CN1112935C - 用作显影剂的微囊包封的氟化气体 - Google Patents
用作显影剂的微囊包封的氟化气体Info
- Publication number
- CN1112935C CN1112935C CN97192870A CN97192870A CN1112935C CN 1112935 C CN1112935 C CN 1112935C CN 97192870 A CN97192870 A CN 97192870A CN 97192870 A CN97192870 A CN 97192870A CN 1112935 C CN1112935 C CN 1112935C
- Authority
- CN
- China
- Prior art keywords
- microgranule
- polymer
- poly
- acid
- gas
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- A61K49/00—Preparations for testing in vivo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
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Abstract
本发明公开了与内掺入空气的微粒相比，向合成聚合物多孔微粒中掺入氟化气体，尤其是全氟化碳，例如，八氟丙烷，可以显著增强回声性。例如，对于经静脉或经口给药而言，制备了具有利于目标组织成像的直径的微囊包封全氟化碳。在一个实施方案中，为了粘膜表明成像的增强，制备了生物粘连微粒。
Description
发明背景
本发明主要涉及诊断显影剂领域，具体涉及微囊包封的超声成像造影剂。
当用超声得到人或动物体内器官和结构的图像时，频率在人耳可分辨频率以上的声能量波，即超声波在其穿过身体时被反射。不同类型的身体组织对超声波的反射不同，检测由不同内部结构反射超声波而产生的回声并将其电信号转变成可视显示。
对于某些医学疾病来说，得到所关注的器官或结构的有用图像是特别困难的，因为在没有对比增强(contrast-enhancing)剂的情况下，通过超声波反射产生的超声图像不足以鉴别结构的详细情况和周围组织。通过将一种试剂注入所关注的器官或其它结构，增强超声图像中的对比，可以从根本上改进特定生理和病理学疾病的检测和观察。在其它情况下，对比增强剂本身运动的检测是特别重要的。例如，已知是因特定心血管失常而导致的特殊血流式样只有通过将造影剂注入血液中并观测血流动态才能分辨出。
当超声波穿过身体并被反射产生了用于医学诊断的图像时，用作超声造影剂的材料因对超声波有作用而得以发挥作用。不同类型的物质以不同的方式影响超声波，而且影响程度不同。此外，由对比增强剂引起的特定作用比其他方式更容易检测观察。在选择用于对比增强剂的理想组合物时，人们更愿意选择那些在超声波穿过身体时对超声波有最大影响的物质。另外，对超声波的影响应很容易检测。在超声波成像中可观察到三种主要的对比增强作用：反散射，束衰减和声速差。
反散射：当通过身体的超声波碰到结构如器官或其它身体组织时，结构反射一部分超声波。体内不同结构以不同方式和不同强度反射超声波能。这种反射的能量可以被检测并用于产生超声波所穿过之结构的图像。术语“反散射”指超声波被具有特定物理特性的物质散射回其源头的现象。
长时间来已经认识到，已知的能引起大量反散射的物质的存在，可以增强在超声波图像中所观察到的对比。将这种物质施用于身体的不同部分时，这部分身体的超声波图像与不含所述物质的周围组织的超声波图像之间的对比被增大。很容易理解的是，由于物理特性不同，所以不同的物质引起反散射的程度不同。因此，有关对比增强剂的研究集中在稳定无毒并有最大反散射的物质上。
物质引起超声波能量反散射的能力取决于该物质的特性，如其被压缩的能力。在试验不同的物质时，需要比较物质引起反散射之能力(称为“散射截面”)的特定测量值。特定物质的散射截面与散射物半径成正比，并取决于超声波能量的波长和所述物质的其他物理特性。J.Ophir and K.J.Parker，Contrast Agents in Diagnostic Ultrasound，Ultrasound in Medicine & Biology，vol.IS，n.4，p319，323(1989)。
在评估不同物质作为成像造影剂的实用性时，人们计算哪种试剂有较大的散射截面和因此哪种试剂在超声成像中可提供最大的对比。可以设想固体颗粒的可压缩性比周围介质的要小得多，并且颗粒的密度大得多。利用该假设，固体颗粒对比增强剂的散射截面估计是1.75。Ophir and Parker，同上文，325页。对于纯液体散射物来说，散射物和周围介质的绝热压缩性和密度可能基本相同，这样可能会产生液体散射截面为零的结果。但是，如果存在大量的液体试剂，液体也可以有某些反散射。例如，如果液体试剂从一个很小的容器穿过进入一个液体基本上占有了所有容器的很大容器，则所述液体就可检测到反散射。然而，本领域技术人员可以理解，与游离气体微泡相比，纯液体是相对无效的散射物。
