CN1221214C - 制备最佳尺寸的充气泡囊的装置和方法 - Google Patents
制备最佳尺寸的充气泡囊的装置和方法 Download PDFInfo
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Abstract
本发明公开了一种适用于用作造影剂的泡囊的制备方法和装置,其中通过往复运动使包含含水悬浮液相和分离的气相的容器进行振动。往复运动是通过振动臂产生的,该振动臂使容器在两个基本垂直的方向上运动,在第一个方向上的运动是沿着弧形路径运行的。运动的整体路径为8字形。振动的频率至少为2800RPM,振动臂的长度至少为6cm,振动臂在第一个方向旋转通过的角度至少为3°,围绕8字形路径运行的总长度至少为约0.7cm。
Description
相关申请
本申请为U.S.申请号307,305申请日1994.9.19的申请的部分继续申请,其又是U.S.申请号159,687申请日1993.11.30申请的部分继续申请,其又是U.S.申请号076,239申请日1993.6.11申请的部分继续申请,其又是U.S.申请号717,084和申请号716,899,两者申请日均为1991.6.18申请的部分继续申请,其又是U.S.申请号569,828申请日1990.8.20申请的部分继续申请,其又是U.S.申请号455,707申请日1989.12.22申请的部分继续申请。
本申请也是U.S.申请号160,232申请日1993.11.30申请的部分继续申请,其又是U.S.申请号076,250申请日1993.6.11申请的部分继续申请,其依次为U.S.申请号717,084和申请716,899,两者申请日均为1991.6.18申请的部分继续申请,其又是U.S.申请号569,828申请日1990.8.20申请的部分继续申请,其又是U.S.申请号455,707申请日1989.12.22申请的部分继续申请。
这些申请的内容全文引入本文作参考。
发明领域
本发明涉及制备充气泡囊的方法和装置,特别是用于超声成像的充气泡囊的制备方法和装置。更具体地说,本发明涉及通过振动制备充气泡囊的方法和装置,其中通过控制振动参数在最短的时间内提供最佳尺寸的泡囊。
发明背景
超声技术是一种较之其它诊断技术有许多优点的诊断成像技术。与核医学及x-射线不同,超声技术并不会让患者接受可能有害的离子化电子辐射,这种辐射有可能造成对生物体物质如DNA、RNA和蛋白质的损害。此外,超声技术与CT诊断或磁共振成像技术比相对价廉。
超声技术的原理是基于以下事实,根据被观察的组织或血管的组成和密度,声波对组织的反射不同。根据组织的组成不同,超声波会通过吸收而消耗、穿透组织或反射回来。反射也称之为背散射或反射能力,它是超声成像的基础。一种超声波振子可用来敏感地测量返回的声波,这种振子通常能在临床上探测到1MHz-10MHz的声波。这些波再整合成为一种定量图像。再将定量波转化成被观测组织的图像。
尽管在超声技术方面已有很大进展,但仍然希望使得到的图像更精细,特别是考虑到充满血液的那些血管和组织。因此,仍要求找到那些有助于观察血管和血管相关的器官的试剂。
泡囊为超声技术理想的造影剂,这是因为,声音在液-气界面如泡囊的表面上的反射极其有效。
作为有效的超声造影剂,泡囊应尽可能大而富有弹性,因为这些泡囊(泡大小和弹性)对于尽可能地反射来自泡囊的声音是非常重要的。此外,泡囊在受压下应对压力稳定,即,在压力下保持超过50%的气体含量。同样,希望泡囊在释放压力后应能重新扩展开。进而,为了得到最大的反射并因此造影,希望有高泡囊浓度。从而,泡囊浓度成为确定泡囊效力的重要因素。具体说来,希望每毫升有泡囊1×108个以上,更优选超过5×108个。
但是,大小依然是确定成像用泡囊适应性的关键因素。对于能安全通过毛细血管的泡囊,反射信号(瑞利散射)可能是泡囊大小的函数,泡囊提高至六次方,使得4μm直径泡囊的散射能力为2μm直径泡囊散射能力的64倍。
由于泡囊直径大于10μm可能是危险的,大小也非常重要。静脉内或血管内注射后,大的泡囊有可能阻塞静微管。因此,重要的是即要使泡囊尽可能大以有效地反射声波,又足以小至能通过毛细血管。
为此,希望99%的泡囊小于10μm。进而,平均泡囊大小应至少为0.5μm,优选超过1μm,更优选接近2μm以便于最有效地造影。此外,体积加权平均值应在7μm数量级。
由于泡囊弹性越大,能挤压通过毛细管的能力越大,因此泡囊的弹性也影响其最大可容许尺寸。不幸的是,有许多因素可能会阻止高弹性泡囊的形成,因而更进一步增加了要使泡囊大小最佳化的重要性。
未包衣的泡囊的弹性最大,但通常它们又是不稳定的。结果,人们通常试图通过包被来增加泡囊的稳定性,但这又会降低它们的弹性。此外,已建议使用包封在蛋白外壳内的气体或气体前体,蛋白质与生物可降解交联剂交联,同时使用与生物相容化合物共价交联的非蛋白泡囊。可以设想,这种交联剂将会增加泡囊的刚性成分,因而降低其弹性。
公所周知,通过振动表面活性剂在液体介质中的溶液制备脂质体(参见U.S.4,684,479,D’Arrigo),但是迄今并未开发出在尽可能少的时间内制备具有最佳大小之泡囊的方法。因此,由于上述各种原因,人们仍希望找到一种制备泡囊的方法和装置,其中可控制振动参数以在最短的时间内生产出最佳大小的泡囊。
发明概述
本发明的目的是提供一种制备泡囊的方法和装置,其中可控制振动变量以在最短的时间内生产出最佳尺寸的泡囊。按以下方法可实现该目的和其它目的,所述方法中,使用往复运动来振动包含含水悬浮液相和气相的容器。往复运动由振动臂产生,该振动臂使容器在两个基本上垂直的方向上运动。第一个方向上的运动是沿着一条弧形路径进行,该路径的曲率半径至少为6cm,并包容至少3°的角度。运动的整体路径以8字形进行。振动频率至少为2800RPM,振动幅度至少为0.3cm,容器在每一循环中的运行总长度至少为0.7cm。
本发明也提供了使用上述方法振动包含含水悬浮液相和气相的装置。该装置优选具有一个振动臂,其长度至少为6cm,旋转通过至少3°的角度。
附图简述
图1为本发明振动装置容器部分的正视图,其中通过本发明的振动方法制备泡囊。
图2为不包括容器的本发明振动装置的立体图。
图3为不含盖子但包括安装图1所示容器的图2所述振动装置的纵剖面图。
图4和5分别为当图1所示容器安装在图2所示振动装置上运行路径的正视图和平面图,图5是沿图4所示V-V线剖开的。
图6为图2所示振动装置的主要内部组件的立体图。
图7和8为振动臂安装于驱动轴上的区域附近图2所示振动装置的纵剖面图,当偏心套管为图8所示取向时振动臂的位置以虚线形式示于图7。
图9(a)和(b)为图7所示振动臂沿IX-IX线剖开的示意图,只是在图9(a)和(b)中偏心套管分别从图7所示的取向旋转了90°和270°。
图10为沿图9(b)所示X-X线的剖面图,虚线示出了当偏心套管旋转180°时套筒的取向。
图11为安装于驱动轴上的偏心套管的立体图。
图12为类似图9的示意图,示出了当采用较低的弹簧张力时振动臂的取向。
图13为表明振动频率(RPM)、振动臂长度L(cm)、轴承偏角θ间关系的关系图,用以获得图14-16所示的试验结果。
图14(a)-(c)为表明轴承偏角θ为6°,根据图13变化振动臂长度和RPM时,泡囊小于10μm的百分数、数目加权平均值大小、颗粒数/ml与振动臂长度L(mm)间关系的关系图。
图15(a)-(c)为类似图14(a)-(c)的关系图,只是比较了轴承偏角θ为9°下与图14(a)-(c)所获得的结果。
图16(a)-(c)为表明泡囊小于10μm的百分数、数目加权平均值大小、颗粒数/ml与振动路径总长度(cm)间关系的关系图。
图17为表明振动频率(RPM)、振动路径总长度(cm)间关系的关系图,用以得到图16所示的试验结果。
图18(a)-(c)为表明泡囊小于10μm的百分数、数目平均值尺寸和颗粒数/ml在三种不同类型的振动设备中的关系图。
优选实施方案描述
按照本发明的方法,如图1所示,首先将优选包含类脂的含水悬浮液34置于容器9中来制备最佳尺寸的泡囊。
本文中术语“泡囊”是指球状实体,特征是在球面内部是中空。优选的泡囊是由类脂制成的,类脂包括本文描述的各种类脂。在任一种给出的泡囊中,类脂可以为单层或双层,单层或双层类脂可用来形成一个或多个单层或双层。对于多于单层或双层的情形,单层或双层通常为同心的。本文所述泡囊有时也被称之为泡或微泡,包括通常被称作脂质体和微胶粒等的实体。因此,类脂可用于形成单层状泡囊(包含一个单层或双层)、几层的泡囊(包含约两个或三个单层或双层)或多层的泡囊(包含多于三个单层或双层)。泡囊的内部空隙可以用液体(包括,例如含水液体)、气体、气体前体和/或固体或可溶性物质(包括,例如导向配体和/或生物活性试剂)。
“脂质体”是指通常为两亲化合物的球形簇或聚集物,包括类脂化合物,通常为一种或多种同心层的形式。充气的脂体最好由单层或单个的单层类脂构成。各种类脂可用于构造脂质体,其包括磷脂和非离子表面活性剂(如niosomes)。在生理温度下,含类脂的充气脂质体最好为凝胶状态。脂质体可被交联或聚合,可在其表面上负载聚合物如聚乙二醇。导向内皮细胞的配体被结合至充气的脂质体表面上。导向配体为结合至泡囊并使泡囊导向特定细胞型(如但不限于内皮组织和/或细胞)的物质。导向配体可通过共价或非共价键与泡囊结合。本文中脂质体也可被称作类脂泡囊。脂质体最好在其内部基本上不含水。
