CN1226836A - 聚合物-脂类微胶囊包封的用作显像剂的气体 - Google Patents
聚合物-脂类微胶囊包封的用作显像剂的气体 Download PDFInfo
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- CN1226836A CN1226836A CN97196876A CN97196876A CN1226836A CN 1226836 A CN1226836 A CN 1226836A CN 97196876 A CN97196876 A CN 97196876A CN 97196876 A CN97196876 A CN 97196876A CN 1226836 A CN1226836 A CN 1226836A
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- microgranule
- polymer
- lecithin
- lipid
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Abstract
长期以来已经发现,将气体尤其是氟化气体如全氟化碳,掺入到由天然或合成聚合物和脂类结合而制成的微粒中时,与不含脂类的微粒相比,可显著地增强回波。将能限制水渗透和/或分散到微粒中的疏水性非脂类化合物加入到微粒中时也可增强回波。在优选的实施方案中,聚合物是可生物降解的合成聚合物。制备得到的微粒直径适合靶组织成像,例如当胃肠道或其它腔成像,血管给药时直径为0.5~8微米,口服给药时直径为0.5~5毫米。优选的聚合物是聚羟基酸如聚(乳酸/乙醇酸),最好是它们与聚乙二醇或其它抑制网状内皮系统(RES)摄取的物质结合。最优选的脂类是磷脂,优选二棕榈酰基卵磷脂(DPPC)、二硬脂酰基卵磷脂(DSPC)、二(二十酰基)卵磷脂(DAPC)、二(二十二酰基)卵磷脂(DBPC)、二(二十三酰基)卵磷脂 (DTPC)、二(二十四酰基)卵磷脂(DLPC),它们以0.01—30的比率(脂类重量/聚合物重量)混合,优选比率为0.1—10(脂类重量/聚合物重量)。用其它诊断试剂显像的微粒也可用类似方法制备。
Description
发明背景
本发明总体上属于诊断显像剂领域,具体地讲,涉及能超时维持回波的含有脂类的微粒超声显像造影剂。
当应用超声来得到人或动物内部器官或结构的影像时,超声波-那些频率大于人耳所能辨别频率的声波,当它们经过身体时被反射。不同类型的身体组织对超声波的反射也不同,检测不同体内组织对超声波所产生的反射,并将之电学转变成直观可视图像。
对于某些医学症状来说,得到靶结构或器官的有用影像是非常困难的,因为没有造影增强剂时,由超声波发射产生的超声影像还不足以把这些结构的细节与周围组织区分开。通过把试剂灌注到器官或其它结构或所关心的其它部位,提高它们的超声波影像的对比,可以基本上改善对某些生理和病理状况的检测和观察。在另一些情况中,检查造影增强剂(contrast-enhancing agent)本身的运动是特别重要的。例如,只有把造影剂融入血液中并观察血流动力学,才能将已知由某些特殊心血管异常所引起的不同血流模式加以辨别。
用作超声造影剂的物质其工作原理是:这些物质影响通过身体并被反射而产生作为诊断根据的影像的超声波。不同类型的物质影响超声波的方式不同,影响程度也有差别。并且,某些由造影增强剂引起的效果更容易被检测和观察。为了选择理想的组合物用作造影剂,人们更希望该物质在超声波通过身体时对超声波产生最强烈的作用。而且,对超声波的所述影响也应容易测得。在超声影像中能看到的三种主要造影增强剂的影响是:反向散射、光弱化和声速差别。
反向散射:当超声波经过身体时遇到结构,例如器官或其它身体组织,该结构就反射一部分超声波。体内不同结构反射超声能量的方式和程度不同,检测所反射回来的能量并将之用于产生超声波所通过的结构的影像。术语“反向散射”所指的现象是具有某些物理性质的物质向波源往回散射超声能量的现象。
长期以来已经认识到,当已知能造成大量反向散射的物质存在时,在超声影像中能观察到强的造影。当将这样的物质施用至身体的不同部位时,该身体部位和不含所述物质的周围组织的超声影像的对比增强。非常容易理解的是:由于它们的物理性质不同,不同物质产生反向散射的程度不同。因此,对造影剂的寻找已经集中于寻找那些稳定、无毒并显示最大反向散射量的物质。
物质产生超声能反向散射的能力取决于该物质的性质如被压缩的能力。测量物质产生反向散射能力的一个特别的参数被称为“散射切面”(scattering cross-section”),当检查不同物质时,比较该特别测量参数是有用的。一个具体物质的散射切面和散射半径成比例,同时还取决于超声能的波长以及该物质的其它物理性质,J.Ophir和K.J.Parker,“超声诊断中的造影剂”(Contrast Agents in Diagnostic Ultrasound),医学和生物学的超声(Ultrasound in Medicine&Biology),IS卷,n.4,319-323页(1989)。