束衰减：在特定固体对比增强剂存在下，可观察到的另一种作用是超声波的衰减。由于特定类型组织之间的定位的衰减差，在传统成像中观察到了图像对比。K.J.Parker and R.C.Wang，“Measurement ofUltrasonic Attenuation Within regions selected from B-Scan Images”，IEEE Trans.Biomed.Enar.BME30(8)，p431-37(1983)；K.J.Parker，R.C.Wang，and R.M.Lerner，“Attenuation of Ultrasound Magnitude andFrequency Dependence for Tissue Characterization，”Radiology，153(3)，p.785-88(1984)。已经假设在注入试剂前后所进行的组织区域衰减的测量可产生增强的图像。但是，以衰减对比为基础的作为检测液体试剂对比增强的方法的技术并未得到很大的发展，即使成功地发展了，可能也受该技术可应用的内部器官或结构的限制。例如，在心血管系统的成像中，不可能观察到因液体造影剂而引起的衰减损失，因为在检测到衰减的实质性差异前，在特定的脉管中需要存在大量的液体造影剂。
由颗粒引起的能量吸收是通过称为“相对运动”的机制发生的。因相对运动引起的衰减的变化随颗粒浓度线性增加而且是颗粒和周围介质之间密度差的平方。K.J.Parker等，“A Particulate Contrast Agentwith Potential for Ultrasound Imaging of Liver，”Ultrasound in Medicine& Biology，vol.13，No.9，p555，561(1987)。因此，在固体颗粒显著积累的情况下，衰减对比对于观察图像对比增强来说是一种可行的机制，尽管效果比反散射现象差很多，而且在心血管诊断中没有太大的用途。
声速差：另一种增强超声成像的对比技术是基于声速随它所通过的介质而变化的事实提出的。因此，如果将足够大量的试剂注入到靶区内(穿过试剂的声速与穿过周围组织的声速不同)，可就测量到穿过靶区的声速差。
总之，诊断超声波是一种能用于得到身体内部器官的信息的有效的非侵入性工具。灰阶成像和彩色多普勒的出现大大提高了该技术的范围和分辨率。尽管用于完成诊断超声波以及制备和使用造影剂的技术已有显著的改进，但是仍需要提高心灌注、心腔成像、实体器官、肾灌注、实体器官灌注的成像分辨率以及在实时成像中血液速度和流动方向的多普勒信号。
各种天然和合成的聚合物已被用于包封成像造影剂，如空气。Schneider等人在Invest.Radiol.，vol.27，pp.134-139(1992)中描述了3微米空气填充的聚合物颗粒。报道这些颗粒在血浆和应用压力下是稳定的。但是，在2.5MHz，它们的回声很低。另一类微泡悬浮液是从声处理的白蛋白得到的。Feinstein等，J.Am.Coll.Cardiol.，vol.11，pp.59-65(1988)。Feinstein描述了微泡的制备，所述微泡按照跨肺通道制成适宜的大小并有极好的体外稳定性。但是，这些微泡由于其在压力下的不稳定性，所以在体内寿命很短，半衰期约为几秒(近似等于一个循环)。Gottlieb，S.等，J.Am.Soc.Echo.，Vol.3，p.328(1990)，摘要；以及Shapiro，J.R.等人，J.Am.Coll.Cardiol.，Vol.16，pp.1603-1607(1990)。Carroll等(Carroll，B.A.等，Invest.Radiol.，Vol.15，pp.260-266(1980)和Carroll，B.A.等，Radiology，Vol.143，pp.747-750(1982))描述了明胶-包囊的空气泡，但由于它们尺寸大(12和80μm)，它们不可能通过肺毛细血管。Rasor Associates，Inc在PCT/US80/00502中已描述了明胶包囊的微泡。这些是通过“结合”明胶而形成的。
Fritzsch等已报道了用半乳糖微晶(SHU454和SHU508)稳定的微泡。Fritzsch，T.等，Invest.Radiol.Vol.23(Suppl 1)，pp.302-305(1988)和Fritzsch，T.等，Invest.Radiol.Vol.25(Suppl 1)，pp.160-166(1990)。所述微泡在体外持续达15分钟，但在体内不到20秒。Rovai，D.等，J.Am.Coll.Cardiol.，Vol.10，pp.125-134(1987)和Smith，M.等J.Am.Coll.Cardiol.，Vol.13，pp.1622-1628(1989)。