“微胶粒”是指当类脂化合物如十二烷基硫酸酯的浓度高于其临界浓度时由类脂化合物形成的胶体。由于形成微胶粒的许多化合物也具有表面活性剂的性质(即能降低表面张力,且既具有亲水性又具有亲油性区域结构),这些相同的物质也可用于稳定泡囊。通常,这些微胶粒物质优先采用单怪或六方形H2相构型,也可采用双层构型。当微胶粒物质用于形成充气的泡囊时,该化合物通常将采用径向构型,其中亲油部分指向泡囊和亲水区背向泡囊表面。为导向内皮细胞,导向配体可附着于微胶粒化合物或与微胶粒化合物混合的亲油物质上。另外,导向配体也可吸附在稳定泡囊的微胶粒物质上。
容器9的其余部分或液面上空间32,于含水悬浮相34的上方为气体相。如果将空气外的其它气体用作气相,则通过用气体吹扫容器9而引入气相,使气体占据含水悬浮液34上面的液面上空间32。因此,在振动以前,容器9包含含水悬浮相及气相。然后,将容器9安装在本发明的振动装置1的振动臂7上,优选的方式示于图2、3和6-11,经充分振动而形成所需的泡囊。
虽然在振动后可使用过滤器来进一步改善泡囊的大小分布情况,但本发明的着眼点是控制振动参数以在任何振动动过滤前生产出具有最佳尺寸的泡囊。为此,本发明人发现,通过振动产生的泡囊的尺寸主要为以下四个变量的函数:
(i)含水悬浮液相的组成;
(ii)液面上空间中气相的组成;
(iii)容器的体积及由气相初始占据的液面上空间的相对体积,及
(iv)主要振动参数的定义,即振动期间由容器传输的路径的形状、振动运动的振幅、振动的持续时间和频率。
根据本发明的方法,可在制备泡囊的过程中调节上述变量以得到所需的泡囊大小分布和浓度,优选的泡囊大小分布是,泡囊的平均大小为至少约0.5μm,优选至少95%、更优选至少99%的泡囊的直径小于10μm,产生的泡囊的浓度至少为100×106个泡囊/ml,更优选至少为500×106个泡囊/ml。下面在第I-IV节,分别讨论上述四个变量。在第V节,描述了实施本发明方法的优选装置。第VI节则讨论了本发明制备的泡囊的一些应用情况。
I.含水悬浮液相的组成
各种泡囊包被剂均可用于含水悬浮液相中。优选该包被剂为类脂。按需要,类脂可为饱和或不饱和的,可为直链或支链形式。这种类脂可包括,例如,含宽范围碳原子的脂肪酸分子,优选含约12-22个碳原子。也可采用由类异戊二烯单元构成的烃基、含异戊二烯基的和/或甾醇部分(如胆甾醇、胆甾醇硫酸酯及其类似物)。类脂也可带有聚合物链,如两亲聚合物聚乙二醇(PEG)或聚乙烯吡咯烷酮(PVP)或其衍生物(用于体内导向),或带电荷的氨基酸如聚赖氨酸或聚精氨酸(用于负电化合物的键合),或碳水化合物(用于体内导向)(如U.S.4,310,505所述),或糖脂(用于体内导向),或抗体和其它肽和蛋白质(用于体内导向)等。这种导向化合物或键合化合物可简单地加至含水类脂悬浮液相中,或者可被特定地化学结合至类脂上。类脂也可为阴离子或阳离子类脂,从而它们自身能键合其它化合物如药物、遗传物质或其它治疗物。
适宜的类脂和特别适宜的类脂的实例包括:磷脂酰胆碱,如二油酰基磷脂酰胆碱、二肉桂酰基磷脂酰胆碱、二棕榈酰基磷脂酰胆碱(DPPC)、二硬脂酰基磷脂酰胆碱;磷脂酰乙醇胺,如二棕榈酰基磷脂酰乙醇胺(DPPE)、二油酰基磷脂酰乙醇胺和N-琥珀酰基-二油酰基磷脂酰乙醇胺;磷脂酰丝氨酸;磷脂酰甘油;鞘脂类;糖脂,如神经节苷脂GM1,糖脂;硫苷脂;糖鞘脂;磷脂酸,如二棕榈酰基磷脂酸(DPPA);棕榈酸;硬脂酸;花生四烯酸;月桂酸;肉豆蔻酸;月桂烯酸;抹香鲸酸;肉豆蔻烯酸;棕榈烯酸;岩芹酸;油酸;异月桂酸;异肉豆蔻酸;异棕榈酸;异硬脂酸;胆甾醇和胆甾醇衍生物,如胆甾醇半琥珀酸酯、胆甾醇硫酸酯及胆甾醇-(4′-三甲基铵基)丁酸酯;聚氧乙烯脂肪酸酯;聚氧乙烯脂肪醇;聚氧乙烯脂肪醇醚;聚氧乙烯化山梨醇脂肪酸酯;甘油聚乙二醇氧基硬脂酸酯;甘油聚乙二醇蓖麻醇酸酯;乙氧基化大豆甾醇;乙氧基化蓖麻油;聚氧乙烯-聚氧丙烯脂肪酸聚合物;聚氧乙烯脂肪酸硬脂酸酯;12-(((7′-二乙氨基香豆素-3-基)-羰基)-甲氨基)-硬脂酸;N-[12-(((7′-二乙氨基香豆素-3-基)-羰基)-甲氨基)硬脂酰基]-2-氨基-棕榈酸;1,2-二油酰基-sn-甘油;1,2-二棕榈酰基-sn-3-琥珀酰基甘油;1,3-二棕榈酰基-2-琥珀酰基-甘油;1-十六烷基-2-棕榈酰基-甘油磷酰乙酰胺和棕榈酰基高半胱氨酸;月桂基三甲基溴化铵;鲸蜡基三甲基溴化铵;肉豆蔻基三甲基溴化铵;烷基二甲基苄基氯化铵,如其中烷基为C12、C14或C16烷基;苄基二甲基十二烷基溴化铵;苄基二甲基十二烷基氯化铵、苄基二甲基十六烷基溴化铵;苄基二甲基十六烷基氯化铵;苄基二甲基十四烷基溴化铵;苄基二甲基十四烷基氯化铵;十六烷基二甲基乙基溴化铵;十六烷基二甲基乙基氯化铵;十六烷基溴化吡啶翁;十六烷基氯化吡啶翁;N-[1-2,3-二油酰氧基-丙基]-N,N,N-三甲基氯化铵(DOTMA);1,2-二油酰氧基-3-(三甲基铵基)丙烷(DOTAP);1,2-二油酰基-e-(4′-三甲基铵基)-丁酰-sn-甘油(DOTB)。
本领域的技术人员可以看出,上述类脂仅为举例性的,通过以上描述,可以采用其它有用的类脂、脂肪酸和其衍生物及其组合,这些化合物同样也属本文中术语类脂的范围。普通的专业技术人员知道,这些类脂和/或其组合经容器振动后会形成脂质体(即具有内部中空的类脂球),这些脂质体能收集在其内部间隙气相中的气体。脂质体可由单一类脂层(类脂单层)、两类脂层(类脂双层)或多于两层的类脂层(类脂多层)组成。
一般说来,优选类脂保持凝胶状态,即低于类脂物质的凝胶态至液晶相转化温度(Tm),特别是在振动过程中。各种类脂从凝胶态至液晶态相转化温度均是公知的。这种温度也易于使用公知技术进行计算。例如,下表1示出了各种代表性饱和磷脂酰胆碱类脂的主链相转化温度,来自于Derek Marsh,“类脂双层的CRC手册(CRC Handbook of LipidBilayers,
139页,CRC Press,Boca Raton,Florida(1990)”。
表1
饱和二酰基-sn-甘油-(3)-磷酰基胆碱:主链熔化转化
酰基链中的碳号 | 主相转化温度℃ |
1,2-(12:0)1,2-(13:0)1,2-(14:0)1,2-(15:0)1,2-(16:0)1,2-(17:0)1,2-(18:0)1,2-(19:0)1,2-(20:0)1,2-(21:0)1,2-(22:0)1,2-(23:0)1,2-(24:0) | -1.013.723.534.541.448.255.161.864.571.174.079.580.1 |
在本发明的优选实施方案中,含水类脂相还包含一种聚合物,优选一种两亲聚合物,并且优选直接键合(化学结合)至类脂上的聚合物。两亲聚合物优选聚乙二醇或其衍生物。最优选的组合是键合至聚乙二醇(PEG),特别是平均分子量为约5000的PEG上的类脂二棕榈酰基磷脂酰乙醇胺(DPPE),即DPPE-PEG5000。可通过共价键如通过酰胺、氨基甲酸酯或胺键将PEG或其它聚合物键合至DPPE或其它类脂上。另外,也可以将PEG或其它聚合物通过酯、醚、硫酯、硫代酰胺或二硫化物(硫酯)键与胆甾醇或其它磷脂键合。特别优选的类脂组合为DPPC、DPPE-PEG5000和DPPA,特别是DPPC∶DPPE-PEG5000∶DPPA的比值约为82%∶8%∶10%(摩尔%)。
其它在含水悬浮液相中可选用或填加的包被剂包括聚合物如蛋白质、天然及半天然碳水化合物和合成聚合物。各种不同的蛋白质可用于本发明中以生产充气的泡囊。这些蛋白质包括:来自天然(人和动物)及重组源的清蛋白、血纤维蛋白、胶原蛋白、抗体和弹性硬蛋白。天然多糖包括:淀粉、纤维素、藻酸、果胶、葡聚糖、肝素、透明质酸。半天然多糖包括:甲基纤维素、羟丙基纤维素羧甲基纤维素和羟乙基淀粉。合成聚合物包括聚乙烯吡咯烷酮、乙二醇和丙二醇的共聚物(如环氧乙烷-环氧丙烷的嵌段共聚物F-68和其它环氧乙烷-环氧丙烷的嵌段共聚物类)、聚乙二醇、聚乙烯醇、聚乳酸、乳酸与乙醇酸的共聚物、聚甲基丙烯酸酯和双酯聚合物。本发明中也可用无机介质如羟基磷灰石和焦磷酸钙。在所有这些情形下,在容器中将泡囊包被剂悬浮在含水相中,液面上空间为所选气体,然后振动。从而形成稳定的包被的泡囊。本领域的技术人员可以看出,根据本发明的原理,通过以上描述,可以采用各种不同的稳定剂制备泡囊。
在采用人血清清蛋白的实验中(BRL-Life Technologies,Gaithersburg,Maryland),将包含清蛋白溶液及液面上空间为全氟丙烷气体的10ml玻璃小管(液体体积为6ml,5mg/ml清蛋白溶液)在2800RPM下用Wig-L-BugTM振动2分钟,生产出浓度为50×106颗粒/ml,平均直径为5μm的血清蛋白包被的全氟丙烷泡囊。