评价不同物质作为显像造影剂的使用价值时,人们能计算出哪些试剂的散射切面较大,相应地,哪些物质在超声显像中可造成最大的差别。可以假定认为固体颗粒的压缩性远远小于周围介质,而其密度远大于周围介质。根据这个假设,固体颗粒造影增强剂的散射切面估计为1.75(Ophir和Parker,同上,325页)。对于纯液体散射体来说,散射体的绝热压缩系数和密度可能基本上和周围介质相同,从而得出的结论是液体的散射切面为零。然而,当存在大量的液体物质时,液体可显示一些反向散射。例如,使液体物质从一个非常小的容器通到一个非常大的容器以致基本上充满整个容器时,该液体显示出能测量到的反向散射。然而,那些本领域技术人员认为:和游离的气体微泡相比,纯液体是相对无效的散射体。
光弱化:某些固体造影增强剂存在时,另一个可观测的效应是超声波的弱化。由于某些组织之间的局部弱化不同,在常规的的影像中可观测到显像差别(image contrast)。K.J.Parker和R.C.Wang,“B-扫描显像中选择的区域超声弱化的测量”(Measurement of Ultrasonic AnenuatonWithin Reagions Selected from B-Scan Images),IEEETrans,Biomed.Enar.BME 30(8),第431-37页,(1983);K.J.Parker,R.C.Wang,和R.M.Lemer,“依赖组织特性的超声振幅和频率的弱化”(Attention ofUltrasound Magnitude and Frequency Dependence for TissueCharacterization),放射学(Radiology),153(3),第785-788页(1984)。有人曾假设在灌注试剂前后测量组织区域的弱化,可得到增强的影像。然而,基于弱化差别的技术作为测量液体试剂增强造影的手段还没有很好的被开发出来,并且即使完全被开发,也将受到应用这些技术的内部器官或结构的限制。例如,在心血管系统的影像中不太可能观察到由液体造影剂引起的弱化损耗,因为在能测出大量的弱化差别之前,需要有大量的液体造影剂存在于给定容器中。
颗粒以被称为“相对运动”(relative motion)的机理来吸收能量。相对运动引起的弱化差别随颗粒浓度直线上升,并可以颗粒和周围介质的密度差异的平方表示。K.J.Parker等,“肝超声显像中潜在的特殊造影剂”(A Particulate Contrast Agents with Potential for Ultrasound Imagingof Liver),医学和生物学的超声(Ultrasound in Medicine&Biology),13卷,第9期,555-561页(1987)。因此,在那些聚集有大量固体颗粒的地方,弱化差别是用于观察显像差别增强的一个可行的机理,尽管该作用与反向散射现象相比非常小,并且在心血管疾病的诊断中几乎没有使用价值。
声速差别:基于声音在不同介质中传播速度不同这样一个事实,曾提出另一项技术用来增强超声显像的差别。因此,如果可将大量物质(声音通过这些物质的速度和周围组织不同)灌注到靶区域时,就可测出通过这些靶区域的声速的差别。
总之,超声诊断是一个强有力的非侵入性的可用来获得体内器官信息的工具。灰度显像和彩色Doppler的出现大大地拓宽了该技术的范围并提高了分辨率。虽然进行超声诊断的技术已经得到显著的改进,然而对于制造和应用造影剂来说,还有必要提高心灌注和心室、固体器官、肾灌注、固体器官灌注和实时显像期间血液流速和流动方向的Doppler信号的影像的分辨率。
大量的天然和合成的聚合物已经被用于包封显像造影剂,如空气。Schneider等,Invest Radiol,Vol.27,pp134-139(1992)描述了空气填充的3微米的聚合物颗粒。据报道这些颗粒在施压下和在血浆中是稳定的。然而,在2.5MHz时,它们的回波较低。另外一类微泡悬浮体已经从用声波处理的清蛋白(sonicated albumin)得到。Feinstein等,J.Am.Coll.Cardiol,第11卷:59-65页(1988)。Fenistein描述了大小适合经肺通道的微泡的制备,该微泡在体外有高度稳定性。然而,由于其在压力下的不稳定性,这些微泡在体内存活期短,其半衰期约为几秒钟(约相当于一个循环通道)。Gottlieb.S等,J.Am.Soc.Echo.,第3卷:328页(1990),摘要;和Shapiro.J.R等,J.Am.Coll.Cardiol.,第16卷:1603-1607页(1990)。Carroll等描述了明胶包封的空气泡,(Carroll,B.A等InvestRadiol,第15卷:260-266页(1980)和Carroll,B.A等Radiology,第143卷:747-750页(1982)),由于它们体积太大(12和80μm),不太可能通过肺毛细管。Rasor Assosciation,Inc.的PCT/US80/00502申请也描述了明胶包封的微泡。这些微泡是通过使明胶凝集而形成的。
Frizch等还报道了经微晶半乳糖(SHU454和SHU508)稳定的微泡,Frizch等,Invest Radiol,第23卷(增刊1):302-305页(1988);和Frizch等,Invest Radiol,第25卷(增刊1):160-161页(1990)。该微泡在体外能持续到15分钟,在体内的持续时间不到20秒。Rovai,D.等,J.Am.Coll.Cardiol.第10卷:125-134页(1987);Smith,M.等,J.Am.Coll.Cardiol.第13卷:1622-1628页(1989)。Molecular Biosystems,Inc.的WO96/04018描述了由含氟物质的壳包封的气体微泡。
