H6O 58.08 5六氟-1,3-丁二烯 10 C4F6 162.03 5.81-丁炔 10 C4H6 54.09 7.91-氘-1-丁烷 10 C4H5D 55.1 8亚甲基环丙烷 10 C4H6 54.09 8.81,2-丁二烯 10 C4H6 54.09 10.842-氟-1,3-丁二烯 10 C4H5F 72.08 11.51H-五氟-1-丁炔 10 C4HF5 144.04 12五氟-丙酮 10 C3HF5O 148.03 13.5一氟氨基乙烷 10 C2H5F2N 81.07 14.9Tetra-B-fluor-B,B′- 10 C2H2B2F4 123.65 15ethenediyl-bis-borane顺-1-氟-1,3-丁二烯 10 C4H5F 72.08 15.6反-1-氟-1,3-丁二烯 10 C4H5F 72.08 16乙胺 10 C2H7N 45.08 16.6二甲基膦 10 C2H7P 62.05 20N-Methyl-imino-schwe- 10 CH3F4NS 137.1 21.8fel-tetra-fluorideMethylschwefelpenta- 10 CH3F5S 142.09 26fluoride2-丁炔 10 C4H6 54.09 26.97一溴五氟丙酮 10 C3BrF5O 226.93 31溴-二甲基甲硼烷 10 C2H6BBr 120.78 31.751-氯-2,3,3,4,4-五氟环 10 C4ClF5 178.49 33丁烯双-三氟甲基二硫化物 10 C2F6S2 202.13 34(±)(1)1,2-环氧丙烷 10 C3H6O 58.08 34.23乙基硅烷 11 C2H8Si 60.17 -141,1,1-三氟丙烷 11 C3H5F3 98.07 -132-氟丙烷 11 C3H7F 62.09 -11全氟甲氧基乙酰氟化物 11 C3F6O2 182.02 -9.7乙基-三氟硅烷 11 C2H5F3Si 114.14 -4.41-氟丙烷 11 C3H7F 62.09 -32,2-二氟丙烷 11 C3H6F2 80.08 -0.61,1,1,3,3,3-六氟丙烷 11 C3H2F6 152.04 -0.5全氟环丁酮 11 C4F6O 178.03 11,1,1,2,2,3-六氟丙烷 11 C3H2F6 152.04 1.22-氯-七氟丙烷 11 C3ClF7 204.47 2.22-氘-二甲基-锗烷 11 C2H6D2Ge 106.69 6.51,1-二氟丙烷 11 C3G6F2 80.08 7乙基-三氘锗烷 11 C2H5D3Ge 107.69 11.3乙硅烷基-甲烷 11 CH8Si2 76.25 141-氯-1,1,2,2-四氟丙烷 11 C3H3ClF4 150.5 19.93三氟甲硅烷基二甲基胺 11 C2H6F3NSi 129.16 21亚乙基-甲基胺 11 C3H7N 57.1 27.5乙硅烷基甲烷 11 CH8Si2 76.25 28二乙烯基醚 11 C4H6O 70.09 281,1,1,3-四氟-丙烷 11 C3H4F4 116.06 29.41-Sila-3-germapropane 11 CH8GeSi 120.75 302-氯-1,1,1-三氟丙烷 11 C3H4ClF3 132.51 302-甲基-1-丁烯-3-炔 11 C5H6 66.1 32双-三氟甲硅烷基二氯甲 11 CCl2F6Si2 253.08 34烷1,2-二氯-六氟-丙烷 11 C3Cl2F6 220.93 34.82-氯丙烷 11 C3H7Cl 78.54 34.8乙基-乙烯基醚 11 C2H8O 72.11 353-methylen-oxetane 11 C4H6O 70.09 352-氯-2-氟丙烷 11 C3H6ClF 96.53 35.2双-三氟甲硅烷基甲烷 11 CH2F6Si2 184.19 35.5一氯二甲基硅烷 11 C2H7ClSi 94.62 35.71,3-二氯-六氟丙烷 11 C3Cl2F6 220.93 36.1双-三氟甲硅烷基氯甲烷 11 CHClF6Si2 218.63 37七氟-1-亚硝基丙烷 12 C3F7NO 199.03 -9.51,1,2,2,3-五氟-3-氟甲 12 C4F8 200.03 -9基环丙烷2-甲基-丙烯 12 C4H8 56.11 -6.9八氟环丁烷 12 C4F8 200.03 -6.421-丁烯 12 C4H8 56.11 -6.31,1,2,2-四氟甲氧基乙 12 C3HF7O 186.03 -2烷顺-八氟-2-丁烯 12 C4F8 200.03 0.4甲基-环丙烷 12 C4H8 56.11 0.7but-2t-ene 12 C4H8 56.11 0.882-丁烯 12 C4H8 56.11 1七氟-丁腈 12 C4F7N 195.04 1八氟-2-丁烯 12 C4F8 200.03 1.21,1-二氟-1-丁烯 12 C4H6F2 92.09 3.71but-2c-ene 12 C4H8 56.11 3.72八氟-1-丁烯 12 C4F8 200.03 4.81,1,1,4,4,4-六氟-2-丁烯 12 C4H2F6 164.05 5.4三氟甲基乙基醚 12 C3H5F3O 114.07 5.52H,3H-hexafluoro-but-2 12 C4H2F6 164.05 6t-ene3,3,3-三氟-2-甲基丙烯 12 C4H5F3 110.08 6甲乙醚 12 C3H8O 60.1 6.62H-七氟-1-丁烯 12 C4HF7 182.04 10环丁烷 12 