Schering Aktiengesellschaft的欧洲专利申请90901933.5公开了用于超声成像的微囊包封的气体或挥发性液体的制备和用途，其中所述微囊是由合成聚合物或多糖形成的。Sintetica S.A.的欧洲专利申请91810366.4(0 458 745 A1)公开了用界面间沉积的聚合物膜结合的空气或气体微球，其可被分散在含水载体中以注射到宿主动物中或用于经口、直肠或尿道给药，以达到治疗或诊断目的。Delta BiotechnologyLimited的WO 92/18164描述了微粒的制备方法，即在严格控制温度、喷雾速率、颗粒大小和干燥条件的条件下，通过喷雾干燥蛋白质水溶液以形成其中封有气体的用于成像的中空球。WO 93/25242描述了用于超声成像的微粒的合成，所述微粒由聚氰基丙烯酸酯或聚酯壳内包含的气体组成。WO 92/21382公开了包括含气体的共价结合的基质的微粒造影剂的制备，其中所述基质是碳水化合物。Unger的美国专利5334381、5123414和5352435描述了用作超声波造影剂的脂质体，其包括气体、气体前体，如pH激活或光激活的气体前体，以及其它的液体或固体对比增强剂。
Quay的美国专利5393524公开了包括碳氟化合物的试剂用于增强超声波图像中的对比的用途。所述试剂由所选气体的极小泡或微泡组成，它们在溶液中有较长的寿命并且很小足以通过肺，从而可用于心血管系统和其他重要器官的超声波成像中。Nycomed的WO95/23615公开了用于成像的微囊，所述微囊是通过含全氟化碳的溶液如蛋白质溶液的凝聚而形成的。Nycomed Imaging A/S的WO95/06518公开了聚合物基的造影剂，其中将气体微泡用非聚合的壁形成的阻断或接枝共聚物表面活性剂包封。制备时将气体掺入造影剂中。没有认识到用氟化气体代替空气可增强微粒的回声性。Glajch等的美国专利5147631描述了用于成像的掺入了气体(可以是氟化气体)的无机多孔颗粒。当然，这些不是合成的聚合物微粒。Massachusetts Institute ofTechnology的PCT/US94/08416公开了由聚乙二醇-聚(丙交酯-共-乙交酯)嵌段聚合物形成的微粒，其中包封了显影剂，包括气体如空气和全氟化碳。如在Sonus Pharmaceuticals，Inc.的WO94/16739中所描述的，尽管固体和液体对声波的反射程度相似，但是已知气体是更有效的而且对于用作超声波造影剂来说是优选的介质。事实上，如Sonus PCT申请的实施例12所表明的，当施用给迷你猪时，与乳化液或胶体悬浮液相比，由于涉及安全性(以及效率问题)，已经不再使用蛋白质微囊。
在这些情况下，都需要增强成像剂的回声性，并提高或保持显影剂的稳定性和制备的容易性。
因此，本发明的目的是提供由具有显著增强的回声性的合成聚合物制备的微粒。
本发明概述
现已发现与包封空气的微球相比，将氟化气体，特别是全氟化碳如八氟丙烷掺入到合成的聚合物微粒，特别是多孔海绵样微球中能显著提高回声性。微囊包封的氟化气体制备成适合于待成像的靶组织的直径，如为用于血管内施用而使直径在0.5-8微米之间，为经口施用用于胃肠系统或其它腔的成像而使直径在0.5-5毫米之间。本发明的详细说明
本发明提供了由含有氟化气体，特别是含有全氟化碳的合成的聚合物微粒组成的聚合物运载体系的合成方法。在许多诊断超声成像应用中，尤其是在例如血管成像和超声心电图检查的超声诊断方法中所述微粒是有用的。与掺入空气的相同合成聚合物微粒相比，氟化气体的掺入大大增强了回声。制备微粒的方法和试剂
除非另有说明，本发明所用术语“微粒”包括微球体、微囊以及微粒。微粒可以是或不是球形。微囊定义为具有包封另一种物质核心的聚合物外壳的微粒，本发明中另一种物质核心是气体。如下所述，微球体一般是固体聚合物球体，其包括由穿过充满了成像用气体的聚合物的孔所形成的蜂窝状构造。聚合物
不能生物降解的和可生物降解的基质均能用于氟化气体的运载，不过尤其是对于静脉注射而言，优选使用可生物降解基质。不易腐蚀的聚合物可用于口服给药。优选合成聚合物，因其更易于重复合成和生物降解。根据体内稳定所需时间，即根据分散到需成像部位所需时间以及成像所需时间来选择聚合物。在一个实施方案中，可以制备体内稳定时间为约20-30分钟或更长时间的微粒，其可用于例如超声心动图检查、neurosonography、子宫输卵管照相术以及对实体器官的诊断方法的应用中。在制备过程中通过使用聚合物，例如，聚(丙交酯-共-乙交酯)与聚乙二醇(PEG)的共聚物能调节包封的造影剂微粒的体内稳定时间。由于PEG是高度亲水的，所以如果PEG暴露于外表面则可延长这些物质的循环时间。