此外,本发明的用途与各种悬浮剂和/或粘度剂相容。本文所使用的术语悬浮剂是指有助于在造影介质中提供相对均匀性或均一性的化合物。可使用许多这类试剂,包括黄原胶、金合欢树胶(阿拉伯胶)、琼脂、藻酸、单硬脂酸铝、黄蓍胶糖、刺梧桐树胶、阿拉伯胶、未纯化的膨润土、纯化的膨润土、膨润土糊、聚羧乙烯934P、羧甲基纤维素钙、羧甲基纤维素钠、羧甲基纤维素钠12、角叉胶、纤维素(微晶纤维素)、葡聚糖、明胶、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、硅酸铝镁、甲基纤维素、果胶、酪蛋白、明胶、聚环氧乙烷、聚乙烯醇、聚乙烯吡咯烷酮、丙二醇、藻酸盐、二氧化硅、二氧化硅胶体、藻酸钠和其它藻酸盐及黄蓍胶。本领域的技术人员可以看出,如果需要的话,各种悬浮剂可用于本发明的造影介质中。
这些试剂的用量可以根据所选的泡囊稳定介质变化,振动参数也可根据所用的物质而改变。由于类脂具有生物相容性、低素性、易于得到纯的药品级物质等性能,因而成为优选的制备本发明充气泡囊的泡囊包被剂。
为了制备含水相,如本领域技术人员公知的那样,使类脂或其它包被剂与水(优选蒸馏水)、生理盐水、磷酸盐缓冲的生理盐水或其它水基溶液混合。
通过以上描述,本领域的技术人员可以看出,在本发明的含水悬浮液相中可采用各种添加剂以稳定悬浮液相,或者稳定振动后的充气的泡囊。如果需要,可将这些添加剂在振动前加到含水悬浮液中。当然,本领域的技术人员也易于看出这种添加剂的使用取决于所形成的充气的泡囊的特定用途。
本发明中可采用许多种稳定剂,它们包括黄原胶、金合欢树胶(阿拉伯胶)、琼脂、琼脂糖、藻酸、藻酸盐、藻酸钠、角叉胶、葡聚糖、糊糖、明胶、瓜尔胶、黄蓍胶、刺槐豆胶、黄蓍胶糖、刺梧桐树胶、阿拉伯胶、果胶、酪蛋白、膨润土、未纯化的膨润土、纯化的膨润土、膨润土糊、胶体、纤维素、纤维素(微晶)、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、羧甲基纤维素钠12,以及其它天然或改性天然纤维素、聚山梨酸酯、聚羧乙烯934P、硅酸铝镁、单硬脂酸铝、聚环氧乙烷、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、丙二醇、聚乙烯吡咯烷酮、二氧化硅、二氧化硅胶体。
此外,诸如全氟辛基溴(PFOB)、全氟辛基碘、全氟三丙基胺及全氟三丁基胺等化合物均可作为稳定剂用于类脂相。在体温下,超过五个碳原子的全氟化碳通常为液体,因此这类全氟化碳也优选用作稳定剂。适宜的全氟化碳包括全氟己烷、全氟庚烷、全氟辛烷、全氟萘烷和全氟十二灵。此外,为了稳定,全氟化类脂或部发氟化的类脂也可使用。本领域的技术人员可以看出,可以使用本发明所述类脂的各种全氟化和部分氟化的类脂物。由于它们相对于烃类脂具有相对的疏水性,考虑稳定性,这种全氟化或部分氟化类脂甚至更有优越性。全氟化或部分氟化的类脂的实例为F6C11磷脂酰胆碱(PC)和F8C5PC。类似物可参见:Santaella等的“Federation of European Biochemical Societies(FEBS)”,Vol.336,No.3,PP.418-484(1993),该文献引入本文作参考。
各种生物相容的油也可用于辅助稳定,如花生油、carola油、橄榄油、红花油、玉米油、杏仁油、棉籽油、桃仁油、芝麻油、豆油、矿物油、矿物油轻馏分、油酸乙酯、肉豆蔻醇、肉豆蔻酸异内酯、棕榈酸异丙酯、十八碳醇、丙二醇、甘油、角鲨烯,或任何其它公知的可消化油。也包括卵磷脂、鞘磷脂、胆甾醇、胆甾醇硫酸酯和甘油三酸酯。
也可以通过加入各种粘度调节剂实现稳定作用,粘度调节剂可用作本发明的稳定剂。这类化合物包括但不限于:(1)碳水化合物和其磷酸化和磺化衍生物;(2)分了量为400-8000的聚醚;(3)二和三羟基烷烃及它们的分子量为800-8000的聚合物。脂质体也可与乳化剂和/或增溶剂一起结合使用,这些试剂包括但不限于:阿拉伯胶、胆甾醇、二乙醇胺、单硬脂酸甘油酯、羊毛脂醇、卵磷脂、单酸和二酸甘油酯、一乙醇胺、油酸、油醇、泊洛沙姆、聚氧乙烯50硬脂酸酯、聚氧35蓖麻油、聚氧10油醚、聚氧20鲸蜡硬脂酰醚、聚氧40硬脂酸酯、聚山梨酯20、聚山梨酯40、聚山梨酯60、聚山梨酯80、丙二醇二乙酸酯、丙二醇单硬脂酸酯、十二烷基硫酸钠、硬脂酸钠、山梨醇单月桂酸酯、山梨醇单油酸酯、山梨醇单棕榈酸酯、山梨醇单硬脂酸酯、硬脂酸、三乙醇胺、乳化蜡、环氧乙烷-环氧丙烷的嵌段共聚物F61、环氧乙烷-环氧丙烷的嵌段共聚物F64和环氧乙烷-环氧丙烷的嵌段共聚物F68。
其它可加入的试剂包括张力剂如聚醇,如甘油、丙二醇、聚乙烯醇、聚乙二醇、葡萄糖、木糖醇、山梨糖醇、氯化钠等。
如果需要的话,在制剂中也可包含抗菌剂和/或防腐剂。这些试剂包括苯甲酸钠、所有的季铵盐、叠氮化钠、对羟苯甲酸甲酯、对羟苯甲酸丙酯、山梨酸、山梨酸钾、山梨酸钠、抗坏血酸棕榈酸酯、丁基化羟基茴香醚、丁基化羟基甲苯、氯丁醇、脱氢乙酸、乙二胺四乙酸(EDTA)、单硫代甘油、苯甲酸钾、偏亚硫酸氢钾、山梨酸钾、亚硫酸氢钠、二氧化硫,有机汞盐。
如果需要的话,可采用渗透性试剂来控制渗透性。透宜的渗透活性物质包括生理相容的化合物如单糖、二糖、糖醇、氨基酸和各种合成化合物。适宜的单糖或糖醇包括,例如:赤藓糖、苏糖、核糖、阿糖、木糖、来苏糖、阿洛糖、阿卓糖、葡萄糖、甘露糖、艾杜糖、半乳糖、塔罗糖、海藻糖、核酮糖、果糖、山梨醇、甘露醇、景天庚酮糖,优选的单糖为果糖、甘露糖、木糖、阿糖、甘露醇和山梨醇。适宜的二糖包括,例如:乳糖、蔗糖、麦芽糖和纤维素二糖。适宜的氨基酸包括,例如甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、天冬氨酸、谷氨酸、赖氨酸、精氨酸、组氨酸。合成化合物包括,例如:甘油、丙二醇、聚丙二醇、乙二醇、聚乙二醇和聚乙烯吡咯烷酮。其它各种适宜的渗透活性物质为本领域技术人员公知的,它们也属本发明所述渗透性剂范围之内。
为各种不同目的和用途也可添加各种如上所述的聚合物。
本领域的技术人员可以看出,添加剂如上述悬浮剂可根据需要,依据具体的最终应用目的,以各种用量用于本发明的含水悬浮液相中。虽然再高或再低一些也可以,但添加剂的用量通常约为形成的造影剂制剂的0.01%-95%(体积)。一般说来,悬浮剂的用量通常为至少约0.5%(体积),优选至少约1%(体积),最好至少约10%(体积)。通常,该悬浮剂的用量应小于约50%(体积),优选小于约40%(体积),最好小于约30%(体积)。例如,悬浮剂之常规用量为约20%(体积)。同样,为实现最佳渗透性,渗透活性物质的用量通常小于约25g/l,优选小于约20g/l,更优选小于约15g/l,最好小于约10g/l,在某些情形下,不用渗透活性物质。渗透活性物质的最佳用量范围是约0.002-10g/l。在理解了本发明后,本领域的技术人员易于看出这些及其它添加剂用量的适宜范围。
通过将所需治疗剂或诊断剂简单地加至含水悬浮液相中可将各种治疗剂和/或诊断剂掺入该相中。在理解本发明后,本领域的技术人员易于想到适宜的治疗剂和诊断剂。这些试剂可掺入类脂膜中或引入类脂膜上,或包被在形成的脂质体中。
为了进一步改善形成的用于MRI的充气泡囊的磁作用,可添加例如一种或多种MRI造影增强剂,如顺磁性或超顺磁性造影增强剂。有用的MRI造影增强剂包括顺磁离子,如过渡金属,包括铁(Fe+3)、铜(Cu+2)和锰(Mn+2)和镧系元素如钆(Gd+3)和镝(Dy+3),硝基氧、氧化铁(Fe3O4)、亚硫酸铁和顺磁颗粒如锰(Mn+2)取代的羟基磷灰石。同样,可采用的其它顺磁性离子的实例为试剂如铬(Cr+3)、镍(Ni+2)、钴(Co+2)和铕(Eu+2)。也可使用其它造影增强剂如硝基氧基团或任何其它具有顺磁性保持不成对电子旋转的原子。最好在振动之前,将造影增强剂加至含水悬液相中,应设法使造影增强剂在振动后进入形成的充气泡囊或在其表面上,当然,也可在制备完泡囊再加入。形成的充气的泡囊其松弛性得到很大增强,对磁共振成像提供了特别有效的造影。至于具体的实例,当磷脂酰胆碱或磷脂酰丝氨酸用于含水类脂相中时,锰(Mn+2)将其自身引入类脂的头部基团上。如果需要的话,可用脂溶性化合物来鳌合金属,这些化合物如可参见U.S.5,312,617,该文献引入本文以作参考。这类脂溶性化合物是非常有用的,其原因就是它们易于引入类脂膜中。为了实现向类脂表面的引入,铁氧化物和其它颗粒通常应较小,优选小于约1μ,更优选小于约200nm,首选小于100nm。为改善引入效果,可使用脂肪族化合物或亲脂化合物包被的铁氧化物,这是因为它们可被引入泡表面的类脂包被中。
含水悬浮液相包含一种引起胶凝的成份也属本发明的范围,所述成份使在类脂聚合物和金属内引起胶凝,它们不会自发凝胶,或者所述成分可增强胶凝作用。可采用的胶凝剂实例为多价金属阳离子、糖和多元醇。用作胶凝剂的多价金属阳离子包括:钙、锌、锰、铁和镁。有用的糖包括:单糖如葡萄糖、半乳糖、果糖、阿糖、阿洛糖和阿卓糖,二糖如麦芽糖、蔗糖、纤维素二糖和乳糖,多糖如淀粉。优选采用简单糖,即单糖或二糖。多元醇胶凝剂包括,例如,缩水甘油、肌醇、甘露醇、山梨醇、季戊四醇、半乳糖醇,和聚乙烯醇。本发明采用的胶凝剂首选蔗糖和/或钙。在理解了本发明后,本领域的技术人员易于看出可用于本发明各种制剂的特定胶凝剂。
类脂如磷脂酸与钙或镁盐和聚合物如藻酸、透明质酸或羧甲基纤维素的组合可用于稳定类脂。可以假设,在类脂和聚合物间二价阳离子形成金属桥,从而稳定了类脂/聚合物体系内充气的脂质体。类似地,可制备包含脱乙酰壳多糖(或壳多糖基物质)、聚赖氨酸、聚乙二胺和藻酸(或其衍生物)或透明质酸混合物的悬浮液。