C4H8 56.11 12五氟-2-甲基丙烯 12 C4H3F5 146.06 12.8甲基-乙烯基硅烷 12 C3H8Si 72.18 13.71,1,1-trifluoro-but-2 12 C4H5F3 110.08 20t-ene1,1,1-trifluoro-but-2 12 C4H5F3 110.08 20t-ene烯丙基三氟硅烷 12 C3H5F3Si 126.15 211,1,2-三氟-2-三氟甲基 12 C4H2F6 164.05 21.5环丙烷1,1,2-三氟-1-氯-2-三氟 12 C3HClF6O 202.48 23甲氧基乙烷七氟丙烷-1-硫醇 12 C3HF7S 202.9 23.7(2-溴-1,1,2,2-四氟-乙 12 C3BrF7O 264.93 24基)-三氟甲基醚环丙基硅烷 12 C3H8Si 72.18 26.83,3-二氟-2-甲基丙烯 12 C4H6F2 92.09 28.11,1,2,2-四氟乙基二氟 12 C3H2F6O 168.04 28.5甲基醚2,2,2-三氟乙基-二氟甲 12 C3H3F5O 150.05 29基醚1,1,1-三氟-2-甲氧基乙 12 C3H5F3O 114.07 31烷2-氯-七氟-2-丁烯 12 C4ClF7 216.49 32.2五氟硝基丙酮 12 C3F5NO3 193.03 32.62H,3H-hexafluoro-but-2 12 C4H2F6 164.05 33.2c-ene2-氯-3H-六氟-2-丁烯 12 C4HClF6 198.5 34.4tetra-B-fluoro-B,B′- 12 C2H4B2F4 125.67 35ethanediyl-bis-borane乙基-三氟甲基硫化物 12 C3H5F3S 130.13 35甲基-(1,1,2,2-四氟乙 12 C3H4F4O 132.06 36.5基)-醚(氯-二氟甲基)-(2,2,2- 12 C3H2ClF5O 184.49 37三氟乙基)醚1,1,2-三氟-1,2-二氯-2 12 C3Cl2F6O 236.93 37-三氟甲氧基乙烷1-亚硝基-2-三氟甲氧基 13 C3F7NO2 215.03 -10四氟乙烷九氟-2-氮杂丁烷 13 C3F9N 221.03 -3.8三甲基胺 13 C3HgN 59.11 3.53,3-二甲基环丙烯 13 C5H8 68.12 181,4-戊二烯 13 C5H8 68.12 243-甲基-1-丁炔 13 C5H8 68.12 263-甲基-环丁烯 13 C5H8 68.12 27.5三氟甲重氮-2,2,2-三氟 13 C3H2F6N2 180.05 28乙烷2-甲-1,3-丁二烯 13 C5H8 68.12 30α-亚硝基-全氟异丁腈 13 C4F6N2O 206.05 31异丙胺 13 C3H9N 59.11 31.72-甲氧全氟丙烯 13 C4H3F5O 162.06 32二甲基乙炔基硅烷 13 C4H8Si 84.19 321,1,2,2-四氘螺戊烷 13 C5H4D4 72.14 33二甲氧硅烷 13 C2H8O2Si 92.17 33.5异丙烯基-甲基醚 13 C4H8O 72.11 34叔丁基硅烷 13 C4H12Si 88.22 34.4螺戊烷 13 C5H8 68.12 353,4,4-三氟异戊二烯 13 C5H5F3 122.09 351-甲基-环丁烯 13 C5H8 68.12 372-甲基-丙烷 14 C4H10 58.12 -13.3十氟丁烷 14 C4F10 238.03 -1.71-氚丁烷 14 C4H9D 59.13 -0.5丁烷 14 C4H10 -0.5全氟乙氧基乙酰氟化物 14 C4F8O2 232.3 0三甲硅烷 14 C3H10Si 74.2 6.7三氟甲基七氟-2-氧杂丙 14 C4F8O2 232.03 8酮2-氟-2-甲基丙烷 14 C4H9F 76.11 11七氟乙基-四氟亚乙基胺 14 C4F9N 233.04 12.82-三氟甲基丙烷 14 C4H7F3 112.09 13全氟-2-氮杂-2-戊烯 14 C4F9N 233.04 13.2氟-三甲基硅烷 14 C3H9FSi 92.19 161,1,1-三氟丁烷 14 C4H7F3 112.09 16.74二甲基-乙烯基甲硼烷 14 C4H9B 67.93 17.1三(三氟甲基)-锗氟化物 14 C3F10Ge 298.61 19.1氟-三甲基硅烷 14 C3H9FSi 92.19 20丙基硅烷 14 C3H10Si 74.2 21.31,1,1,3,3,3-六氟-2-甲 14 C4H4F6 166.07 21.5基丙烷2-氟-丁烷 14 C4H9FF 76.11 241,1,1,4,4,4-六氟丁烷 14 C4H4F6 166.07 24.5甲氧基-二甲基甲硼烷 14 C3H9BO 71.91 24.6三氟-丙基硅烷 14 C3H7F3Si 128.17 25氘化三甲锗 14 C3H9DGe 119.71 26三甲锗 14 C3H10Ge 118.7 26三甲基-羟胺 14 C3H9NO 75.11 302,2-二氟-丁烷 14 C4H8F2 94.1 30.921-氟-丁烷 14 C4H9F 76.11 31三(三氟甲基)-锗氯化物 14 C3C1F9Ge 315.06 37九氟-1-亚硝基-丁烷 15 C4F9NO 249.04 163-甲基-1-丁烯 15 C5H10 70.13 201,1-二甲基-环丙烷 15 C5H10 70.13 203-甲基-1-丁烯 15 C5H10 70.13 