具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-共-乙醇酸)，聚乙交酯，聚丙交酯，丙交酯与乙交酯的共聚物和掺混物，聚酐，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，聚烯化氧如聚环氧乙烷，聚对苯二甲酸亚烷基二酯如聚对苯二甲酸乙二酯，聚乙烯基醇，聚乙烯基醚，聚乙烯基酯，聚卤乙烯如聚氯乙烯，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，聚氨酯及其共聚物，衍生的纤维素如烷基纤维素、羟烷基纤维素、纤维素醚、纤维素酯、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、乙酸纤维素、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、三乙酸纤维素和硫酸纤维素钠盐(本发明中统称为“合成纤维素”)，丙烯酸、甲基丙烯酸的聚合物或其共聚物或衍生物，包括酯、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、聚甲基丙烯酸异葵酯、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、聚丙烯酸异丁酯和聚丙烯酸十八醇酯(本发明中统称为“聚丙烯酸”)，聚丁酸，聚戊酸和聚(丙交酯-共-己内酯)，其共聚物和混合物。本发明中所用术语“衍生物”包括经过了取代作用、化学基团，例如，烷基、亚烷基的加成作用、羟基化作用、氧化作用和本领域技术人员按常规进行的其它修饰作用的聚合物。
优选的非生物降解的聚合物实例包括乙烯乙酸乙烯酯、聚(甲)丙烯酸、聚酰胺及其共聚物和混合物。
优选的可生物降解的聚合物实例包括羟基酸，例如，乳酸和乙醇酸的聚合物、聚丙交酯、聚乙交酯、聚(丙交酯-共-乙交酯)及其与PEG的共聚物、聚酐、聚原酸酯、聚氨酯、聚丁酸、聚戊酸和聚(丙交酯-共-己内酯)。通常，这些物质通过非酶催和酶催水解并通过表面和整体腐蚀在体内降解。
如在胃肠系统中的粘膜表面成像中，人们尤其愿意使用的生物粘合剂聚合物包括聚酐、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、聚甲基丙烯酸异葵酯、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、聚丙烯酸异丁酯和聚丙烯酸十八醇酯。溶剂
如本发明所定义，聚合物溶剂是挥发性的或具有相对低沸点或能在真空条件下去除且以痕量对人体进行给药是可接受的有机溶剂，例如，二氯甲烷。也可使用其它溶剂，例如，乙酸乙酯、丙酮、乙腈、四氢呋喃(THF)、乙酸、DMSO、氯仿或其混合物。通常，将聚合物溶解在溶剂中以形成重量对体积浓度为0.1-60％(w/v)，更优选为0.5-30％的聚合物溶液。氟化气体
任何生物相容的或药理上可接受的氟化气体均能被掺入微粒中。术语“气体”是指任何是气体或在成像温度下能形成气体的化合物。气体可以由单一化合物或化合物的混合物组成。优选全氟化碳气体。气体的实例包括CF4、C2F6、C3F8、C4F8、SF6、C2F4和C3F6。特别优选全氟丙烷，因为它是一种在使用温度下不冷凝且药理上可接受的不溶气体。微粒及其制备方法
在最优选的实施方案中，通过喷雾干燥制备微粒。如下所述，制备微粒也可使用其它技术，例如，溶剂萃取、热融包封和溶剂蒸发。
在优选的实施方案中，然后通过使所需气流与微球体相接触或对微球体抽真空除去包封的气体后填充所需气体，从而完成气体的替换。
a.
溶剂蒸发法.在该方法中，将聚合物溶解在挥发性有机溶剂，如二氯甲烷中。将固态的或在水溶液中的造孔剂加入该溶液中。声处理或均化混合物，所得分散液或乳化液加入含有表面活性剂，例如，TWEENTM20、TWEENTM80、PEG或聚乙烯醇的水溶液中并均化以形成乳化液。搅拌所得乳化液直至大部分有机溶剂蒸发，得到微球体。可使用一些不同的聚合物浓度(0.05-0.60g/ml)。用该方法能得到不同大小(1-1000微米)和形态的微球体。该方法对相对稳定的聚合物如聚酯和聚苯乙烯是有效的。
E.Mathiowitz等人在
J.Scanning Microscopy，4，329(1990)中，L.R.Beck等人在
Fertil.Steril.，31，545(1979)中以及S.Benita等人在J.Pharm.Sci.，73，1721(1984)中均描述了溶剂蒸发的方法。
然而，由于水的存在，所以在制备过程中不稳定的聚合物如，聚酐是可降解的。对于这些聚合物，下述两种在完全的有机溶剂中进行的方法是有效的。
b.
热融微囊包封法.在该方法中，首先熔化聚合物，然后与造孔剂的固体颗粒相混合。混合物悬浮在不溶混的溶剂(如硅油)中，在连续搅拌的同时，将其加热至聚合物熔点以上5℃。一旦乳化液稳定，则将其冷却直至聚合物颗粒固化。通过用聚合物非溶剂，如石油醚进行滗析来洗涤所得微球体以得到自由流动的粉末。用该方法能得到大小为1-1000微米的微球体。用该技术制得的球体外表面一般是光滑和致密的。该方法用于制备由聚酯和聚酐制得的微球体。然而，该方法仅适用于分子量为1000-50,000的聚合物。
E.Mathiowitz等人在
Reactive Polymers，6，275(1987)中描述了热融微囊包封方法。用热融微囊包封方法能制备，例如，由羧基苯氧基丙烷和癸二酸按20∶80的摩尔比(P(CPP-SA)20∶80)(分子量20,000)制成的聚酐或可制备聚(富马酸-共-葵二酸)(20∶80)(分子量15,000)空心微球体。
c.