业已发现,含水相中的不同物质对控制形成的气体增充泡囊大小是非常重要的。表2显示出振动装有含水相及液相上空间的氮气的无菌容器而生产的脂质体的尺寸。在各种情形下,可用颗粒测定大小系统770型光测颗粒仪(Particle Sizing Systems,Santa Barbara,CA)测量脂质体的大小。如数据表明,含水相中类脂的比例影响形成的充气脂质单元大小分布。具体而言,下表2显示出类脂组成对平均脂质体大小的影响。
表2
类脂组成对平均脂质体大小的影响
类脂组成* | 平均脂质体大小 |
77.5∶15∶7.5 | 5.26μm |
77.5∶20∶2.5 | 7.33μm |
82∶10∶8 | 6.02μm |
*二棕榈酰基磷脂酰胆碱∶二棕榈酰基磷脂酸∶二棕榈酰基磷脂酰乙醇胺-PEG5000间的摩尔%。
表3示出了限定类脂组成的混合物浓度对平均脂质体大小的影响。如表3所示,类脂的总浓度在影响振动后脂质体大小方面也是重要的。在这些实验中,三种不同类脂成分的比值保持恒定,而类脂在水相中的浓度在0.5-5.0mg/ml间变化。所用的气体为氮气。当含水相中类脂的浓度为1.0mg/ml时,生产液面上空间的全氟丁烷的最佳尺寸的超声诊断用泡囊。
表3
类脂浓度对平均脂质体大小的影响
类脂浓度* | 平均脂质体大小 |
1mg/ml | 1.8μm |
3mg/ml | 4.0μm |
5mg/ml | 7.2μm |
*对各个试样类脂浓度均基于摩尔%比为82∶10∶8(二棕榈酰基磷脂酰胆碱∶二棕榈酰基磷脂酸∶二棕榈酰基磷脂酰乙醇胺-PEG5000。所用气体为氮气。
泡囊大小也取决于稳定介质如类脂的浓度。例如,已发现,使用氮气对类脂浓度为1.0mg/ml与使用全氟丁烷时类脂浓度为5.0mg/ml所产生的充气脂质体直径基本相同。但是,还发现,浓度高可能会使分布更偏向于较大的充气脂质体。这种现象反映出类脂浓度高会增加充气脂质体的稳定性。因而可以相信,高浓度类脂可作为含水相稳定剂起到稳定作用,或可在气体周围提供更多的薄片,使其更稳定,因而,可保持更大比例的大的脂质体。
同样可相信,当考虑其它变量时,在充气泡囊界面和含水介质的表面张力也是优化充气泡囊大小的附加决定因素。
II.气相组成
本发明的气相中可以采用各种不同的气体。优选气体基本上不溶于含水悬浮液相。所谓“基本上不溶”是指气体在20℃和1大气压下的溶解度等于或小于18ml气体/kg水。照此,基本上不溶性气体的溶解度应小于氮气的溶解度。溶解度优选等于或小于15ml气体/kg水,更优选等于或小于10ml气体/kg水(20℃,1大气压)。在上述温度和压力下,优选气体的溶解度为约0.001-18ml气体/kg水,或约0.01-15ml气体/kg水,或约0.1-10ml气体/kg水,或约1-8ml气体/kg水,或约2-6ml气体/kg水。例如在20℃及1大气压下,全氟化碳和氟化气体六氟化硫的溶解度小于10ml气体/kg水,因此而成为优选的气体。本文中将那些非“基本上不溶”的气体称之为可溶性气体。
其它适宜的基本上不溶性或可溶性气体包括但不限于:六氟丙酮、异丙基乙炔、丙二烯、四氟丙二烯、三氟化硼、1,2-丁二烯、1,3-丁二烯、1,2,3-三氯丁二烯、2-氟-1,3-丁二烯、2-甲基-1,3-丁二烯、六氟-1,3-丁二烯、丁二炔、1-氟丁烷、2-甲基丁烷、十氟丁烷(全氟丁烷)、十氟异丁烷(全氟异丁烷)、1-丁烯、2-丁烯、2-甲基-1-丁烯、3-甲基-1-丁烯、全氟-1-丁烯、全氟-2-丁烯、4-苯基-3-丁烯-2-酮、2-甲基-1-丁烯-3-炔、硝酸丁酯、1-丁炔、2-丁炔、2-氯-1,1,1,4,4,4-六氟-丁炔、3-甲基-1-丁炔、全氟-2-丁炔、2-溴-丁醛、硫化羰、丁烯腈、环丁烷、甲基环丁烷、八氟环丁烷(全氟环丁烷)、全氟异丁烷、3-氯环戊烯、环戊烷、1,2-二甲基环丙烷、1,1-二甲基环丙烷、乙基环丙烷、甲基环丙烷、联乙炔、3-乙基-3-甲基二氮环丁烷、1,1,1-三氟重氮乙烷、二甲胺、六氟二甲胺、二甲基乙基胺、双(二甲基膦)胺、2,3-二甲基-2-降冰片烷、全氟二甲胺、氯化二甲基氧翁、1,3-二氧杂戊烷-2-酮、1,1,1,1,2-四氟乙烷、1,1,1-三氟乙烷、1,1,2,2-四氟乙烷、1,1,2-三氯-1,2,2-三氟乙烷、1,1-二氯乙烷、1,1-二氯-1,2,2,2-四氟乙烷、1,2-二氟乙烷、1-氯-1,1,2,2,2-五氟乙烷、2-氯-1,1-二氟乙烷、1-氯-1,1,2,2-四氟乙烷、2-氯-1,1-二氟乙烷、氯乙烷、氯-五氟乙烷、二氯三氟乙烷、氟乙烷、硝基五氟乙烷、亚硝基五氟乙烷、全氟乙烷、全氟乙胺、乙基乙烯基醚、1,1-二氯乙烯、1,1-二氯-1,2-二氟乙烯、1,2-二氟乙烯、甲烷、三氟磺酰氯、三氟甲磺酰氟、(五氟硫代)三氟甲烷、溴-二氟-亚硝基甲烷、溴-氟-甲烷、溴-氯-氟甲烷、溴-三氟甲烷、氯-二氟-硝基甲烷、氯-二硝基甲烷、氯-氟甲烷、氯-三氟甲烷、氯-二氟甲烷、二溴-二氟甲烷、二氯二氟甲烷、二氯氟甲烷、二氟甲烷、二氟碘甲烷、乙硅烷甲烷、氟甲烷、碘三氟甲烷-碘甲烷、硝基三氟甲烷、亚硝基三氟甲烷、四氟甲烷、三氯氟甲烷、三氟甲烷、三氟甲亚磺酰氯、2-甲基丁烷、甲醚、甲基异丙基醚、乳酸甲酯、亚硝酸甲酯、二甲硫、甲基乙烯基醚、新戊烷、氮气(N2)、一氧化二氮、1,2,3-十九烷三甲酸-2-羟基三甲基酯、1-壬烯-3-炔、氧气(O2)、氧17(17O2)、1,4-戊二烯、正戊烷、十二氟戊烷(全氟戊烷)、十四氟己烷(全氟己烷)、全氟异戊烷、全氟新戊烷、4-氨基-4-甲基-2-戊酮、1-戊烯、2-戊烯(顺)、2-戊烯(反)、3-溴-1-戊烯、全氟1-戊烯、四氯苯二酸、2,3,6-三甲基哌啶、丙烷、1,1,1,2,2,3-六氟丙烷、1,2-环氧丙烷、2,2-二氟丙烷、2-氨基丙烷、2-氯丙烷、七氟-1-硝基丙烷、七氟-1-亚硝基丙烷、全氟丙烷、丙烯、1,1,1,2,3,3-六氟-2,3-二氯丙烷、1-氯丙烯、氯丙烯(反)、2-氯丙烯、3-氟丙烯、全氟丙烯、丙炔、3,3,3-三氟丙炔、3-氟苯乙烯、六氟化硫、十氟化二硫(S2F10)、2,4-二氨基甲苯、三氟乙腈、三氟甲基过氧化物、三氟甲基硫化物、六氟化钨、乙烯基乙炔、乙烯基醚、氖、氦、氪、氙(特别是富铷的超极性氙气体)、二氧化碳、氦和空气。优选氟化气体(即,包含一个或多个氟分子的气体,如六氟化硫)和全氟化碳气体(即氟化碳气体,全部氟化,如全氟丙烷和全氟丁烷)。
虽然实际上任何气体在理论上均可用于本发明的气相中,但是,可选择特定的气体以优化形成的造影介质的所需性质,以及满足特定的诊断需求。例如,业已发现,某些气体比起另一些气体来更适合制备更稳定的充气泡囊,这类气体是优选采用的。已发现,某些气体对诊断成像如超声或MRI提供了更好的成像结果。
作为增加充气泡囊稳定剂的实例,业已发现,二氧化碳<氧气<空气<氮气<氖气<氦气<全氟化碳气体。因为这些及其它原因,优选氟化气体,特别是全氟化碳气体。
同样,虽然在一些情形下可溶性气体也适宜作本发明的气相,但基本上不溶的气体趋于比较高溶解性的气体有更大的稳定性,特别是对经振动产生造影剂更是如此。另外,根据本发明,在振动前易于使这种不溶性气体基本上与含水悬浮液相分离。因此,优选前面定义的基本不溶性气体。
超声成像的质量和这种图像的持续时间也与含水介质中气体的溶解性相关。通常,气体溶解性降低会使超声波得到的图像分辨率更好,更持久。
此外,业已观测到,通过振动产生的充气泡囊的大小与含水介质中气体的溶解性有关,气体溶解度大会导致充气的泡囊大。
同样可以相信,泡囊的大小也受气体与泡囊内壁间界面的影响。具体而言,据信界面处的相互作用会影响张力,结果内部气体对泡囊的内部泡囊壁有向外的力。通过降低由内部气体施加的力而使张力降低从而使泡囊减小,由此通过水介质与气体增充泡囊接触使力施加至泡囊的外部。
使用亨利定律可估算气体在含水溶剂中的溶解度,该定律适用于至多1个大气压的压力及微溶性气体(Daniels,F.和Alberty,R.A.的《物理化学》第三版,Wiley&Sons,Inc.,New York,1966)。例如,25℃时,氧气的溶解度为31.6ml/kg水,大气的溶解度为21.36ml/kg水,氮气的溶解度为18.8ml/kg水。而六氟化硫在25℃时的溶解度约为5.4ml/kg。
总而言之,由于稳定性、不溶性和形成的泡囊大小,优选采用氟化气体,氟化碳气体及全氟化碳气体。特别优选氟化气体六氟化硫,和全氟化碳气体全氟丙烷、全氟丁烷、全氟环丁烷、全氟甲烷、全氟乙烷、全氟戊烷,特别是全氟丙烷和全氟丁烷。
需要指出,少于5个碳原子的全氟化碳在室温下为气体。例如在全氟戊烷直至约27℃才为液体。在高于该温度时,它将占据容器液面上的空间。业已表明,即使在室温下,全氟戊烷也可用于填充液面上空间(即小瓶中类脂悬浮相上面的空间)。选择经计算确定量的液体全氟戊烷填充到液面上空间中,在低温如-20℃下将液体加入容器中,然后抽空容器(有效地除去空气占据的液面上空间),然后密封容器,全氟戊烷将在低于其1大气压的沸点温度下实现从液相至汽相的相变。因此,在室温下,它将占据气体的液面上空间的部分或全部。本领域的技术人员可以看出,通过应用常规“经验法则”估计,可估算出从液相至气相转变温度的下降。具体说来,压力降低一半,沸点将降低约10℃。另外,使用基于理想气体定律(基于波尔定律)的关系式,可以温度降低作为压力降低的函数进行计算。另一种用全氟戊烷填充液面上空间的方法是,首先抽空,然后用高于27C的全氟戊烷填充液面上空间。当然,该方法并不仅限于全氟戊烷,而可应用于所有全氟化碳气体,及一般意义上的其它气体,只要这种气体的沸点是公知的。