201,1-二甲基环丙烷 15 C5H10 70.13 20.6十氟环戊烷 15 C5F10 250.04 22.481,1,1,3,3,3-六氟-2-亚 15 C4F9NO 249.04 24硝基-2-三氟甲基-丙烷±反式-1,2-二甲基-环 15 C5H10 70.13 28.2丙烷1,2-二甲基环丙烷 15 C5H10 70.13 28.81-戊烯 15 C5H10 70.13 291-亚硝基-4-一氢八氟丁 15 C4HF8NO 231.05 30烷三氟乙酸-(双三氟甲酰 15 C4F9NO 249.04 30胺)异丙基-甲基醚 15 C4H10O 74.12 30.772-甲基-1-丁烯 15 C5H10 70.13 30.95全氟丙基甲醚 15 C4H3F7O 200.06 34乙醚 15 C4H10O 74.12 34.6乙基环丙烷 15 C5H10 70.13 35.8甲基环丁烷 15 C5H10 70.13 36戊烯-2 15 C5H10 70.13 36.15pent-2c-ene 15 C5H10 70.13 36.55顺式-1,2-二甲基环丙烷 15 C5H10 70.13 37.032-甲基-2-丁烯 15 C5H10 70.13 37.2β-亚硝基-九氟二乙基 16 C4F9NO2 265.04 15醚亚硝酸乙酯 16 C2H5NO2 75.07 17.4全氟二乙胺 16 C4F11N 271.03 23.9全氟-2-氮杂戊烷 16 C4F11N 271.03 24.34-Methylpent-4- 16 C6H9N 95.14 30ensaeurenitrile丁基-二氟-甲硼烷 16 C4H9BF2 105.92 35乙基-二甲胺 16 C4H11N 73.14 36.43,3-二甲基-1-丁炔 16 C6H10 82.15 372,2-二甲基-丙烷 17 C5H12 72.15 0.95(-)S-1-氟-2-甲基-丁烷 17 C5H11F 90.14 14.1(-)(R)-2-chloro- 17 C5H11C1 106.59 24.7pentaine四甲基锡烷 17 C4H12Sn 178.83 262-甲基丁烷 17 C5H12 72.85 27.85九氟-2-三氟甲基-丁烷 17 C5F12 288.04 30.12四(三氟甲基)锗 17 C4F12Ge 348.61 31.7戊烷 17 C5H12 72.15 36实施例50
在优选的实施方案中,分散相可以由在标准压力条件下沸点低于给予制剂的有机体体温并且在给药后能通过超声来检测的任何化学物质组成。实施例45讨论了如何基于考虑所选择化学物质的沸点和制备方法的参数而获得的温度范围来选择合适的分散相化学物质。
戊烷(十二氢戊烷)和全氟戊烷(十二氟戊烷)的沸点分别为36-37℃和28-29℃。这是选择适于作为分散相的化学物质极好的温度范围。因此,含有五个碳原子和可变的氢和氟原子的化学物质的沸点将在28和37℃之间并将成为合适的分散相化学物质。下列合适化学物质的表中包括某些并非全部含有五个碳,和可变的氢和氟原子的化学物质,即,C5HxFy:5,5-二氟-1,3-环戊二烯;1-氟-3-亚甲基-环丁烷;2H-氟化物(Fluorinium);(氟亚甲基)-环丁烷;环丁基氟代甲烷;2-氟-2,4-环戊二烯-1-基;(非定域-2,3,4,5,6)-2H-氟化物离子(-1);6-Fluoronia二环(3.1.0)己环烷;6-Fluoronia二环(3.1.0)己-2-烯氢氧化物内盐;1,3-戊二烯-1-基-5-亚基-氟(2+);1,3-戊二烯,氟配位物;氟化物;4-氟-环戊炔;3-(三氟甲基)-环丁烯;1,1,2,2,3,3-六氟-环戊烷;氟-三环(1.1.1.01.3)戊烷离子(1-);氟-螺(2.2)戊烷离子(-1);氟-三环(1.1.1.01.3)戊烷;反式-1,2-二氟-环戊烷;1,1-二氟-3-亚甲基-环丁烷;2-氧-1,3-环戊二烯;1-氟-1,3-环戊二烯;1,3-二氟-二环(1.1.1)戊烷;1,2,3,4,5-五氟-1,3-环戊二烯二聚物;1,2,3,4-四氟-1,3-环戊二烯;1,2,3,4,5-五氟-1,3-环戊二烯;1,2,3,3,4,5-六氟-环戊烯;1,1,2,2,3-五氟-3-(三氟甲基)-环丁烷;3,3,4,4-四氟-1-甲基-环丁烯;1-氟-1-甲基-环丁烷;2,2,3,3-四氟-二环(2.1.0)戊烷;3,3-二氟-环戊烯;5-氟-1,3-环戊二烯;2-(二氟亚甲基)-1,1,3,3-四氟-环丁烷;1,1,2,2,4,4-六氟-螺(2.2)戊烷;1-氟-二环(1.1.1)戊烷;4,4-二氟-环戊烯;(二氟亚甲基)-环丁烷;1,1-二氟-2-亚甲基-环丁烷;1,1-二氟-螺(2.2)戊烷;1,1,3,3-四氟-2-亚甲基-环丁烷;2-(二氟亚甲基)-1,1-二氟-环丁烷;1,1,4,4-四氟-螺(2.2)戊烷;1,1-双(三氟甲基)-环丙烷;1,1,2,2-四氟-螺(2.2)戊烷;(三氟甲基)-三环(1.1.0.02.4)丁烷;1,4-二氟-螺(2.2)戊烷;1,2-二氟-螺(2.2)戊烷;氟-螺(2.2)戊烷;1-(三氟甲基)-二环(1.1.0)丁烷;顺式-1,2-二氟-环戊烷;(1,1,2-三氟乙基)-环丙烷;1,1,1-二氟乙基)-环丙烷;(1,2,2-三氟乙基)-环丙烷;(2,2-二氟乙基)-环丙烷;(2-氟乙基)-环丙烷;1-氟-2,2-二甲基-环丙基;顺式-1-氟-2,3-二甲基-环丙烷;(三氟甲基)-环丁烷;三甲基Fluoriranium;1-氟-环戊化物(Cyclopentylium);1,1-二氟-2-甲基-2-(三氟甲基)-环丙烷;1-氟-2,3-二甲基-(1.