溶剂去除法.该技术主要适用于聚酐。在该方法中，将造孔剂分散或溶解在含有所选聚合物的挥发性有机溶剂如二氯甲烷中。通过搅拌将该混合物悬浮在有机油(如硅油)中以得到乳化液。与溶剂蒸发方法不同，该方法能用于由具有高熔点和不同分子量的聚合物制备微球体。用该技术制得的球体的外形很大程度上取决于所用聚合物的类型。
d.
微粒的喷雾干燥法.通过喷雾干燥法能制备微粒，即将生物相容的聚合物溶解在适当的溶剂中，将造孔剂分散在聚合物溶液中，然后喷雾干燥聚合物溶液以形成微粒。如本发明所定义，“喷雾干燥”聚合物与造孔剂的溶液的过程是指将溶液雾化以形成细雾并通过与热载运气体的直接接触进行干燥的过程。使用现有的喷雾干燥器，聚合物溶液由喷雾干燥器的入口部分引进，流过干燥器中的导管，然后雾化通过出口部分。温度随所用气体或聚合物而改变。可控制入口和出口部分的温度来制备所需产物。
聚合物溶液的微粒大小随喷雾聚合物溶液所用的喷嘴、喷嘴压力、流速、所用聚合物、聚合物浓度、溶剂类型、喷雾温度(入口和出口温度)以及分子量而改变。一般，假设浓度相同，那么分子量越高，包囊体积越大。喷雾干燥的典型操作参数如下：聚合物浓度＝0.005-0.10g/ml，入口温度＝30-200℃，出口温度＝20-100℃，聚合物流速＝5-200ml/min，喷嘴直径＝0.2-4mm(内径)。能得到具有一定形态的直径为1-10微米的微球体，其形态取决于所选择的聚合物、浓度、分子量和雾状流动。
e.
水凝胶微球体.通过下述步骤可制备由凝胶型聚合物，例如，聚磷腈或聚甲基丙烯酸甲酯制成的微球体：将聚合物溶解在水溶液中，将造孔剂悬浮在该混合物中并经微滴形成装置挤出，形成的微滴流入由电荷相反离子或聚电解质溶液组成的缓慢搅拌的硬化浴中。该方法的优点在于：在制备完成后，通过用聚阳离子聚合物，如多熔素覆盖产物的表面可以进一步修饰微球体表面。通过使用不同大小的挤出机来控制微球体颗粒。促进微粒形成的添加剂
在含造影剂的微粒合成过程中可加入各种表面活性剂。可使用的典型乳化剂或表面活性剂(0.1-5重量％)包括大多数生理上可接受的乳化剂，例如，蛋卵磷脂，大豆卵磷脂或合成卵磷脂，如饱和合成卵磷脂，例如，二肉豆蔻酰卵磷脂、二棕榈酰卵磷脂或二硬脂酰卵磷脂或不饱和合成卵磷脂，例如，二油酰卵磷脂或二亚油酰卵磷脂。乳化剂还包括表面活性剂，例如，游离脂肪酸，脂肪酸与聚氧化烯化合物的酯，如聚氧亚丙基二醇和聚氧亚乙基二醇，脂肪醇与聚氧亚烷基二醇的醚，脂肪酸与聚氧亚烷基化脱水山梨糖醇的酯，皂，甘油聚烯烃硬脂酸酯，甘油聚氧乙烯蓖麻醇酯，聚亚烷基二醇的均聚物和共聚物，聚乙氧基化的豆油和蓖麻油及其加氢衍生物，蔗糖或其它碳水化合物与脂肪酸、脂肪醇的醚和酯(可任选被聚氧化烷基化)，饱和或不饱和脂肪酸、甘油酯或豆油的单、双或三甘油酯以及蔗糖。
其它乳化剂包括与氨基酸相连或不相连的天然或合成的胆汁盐或胆汁酸，例如，牛磺脱氧胆酸盐和胆酸。所列乳化剂能稳定喷雾干燥前产生的微泡。
用量为0.01％-75％(重量对体积)之间的造孔剂能促进孔的形成。例如，在溶剂蒸发方法中首先将造孔剂，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低温干燥的盐溶解在水中。将含造孔剂的溶液与聚合物溶液一起乳化以便在聚合物中形成造孔剂液滴。然后喷雾干燥该乳化液或将其进行溶剂蒸发/萃取。在聚合物沉淀后，冷冻和低温干燥硬化的微粒以除去造孔剂。微粒大小
在优选的实施方案中，为了制备能透过肺状毛细血管床的可注射微粒，所制微粒应具有约1-10微米的直径。较大的微粒会堵塞肺状床，而较小的微粒不能提供足够的回声。较大的微粒对于注射以外的给药途径是有效的，注射之外的给药途径可以是，例如，口服(用于胃肠系统的评估)，经其它粘膜表面(直肠、阴道、口、鼻)的给药途径或经吸入法。口服给药的优选颗粒大小为约0.5微米和5毫米。有效的药理上可接受的载体包括含甘油和TWEENTM20的盐水以及含TWEENTM20的等渗压甘露糖醇。用光显微镜、扫描电镜、透射电镜在库耳特颗粒计数器上可进行颗粒大小的分析。靶向
通过选择形成微粒的聚合物、微粒的大小和/或配体对微粒的结合或附着，可使微粒被特定或非特定靶向。例如，可将生理活性分子或能影响微粒的电荷、亲油性或亲水性的分子结合到微粒的表面。另外，可将那些能最小化组织粘合或能利于体内微球体的特定靶向的分子与微粒相结合。有代表性的靶向分子包括抗体、外源凝集素以及其它的能被特定类型的细胞表面的受体特定结合的分子。对网状内皮系统的摄入的抑制