如果需要的话,可用两种或多种不同气体一起来填充液面上空间。气体混合物在形成的气体填充泡囊的各种应用中有许多优点(如用于超声成像,MR成像等)。业已发现,可将少量基本不溶的气体与可溶性气体混合,其稳定剂将超过预期的组合的稳定性。例如,少量的全氟化碳气体(如通常至少约1mol%)可与空气、氮气、氧气、二氧化碳或其它更易溶的气体混合。采用这种混合气体经后振动处理产生的充气泡囊造影剂其稳定性优于单独采用空气、氮气、氧气、二氧化碳或其它更易溶的气体所得结果。
此外,使用气体混合物可用于抵消充气泡囊尺寸的增加,这种增加是包含纯全氟化碳气体泡囊被注入体内时会在体内发生的。业已发现,一些全氟化碳气体可能会吸收其它气体如氧气。因此,如果全氟化碳气体经静脉内注入体内时,它可能会吸收溶解在循环血液中的氧气或其它可溶性气体。然后,形成的泡囊可能在体内由于这种吸收而膨胀。从这种现象可以看出,我们可以使全氟化碳气体与可溶性气体如空气、氮气、氧气、二氧化碳预混合,从而饱和全氟化碳的吸收性。从而,这将延缓甚至消除充气泡囊在血流中的膨胀可能性。考虑到如下事实这一点显得更为重要,即如果给药于血液中,泡囊会长至其尺寸大于10μm,可能发生很危险的栓塞事故。通过用比全氟化碳气体更易溶的气体与全氟化碳一起填充液面上空间,形成的充气泡囊在注射到体内后通常将不会发生这种尺寸的增长。因此,根据本发明,由于泡囊膨胀而引起的栓塞问题可通过生产已消除或充分延缓了这种膨胀的泡囊而得以解决。
因此,根据本发明,如果需要的话,基本不溶性气体可与可溶性气体合并以便有效地生产高效且稳定的充气泡囊。
将于2ml小瓶(实际大小为3.7ml)(Wheaton Industries(Millville NJ))中的多种类脂溶液样品(1mg/ml;82∶10∶8mol%比,DPPC∶DPPA∶DPPE-PEG-5000),溶剂为8∶1∶1重量比的生理盐水∶甘油∶丙二醇,置于改进型Edwards S04型冻干机中(容积4立方英寸),进行减压。小瓶上的空间为总体积的60%,其被分别充入80%PFP与20%空气,60%PEP与40%空气,50%PFP与50%空气,20%PFP与80%空气,100%空气。通过气相色谱确定不同样品的液面上空间中气体的百分比(Hewlett PackardGas Chromatograph Model 1050L,采用Hewlett Packard ChemTMsoftward。检测方式为火焰电离检测法。然后用标准Wig-L-BugTM3110B型在3,300RPM下振动样品60秒,通过光学粒度仪大小测量法测定泡囊数和其大小。光学粒度仪(Particle Sizing Systems,Santa Barbara,CA)用于分析充气泡囊的大小和总数。每次分析采用5μl的样品,每次检测采用4份样品。结果示于表4中。
如表4所示,即使当仅有20%的气体为PFP(基本上不溶的气体)和80%的气体为空气(可溶性气体的混合物),比仅使用空气(0%PFP)产生的泡囊数多100倍。进而,当仅使用空气(0%PFP)时,泡囊的稳定性更低,大部分超过10μm。但是,20%PFP和80%空气泡囊其稳定性恰好与80%PFP和20%空气泡囊相同,也与其它中间PFP浓度试样相同,而20%PFP与80%空气和80%PFP与20%空气相比,产生大致相同数目的充气泡囊。
表4
全氟丙烷百分比对泡囊大小和数目的影响
PFP气体% | 数目加权平均 | 体积加权平均 | 估计的颗粒数 | <10μm颗粒的百分比 | 每ml估计的颗粒数# | >10μm的颗粒百分比 |
80%平均STDevCV | 2.370.073% | 28.760.823% | 5.45E+054.67E+049% | 98.940.080% | 1.10E+098.20E+077% | 1.050.077% |
60%平均STDevCV | 2.140.021% | 20.755.9329% | 5.87E+057.08E+0412% | 99.360.100% | 1.15E+091.27E+0811% | 0.640.0914% |
50%平均STDevCV | 2.130.073% | 30.3512.1540% | 5.23E+051.49E+043% | 99.290.110% | 1.07E+094.37E+074% | 0.680.1015% |
20%平均STDevCV | 2.000.042% | 13.646.7950% | 5.35E+052.26E+044% | 99.610.060% | 1.07E+093.92E+074% | 0.410.0716% |
0%平均STDevCV | 2.300.219% | 93.2866.0571% | 5.03E+034.96E+0210% | 98.230.260% | 1.00E+078.60E+059% | 1.930.3619% |
表4中,STDev=标准偏差,CV=方差系数。E+表示方次,例5.45E+05=5.45×105。
业已发现,仅需少量相对不可溶的气体(如PFP)来稳定泡囊,而大部分气体仍是可溶性气体。虽然由下式计算的两种或多种气体成分的实际溶解度仅与可溶性气体的溶解度略有差异,但是,仅用少量的不溶性气体就可使充气泡囊的数目和稳定性均提高:
虽然并无确切的理论给予解释,但据信,基本上不溶的气体对膜稳定作用是重要的。的确,据信,基本上不容的气体(如PFP)作用为抗类脂膜的屏蔽,可在膜的内表面上形成一层,它可延缓可溶性气体(如空气、氮气等)的流出。这一发现是惊人的也是有用的,这使得我们仅需要少量的基本不溶的气体(如全氟化碳或其它氟化气体),主要为更具生物相容性(较少毒性)气体,如空气或氮气占据泡囊的大部分。
如本领域技术人员所能看出的,基本上不溶的气体和可溶性的气体在任一混合物中的量是可变的。通常,气体总量的至少约0.01%为基本上不溶的气体,更优选至少约0.1%,最好至少为约1%,首选至少约10%。基本上不溶性气体的适宜范围可根据诸如所采用的可溶性气体、类脂的类型、特定用途等因素而改变。举例性范围包括约0.01%-99%上不溶的气体,优选约1%-95%,更优选10%-90%,首选约30%-85%。
对于除诊断超声成像外的其它用途如诊断磁共振成像(MRI),虽说也可采用其它的气体,但优选采用顺磁性气体如强顺磁性氧17气体(17O2)、氖、氙、氦、氩(特别是富铷的超极性氙气)或氧气(虽说其顺磁性强度稍弱)来填充液面上空间。首选采用17O2气体、氖、富铷的超极性氙气体或氧气与基本上不溶的气体如全氟化碳气体结合使用。顺磁性气体在本领域中是公知的,对本领域技术人员而言,顺磁性气体是很明显的。MRI应用中最优选的气体17O2,不论它是单独使用还是与其它气体组合使用。
通过使用气体混合物,17O2或其它顺磁性气体提供了最佳的造影剂,而全氟化碳稳定了振动后截留气体内的17O2气体。如果不加全氟化碳气体,气体如17O2通常有效性会较差,其原因是,它的溶解度决定了它将会在静脉内注射后扩散出类脂的束缚。此外,17O2气体是非常昂贵的。使全氟化碳气体与17O2结合使用将大大增加产品的效能,降低费用,这是通过更有效地使用昂贵的17O2气体而实现的。类似地,其它具有理想顺磁性的气体如氖也可与全氟化碳气体混合。
下表5显示出各种可用于MR成像应用的不同气体。表5中,示出了在充气泡囊中不同气体的R2(1/T2/mmol/L·秒),如表5所示,不同充气的泡囊其松驰值越高表明泡囊作为MR成像剂的有效性越好。所示的气体中,空气的R2值最高。据信,空气的该值最高是因为空气中氧的顺磁作用。但是纯氧气的有效性又低一些,可能是由于氧气的高溶解性及氧气与包围泡囊的含水介质的平衡。而采用空气时,氮气(空气中约80%为氮气则有助于将氧气稳定在泡囊内。氮气在水中的溶解度小于空气。如上指出,PFP或其它全氟化碳气体可与更具顺磁活性的气体混合,如空气、氧气、17O2或富含铷的超极性氙。如此,优选稳定高顺磁活性充气的泡囊。
表5
大小分布和松驰度
气体 | 数目权重分布(μm) | 体积权重分布(μm) | R2 |
氮气 | 6.96±0.63 | 31.08±7.42 | 474.6±59.9 |
六氟化硫 | 4.31±0.13 | 44.25±1.23 | 319.3±42.5 |
氙(Rb) | 7.02±1.19 | 160.90±92.46 | 191.2±30.8 |
氩 | 8.14±0.49 | 41.45±13.02 | 55.29+41.3 |
空气 | 6.05±1.05 | 23.28±0.41 | 1510.4±0.41 |
全氟丙烷 | 4.24±0.72 | 49.88±11.11 | 785±31.8 |
氧 | 7.26±0.98 | 30.99±3.90 | 732.4±73.9 |
氖 | 7.92±0.71 | 26.20±1.03 | 595.1±97.2 |