α,2.α,3.α)-环丙烷;1-氟-2,3-二甲基(1.α,2β,3.β)-环丙烷;1-乙基-2-氧-环丙烷;反式-1-乙基-2-氟-环丙烷;1-氟-2,3-二甲基-(1.α,2.α,3.β)-环丙烷;1,1,2-三氟-2-(三氟甲基)-环丁烷;反式-1-(二氟甲基)-1-氟-2-甲基-环丙烷;顺式-1-(二氟甲基)-1-氟-2-甲基-环丙烷;1,1,2,2,3-五氟-3-甲基-环丁烷;1,1,2,3-四氟-2-(三氟甲基)-环丁烷;(2-氟乙烯基)-环丙烷;(1-氟乙烯基)-环丙烷;5,5-二氟二环(2.1.0)戊烷;1,4,4-三氟-3-亚甲基-环丁烯;2-乙烯基-1,1-二氟-环丙烷均聚物;3-(二氟亚甲基)-1,1-二氟-环丁烷;1,1,2-三氟-2-(三氟乙烯基)-环丙烷;1-氟-环戊烯;2-乙基-1,1-二氟-环丙烷;3,3-二氟-1-(五氟乙基)-环丙烯;顺式-1-甲基-2-(三氟甲基)-环丙烷;反式-1-甲基-2-(三氟甲基)-环丙烷;1-亚甲基-2-(三氟甲基)-环丙烷;1,1,2,2,3,3,4,5-八氟-环戊烷;顺式-1-(二氟甲基)-1-氟-2-甲基-环丙烷;反式-1-(二氟甲基)-1-氟-2-甲基-环丙烷;1,1,2,2,3,3,4-七氟-环戊烷;1,2,4,5,5-五氟-1,3-环戊二烯二聚物;1,2,3,5,5-五氟-1,3-环戊二烯二聚物;1,2,3,5,5-五氟-1,3-环戊二烯;1,2,4,5,5-五氟-1,3-环戊二烯;1,2,3,4,5-五氟-环戊烷立体异构体;1,1,2,3,4,5-六氟-环戊烷立体异构体;3-氟-1-甲基-环丁烯;1,4,5,5-四氟-环戊烯;3,3,4,4-四氟-环戊烯;3,3,4,4,5-五氟-环戊烯;1,4,4,5,5-五氟-环戊烯;1,3,3,4,4,5-六氟-环戊烯;(2,2,2-三氟乙基)-环丙烷;1,1,2,3,3,4,5-七氟-环戊烷;2,3,3-三氟-1-(三氟甲基)-环丁烯;1,2,3,3,4,5,5-七氟-环戊烯;1,2,3,3,4,4,5-七氟-环戊烯;3,3,4,4-四氟-1-(三氟甲基)-环丁烯;1,3,3,4,4,5,5-七氟-环戊烯;2-氟-1,1-二甲基-环丙烷;1,1,2,2,3,4,5-七氟-环戊烷;1,1,2,2-四氟-3-(三氟甲基)-环丁烷;氟代环戊烷;反式-1,2,3,3,4,5-六氟-环戊烯;1,1,-二氟-环戊烷;1,1,2,3,3,4,5-七氟-环戊烷立体异构体;1,1,2,3,3,4,5-七氟-环戊烷立体异构体;顺、顺-1,1,2,3,3,4,5-七氟-环戊烷;1,3,3,4,5,5-六氟-环戊烯;顺式-1,2,3,3,4,5-六氟-环戊烯;1,1,2,3,4,5-六氟-环戊烷立体异构体;1,1,2,3,4,5-六氟-(2.α,3.α,4.β,5.α)-环戊烷;1,1,2,3,4,5-六氟-环戊烷立体异构体;1,3,4,4,5,5-六氟-环戊烯;3,3,4,4,5,5-六氟-环戊烯;1,2,3,4,5-五氟-环戊烯;1,3,4,5,5-五氟-环戊烯;1,1,2,3,3,4,5-八氟-环戊烯烷;1,1,2,2,3,4,4,5-八氟-环戊烷;1,1,2,3,4,5-六氟-环戊烷;2-乙烯基-1,1-二氟-环丙烷;反式-1,1-二氟-2,3-二甲基-环丙烷;顺式-1,1-二氟-2,3-二甲基-环丙烷;1,1,2,2-四氟-3-亚甲基-环丁烷;1,1,2,2,3,4-六氟-3-(三氟甲基)-环丁烷;九氟-环戊烷;1,1,2,2-四氟-3-甲基-环丁烷;1,2-双(三氟甲基)-环丙烷;1,3,3,4,4-五氟-2-甲基-环丁烯;1,1-二氟-2,3-二甲基-环丙烷;1-甲基-1-(三氟甲基)-环丙烷;1,1-二氟-2,2-二甲基-环丙烷;1,3,4,4,4-五氟-3-(三氟甲基)-1-丁炔;1,1,2,3,4,5,5,5-八氟-1,3-戊二烯;1,2,3,3,4-五氟-4-(三氟甲基)-环丁烯;1,1,2,3,4,5,5,5-八氟-1,3-戊二烯;八氟-螺(2.2)戊烷;八氟-戊二烯;1,1,4,4,4-五氟-3-(三氟甲基)-1,2-丁二烯;1,1,3,4,4,5,5,5-八氟-1,2-戊二烯;五氟(三氟乙烯基)-环丙烷;1,1,2,3,4,5,5,5-八氟-1,3-戊二烯;1,1,2,3,3,4,5,5-八氟-1,4-戊二烯;3,3-二氟-1,2-双(三氟甲基)-环丙烯;八氟-环戊烯;1,1,2,4,4-五氟-3-(三氟甲基)-1,3-丁二烯;1,3,3,4,4-五氟-2-(三氟甲基)-环丁烯;1,1,1,4,4,5,5,5-八氟-2-戊炔;1,1,1,2,3,4,4,5,5,5-十氟-2-戊烯;1,1,3,3,4,4,4-七氟-2-(三氟甲基)-1-丁烯;顺式-1,1,2,3-四氟-2,3-双(三氟甲基)-环丙烷;反式-1,1,2,3-四氟-2,3-双(三氟甲基)-环丙烷;1,1,1,2,3,4,4,5,5,5-十氟-2-戊烯;五氟(五氟乙基)-环丙烷;1,1,2,3-四氟-2,3-双(三氟甲基)-环丙烷;1,1,2,2-四氟-3,3-双(三氟甲基)-环丙烷;十氟-环戊烷残基离子(1-);1,1,1,2,3,4,4,5,5,5-十氟-2-戊烯;1,1,1,2,4,4,4-七氟-3-(三氟甲基)-2-丁烯;1,2,2,3,3,4,4,5,5,5-十氟-亚戊基;1,1,2,3,4,4,4-七氟-3-(三氟甲基)-1-丁烯;十氟-戊烯;七氟(三氟甲基)-环丁烷;1,1,2,3,3,4,