通过选择聚合物和/或选择能使粘合或摄入最小化的分子的结合或偶合，也能使微粒的摄入和去除最小化。例如，通过聚亚烷基二醇部分与微粒表面的共价结合能使由微粒引起的组织粘合最小化。微粒表面的聚亚烷基二醇部分对水具有高亲和力，从而降低了颗粒表面对蛋白质的吸附作用。因而也就降低了网状内皮系统(RES)对微粒的识别和摄入。
例如，聚亚烷基二醇的末端羟基能使生理活性分子或能影响微粒电荷、亲油性或亲水性的分子共价结合到微粒的表面。本领域现有方法可用来使很宽范围内的任何配体结合到微粒上以提高微粒在体内的运载特性、稳定性或其它的性质。诊断应用
微粒一般与药理上可接受的载体，例如，磷酸盐缓冲盐水或盐水或甘露糖醇相结合，然后经适当途径，一般是经血管注射(静脉注射)或经口服对患者进行有效量给药。含包封显影剂的微粒可用于脉管成像、肝肾疾病的检测应用、心脏病学的应用、肿瘤块和组织的检测和表征以及外围血流速度的检测中。如下所述，微粒还能与那些能最小化组织粘连或能将微粒靶向体内特定区域的配体相结合。
参照下述非限制性实施例进一步说明上述方法和组合物。实施例1：充有空气的PEG-PLGA微球体的制备
将6.0克PEG-PLGA(75∶25)(120,000 Da mw)溶解在400ml二氯甲烷中。向聚合物中加入6.7ml水，并且用Virtis均化器以10,000RPM均化聚合物/水混合物1分钟。用蠕动泵以20ml/min的流速泵送溶液并用Bucchi Lab喷雾干燥器进行喷雾干燥。入口温度是50℃，出口温度是30℃。收集微球体粉末并在室温下低温干燥48小时。在数均值为2.0微米和体积平均值为4.5微米的库耳特颗粒计数器上测得颗粒直径为1-10微米。扫描电镜表明具有光滑表面和不规则表面细褶皱的颗粒一般是球形的。透射电镜表明颗粒是包囊状颗粒与海绵状颗粒的混合物。实施例2：充有空气的PEG-PLGA微球体的制备
将7.1克PEG-PLGA(75∶25)(120,000 Da mw)溶解在320ml二氯甲烷中。向聚合物中加入11ml浓度为0.74g/ml的乙酸铵，并且用Virtis均化器以16,000RPM均化聚合物/乙酸铵混合物1分钟。用蠕动泵以20ml/min的流速泵送溶液并用Bucchi Lab喷雾干燥器进行喷雾干燥。入口温度是32℃，出口温度是19℃。收集微球体粉末并在室温下低温干燥48小时。在数均值为1.8微米和体积平均值为5.1微米的库耳特颗粒计数器上测得颗粒直径为1-10微米。扫描电镜表明具有光滑表面和不规则表面细褶皱的颗粒一般是球形的。实施例3：充有八氟丙烷的PEG-PLGA微球体的制备
将实施例2中制备的微球体分散在54mg甘露糖醇/ml和0.5％PLURONICTMF127的溶液中。将分散液等分到5ml管瓶中。在-80℃下冷冻管瓶并低温干燥过夜。实施例4：充有八氟丙烷的PLGA微球体的制备
将7.4克PLGA(75∶25)(120,000 Da mw)溶解在360ml二氯甲烷中。向聚合物中加入7.3ml浓度为0.74g/ml的乙酸铵，，并且用Virtis均化器以16,000RPM均化聚合物/乙酸铵的溶液1分钟。用蠕动泵以20ml/min的流速泵送溶液并用Bucchi Lab喷雾干燥器进行喷雾干燥。入口温度是32℃，出口温度是20℃。收集微球体粉末并在室温下低温干燥48小时。在数均值为2.0微米和体积平均值为5.2微米的库耳特颗粒计数器上测得颗粒直径为1-10微米。扫描电镜表明具有光滑表面和不规则表面细褶皱的颗粒一般是球形的。将实施例2中制备的微球体分散在54mg甘露糖醇/ml和0.5％PLURONICTMF127的溶液中。将分散液等分到5ml管瓶中。在-80℃下冷冻管瓶并低温干燥过夜。在10pisg压力下向管瓶中填充八氟丙烷并在气体中连续吹洗3分钟。此后在-20℃下保存管瓶24小时然后在4℃保存直至被使用。实施例5：微囊包封空气颗粒的体内评估
将雄性新西兰兔(2-2.5kg)固定过夜。用盐酸氯胺酮(100mg/ml，0.7ml)和tompum(20mg/ml，0.5ml)麻醉动物。通过位于左耳静脉中的导液管以一定的剂型经大约5秒进行静脉注射给药。给药后，用1ml普通盐水冲洗导液管。重构之前将所有管瓶平衡至室温。在注射前不超过2分钟的时间内进行剂型重构。重构过程是将1ml水加入管瓶中，同时通过拉出5ml注射器上的活塞使得管瓶中的气压平衡至大气压，抽出注射针并回荡管瓶直至亲液物全部溶解从而可。用装备有C7-4高分辨换能器的ATL HDI 3000临床超声成像仪进行心脏超声成像。发射强度应使Tls为0.3和MI为0.8。帧速为39Hz，深度设为9.7cm，以Map 6和55dB的动态范围进行成像。在进行给药之前、给药之间和给药之后进行成像。用B-型进行心脏成像，并调节仪器设置以使心腔尽可能无回声。将成像的所有设置记录在VHS带上，同时继续成像直至检测不到信号。