Schering Aktiengesellschaftd的90901933.5号欧洲专利申请公开了用于超声显像的微胶囊包封的气体或挥发性液体的制备和应用,其中的微胶囊由合成聚合物或多糖制成。Sintetica S.A的91810366.4号欧洲专利申请(0 458 745A1)公开了在界面存积的聚合物膜围成的空气或气体微球体,为了实现治疗或诊断目的,该微球体能分散在含水载体中用于注射至宿主动物或用于口服、直肠或尿道给药。Deta BiotechnologyLimited的WO92/18164公开了通过喷雾干燥制备微粒,在严格控制条件如温度、喷雾速度、粒子大小和干燥条件的情况下,蛋白质水溶液形成空心球体,气体被包入其中,用于显像。WO93/25242公开用于超声显像的微粒的合成,该微粒由聚腈丙烯酸酯或聚酯壳包封的气体组成。WO92/21382公开了微粒造影剂的制备,该微粒造影剂包括含有气体的共价键结合的基质,其中的基质是烃。授权给Unger的美国专利5,334,381号、5,123,414号和5,352,435号专利描述了用作超声造影剂的脂质体,它包括气体、气体前体如pH活化的或光活化的气体前体以及其它液体或固体造影增强剂。
授权给Quay的美国5,393,524号专利公开了包括用于在超声显像中增强造影的碳氟化合物在内的试剂的应用。这些试剂由所选择气体的非常小的气泡或微泡组成,它们在溶液中的寿命长,其大小足以穿过肺,使之在心血管系统或其它重要器官的超声显像中有使用价值。Nycomed的WO95/23615公开了显像用的微胶囊,它由溶液的凝聚形成,所述的溶液例如为含有全氟化碳的蛋白质溶液。MassachusettsInstitute of Technology的PCT/US94/08416公开的微粒由聚乙二醇-聚(丙交酯/乙交酯)的嵌段共聚物组成,包括气体如空气和全氟化碳的显像剂被包封在其中。正如Sonus Pharmaceuticals,Inc.的WO 94/16739所述,在固体和液体反射声音的程度相同时,对于用作超声造影剂来说,已知气体是更有效的和优选的介质。事实上,如Sonus的PCT申请的实施例12所述,给小猪服药时,和乳剂或胶体悬浮剂相比,蛋白质微胶囊解散时其安全性(同时还有有效性)较高。
应用其它的检测方法如X-光、正电子或光子发射断层X射线照相术或核磁共振成像术均不能检测出上面所述的微粒。
在所有这些情况中,人们希望增强显像剂的回波,同时希望增加或维持显像剂的稳定性,简化显像剂的制备。增强微粒回波的一个途径是使被包封的气体在循环微粒中的存留时间增长。不幸的是,大多数情况下,不管气体或包封物质的性质如何,特别在血循环的含水环境中,气体迅速溢散。
因此,本发明的一个目的是提供能显著增强回波的微粒。本发明的另一个目的是提供含有显像剂的微粒,所述微粒在体内能维持若干个循环周期以上。本发明一个更进一步的目的是提供一些微粒,其所包封的气体在该微粒中存留较长一段时间,从而增加微粒在体内的回波。
本发明的另一个目的是提供含有显像剂的微粒。本发明一个进一步的目的是提供含有以体内特定区域为靶目标的显像剂的微粒。本发明还有一个目的是提供包有显像剂的微粒的制备方法。发明概述
长期以来已经发现,气体尤其是氟化气体如全氟化碳,被掺入到由天然或合成聚合物和脂类组合而制成的微粒中时,与不含脂类的微粒相比,可显著地增强回波。将能限制水分散到微粒中的疏水性非脂类化合物加入到微粒中时也可增强回波。在优选的实施方案中,聚合物是可生物降解的合成聚合物物质。制备得到的微粒直径适合靶组织成像,例如当对胃肠道或其它腔成像时,血管给药时直径为0.5~8微米,口服给药时直径为0.5~5毫米。优选的聚合物是聚羟基酸如聚(乳酸/乙醇酸)(polylactic acid-co-glycolic acid)、聚丙交酯或聚乙交酯,最好是它们与聚乙二醇或其它抑制网状内皮系统(RES)摄取的物质结合。最优选的脂类是磷脂,优选二棕榈酰基卵磷脂(DPPC)、二硬脂酰基卵磷脂(DSPC)、二(二十酰基)卵磷脂(DAPC)、二(二十二酰基)卵磷脂(DBPC)、二(二十三酰基)卵磷脂(DTPC)、二(二十四酰基)卵磷脂(DLPC),它们以0.01-30的比率(脂类重量/聚合物重量)掺合,优选掺合比率为0.1-10(脂类重量/聚合物重量)。
通过对生物粘性聚合物的选择来增强或减弱这些微粒的粘性。例如当聚合物经口服使用时,粘度可以增加。通过选择聚合物或者将之加入或与聚合物配体偶联也能够达到目的,所述的聚合物配体特异性地与特定类型组织或细胞表面分子相结合。并且,配体可与微球体结合,影响该颗粒的电荷、亲水性或亲脂性。该多聚物微粒在许多诊断成像程序中有使用价值,这些成像程序包括超声成像、核磁共振成像、荧光镜透视检查、X-光和计算机化断层X射线显像。所述微球体在许多成像应用中有使用价值,这些成像应用包括心脏病学应用、血管融合以及器官和周围血管成像。
附图的简要说明
图1表示掺合到聚合物微粒中的脂类的碳链长度所起的作用,图中显示卵磷脂(实心园)、DPPC(正方形)、DSPC(菱形)和DAPC(×)随时间(分钟)的反向散射程度。
本发明详述
本发明提供聚合物传递系统的合成方法,所述的聚合物传递系统由含有气体特别是全氟化碳的聚合物-脂类微粒组成。所述微粒对许多诊断超声成像应用特别是超声程序如血管成像和心电波描记术有使用价值。对于同样的聚合物微粒来说,与没有脂类加入其中的微粒相比,加入了脂类的微粒可显著增加回波。制备微粒的试剂和方法