4,5,5,5-十氟-1-戊烯;十氟-环戊烷;2,3,4,4-四氟-2-环丁烯-1-酮;四氟呋喃;四(三氟甲基)-硅烷;三氟(九氟丁基)-硅烷;1,1,1,2,2,4,5,5,5-九氟-戊烷;1,1,1,2,2,3,5,5,5-九氟-戊烷;1,1,1,2,2,3,3,4,5-九氟-戊烷;1,1,1,3,3,3,5,5,5-九氟-戊烷;1,1,1,3,3,3-六氟-2-甲基-2-(三氟甲基)-丙烷;1,1,1,2,4,4-六氟-2-(三氟甲基)-丁烷;1,1,2,2,3,3,4,4,5-九氟-戊烷;1,1,1,4,4,4-六氟-2-(三氟甲基)-丁烷;1,1,1,3,3,3-六氟-2,2-二甲基-丙烷;1,1,3,3,5,5-六氟-戊烷;1,1,1,2,3,3-六氟-2-甲基-丁烷;六氟-戊烷;1,2,3,3,4,5-六氟-戊烷;2-(二氟甲基)-1,1,1,2-四氟-丁烷;1,1,1-三氟-2-(三氟甲基)-丁烷;4,4,4-三氟-3-(三氟甲基)-丁烷-1-13C;1,1,1,5,5,5-六氟-戊烷;1,1,1,2,3,3-六氟-戊烷;2,2,3-三氟-戊烷;2,2,4-三氟-戊烷;1,1,1-三氟-2-甲基-丁烷;1,1,1-三氟-2-甲基-丁烷;1,2,2-三氟-3-甲基-丁烷;1,3,3-三氟-2-甲基-丁烷;2,2,3-三氟-3-甲基-丁烷;1,1,1-三氟-2-甲基-丁烷;1,1,2-三氟-3-甲基-丁烷;1,1,2-三氟-戊烷;1,1,1-三氟-2,2-二甲基-丙烷;1,1,1-三氟-戊烷;1,1,1-三氟-3-甲基-丁烷;(九氟丁基)-硅烷;二甲基双(三氟甲基)-硅烷;(二氟甲基)(氟甲基)甲基(三氟甲基)-硅烷;双(二氟甲基)双(氟甲基)-硅烷;(3,3,3-三氟-2-(三氟甲基)丙基)-硅烷;三甲基(三氟甲基)-硅烷;三氟(1-甲基丙基)-硅烷;(二氟甲基)(氟甲基)二甲基-硅烷;三(氟甲基)甲基-硅烷;(1,1-二甲基乙基)三氟-硅烷;三氟(2-甲基丙基)-硅烷;甲基(3,3,3-三氟丙基)-硅烷;丁基三氟-硅烷;实施例51
在优选的实施方案中,分散相可以由在标准压力条件下沸点低于给予制剂的有机体的体温并且在给药后能通过超声来检测的任何化学物质组成。实施例45讨论了如何基于考虑所选择的化学物质的沸点和制备方法的参数而获得的温度范围来选择合适的分散相化学物质。
碳氟化合物因其低毒性,良好的乳化性质和低水溶性,产生持续的微泡,而特别适合作为从中选择分散相的化学物质:1,2,2-三(三氟甲基)丙烷、2,2-双(三氟甲基)丙烷、2-甲基-2-三氟甲基丙烷、四(三氟甲基)硅烷、甲基三(三氟甲基)硅烷、双(三氟甲基)二甲基硅烷、三氟甲基三甲基硅烷、1,1-双(三氟甲基)-2,2,3,3-四氟环丙烷、1,1-双(三氟甲基)环丙烷、1,1-双(三氟甲基)2,2-二氟环丙烷、1,1-二甲基-(2.2.3.3.)-四氟环丙烷、2,2-二氟-1-甲基-1-三氟甲基环丙烷;(顺式+反式)1,2-双(三氟甲基)-1,2,3,3-四氟环丙烷、(顺式+反式)1,2-双(三氟甲基)-1,2-二氟环丙烷、1,2-双(三氟甲基)-3,3-二氟环丙烷、(顺式+反式)1,2-双(三氟甲基)环丙烷、1,1,2,2,4,4,5,5-八氟螺[2.2]戊烷、1,1,2,2-四氟螺[2.2]戊烷、1,1,4,4-四氟螺[2.2]戊烷、1,1,5,5-四氟螺[2.2]戊烷、3,3,4,5-四氟呋喃、三(三氟甲基)膦、1,1,2,2,3,3,4,4,5,5-十氟环丙烷、1,2,2,3,4,4,5,5-八氟二环[1.1.1]戊烷、2,2,4,4,5,5-六氟二环[1.1.1]戊烷、1,2,2,3,4,4-六氟二环[1.1.1]戊烷、1,2,2,3-四氟二环[1.1.1]戊烷、2,3,3,3-四氟二环[1.1.1]戊烷、1,2,2,3,3,4,4-七氟-1-三氟甲基环丁烷、2,2,3,4,4-五氟-1-三氟甲基二环[1.1.0]丁烷、2,2,4,4-四氟-1-三氟甲基二环[1.1.0]丁烷,二环[2.1.0]戊烷。实施例52
制备下列乳剂并按实施例18描述的方法测定。
所有溶液都制成2%的盐水溶液。用5cc盐水通过三通活塞25次来粉碎0.1cc的每种化学物质。通过1.2μm的滤布将1.0mL的混合物立即注射到含1000mL水的37℃下的搅拌的水浴中。然后使用Hewlett-Packard 77020A超声仪在5.0mHz记录产生的反散射。化学物质 沸点 蒸气压 分子量 持久性 强度
(℃) 之比 之比盐水+空气 1 0.0壬烷 151 20℃时10mmHg 128.3 9 0.51,2-二氯乙烷 83 25℃时87mmHg 98.9 6 0.25卤代烷 50 25℃时300mgHg 197.4 6 0.25(Halothame)全氟萘烷 141 25℃时6.6mmHg 462.1 9 2.0十二氟戊烷 29 25℃时646mmHg 288.1 24 5.0
具有最低沸点和最高蒸气压的化学物质(十二氟戊烷)产生最大的反向散射(最亮的对照)其持续时间最后并在4-5分钟内缓慢减弱。最高沸点和最低蒸气压的化学物质(壬烷和全氟萘烷)产生一些反向散射(不如十二氟戊烷显著)并且它在1.5分钟内快速减弱,其中全氟萘烷产生的反向散射比壬烷大。乙烷,二氯乙烷和卤代烷也产生在1分钟内减弱到基线的微小的反向散射。盐水和空气的混合物产生持续5-10秒的最小量的反向散射。
如果将盐+空气的持久度确定为1,那么十二氟戊烷为其24倍。如果将反向散射强度从0-5定性排列,那么盐+空气为0,而十二氟戊烷为5,同时壬烷,1,2-二氯乙烷,卤代烷和全氟萘烷分别为0.5,0.25,0.25和2.0。实施例53