全氟丁烷 | 5.88±0.36 | 51.25±3.97 | 580.1±45.5 |
容器的液面上空间根据需要可用在环境压力、降压或增压下的气体进行填充。
在本发明的容器中,气相与含水悬浮液相基本分开。所谓“基本分开”是指在振动前,少于50%的气体与含水悬浮液相结合。优选少于约40%,更优选少于约20%,首选少于10%气体与含水悬浮液相结合。气相保持与含水悬浮液相基本分开,直至使用时,此时振动容器,气相与含水悬浮液相结合而形成充气泡囊的含水悬浮液相。以这种方式,生产出优良的超声或磁共振成像用造影剂。进而,由于在使用前即刻制备造影剂,减少了贮存稳定问题。
III.容器体积和液面上空间
业已发现,液面上空间气体的大小也可用于影响充气泡囊的大小。由于液面上空间大,相对于含水相大小就会成正比地包含更多的气体,液面上空间大通常比空间小能产生更大的泡囊。因此,以占容器总体积百分数表示的液面上空间不应超过最大值。但是,如果液面上空间太小,又使得没有充足的空间使流体在振动时运动以有效地形成泡囊。
例如,本发明发现,当使用实际体积为3.7ml的小瓶(Wheaton 300Borosilicate glass,Wheaton Industries,Millville,NJ,称为2ml公称尺寸,直径×高度=15mm×32mm),含气体的液面上空间的体积最好为小瓶总体积的约10%-60%。通常,小瓶中含气的液面上空间体积为小瓶总体积的约10%-80%,虽说这取决于特定的环境及所要求的应用场合,气体或多或少均是适宜的。更优选的是,液相上空间为总体积的约30%-70%。业已发现,最好的含气液面上空间的体积为容器总体积的约60%。
IV.振动参数的最佳值
A.运动路径的形状和振动幅度
如前所述,除了含水悬浮液相与气相的组成外,包含这两相的容器的具体振动方式也将影响泡囊的大小分布。通过四个参数可限定最佳振动条件,即振动期间容器的运动路径的形状、振动的幅度、振动的频率及振动的持续时间。
业已发现,在形成适当大小的泡囊方面,特别重要的就是振动时容器运动的路径。具体而言,已发现,当振动采取往复运动时可在最短的时间内产生小泡囊。其它类型的振动,如涡旋运动也能产生小泡囊。但往复运动可大大减少振动持续时间,而持续时间也是达到小泡囊高浓度所必要的。
本发明人发现,当振动幅度(具体说即振动期间,容器运动往复路径的长度C)至少为0.3cm时,在相对较短的时间即2分钟或更少时可获得小尺寸的泡囊。通常,振幅越大,泡囊越小。但是,如下所述,振动频率也是一个重要参数。由于当振幅增至某一最大值时,通常考虑到振动设备,振动频率会降至非常低,因此,应使振幅保持在足够低以确保振动频率保持适中值。对于Wig-L-BugTM3110B型振动设备,最大幅度约为2.5cm。
本发明人还发现,往复运动优选沿图4所示的弧形路径20进行,其中振动幅度为C,由于高频振动更易于以这种方式完成。在本发明的优选实施方案中,弧形路径20定义为:曲率半径L,它是由振动臂长度L形成的。优选振动臂7的长度L至少为6cm,旋转通过的角度θ至少为3°。如下面将作的进一步讨论,根据本发明的优选实施方案,振动臂的旋转角θ是通过具有偏角等于θ的轴承达到的。进而,振动臂的长度L定义为偏心套管40的中心线与容器9的中心线(如图3所示)间的距离,所说的套管40上安装了振动臂7轴承50(下面将进一步讨论)。
使用较长的振动臂长L和较大的旋转角θ将会增加振动幅度,从而将减小泡囊大小。但是,如前所述,所采用的振动臂长L和旋转角θ的最大值应加以限制,以确保振幅C不至于大得使振动频率不适当。此外,机械考虑也将限制振动臂7的旋转角的大小。对Wig-L-BugTM3110B型,所采用的最大振动臂长度和旋转角分别约为15cm和9°。
此外,优选振动装置在第一方向的往复运动上叠加第二方向近似垂直方向上的往复运动。优选第二方向上的振幅C′至少约为第一方向上振幅C的十分之一。为便于说明,往复运动的第一方向称之为纵向,而往复运动的第二方向称之为横向。
最好调节在纵向和横向上运动的时间以使在两个方向上运动的总和形成容器9呈8字形振动。
以如前所述为基础,当本发明振动装置1的振动臂7末端结合容器9时,图4和5示出了由容器9所运动的优选振动路径20。如图5所示,振动臂7使容器9随容器在纵向中向后向前运动而在横向上运动,这样,容器9上的点以8字形运动,8字形的长度即是纵向振幅C,8字形的宽度即为横向振幅C′。当从侧面观察时,如图4所示,在纵向上路径为弧形,具体而言,为曲率半径等于振动臂7长度L的弧。弧长度C是振动臂长度L与振动臂在纵向旋转占据的角度θ的乘积,以弧度表示,即C=L·θ。
优选8字形是由大约两个直的部分21(这两部分以角φ相交)及两个近似半圆部分22组成。如下面进一步讨论,在本发明的优选实施方案中,由8字形所形成的角φ大约等于振动臂7在纵向上旋转的角度θ。如下讨论,这是由弹簧46向振动臂7施加足够的力实现的,从而在振动期间保持在横平面内基本上在垂直方向,如图9和10所示。如果调节弹簧的张力以使振动臂7旋转通过横平面上一角度w,如图12所示,那么容器9所经过的8字形振动的角φ将会大于θ。
如果φ等于θ,那么,在围绕路径20的一个循环中运行的总距离D将成为两个变量的函数,即随振动臂在纵平面中运行所形成的角度θ以及振动臂的长度L。该距离D可近似由下列方程式表示:
D=2L[(2sinθ/2+∏tan2θ/2)/(1+tanθ/2)]
由于优选长度L至少为6cm,角度θ至少为3°,因此,距离D应优选至少为约0.6cm。
进而,假如φ=θ,横向上的振幅C′将成为纵向上振幅C和角θ的函数,其可近似由下列方程式表示:
C′=(2Ctanθ/2)/(1+tanθ/2)
由于优选纵向振幅C至少约0.3cm,角度θ至少约3°,因此,横向振幅C′优选应至少为约0.02cm。
通过一系列实验将可以确定如上所讨论的振动的振幅的最佳值和形状,它们将在以下第C节讨论。
B.振动频率和持续时间。
除了振动的形状和幅度外,振动频率也是形成适宜大小泡囊的重要参数。振动频率是以振动臂7每分钟的转数“(RPM)”定量确定的,它定义为1分钟内振动臂及与其相连的容器9穿过整个振动路径的次数。因此,在本发明的优选实施方案中,振动频率为3600RPM是指1分钟内容器9围绕8字形路径20进行振动3600次,或每秒钟振动了60次。
业已发现,可使用100-10,000RPM的振动频率制备泡囊。但是,也发现,存在一个最小频率值,在该频率值下可在相当短的时间生产出最佳大小的泡囊。如在第C节将讨论的那样,业已发现,该最小频率为2800RPM。一般说来,增加振动频率将减小泡囊大小,但振动装置的限制通常会设置最大可用率。对Wig-L-BugTM,最大可用频率为约3300RPM。
在频率范围2800-3300RPM内,最佳振动时间至少为约60秒,但是,最佳振动时间与频率相关,频率高可减少振动时间。因此,例如在4500RPM时,最佳振动时间仅为50秒。
C.试验结果
通过如下的一系列试验,可找出最佳振动频率以及振动形状和幅度。
第一组试验用于确定振动频率对泡囊大小的影响。将1mg/ml的类脂试样加至稀释剂中,由摩尔比为82mol%∶10mol%∶8mol%的二棕榈酰基磷脂酰胆碱(DPPC)(Avanti Polar Lipids,Alabaster,Ala)、二棕榈酰基磷酸(DPPA)(Avanti Polar Lipids,Alabaster,Ala)和二棕榈酰基磷脂酰乙醇胺共价键合的聚乙二醇单甲酯(分子量5000)(DPPE PEG-5000)(AvantiPolar Lipids,Alabaster,Ala)组成的类脂试样加到由生理盐水、甘油(Spectrum Chemical Co.,Gardena,Calif)组成(8∶1∶1,v∶v∶v)组成的稀释剂中。然后,将试样在45℃下加热10分钟,然后使其平衡到室温(25℃)。
将样品加至图1所示类型的硼硅酸盐小瓶中(VWR Scientific,Boston,Mass),小瓶的标定尺寸为2.0ml(实际体积3.7ml)。用丁基橡胶塞将小瓶密封,并用铝卷气密封闭。小瓶的液相上空间约为小瓶总体积的60%。然后,将样品用全氟丙烷(Flura Corporation,Nashville,Tenn)吹扫,并置于图3所示振动装置中,该装置将在第V节讨论。
使用图4和5所示8字形运动振动容器2分钟。振动臂长度L为7.7cm,轴承偏角θ及纵平面中振动臂旋转角为6°。使用如上讨论的关系式,可以确定,纵向和横向的振幅C和C′分别为0.8cm和0.1cm。所用的振动频率1500、2800和3300RPM。由Code-Palmer Model 08210Pistol Grip Tachometer(Code Palmer,Nile,Ill)测量频率。由ParticleSizing System light obscuration particle sizer(Santa,Barbara,Calif)通过小颗粒光学大小测定法测量大小。
表6显示了这些试验的结果,结果表明,振动频率对形成的平均泡囊大小有影响。
表6
振动频率对平均泡囊尺寸的影响
频率(RPM) | 平均泡囊大小 |
1500 | 3.4μm |
2800 | 3.3μm |
3300 | 2.9μm |