在本申请中所用的术语“微粒”,除另有说明外包括微球体和微胶囊,同时也包括微粒体。微粒可为球形也可不为球形。将具有包围另一种核心物质(在本案中该核心物质为气体)的聚合物外壳的微粒定义为微胶囊。微球体一般是固体聚合物球体,可包括由贯穿聚合物的孔构成的蜂窝状结构,孔中充有用于成像目的的气体,如下所述。聚合物
为了传递气体,生物不可降解的和可生物降解的基质均可用来和脂类混合,虽然可生物降解的基质是优选的,尤其静脉注射时更是如此。口服给药时可应用非侵蚀性的聚合物。优选合成的聚合物,因为其更容易再生和降解。基于所需的其体内稳定性时间,即分布到所需要成像的部位的时间和成像时间来选择聚合物。在一个实施方案中,可制备在约20~30分钟或更长时间在体内保持稳定的微粒,例如用作心回波描记术、神经声波描记术(neurosonography)、子宫输卵管照相术和固体器官的诊断程序。在制备包封造影剂的微粒的过程中,采用聚合物例如聚(丙交酯/乙交酯)与聚乙二醇(PEG)的共聚物可调整微粒在体内的稳定性。由于PEG是亲水性的,当它曝露在外表面时可延长这些物质循环的时间。
代表性的合成聚合物是:聚羟基酸如聚乳酸、聚乙醇酸和聚(乳酸/乙醇酸),聚丙交酯、聚乙交酯、聚(丙交酯/乙交酯)、聚丙交酯和聚乙交酯的共混物,聚酸酐,聚原酸酯,聚酰胺,聚碳酸酯,聚烯烃如聚乙烯和聚丙烯,聚亚烷基二醇如聚乙二醇,聚烷撑氧如聚环氧乙烷,聚对苯二甲酸亚烷基二醇酯如聚对苯二甲酸乙二醇酯、聚乙烯醇,聚乙烯酯,聚乙烯醚,聚卤化乙烯如聚氯乙烯,聚乙烯吡咯烷酮、聚硅氧烷、聚(乙烯醇)、聚乙酸乙烯酯,聚苯乙烯,聚氨基甲酸乙酯及它们的共聚物,纤维素衍生物如烷基纤维素、羟烷基纤维素、纤维素酯、纤维素醚、硝基纤维素、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丁基甲基纤维素、醋酸纤维素、丙酸纤维素、乙酸丁酸纤维素、乙酸邻苯二甲酸纤维素、羧乙基纤维素、三醋酸纤维素和纤维素硫酸钠盐(在此统称为“合成纤维素”),丙烯酸聚合物、甲基丙烯酸聚合物或它们的共聚物或它们的衍生物包括酯如聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸丁酯、聚甲基丙烯酸异丁酯、聚甲基丙烯酸己酯、聚甲基丙烯酸异癸酯、聚甲基丙烯酸十二酯、聚甲基丙烯酸苯酯、聚丙烯酸甲酯、聚丙烯酸异丙酯、聚丙烯酸异丁酯、聚丙烯酸十八酯(在此统称为聚丙烯酸类),聚丁酸(poly(butyric acid))、聚戊酸(poly(valeric acid))和聚(丙交酯/己内酯)、它们的共聚物和组合物。此处所用的“衍生物”包括有取代基的聚合物,附加有化学基团例如烷基、亚烷基的聚合物或经羟基化、氧化和本领域技术人员所作的其它常规修饰而得的聚合物。
优选的生物不可降解性聚合物的例子包括乙烯基醋酸乙烯酯、聚(甲基)丙烯酸、聚酰胺,它们的共聚物和混合物。
优选的可生物降解聚合物的例子包括羟基酸如乳酸和乙醇酸的聚合物,聚丙交酯,聚乙交酯,聚(丙交酯/乙交酯),和它们与PEG的共聚物,聚酸酐,聚(原)酸酯,聚氨基甲酸乙酯,聚丁酸,聚戊酸,聚(丙交酯/己内酯),它们的组合物和共聚物。
优选的天然聚合物的例子包括蛋白质例如清蛋白和醇溶谷蛋白例如玉米醇溶蛋白和多糖如藻酸盐、纤维素和聚羟基链烷酸酯如聚羟基丁酸酯。
用于粘性表面如胃肠道成像的特别有用的生物粘性聚合物包括聚酸酐、聚丙烯酸、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸丁酯、聚甲基丙烯酸异丁酯、聚甲基丙烯酸己酯、聚甲基丙烯酸异癸酯、聚甲基丙烯酸十二酯、聚甲基丙烯酸苯酯、聚丙烯酸甲酯、聚丙烯酸异丙酯、聚丙烯酸异丁酯、聚丙烯酸十八酯。溶剂
此处定义的聚合物溶剂是指微量给药至人体能接受的并且是挥发性的或低沸点的或真空下能除去的有机溶剂,例如二氯甲烷。其它的溶剂例如乙酸乙酯、乙醇、甲醇、二甲基甲酰胺(DMF)、丙酮、乙腈、四氢呋喃、乙酸,二甲亚砜(DMSO)和氯仿也可使用,或者使用它们的混合体。一般来说,将聚合物溶于溶剂形成聚合物溶液,其重量/体积比(w/v)浓度为0.1~60%,优选0.25~30%。疏水性化合物脂类
一般来说,疏水性化合物可限制微粒对水的渗透和摄取,因此在微粒中掺入有效量的这些化合物可有效地增强聚合物微粒的回波,其中所述的聚合物微粒包封有气体,尤其是氟化气体例如全氟化碳。可用来增加气体在聚合物内的稳定性的脂类包括(但不仅仅限于)下列类型的脂类:脂肪酸及其衍生物,甘油单酯、二酯和三酯、磷脂,鞘脂,胆甾醇和甾体衍生物,萜类和维生素。其中的脂肪酸及其衍生物包括(但不仅仅限于)饱和与不饱和脂肪酸、奇数和偶数碳脂肪酸、顺式和反式异构体,和脂肪酸衍生物包括醇、酯、酸酐、羟基脂肪酸类和前列腺素类。所用的饱和与不饱和脂肪酸包括(但不仅仅限于)含有12-22个碳原子的支链或直链形式的分子。可用的饱和脂肪酸的例子包括(但不仅仅限于)月桂酸、十四烷酸、软脂酸和硬脂酸。所用的不饱和脂肪酸的例子包括(但不仅仅限于)月桂烯酸、5-十四烯酸、9-十四烯酸、9-十六烯酸、6-十八烯酸和油酸。可用的支链脂肪酸的例子包括但并不仅仅限于异月桂酸、异十四烷酸、异软脂酸、异硬脂酸和类异戊二烯类。脂肪酸衍生物包括12-(((7′-二乙氨基香豆素-3-基)羰基)甲基氨基)十八烷酸;N-[12-(((7′二乙氨基香豆素-3-基)羰基)甲基-氨基)十八酰基]-2-氨基软脂酸,N-琥珀酰基二油酰基磷脂酰基乙醇胺和软脂酰基高半胱氨酸;和/或它们的组合物。可以应用的甘油单酯、二酯和三酯衍生物包括(但不仅仅限于)含有脂肪酸或含有6-24个碳原子脂肪酸混合物的分子,二半乳糖基二甘油酯,1,2-二油酸-sn-甘油酯,1,2-二软脂酸-sn-3-琥珀酸甘油酯,和1,3-二软脂酸-2-琥珀酸甘油酯。