以26.2mg/kg的剂量用实施例1制备的微球体(Lot 943-110-1)对兔(#13)实施给药。在10秒内，观察到大量可产生回声的物流流入并装满右心房。该物流流入右心房并装满右心室。实际上，两个心腔中的强度是相等的。流入左心室时观察不到回声。右心房和右心室的增强持续大约30秒。实施例6：微囊包封全氟化碳颗粒的体内评估
以24mg/kg的剂量用实施例3制备的微球体(Lot 952-7-3)对兔(#18)实施给药。右心室强度增强，随后左心室强度增强。观察到极好的心腔不透光性。2.5分钟后，心腔强度恢复到基线。
以22mg/kg的剂量用实施例4制备的微球体(Lot 952-49-1)对兔(#19)实施给药。右心室强度增强，随后左心室强度增强。观察到极好的心腔不透光性。2分钟后，心腔强度恢复到基线。
这些实施例显示了极好的心腔不透光性。
用不同的氟化气体、六氟化硫和六氟环丁烷进行了类似试验。
Claims (26)
1.一种增强由空气和溶解在有机溶剂中的聚合物形成的多孔微粒的回声性的方法，包括经孔除去空气并用氟化气体代替空气，所述用于替代空气的氟化气体的量在对患者实施给药后对微粒成像应是有效的。
2.根据权利要求1的方法，其中气体是全氟化碳。
3.根据权利要求1的方法，其中气体选自CF4、C2F6、C3F8、C4F8、SF6、C2F4和C3F6。
4.根据权利要求3的方法，其中气体是八氟丙烷。
5.根据权利要求1的方法，其中微粒是微囊。
6.根据权利要求1的方法，其中微粒是内具孔隙的微球体，其中通过向生理相容聚合物的溶液中混入有效量挥发性盐，除去聚合物溶剂，然后经低温干燥除去挥发性盐以形成孔隙。
7.根据权利要求1的方法，其中微粒由生物粘合的合成聚合物形成。
8.根据权利要求1的方法，其中微粒由选自聚羟基酸、聚酐、聚原酸酯、聚酰胺、聚碳酸酯、聚烯烃、聚亚烷基二醇、聚烯化氧、聚对苯二甲酸亚烷基二酯、聚乙烯基醇、聚乙烯基醚、聚乙烯基酯、聚卤乙烯、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-共-己内酯)、乙烯乙酸乙烯酯及其共聚物和掺混物的合成聚合物形成。
9.用于对患者实施给药以进行超声成像的组合物，包括生理相容的多孔聚合物微粒和用微粒对患者实施给药时药理上可接受的载体，其中微粒由空气和除聚乙二醇和聚(丙交酯-共-乙交酯)共聚物以外的溶解在有机溶剂中的聚合物形成，且其中经孔除去空气并用有效量的氟化气体代替空气，从而在对患者实施给药后，与内掺入等体积空气的微粒相比，所述掺入有效量氟化气体的微粒能增强超声成像。
10.根据权利要求9的组合物，其中氟化气体是全氟化碳。
11.根据权利要求9的组合物，其中氟化气体选自CF4、C2F6、C3F8、C4F8、SF6、C2F4和C3F6。
12.根据权利要求11的组合物，其中全氟化碳是八氟丙烷。
13.根据权利要求9的组合物，其中微粒是微囊。
14.根据权利要求9的组合物，其中微粒是内具孔隙的微球体，其中通过向生理相容聚合物的溶液中混入有效量挥发性盐，除去聚合物溶剂，然后经低温干燥除去挥发性盐以形成孔隙。。
15.根据权利要求9的组合物，其中微粒由生物粘合的合成聚合物形成。
16.根据权利要求9的组合物，其中微粒由选自聚羟基酸、聚酐、聚原酸酯、聚酰胺、聚碳酸酯、聚烯烃、聚亚烷基二醇、聚烯化氧、聚对苯二甲酸亚烷基二酯、聚乙烯基醇、聚乙烯基醚、聚乙烯基酯、聚卤乙烯、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-共-己内酯)、乙烯乙酸乙烯酯及其共聚物和掺混物的合成聚合物形成。
17.一种由具有增强的回声性的溶解在有机溶剂中的生理相容聚合物形成的微粒的制备方法，其中微粒的制备是通过向溶解在聚合物溶剂中的生理相容聚合物溶液中混入有效量挥发性盐，除去聚合物溶剂，然后经低温干燥除去挥发性盐以形成多孔微粒。
18.根据权利要求17的方法，其中微粒是微囊。
19.根据权利要求17的方法，其中微粒是内具孔隙的微球体。
20.根据权利要求17的方法，其中微粒由生物粘合的合成聚合物形成。
21.根据权利要求17的方法，其中微粒由选自聚羟基酸、聚酐、聚原酸酯、聚酰胺、聚碳酸酯、聚烯烃、聚亚烷基二醇、聚烯化氧、聚对苯二甲酸亚烷基二酯、聚乙烯基醇、聚乙烯基醚、聚乙烯基酯、聚卤乙烯、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-共-己内酯)、乙烯乙酸乙烯酯及其共聚物和掺混物的合成聚合物形成。