从上表看出,当频率超过2800RPM后,会大大降低振动2分钟后获得泡囊的平均大小。
第二组试验用于确定增加振动臂长度L从而增加纵向和横向振幅C和C′及每一循环的振动距离D对泡囊大小的影响。除了振动臂长度L为6.7-14.8cm的振动臂振动60秒外,该试验与上述试验过程相同。
振动臂长度变化导致振动的频率在2250-3260RPM间变化,随振动臂长的增加,振动频率降低。图13示出了振动频率随振动臂长度L和振动臂旋转角θ的变化情况。因此,例如,当振动臂长度L为6.7cm,旋转角θ为6°时,振动频率约为3200RPM,而当振动臂长度增至13.8cm时,保持同样的旋转角,频率则降至约2700RPM。
该组试验的结果示于图14(a)-(c)。如图14(a)所示,当在纵平面上的旋转角θ为6°时,不论振动臂长度L为7.7cm或更大即当纵向振幅C大于0.8cm时,至少98%的泡囊小于10μm。然而,在振动臂长度L为9.8cm或更长即当纵向振幅为1.0cm或更大时,泡囊小于10μm百分比平稳达到99-99.5%。如图14(b)所示,在这些相同的条件下,泡囊的数目加权平均大小平稳达到2μm。
虽然当所有其它变量保持恒定时增加振动频率的作用通常会减小泡囊大小(如前讨论及表6所示),而如图13所示,数据表明,通过增加振动臂长度而增加振幅即使同时降低振动频率也会使泡囊大小下降。
如图14(c)所示,在所有振动臂长度下得到泡囊超过400×106个/ml,事实上,振动臂长为约10-12cm会导致产生超过1000×106泡囊/ml。但是,如果振动臂长度增至超过12cm时,颗粒/ml开始下降,当14.8cm时达到800×106泡囊/ml。尽管图13未示出,当振动臂长度为14.8cm,旋转角为6°时,测得的频率仅为2550RPM。因此,振动臂长度为14.8cm产生的泡囊浓度下降的原因被认为是由于振动频率下降,而这种频率下降是随如前讨论的振幅增长而引起的。从而,这些数据表明,当使用Wig-L-BugTM振动装置时,振动臂长度优选应小于约15cm以使泡囊浓度达到最大。
第三组试验采用如上讨论的相同的原料和过程,只是轴承偏角及随之在纵向振动臂的旋转角θ从6°增至9°,从而增加了纵向上振动幅度。此外,振动臂长度超过11.8cm未采用。这些试验的结果示于图15(a)-(c),并与前面两组试验结果进行了比较。
从图15(a)看出,将振动臂的旋转角θ从6°增至9°将减小泡囊大小,如图13所示,它还具有减少振动频率的作用。因此,采用9°的振动臂旋转角。即使振动臂长仅为6.7cm也会使99.5%以上的泡囊小于10μm,平均大小约为2μm。此外,如图15(c)所示,在所有的振动臂长度下,得到超过1000×106泡囊/ml的泡囊数。
第四组试验采用如上讨论的相同的原料和过程,只是轴承偏角及随之在纵向上振动臂的旋转角θ为3°、5.2°、6°、7.8°和9°,同时振动臂长为6.7cm-13.8cm(每次增加约1cm)。在每种情况下估计振动路径20的总长度D。如图17所示,频率成为总路径长度的函数。结果作为总路径长度D的函数示于图16(a)-(c)。可以看出,在所有试验条件下,即在总路径长度D为0.7cm和大于0.7cm时,超过95%的泡囊小于10μm,产生的泡囊浓度超过100×106/ml。进而,在所有条件下,其中总路径长度D为2.19cm或更大,超过98%的泡囊小于10μm。这表明,振动的总路径长度应至少为0.7cm,更优选至少2.2cm。
因此,前述事实显示出,当进行往复振动并使振动频率至少约为2800RPM时,在约2分钟或更少的时间里可得到小尺寸的泡囊。此外,振动应在两个基本垂直的方向上完成,优选以8字形完成。进而,在主方向上的振幅应至少为0.3cm,更优选至少0.8cm,或振动路径总长度应至少为0.7cm,更优选至少为2.2cm。
V.本发明的装置
A.优选的振动装置
本发明优选的振动装置示于图2和3。该装置由基底2和铰接的安全盖3构成。在外壳4上安装有开一停扭6和速度控制拨盘5,外壳4包起基底2。臂7通过外壳4上部的开口12向上伸出。顺时针转动拨盘5增加振动速度,而逆时针转动拨盘会降低振动速度。
根据本发明,固定托架8连接在臂7的末端,由该托架将下面将讨论的容器9卡紧在臂上。托架8配有几个弹簧夹11和10,夹子将容器9紧固在位置上。另外,指旋螺丝型的托架也可用来甚至更紧固地连结容器9。如图3所示,托架也可以角δ至水平方向取向,从而当容器9安装在装置1上时,容器9的轴也将以角度δ取向至水平取向。优选角δ为-5°至+5°,首选δ为0°。使用时,容器9紧固至托架8上,开启振动装置1沿图4和5所示运行路径剧烈振动容器。
图6-12示出了本发明振动装置1的主要内部构件。可以看出,振动臂7旋转安装在电机44的轴42上。如在图6和9中所示,在振动臂7的最近端形成圆筒形套筒41。套筒41包围轴50,轴承50支撑着圆筒形偏心套管40。图11示出的套管40与轴42固定连接,例如将其压在轴上或与轴成一体地形成,并且套管40在轴承内旋转。
如图11所示,套管40的一端43相对轴42是偏心的,而其另一端45与轴同心。结果,如图7所示,套管40的中心线间形成锐角θ/2。角θ被称之为轴承偏角。如前所述,轴承偏角θ优选至少为约3°。如图7和8所示,当轴42和套管40旋转360°时,振动臂在纵平面上向后和向前旋转的角度等于θ(当套管40如图8所示取向时,振动臂7的位置如图7中虚线所示)。因此,轴42的旋转使套筒41在纵平面上旋转,并使其沿弧形路径作直线运动至振动臂7的远端,而振动臂上如图4所示紧固着容器9。
由于套管40的偏心特性,轴42旋转也使振动壁7的套筒41如图10所示旋转通过横平面中轴承偏角θ(当套管旋转180°时,振动臂的位置为图10中虚线所示)。因此,如果从图7中由左向右观察时,轴42顺时针旋转,那么当偏心套管40为0°时由图7中实线所示的是振动臂7的取向,当套管40为90°时,取向示于图10的虚线,当套管为180°时,取向示于图8,当套管为270°时取向示于图10的实线。因此,如偏心套管40在轴承50内旋转360°,振动臂使容器9在纵向和横向两个方向上运动,从而达到如前所述的8字形。
如图6所示,弹簧46从套筒41底部的固定中心延伸至振动外壳的基板49。弹簧46的张力的作用是在套管40旋转时使振动臂7保持竖直位置。优选弹簧具有足够的张力,从而使振动臂在横平面中保持基本垂直取向,如图9(a)和(b)所示,尽管它会偏离纵平面θ/2角,如图7所示。如图12所示,采用较小弹簧常数的弹簧46将使振动臂7在横平面内旋转通过角ω。其作用是增加横向振幅C′。
优选振动装置1通过对商购振动装置进行改造而构成,商购装置由Crescent Dental Manufacturing,Inc.,(7750 West,47th Street,Lyons,IL60534)生产,商品名为Wig-L-BugTM3110B振动器。这种Wig-L-BugTM装置采用8字形振动式,并以下述参数值装置出售,振动臂长度L为4cm,轴承偏角及随之纵向上振动臂旋转角θ为6°,并以固定速度3200RPM运行。进而,Wig-L-Bug的振动臂特点是用一对匙状物固定样品。
因此,本发明的振动装置可以通过改进Wig-L-BugTM3110B振动器制得,将加入含水悬浮液相和气相(如前讨论)的容器9引入振动臂7的远端。优选也对Wig-L-BugTM振动器改进以使固定容器9的紧固托架8置于振动臂7上,如图3和6所示。此外,根据含水相和气相的组成及容器的大小等,通过进一步改进Wig-L-BugTM可获得最佳结果,从而(i)提供以3200RPM之外的频率振动或使操作过程在振动频率范围之外,(ii)采用除4cm外的振动臂长度,或(iii)通过改进偏心套管40使轴承偏角非6°。
其它类型的往复式振动装置也可用于本发明,最优选采用8字形振动的装置。除了Wig-L-BugTM外,这类装置包括:(i)Degussa HG,Frantfurt,Germany出售的Mixomat;(ii)Espe Fabrik PharmazeutischerPraeparate GMBH&Co.,Seefeld,Oberay Germany出售的Capmix;(iii)Vivadent,Lechtenstein出售的Silamat Plus和(iv)Quayle Dental,Sussex,England出售的Vibros。
图18(a)-(c)示出并比较了Mixomat和Capmix与Wig-L-BugTM3110B装置在采用相同原料和过程所得试验结果,所说原料及过程如前讨论,相应于图13-17所示的试验结果,试验中振动时间为60秒,Wig-L-BugTM在3200RPM下运行,Mixomat在4100RPM下运行,Capmix在4500RPM下运行。结果看出,在每种情况下,超过98%的泡囊小于10μm,超过800×106泡囊/ml。
B.优选的容器
根据本发明,紧固在振动装置1上的容器9可用各种不同形式。优选的容器9如图1所示,其包含壳体30和气案帽10。填充后,容器9形成了液面上空间的气体32和与气体基本分开的含水悬浮液相34。另外,容器也可采用预填充注射器,如果需要的话,该注射器可配备一个或多个过滤器。相应地,本发明中术语“容器”包括注射器。用含水相及液面上空间的预选立体填充的注射器优选以其横向取向的长轴安装在振动装置1中,即其方向应垂直于弧长度C。振动后,在注射器中产生充气的泡囊以备使用。不论采用何种容器,优选应使容器及其内容物为无菌的。