本研究的目的在于评价通过静脉给予新西兰白兔有效产生超声造影剂的本发明乳剂而引起高度膨胀不萎陷肺(HNCL)症状的潜力。许多氟碳化合物乳剂引起了HNCL症状,包括20%的Fluosol,F.D.A认可的血管内给药的全氟化学物质乳剂(日本专利1609986中描述,引入本文供参考),含全氟辛基溴化物的乳剂(美国专利4987154中描述,引入本文供参考)和其它碳氟化合物乳剂(EP 231091,JP63060943,US 4859363,US 5171755和JP 21196730的专利或申请中描述,引入本文供参考)。尚不知道HNCL症产生的机理、其潜在可逆性和其临床意义。该病症的特点是尸检可见高度膨胀的肺,全容积增加,平均密度减小并在组织中包含可检测量的给予的碳氟化合物。HNCL的发现者Leland Clark声明(见Clark LC等人,Biomat.,Art.Cells和Immob.Biotech.20,1085-1099,1992,引入本文仅供参考)“如果HNCL发生于其它物种(即人),那么只有沸点超过150℃的碳氟化合物可被认为是安全的”。
四组雄性新西兰白兔(每组3只)静脉给予实施例44乳剂(按0.2或1.0mL/kg体重给药),Fluosol(Alpha Therapeutie Corp.)(按24mL/kg体重给药)或盐(按24mL/kg给药)。基于产生超声造影的剂量来选择给药剂量。给药期间和给药后立即进行体重、食物消耗和临床观察。给药后24小时,无痛苦处死白兔,切除肺,给膨胀程度定级,测定肺的重量和体积并按气相色谱法,使用液上气体分析仪测定组织中存在的全氟碳化物。
接受盐水或实施例44的乳剂的兔子的肺,尸检正常,它在打开的胸部萎陷。接受Fluosol的兔子的肺显示使严重膨胀延时。
在各组之间,肺重量或肺重量与体重的比没有与治疗相关的改变。与对照组相比,给予实施例44乳剂的兔子的肺体积,肺体积与体重的比和肺密度都没有改变。与对照组相比,给予Fluosol导致肺体积增加175%,肺与体重之比增加185%和肺密度减少45%。这些改变是相当显著的(p=0.001)。
在分析接受实施例44乳剂的任何动物的肺组织中,没有测出十二氟戊烷。通过气相色谱分析,Fluosol含有四个主峰和一个小峰。在气相色谱液面上加上来自接受Fluosol的动物组织样品,发现全部五个峰。
在本研究条件下,以产生极好超声造影的剂量一次给予实施例44乳剂不影响肺膨胀、重量或密度,在肺组织中不产生可见浓度的十二氟戊烷,并认为不引起白兔高度膨胀不萎陷肺症状。
按先前工艺中描述的方法制备的乳剂,以产生超声造影必需的剂量给药产生这种不安全疾病,同时出人意料地发现,按本申请中描述的方法制备的29℃低沸点碳氟化合物的乳剂不产生HNCL。实施例54
在5-8秒内,以0.05,0.1和0.15mL/kg剂量单次静脉给予小猎兔犬实施例44的乳剂,通过获得多次的,成倍的血样并按法定气相色谱法确定十二氟戊烷的含量来进行药化动力学研究。二十四只狗,十二只雄性和十二只雌性,分成三个剂量组进行研究。
数据符合以去药丸输入和以一级排出的二室模型。当分别进行雄性和雌性比较时或当进行三个剂量组比较时没有显著区别。
分布相在0.9到1.3分钟之间变化。消除相在30-48分钟之间变化。tmax(在二室中最大浓度时的时间)在5.1-6.6分钟之间变化。将这些消除时间与进行数月测定的先前的碳氟化合物乳剂的消除时间进行比较。(见上文Clark等)。显然,在几小时内从体内清除的成像剂是优选的。实施例55
制备十二氟戊烷(沸点28-29℃),十二氟戊烷和沸点为20.0℃的十二氟丁烷的混合物,和全氟环戊烷(沸点22.5℃)的乳剂并测定它们产生回声的性质。该乳剂含表面活性剂Fluorad 170 C并利用水浴声处理器(Sonicator)产生的声能进行配制。通过将0.2mL每种乳剂经过1.2微米的滤器加到1000mL 37℃的水中并按实施例1描述的方法测定视频密度来测定产生回声的性质。含十二氟戊烷的乳剂在给药58.5单位(背景2.9)的6秒钟产生灰度(grayscale)强度,碳氟化合物的混合物在同样条件下从3.0增加到133.3,而全氟环戊烷增加最大,从2.6到158.9。因此,低沸点碳氟化合物比高沸点碳氟化合物产生更大的回声。实施例56
用含一种在进行超声检测的有机体体温下本身不明显挥发的化学物质构成的分散相的乳剂稳定低沸点化学物质的分散体,以此制备有用的超声造影剂制剂。例如,由高沸点分散相组成的含碳氟化合物或碳氢化合物的乳剂,(描述见US 4,767,410,US 4,987,154,JP 2196730,JP 1609986,JP 63060943和EP 245019,引入本文供参考)可形成制剂的基础,其中,通过加入高蒸气压的化学物质大大地加强反向散射效率。例如,如果在粉碎前将全氟环戊烷(沸点=22℃)加到分散相中,那么卵磷脂稳定的全氟辛基溴化物乳剂产生回声的性质显著增加。其它低沸点有机卤化物、碳氢化合物或醚也具有同样的作用。
尽管参照具体的优选的实施方案描述了本发明的某些方面,但对专业技术人员来说各种变化和修饰是显而易见的。因此,本发明的权利要求不给予限定性的解释而应当认为包含由本文主题按常规衍生的变化和改变。
Claims (33)
1、一种稳定的生物相容的胶态分散体,含有液体分散相和水性连续相,所说的分散相含有沸点低于约40℃的液体。
2、按权利要求1的胶态分散体,其中所说化学物质选自脂肪族碳氢化合物、有机卤化物和醚,其中各物质具有6个或更少的碳原子。
3、按权利要求1的胶态分散体,其中所述化学物质为含氟的化合物。