22.根据权利要求17的方法，其中挥发性盐选自碳酸氢铵、乙酸铵、氯化铵、苯甲酸铵及其混合物。
23.根据权利要求17的方法，其中按0.01-75％的重量对体积比将挥发性盐混入聚合物溶液中。
24.根据权利要求17的方法，其中将挥发性盐溶解在水溶液中，与聚合物溶液一起乳化以便在聚合物中形成挥发性盐的液滴，然后喷雾干燥乳化液。
25.根据权利要求24的方法，进一步包括下述步骤：通过喷雾干燥将聚合物沉淀后，冷冻和低温干燥沉淀的聚合物以除去挥发性盐。
26.根据权利要求17的方法，进一步包括向多孔微粒中掺入氟化气体。
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| US6723303B1 (en) | 1991-09-17 | 2004-04-20 | Amersham Health, As | Ultrasound contrast agents including protein stabilized microspheres of perfluoropropane, perfluorobutane or perfluoropentane |
| US6582728B1 (en) * | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
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| HUT72323A (en) * | 1993-01-25 | 1996-04-29 | Sonus Pharma Inc | Phase shift colloids as ultrasound contrast agents |
| DE59409568D1 (de) * | 1993-09-09 | 2000-11-30 | Schering Ag | Wirkstoffe und gas enthaltende mikropartikel |
| US20030113273A1 (en) * | 1996-06-17 | 2003-06-19 | Patton John S. | Methods and compositions for pulmonary delivery of insulin |
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| GB9106673D0 (en) * | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
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1996
- 1996-03-05 US US08/611,248 patent/US5611344A/en not_active Expired - Lifetime
- 1996-11-08 US US08/745,676 patent/US5853698A/en not_active Expired - Lifetime
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1997
- 1997-02-27 CN CN97192870A patent/CN1112935C/zh not_active Expired - Fee Related
- 1997-02-27 KR KR10-1998-0706964A patent/KR100477857B1/ko not_active IP Right Cessation
- 1997-03-03 ZA ZA971812A patent/ZA971812B/xx unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| US5853698A (en) | 1998-12-29 |
| KR19990087529A (ko) | 1999-12-27 |
| CN1222860A (zh) | 1999-07-14 |
| US5611344A (en) | 1997-03-18 |
| ZA971812B (en) | 1998-11-03 |
| KR100477857B1 (ko) | 2005-09-30 |
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