可以应用的磷脂类包括(但不仅仅限于)磷脂酸、含有饱和脂类和不饱和脂类的卵磷脂、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、磷脂酰肌醇、溶血磷脂酰衍生物、心肌磷脂和β-酰基-y-烷基磷脂。磷脂的例子包括(但不仅仅限于)卵磷脂例如二油酰基卵磷脂、二(十四酰基)卵磷脂、二(十五酰基)卵磷脂、二月桂酰基卵磷脂、二棕榈酰基卵磷脂(DPPC)、二硬脂酰基卵磷脂(DSPC)、二(二十酰基)卵磷脂(DAPC)、二(二十二酰基)卵磷脂(DBPC)、二(二十三酰基)卵磷脂(DTPC)、二(二十四酰基)卵磷脂(DLPC);和磷脂酰基乙醇胺例如二油酰基磷脂酰基乙醇胺或1-十六烷基-2-硬脂酰基甘油磷酸乙醇胺。也可使用合成的具有不对称酰基链的磷脂(如一个酰基链有6个碳原子,另一个酰基链有12个碳原子)。
可以应用的鞘脂包括神经酰胺、鞘磷脂、脑苷脂、神经节苷脂、硫苷脂和溶血硫苷脂。鞘脂的例子包括(但不仅仅限于)神经节苷脂GM1和GM2。
可以应用的甾体包括(但不仅仅限于)胆甾醇、硫酸胆甾醇、半琥珀酸胆甾醇、6-(5-胆甾醇-3β-酰基氧)己基-6-氨基-6-脱氧-1-硫-α-D-半乳糖吡喃糖甙,6-(5-胆甾醇-3β-酰基氧)己基-6-氨基-6-脱氧-1-硫-α-D-甘露糖吡喃糖甙,和胆甾醇-4′-三甲基35铵丁酸酯(cholesteryl(4′-trimethyl 35ammonil)butanoate)。
可以应用的另外的脂类化合物包括生育酚及其衍生物,油和油的衍生物如硬脂酰胺。
大量的阳离子脂类如DOTMA,N-[1-(2,3-二油酰基氧)丙基-N,N,N-三甲基铵氯化物;DOTAP,1,2-二油酰基氧-3-(三甲基铵)丙烷;和DOTB,1,2-二油酰基-3-(4′-三甲基铵)丁酰基-sn-甘油,均可以应用。
最优选的脂类是磷脂,优选DPPC、DDSPC、DAPC、DSPC、DTPC、DBPC、DLPC,最优选DPPC、DAPC和DBPC。
脂类的含量范围是0.01-30(脂类重量/聚合物重量);最优选0.1-10(脂类重量/聚合物重量)。其它疏水性化合物
优选的其它疏水性化合物包括氨基酸例如色氨酸、酪氨酸、异亮氨酸、亮氨酸和缬氨酸,芳香化合物例如对羟基苯甲酸烷基酯如对羟基苯甲酸甲酯,和苯甲酸。显像剂气体
所有生物相容的或药学上可接受的气体均可被掺入到微粒中。术语“气体”是指本身为气体或在进行成像时的温度下能变成气态的任何化合物。该气体可由一种化合物如氧气、氮气、氙气、氩气组成或由混合物如空气组成。优选含氟的气体。氟化气体的例子包括CF4、C2F6、C3F8、C4F8、SF6、C2F4和C3F6。特别优选全氟丙烷,因为它是不溶解的气体,在所用温度下不会浓缩,并且在药学上可以接受。其它显像剂
可加入能代替气体或与气体共用的其它显像剂。可以应用的显像剂包括商业上能得到的用于正电子发射断层X射线照相术(PET)或计算机辅助断层X射线照相术(CAT)、单光子发射计算机化断层X射线照相术、X-光、荧光镜透视检查和核磁共振成像(MRI)的试剂。应用本领域可获得的标准技术和商业上可得到的设备可检测出装有这些试剂的微粒。
在MRI中作为造影剂的合适物质的例子包括目前能得到的gatalinium络合剂,例如二亚乙基三胺五乙酸(DTPA)和gatopentotatedimeglumine,另外还有铁、镁、锰、铜和铬。
可用于CAT和X-光照像术的物质的例子包括用于静脉内给药的基于碘的物质,例如离子单体以泛影葡胺和碘拉酸盐为代表,非离子单体如碘帕醇、isohexol和ioversol,非离子二聚体如iotrol和iodixanol,和离子二聚体例如碘克沙酸盐。其它可用的物质包括经口服用的钡。微粒及其制备方法
在最佳实施方案中,用喷雾干燥法制备微粒。也可用其它技术例如溶剂提取、热熔包封和溶剂蒸发,如下文所述。一个主要标准是:形成微粒之前,聚合物必须与脂类一起溶解或熔融。尽管对脂类的掺入有具体的描述,但必须明白,所述脂类可用其它有用的疏水性物质代替。
在优选实施方案中,通过用所需气体的气流取代原来的气体,或者把微粒置于真空中除掉所包含的气体,然后充入所需要的气体。
a.溶剂蒸发。在该方法中,将聚合物和脂类溶于挥发性有机溶剂如二氯甲烷。固态或溶于溶剂中的孔形成试剂(pore forming agents)可加入到溶液中来形成微粒,该微粒用来包含作为显像剂的气体。如果要包含其它的显像剂,将该显像剂以固体的形式或以溶液的形式加入到聚合物溶液中。对该混合物进行声波处理或使之均质化,并将所得的分散体或乳浊液加入到含有表面活性剂如TWEENTM20、TWEENTM80、PEG或聚乙烯醇的水溶液中,再次使之均化以形成乳浊液。搅拌所得到的乳浊液直到大部分有机溶剂蒸发掉而剩下微粒为止。可以采用几种不同的聚合物浓度(0.05-0.60g/ml)。通过这种方法可得到不同大小(1-1000微米)和形状的微粒。该方法对相对稳定的聚合物如聚酯是有用的。
关于溶剂的蒸发已有记载:E.Mathiowitz等,J.ScanningMicroscopy,4.329(1990);L.R.Beck等Fertil Steril,31,545(1979);和S.Benita等,J.Pharm.Sci,73,1721(1984)。