4、按权利要求1的胶态分散体,其中所述含氟的化合物的分子量低于300。
5、按权利要求2的胶态分散体,其中所述化学物质选自正戊烷、异戊烷、新戊烷、环戊烷、丁烷、环丁烷、十氟丁烷、十二氟戊烷、十二氟新戊烷、全氟环戊烷。
6、按权利要求1的胶态分散体,其中所述分散体还含有两亲物质。
7、按权利要求6的胶态分散体,其中所述两亲物质具有与所述分散相液体匹配的相对HLB。
8、按权利要求6的胶态分散体,其中所述两亲物质包括生物相容蛋白质。
9、按权利要求6的胶态分散体,其中所述两亲物质包括至少一种表面活性剂。
10、按权利要求8的胶态分散体,其中所述蛋白质选自白蛋白、纤维蛋白原、纤维蛋白、血清球蛋白、血红蛋白、肌红蛋白和免疫球蛋白。
11、按权利要求6的胶态分散体,其中所述两亲物质包括聚氧丙烯-聚氧乙烯乙二醇非离子嵌段共聚物。
12、按权利要求11的胶态分散体,其中所述两亲物质选自Poloxamer 181、188、231、282、331、401、402和403。
13、按权利要求7的胶态分散体,其中所述两亲物质包括含氟表面活性剂。
14、按权利要求13的胶态分散体,其中所述含氟表面活性剂选自Zonyl FSO、FSN、FSA和FSJ。
15、按权利要求7的胶态分散体,其中所述两亲物质选自阴离子、阳离子、非离子或两性离子分子的表面活性剂。
16、按权利要求7的胶态分散体,其中所述两亲物质包括至少一种选自含有一个或多个亲水基的和一个或多个疏水基的表面活性剂,亲水基有:磺酸根、硫酸根、羧酸根、磷酸根、铵、季铵、甜菜碱、硫代甜菜碱、聚氧乙烯、多元醇、醇、醚、多肽或聚缩水甘油基;疏水基有:脂肪酸、石蜡、烯烃、烷基苯、醇、烷基酚、聚氧丙烯、多肽、碳氟化物和聚硅氧烷。
17、按权利要求7的胶态分散体,其中所述两亲物质以能使水和液体分散相之间的界面张力低于26达因/厘米的浓度存在。
18、按权利要求7的胶态分散体,其中所述两亲物质以高于0.001%(重量/体积)的浓度存在。
19、按权利要求1的胶态分散体,其中所述分散体还含有生粘剂(viscogen)。
20、按权利要求19的胶态分散体,其中所述生粘剂选自葡萄糖、碘海醇、碘帕醇、碘喷托、山梨醇、蔗糖和聚乙二醇。
21、按权利要求19的胶态分散体,其中生粘剂以足以产生高于1.1cP粘度的浓度存在。
22、按权利要求19的胶态分散体,其中生粘剂以0.001到75%(重量/体积)的浓度存在。
23、按权利要求1的胶态分散体,其中所述液体分散相含有平均直径小于1000nm的颗粒。
24、按权利要求1的胶态分散体,其中所述液体分散相的浓度为0.00001到166%(重量/体积)。
25、按权利要求1的胶态分散体,其中水性介质含有选自下列物质的添加剂:酸化剂、碱化剂、抗微生物防腐剂、抗氧剂、缓冲剂、螯合剂、络合剂、助溶剂、湿润剂、溶剂、混悬剂、增粘剂和张力剂(tonicity agent)。
26、按权利要求25的胶态分散体,其中所述添加剂以能使所述水性介质的渗透性至少为250mOm的浓度存在。
27、按权利要求1的胶态分散体,其中所述液体包括选自含4到17个原子的化学物质的化合物。
28、按权利要求1的胶态分散体,其中所述液体包括选自化学式为C5HXFY的化学物质。
29、一种用于对体温为T的动物进行超声成像的生物相容的胶态分散体,含有分散相和水性连续相,所述分散相包括具有足够高的蒸汽压的化学物质,该化学物质在温度T时,一部分为气体。
30、一种动物超声成像的方法,包括下列步骤:
(1)制备一种稳定的,生物相容的胶态分散相,它含有液体分散相和水性连续相,所述分散相包括沸点低于所述动物体温的液体;
(2)将所述分散体给予待成像的动物并等待足以使所述液体分散相形成微泡的时间;和
(3)在动物分布有所述微泡的部位上进行超声扫描。
31、按权利要求30的方法,其中所述化学物质选自具有6个或低于6个碳原子的脂肪族碳氢化合物、有机卤化物和醚。
32、一种制备贮存稳定的胶态分散体的方法,包括下列步骤:
(a)将至少一种两亲物质与水混合形成水性连续相;
(b)将沸点低于37℃的液体加到所述连续相中;
(c)手工、机械或经超声作用将混合物粉碎足够时间,以形成平均粒径低于5000nm的颗粒分散体。
33、一种制备贮存稳定的胶态分散体的方法,包括下列步骤:
(a)将至少一种两亲物质与水混合形成水性连续相;
(b)将一定量的沸点低于37℃气体加到所述连续相中;和
(c)凝缩所述气体形成平均粒径低于5000nm的颗粒的液体分散相。
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- 1994-01-19 DE DE69427185T patent/DE69427185T2/de not_active Expired - Fee Related
- 1994-01-19 WO PCT/US1994/000422 patent/WO1994016739A1/en not_active Application Discontinuation
- 1994-01-19 CN CN94191564A patent/CN1068230C/zh not_active Expired - Fee Related
- 1994-01-19 AT AT94908587T patent/ATE200985T1/de active
- 1994-01-19 CA CA002154590A patent/CA2154590C/en not_active Expired - Fee Related
- 1994-01-19 PL PL94309986A patent/PL176116B1/pl unknown
- 1994-01-19 JP JP51708494A patent/JP3621413B2/ja not_active Expired - Fee Related
- 1994-01-19 ES ES94908587T patent/ES2158892T3/es not_active Expired - Lifetime
- 1994-01-19 HU HU9502163A patent/HUT72323A/hu unknown
- 1994-01-19 SG SG1995002382A patent/SG52198A1/en unknown
- 1994-01-19 NZ NZ262237A patent/NZ262237A/en unknown
- 1994-01-19 SK SK930-95A patent/SK281535B6/sk unknown
- 1994-01-19 CZ CZ951916A patent/CZ191695A3/cs unknown
- 1994-01-19 EP EP94908587A patent/EP0680341B1/en not_active Expired - Lifetime
- 1994-01-19 BR BR9405667A patent/BR9405667A/pt not_active Application Discontinuation
-
1995
- 1995-06-06 US US08/469,472 patent/US5707607A/en not_active Expired - Fee Related
- 1995-07-17 NO NO952819A patent/NO952819L/no not_active Application Discontinuation
- 1995-07-24 FI FI953546A patent/FI953546A/fi unknown
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1996
- 1996-04-18 US US08/634,654 patent/US5876696A/en not_active Expired - Lifetime
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1083280C (zh) * | 1995-06-07 | 2002-04-24 | ImaRx药物公司 | 用于诊断和治疗的新的靶向组合物 |
CN105374266A (zh) * | 2015-12-16 | 2016-03-02 | 中山大学附属第三医院 | 一种用于模拟肿瘤超声造影的仿体模型 |
CN105374266B (zh) * | 2015-12-16 | 2018-11-13 | 中山大学附属第三医院 | 一种用于模拟肿瘤超声造影的仿体模型 |
Also Published As
Publication number | Publication date |
---|---|
CN1068230C (zh) | 2001-07-11 |
NO952819D0 (no) | 1995-07-17 |
CA2154590C (en) | 2001-06-12 |
ES2158892T3 (es) | 2001-09-16 |
JPH08508977A (ja) | 1996-09-24 |
HU9502163D0 (en) | 1995-09-28 |
SG52198A1 (en) | 1998-09-28 |
DE69427185D1 (de) | 2001-06-13 |
ATE200985T1 (de) | 2001-05-15 |
NO952819L (no) | 1995-09-22 |
PL176116B1 (pl) | 1999-04-30 |
SK93095A3 (en) | 1995-11-08 |
EP0680341B1 (en) | 2001-05-09 |
AU680652B2 (en) | 1997-08-07 |
CZ191695A3 (en) | 1996-05-15 |
BR9405667A (pt) | 1995-11-21 |
US5558853A (en) | 1996-09-24 |
CA2154590A1 (en) | 1994-08-04 |
WO1994016739A1 (en) | 1994-08-04 |
AU6162494A (en) | 1994-08-15 |
FI953546A0 (fi) | 1995-07-24 |
SK281535B6 (sk) | 2001-04-09 |
US5707607A (en) | 1998-01-13 |
US5876696A (en) | 1999-03-02 |
FI953546A (fi) | 1995-09-22 |
HUT72323A (en) | 1996-04-29 |
DE69427185T2 (de) | 2001-12-06 |
PL309986A1 (en) | 1995-11-13 |
NZ262237A (en) | 1997-06-24 |
EP0680341A1 (en) | 1995-11-08 |
JP3621413B2 (ja) | 2005-02-16 |
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