然而,不稳定的聚合物如聚酸酐类,由于水的存在,在制备过程中可能产生分解。对于这些聚合物,下面两种完全在有机溶剂中进行的方法更有用处。
b.热熔融微囊包封。在该方法中,首先将聚合物和脂类熔融,然后与固体颗粒的孔形成试剂或与固体或液体诊断试剂混合。将该混合物悬浮在不混溶的溶剂(如硅油)中,在持续搅拌下加热到高于聚合物熔点5℃的温度。一旦该乳浊液稳定后,将之冷却直至聚合物颗粒凝固。用非溶剂聚合物如石油醚通过滗析法洗涤得到的微粒,可得到能自由流动的粉末。通过此方法可得到1-1000微米的微粒。应用此技术得到的微粒外表面光滑并且密实。这种方法用于制备由聚酯和聚酸酐制成的微粒。然而该方法仅仅限于分子量为1000-50000的聚合物。
关于热熔融微囊包封的方法也有记载:E.Mathiowitz等,ReactivePolymers.6,275(1987)。聚酸酐类(例如,其由摩尔比20∶80的双羧基苯氧基丙烷和癸二酸制成)(P(CPP-SA)20∶80)(Mw20,000),可通过热熔微胶囊包封法制备。或者例如聚(富马酸/癸二酸)(20∶80)(Mw15,000)的微粒,可通过热熔微囊包封法制备。
c.除去溶剂。该技术主要为聚酸酐类设计的。在此方法中,将所选择的聚合物和脂类溶于挥发性有机溶剂如二氯甲烷中形成溶液,把孔形成试剂分散或溶解到此溶液中。在搅拌下,将混合物悬浮在有机油(如硅油)中并形成乳浊液。与溶剂蒸发的方法不同,本方法可用来制备由高熔点和不同分子量的聚合物组成的微粒。用本方法制备的颗粒,其外部形状很大程度上取决于选用的聚合物类型。
d.微粒的喷雾干燥。通过喷雾干燥的方法制备微粒:把生物相容性聚合物和脂类溶于合适的溶剂中,再将孔形成试剂分散到该聚合物溶液中,然后喷雾干燥该聚合物溶液,产生微粒。在此,“喷雾干燥”聚合物和孔形成试剂的溶液的方法是指这样一个方法:将溶液雾化形成细雾状,然后通过与热载气的直接接触来干燥溶液。应用可在本领域中得到的喷雾干燥设备,可将聚合物溶液输送到喷雾干燥器的进气口,使之经过干燥器内的管道,然后雾化,经过出气口出来。根据所用的气体或聚合物,可调节温度。为了产生符合需要的产品,可控制入气口和出气口的温度。
聚合物溶液的颗粒大小是用于喷射聚合物溶液的喷嘴、喷嘴压力、溶液流动速度、所用的聚合物类型、聚合物浓度、溶剂类型和喷雾温度(入口和出口温度)和分子量的函数。一般来说,浓度相同时,分子量越大,颗粒越大。喷雾干燥的典型方法参数如下:聚合物浓度=0.005-0.20g/ml,入口温度=30-1000℃,出口温度=20-100℃,聚合物流速=5-200ml/分,喷嘴直径=0.2-4mmID。可得到直径1-10微米的微粒,其形状取决于所选的聚合物类型、浓度、分子量和喷雾流量。
如果显像剂是固体时,在喷雾之前将固体颗粒加入到聚合物溶液中,该试剂以固体颗粒被包封;或者将显像剂溶于水溶液中并在喷雾前将其和聚合物溶液一起乳化,或者在喷雾前把显像剂固体和聚合物共同溶于合适的溶剂中。
e.水凝胶微粒。由凝胶类型的聚合物如聚磷腈或聚甲基丙烯酸甲酯制成的微粒的制备方法是:把聚合物溶于水溶液中,将孔形成试剂(如需要的话)和脂类悬浮其中,均质化所得的混合物,通过微滴形成设备挤出该物质,将产生的微滴加到由相反电荷离子或多种电解质组成的固化浴中,并慢慢搅拌,即可产生所述的微粒。这些系统的优点是:制备之后,通过多阳离子聚合物如聚赖氨酸覆盖微粒,能进一步改善微粒的表面。选择不同大小的挤出器可控制微粒的大小。有助于微粒形成的添加剂
在含显像剂的微粒合成期间可加入许多表面活性剂。可以应用的示范性乳化剂或表面活性剂(0.1-5%重量比)包括生理上最能接受的乳化剂。其例子包括天然或合成形式的胆汁酸或胆汁盐,与氨基酸结合的胆汁酸或胆汁盐和不与氨基酸结合的胆汁酸或盐例如牛黄去氧胆酸盐和胆酸。
为增加孔形成,可加入孔形成试剂,其含量为0.01%-90%(重量/体积比)。例如,在喷雾干燥、溶剂蒸发中,孔形成试剂如挥发性盐例如碳酸氢铵、乙酸铵、氯化铵或苯甲酸铵或其它可冷冻干燥的盐,首先溶于水中,然后含有孔形成试剂的溶液用聚合物溶液将乳化,因此在聚合物溶液中形成孔形成试剂的液滴。该乳化液再喷雾干燥或进行溶剂蒸发/提取过程。聚合物沉淀后,冻结硬化的微粒,并将之冷冻干燥以除掉孔形成试剂。微粒大小
在优选的实施方案中,制备能通过肺毛细血管床的可注射微粒,该微粒直径应该为约1-10微米。更大的微粒可能阻塞肺毛细血管床,更小的微粒不能提供足够的回波。如果不是经注射给药途径,例如经口服(用来检测胃肠道)、给药至其它粘膜表面(直肠、阴道、口腔、鼻腔)或经吸入给药时,更大的微粒是有用的。口服时,优选的颗粒大小为约0.5微米-5毫米。药学上可接受的有用的载体包括含有甘油和TWEENTW20的盐和含有TWEENTW20的等渗甘露糖醇。在库尔特粒度仪上,应用光学显微镜、电子扫描显微镜或透射电子显微镜可进行颗粒大小的分析。靶定位
通过选择组成微粒的聚合物、微粒大小和/或与微粒结合或附着的配体,可特异性或非特异性地使微粒定向于靶部位。例如可将生物活性分子或影响颗粒电荷、亲脂性或亲水性的分子附着到微粒的表面。并且,附着到微粒上的分子可降低组织粘附力或者有利于微粒在体内特异性的导向目标。有代表性的靶分子包括抗体、凝集素和其它的与特定类型细胞表面的受体特异结合的分子。抑制RES的摄取
通过选择聚合物和/或与减少粘附或摄取的分子结合或偶合,可以减少微粒的被摄取和除去。例如,聚乙二醇部分和微粒表面共价结合时,可减小微粒对组织的粘性。该表面的聚乙二醇部分与水有高度亲和力,由此减少蛋白质吸附到颗粒的表面。因此减少网状内皮系统(RES)对微粒的识别和摄取。
例如,可以用聚乙二醇的末端羟基把生物活性分子,或者能影响颗粒的电荷、亲脂性或亲水性的分子和微粒的表面共价结合。可以应用本领域能获得的方法把宽范围内的任何配体与微粒结合,以增强微粒在体内的传递性质、稳定性或其它性质。诊断应用
典型地,微粒与药学上可接受的载体如磷酸盐缓冲液或盐水或甘露糖醇混合,然后,用适当的途径(典型的途径是血管注射(i.v.)或口服),以检测有效量给患者服药。含有被包封的显像剂的微粒可用于血管显像,也可用于检测肝肾疾病、心脏病学的应用、检测肿瘤块和组织并描绘其特性和用来测量外周的血流速。所述微粒也可与这样的配体相连:所述配体可减小组织粘附或者如前所述能使微粒在体内导向身体的特定区域。
通过下面的实施例可更进一步地理解上面所述的方法和组合物,显然,本发明并不限于这些实施例。实施例1:含卵磷脂的八氟丙烷PEG-PLGA/PLGA微粒的制备
3.2g PEG-PLGA(75∶25)(Ⅳ=0.75dL/g Birmingham聚合物)、6.4克PLGA(50∶50)(Ⅳ=0.4dL/g Henley化学品)、23g卵磷脂(Spectrum化学品)和193mg软脂酸(Spectrum化学品)溶于190ml二氯甲烷中。往该聚合物溶液中加入10.8ml的0.70g/ml的乙酸铵并将该聚合物/乙酸铵加入上述聚合物溶液中,用Virtis均化器以10,000RPM的速度对该聚合物/乙酸铵溶液进行均质化1分钟。用Bucchi Lab喷雾干燥器以20ml/min的流速抽吸该溶液进行喷雾干燥,入口温度为40℃。收集微粒粉末,用FTS盘冷冻干燥器冷冻干燥120小时。将微粒等份量地装入5ml的Purform小瓶中,用丁基阻聚剂密封,使之卷曲。在10psig压力下用八氟丙烷充满这些小瓶,用该气体持续清洗3分钟。然后在4℃下储存直至应用。用库尔特粒度仪测量时,微粒直径范围为1-10微米,平均2.0微米。扫描电子显微镜检查显示颗粒一般为球形,表面光滑,偶然表面皱缩。实施例2:含二软脂酰基卵磷脂(DPPC)的八氟丙烷PEG-PLGA/PLGA微粒的制备
按照实施例1所述的方法制备微粒,只是用29.6mg二软脂酰基卵磷脂(Avanti,Bitmingham A1)代替卵磷脂。实施例3:含二硬脂酰基卵磷脂(DSPC)的八氟丙烷PEG-PLGA/PLGA微粒的制备
按照实施例1所述的方法制备微粒,只是用29.9mg二硬脂酰基卵磷脂(Avanti,Bitmingham A1)代替卵磷脂。实施例4:含二(二十酰基)卵磷脂(DAPC)的八氟丙烷PEG-PLGA/PLGA微粒的制备
按照实施例1所述的方法制备微粒,只是用29.9mg二(二十酰基)卵磷脂(Avanti,Bitmingham A1)代替卵磷脂。实施例5:体外测量微粒的反向散射
从实施例1-4制备的含八氟丙烷的不同的聚合物微粒,各取10微升微粒的悬浮液置于聚焦的超声波下,可得到它们的反向散射。作为样品深度的函数的反向散射声能的测定如下:用脉冲接受器(PanametricsModel 5800)震激聚焦的超声传感器(2.25MHz),该传感器把超声的脉冲信号传送到生理盐水中的悬浮微粒。
把悬浮液加入到在控制温度为37℃水浴中的圆筒形样品腔(55ml生理盐水)中。该样品腔与传感器相距1.5英寸,使传感器对准样品腔的声波窗口。样品腔以15rpm的速度旋转维持微粒呈悬浮状态。用溶解氧测量仪(dissolved oxygen meter)(Orionmodel 840)测量,使盐水中溶解的气体含量维持在90%左右的空气饱和度。按照LabVIEW(NationalInstruments)记录的PC运转专有程序来控制声波测试系统的操作。计算机触发脉冲接受器以震激超声传感器。
用该相同的传感器接受反向散射信号,返回的信号通过脉冲接受装置被扩大。扩大的信号传递到数字化示波器(LeCroymodel 9310AM)在100MSa/s下进行数字化。对该数字化后的信号作进一步处理。信号平方后,通过FFT分析,在传感器的6dB波带宽度范围积分。该系统收集的数据转换成积分反向散射强度(IBP),以任意单位,作为微粒悬浮体的浓度函数。将该IBP对50次脉冲深度数据平均化,确定通过平均IPB数据的最合适的直线,并确定与反向散射系数成比例的纵截距。测试每个样品的时间间隔为2.5分钟,总时间为10分钟。
在四批不同微粒中,反向散射作为时间的函数如图1所示。卵磷脂是不同链长度的磷脂的混合物。当与磷酸胆碱结合的脂肪酸的碳链长度增加时,反向散射的大小更能持续较长的一段时间,从而表明八氟丙烷在微粒中的稳定性增加。与卵磷脂中含有磷脂的混合物相对照,应用高度纯化的磷脂可更有效地增加气体的稳定性。
Claims (30)
1.一种制备用于诊断显像的微粒的方法,所述的微粒由生物相容的聚合物制成并在其中包含有显像剂,该方法包括:
将疏水性化合物以能增加水渗入或吸收入微球体速率的量与聚合物掺合。
2.根据权利要求1所述的方法,其中疏水性化合物与聚合物按疏水性化合物重量/聚合物重量计,以0.01-30的比率相掺合。
3.根据权利要求2所述的方法,其中的疏水性化合物是与聚合物以0.01-30的比率(脂类重量/聚合物重量)掺合的脂类。
4.根据权利要求1所述的方法,其中的脂类选自由如下物质组成的组:脂肪酸及其衍生物,甘油单酯、二酯和三酯,磷脂、鞘脂、胆甾醇和甾体衍生物、油类、维生素和萜类。
5.根据权利要求4所述的方法,其中的脂类是磷脂,选自磷脂酸、含饱和不饱和脂类的卵磷脂、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、磷脂酰肌醇、溶血磷脂酰衍生物、心肌磷脂和β-酰基-y-烷基磷脂。
6.根据权利要求5所述的方法,其中的磷脂选自二油酰基卵磷脂、二(十四酰基)卵磷脂、二(十五酰基)卵磷脂、二月桂酰基卵磷脂、二棕榈酰基卵磷脂、二硬脂酰基卵磷脂、二(二十酰基)卵磷脂、二(二十二酰基)卵磷脂、二(二十三酰基)卵磷脂、二(二十四酰基)卵磷脂;和磷脂酰乙醇胺。
7.根据权利要求1所述的方法,其中的显像剂是气体,选自氟化气体、氧气、氙气、氩气、氦气和空气。
8.根据权利要求7所述的方法,其中的气体选自CF4、C2F6、C3F8、C4F8、SF6、C2F4和C3F6。
9.根据权利要求8所述的方法,其中的气体是C3F8。
10.根据权利要求1所述的方法,其中的显像剂是能由成像技术检测的显像剂,所述成像技术选自核磁共振成像、计算机断层X-射线照像、X-射线、正电子发射断层X-射线照像和单光电子发射计算机化断层X-射线照像。
11.根据权利要求1所述的方法,其中的微粒由合成聚合物制成。
12.根据权利要求1所述的方法,其中的微粒由天然聚合物制成。
13.根据权利要求1所述的方法,其中的微粒由生物粘性聚合物制成。
14.根据权利要求11所述的方法,其中的微粒由合成聚合物制成,所述的合成聚合物选自聚羟基酸、聚酸酐、聚原酸酯、聚酰胺、聚碳酸酯、聚烯烃、聚亚烷基二醇、聚烷撑氧、聚对苯二甲酸亚烷基二醇酯、聚乙烯醇、聚乙烯醚、聚乙烯酯、聚卤化乙烯、聚乙烯吡咯烷酮、聚硅氧烷、聚(乙烯醇)、聚乙酸乙烯酯、聚苯乙烯、聚氨基甲酸乙酯及其共聚物、合成纤维素、聚丙烯酸、聚丁酸、聚戊酸,和聚(丙交酯/己内酯)、乙烯醋酸乙烯酯、其共聚物和它们的混合物。
15.一种用于诊断显像的微粒,所述的微粒由生物相容的聚合物制成并在其中包含有显像剂,包括将疏水性化合物以能增加水渗入或吸收入微球体速率的量与聚合物掺合。
16.根据权利要求15所述的微粒,其中疏水性化合物与聚合物按疏水性化合物重量/聚合物重量计,以0.01-30的比率相掺合。
17.根据权利要求16所述的微粒,其中的疏水性化合物是与聚合物以0.01-30的比率(脂类重量/聚合物重量)掺合的脂类。
18.根据权利要求17所述的微粒,其中的脂类选自由如下物质组成的组:脂肪酸及其衍生物,甘油单酯、二酯和三酯,磷脂、鞘脂、胆甾醇和甾体衍生物、油类、维生素和萜类。
19.根据权利要求18所述的微粒,其中的脂类是磷脂,选自磷脂酸、含饱和不饱和脂类的卵磷脂、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、磷脂酰肌醇、溶血磷脂酰衍生物、心肌磷脂和β-酰基-y-烷基磷脂。
20.根据权利要求19所述的微粒,其中的磷脂选自二油酰基卵磷脂、二(十四酰基)卵磷脂、二(十五酰基)卵磷脂、二月桂酰基卵磷脂、二棕榈酰基卵磷脂、二硬脂酰基卵磷脂、二(二十酰基)卵磷脂、二(二十二酰基)卵磷脂、二(二十三酰基)卵磷脂、二(二十四酰基)卵磷脂;和磷脂酰乙醇胺。
21.根据权利要求15所述的微粒,其中的成像剂选自氟化气体、氧气、氙气、氩气、氦气和空气。
22.根据权利要求21所述的微粒,其中的气体选自CF4、C2F6、C3F8、C4F8、SF6、C2F4和C3F6。
23.根据权利要求22所述的微粒,其中的气体是C3F8。
24.根据权利要求15所述的微粒,其中的显像剂是能由成像技术检测的显像剂,所述成像技术选自核磁共振成像、计算机断层X-射线照像、X-射线、正电子发射断层X-射线照像和单光电子发射计算机化断层X-射线照像。
25.根据权利要求15所述的微粒,其中的微粒由合成聚合物制成。
26.根据权利要求25所述的微粒,其中所述的合成聚合物选自聚羟基酸、聚酸酐、聚原酸酯、聚酰胺、聚碳酸酯、聚烯烃、聚亚烷基二醇、聚烷撑氧、聚对苯二甲酸亚烷基二醇酯、聚乙烯醇、聚乙烯醚、聚乙烯酯、聚卤化乙烯、聚乙烯吡咯烷酮、聚硅氧烷、聚(乙烯醇)、聚乙酸乙烯酯、聚苯乙烯、聚氨基甲酸乙酯及其共聚物、合成纤维素、聚丙烯酸、聚丁酸、聚戊酸,和聚(丙交酯/己内酯)、乙烯醋酸乙烯酯、其共聚物和它们的混合物。
27.根据权利要求17所述的微粒,其中脂类与聚合物一起被液化以制备微粒。
28.根据权利要求27所述的微粒,其中将脂类和聚合物溶于一种溶剂后再制成微粒。
29.根据权利要求27所述的微粒,其中气体是在聚合物和脂类凝固后再掺入到微粒中的。
30.根据权利要求15所述的微粒,其中的聚合物是天然聚合物,选自蛋白质和多糖。
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CN102600485A (zh) * | 2004-06-04 | 2012-07-25 | 阿库斯菲尔公司 | 超声对比剂剂量配方 |
CN1993147B (zh) * | 2004-06-04 | 2013-03-06 | 阿库斯菲尔公司 | 超声对比剂剂量组合物 |
CN102600485B (zh) * | 2004-06-04 | 2014-10-22 | 阿库斯菲尔公司 | 超声对比剂剂量配方 |
CN113499454A (zh) * | 2021-06-02 | 2021-10-15 | 上海市东方医院(同济大学附属东方医院) | 一种超声纳米诊疗剂及其制备方法和应用 |
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