一般来说,虽然本发明根据用途有同已使含水相存于容器中,而采用的这种容器是无菌的, 但稳定介质可以干态或冻干态贮存于容器内。此时,只在振动之前才将水溶液如无菌磷酸盐缓冲液加至无菌容器中。这样,在振动过程中,含水相中再水合的稳定介质将再与液面上空间的气体作用,从而产生如上所述的充气泡囊。干燥或冻干的悬浮介质的再水合必然进一步使产品复杂化,通常这是不希望发生的。但对某些应用来说,此举可用于进一步延长产品的储存期限,例如,某些治疗剂如环磷酰胺、肽和基因物质(如DNA)长期贮存于水中会水解。以前冻干的样品在振动前再水合形成水相和液面上空间使得可生产出包含化合物的泡囊,否则这些化合物的储存期限可能不足。
可采用各种不同材料来生产容器,如玻璃、硼硅酸盐玻璃、硅酸盐玻璃、聚乙烯、聚丙烯、聚四氟乙烯、聚丙烯酸酯、聚苯乙烯或其它塑料。容器最好是不透气的或在用充气前包裹有外层不透气的隔气层。当然,希望保护预选气体在容器内的一体性。气密性注射器材料的实例包括但不限于硅酸盐玻璃或硼硅酸盐玻璃,硅化注射器或Luer-Lock注射器及特氟隆尖瑞或特氟隆涂层的柱塞。
更具体地说,容器的大小及其重量将会影响充气泡囊的大小。随着容器重量增长超过一定值,振动装置通常会减慢振动,如Wig-L-BugTM3110B振动器,2ml小瓶(实际体积为3.7ml)的振动快于10ml小瓶的。因而,根据所采用的特定振动装置,容器的体积不应超过一定值。
用10ml清洁的小瓶(Wheaton Industries,Millville,New Jersey)和2ml(实际体积3.7ml)安瓿小瓶(Wheaton Industries,Millville,New Jersey)在Wig-L-Bug上进行了试验。开始试验后,用Code-Palmer Pistol Grip转速计(Code-Palmer,Nile,Ill.)测量振动速度。表7列出了结果,结果表明增加小瓶容积会降低振动频率。
表7
小瓶大小对Wig-L-BugTM振动频率的影响
小瓶大小 | 测得频率(RPM) |
2ml小瓶 | 3250 |
10ml小瓶 | 2950 |
从表中看出,对于Wig-L-Bug而言,标定大小2ml的容器充许采用高振动频率。参考图1所示尺寸,2ml标定大小(实际3.7ml)的容器9其直径D优选为约0.7英寸,总高Ho约为1.4英寸,体高HB约为1英寸。
VI.本发明生产的泡囊的应用
上面给出了影响充气泡囊大小的各种参数。就最大生产效率和最小毒性而言,泡囊尺寸非常重要。此外,泡囊应尽可能柔软以提高效能并减少有害的组织相互作用如在肺内的沉积。本发明产生了具有非常薄且柔性膜的理想尺寸的泡囊。因为泡囊膜如此薄且柔软,如为稳定膜仅需要1mg/ml的类脂,业已发现,可以使用大直径的充气泡囊,不会产生肺动脉高压。例如,向猪给药,剂量为必要诊断成像剂量的5倍,无肺动脉高压迹象出现。作为比较,在这些动物中更低剂量的较小直径的清蛋白包被空气则会引起严重的肺动脉高压。由于本发明的泡囊如此柔软及可变形,它们易于滑过肺毛细血管。另外,采用本申请的类脂(如聚乙二醇负载类脂)的包被技术也可降低有害的肺作用,同时,增强了产品体外和体内的稳定性及功效。
由于普通超声造影介质的充气泡囊的尺寸应尽可能大(但不引起栓塞作用),这是因为当频率使充气泡囊在瑞利散射范围时,背散射或超声作用是与半径的六次方成正比关系。对MRI而言,也优选采用本发明的大泡囊。与其它产品相比,本发明能制备并采用大尺寸的泡囊,且其无毒副作用,这增加了其功效。
影响超声造影的其它参数是泡囊膜的弹性。弹性越大则造影效果越好。由于本申请的泡囊用超薄类脂包被,其弹性类似于“裸气体”,反射性和造影作用均可达到最大。
本发明的振动方法易于在无菌容器内由水相和液面上空间气体生产泡囊。本发明可有效地生产具有理想性能并用于超声或磁共振成像的泡囊。但是,对选择的应用领域,可采用过滤器以产生具有大小分布更均匀及理想直径的泡囊。例如,为了利用充气泡囊的谐振现象以测量对超声的体内压力,窄尺寸分布及严格限定泡囊直径是有用的。通过注射泡囊(通过振动含水相和液面上空间气体的容器得到)通过限定尺寸的过滤器很容易达到此目的。形成的泡囊将不会超过过滤膜中过滤孔尺寸的最接近近似值。如上指出,对于大多数超声或MRI应用来说,充气泡囊尽可能大是理想的。但是,对某些应用领域,则希望更小的充气泡囊。例如,导向肿瘤或其它患病组织时,充气泡囊必须离开血管空间而进入组织小间隙中,更小的充气泡囊可用于这些用途中。这些更小的充气泡囊(如直径在1μm以下)基本上可通过改变水相中的化合物(组成和浓度)以及液面上空间(气体组成及液面上空间的体积)来改变,但也可通过使其注射通过过滤器来完成。经注射通过例如0.22μm的过滤器可生产基本无效大小基本均匀的非常小的充气泡囊。形成的nm级大小的充气泡囊具有理想的导向性能。
上述实例的类脂悬浮液也可经高压锅杀菌而无需明显改变悬浮液的尺寸。在振动步骤之前或之后,可通过高压锅和/或杀菌过滤或本领域技术人员公知的方法完成造影介质的杀菌。
在用含水相及液面上空间的预选充气容器后,可长期贮存密封瓶。要求颗粒不沉淀,充气泡囊不破裂,及在充气泡囊、颗粒、胶体或乳液间无不希望发生的相互作用。用含水相和液面空间充气的容器的储存期限应仅与含水相中化合物的稳定剂有关。本发明与现有技术相比其突出优点就是储存期限长及具有杀菌性能。在超声造影领域稳定性问题如颗粒的聚集和沉淀问题是普通存在的,这些问题本文已给出建议。
业已发现,通过对本发明的多相容器振动产生的充气泡囊具有优良的实用性,可用作诊断成像如超声诊断成像或磁共振诊断成像用的造影剂。通常,泡囊可用于对患者成像,和/或诊断患者疾病组织的存在。成像过程包括:将本发明的充气泡囊施用于患者,然后用超声或磁共振成像对患者扫描,得到患者内部区域的可视图像。所谓患者的区域是指整个患者,或患者的特定区域或部位。脂质体造影剂可用于提供血管、心脏、肝和脾脏的图像,及对胃肠区域或其它体腔成像,或用于对本领域技术人员显而易见的其它方式如组织表征、血液池成像等。各种类型的超声或磁共振成像装置均可用于实施本发明,对本发明方法而言,装置的具体类别或型号并不重要。
本发明的充气泡囊也可用于向患者传输各种治疗剂以治疗各种病症和疾病,如本领域技术人员公知的那样。
同样,磁活性泡囊可用于由MRI估测压力。泡囊增加了总体敏感度,从而增加了T2驰豫,但更增加了T2 *驰豫。由于静电场梯度的作用主要补偿自旋回波实验(通过180°射频重聚焦脉冲),泡囊的作用对T2 *加权脉冲序列较多,而对T2较小,而对T2 *加权脉冲序列,静电场梯度未起补偿作用。增加压力会使泡囊损失或泡囊破坏(对更易溶气体),同时使泡囊直径降低。相应地,1/T2随压力增长而降低。释放压力后,一些残余泡囊会再次膨胀,1/T2会再次稍稍增加。由约80%PFP和20%空气组成的泡囊随释压后压力回至基线表现出稳定性增加,而1/T2略有下降(即,泡囊稳定但显示轻微1/T2压力效应)。当得到梯度回声图像时,信号强度测量的这些作用更加明显。信号强度随压力增力而增加(1/T2 *随压力增加而降低)。由于实验进行的相当快(与测量T2相比仅花费少于1/10的时间进行梯度回声成像),暴露于压力的持续时间更少,填充氮气的泡囊在释压后返回接近基线(即,仅有很少的泡囊损失)。因此,在回到常压时,对梯度回声的信号强度回落至接近基线。为了用MRI测量压力,可将泡囊设计成随压力增加分解,或随压力增加时稳定但泡囊直径下降。由于对MRI泡囊半径影响1/T2 *,这种关系可用于经MRI估测压力。
本领域的技术人员可以看出,可以各种方式向患者施用充气的泡囊,如静脉内或动脉内注射、口服或直肠给药,根据年龄、重量和待扫描或治疗的具体哺乳动物区域,采用的具体造影介质或治疗剂,改变给药剂量和给药方式。通常,初始剂量较低,并增加直至达到所需造影增强或治疗作用。患者可为任何类型的哺乳动物,首选人类。
本文中引用或参考的专利和公开物的所有内容完整引入本文作参考。
除了本文中显示及描述的内容,从以上说明,本领域的技术人员易于看出本发明的各种改进。这种改进也属本申请权利要求保护范围。
Claims (33)
1.一种制备最佳尺寸的泡囊的装置,所说的装置包括:
a)包含有含水悬浮液相和基本上与所说的含水悬浮液相分离的气相的容器,其中所说的含水悬浮液相含有类脂,并且所说的类脂包含二棕榈酰基磷脂酰胆碱、二棕榈酰基磷脂酸和二棕榈酰基磷脂酰乙醇胺;
b)用于通过对所说的容器施加往复运动使其振动而形成泡囊的部件,所说的部件包括:
(i)振动臂,
(ii)用于将所说的容器与所说的振动臂连接的部件,和
(iii)用于使所说的振动臂在第一和第二相互垂直的方向上往复振动的部件;
其特征在于,所说的振动臂的长度为至少6cm;
所说的用于使所说的振动臂振动的部件包括用于在沿弧形路径的第一方向上使所说的振动臂旋转的部件,所说的弧形路径的曲率半径为至少6cm,并占据至少3°的角度,和
所说的往复运动的总路径呈8字形。
2.根据权利要求1的装置,其中所说的用于振动的部件还包括用于以至少为约0.3cm的幅度进行振动的部件。
3.根据权利要求2的装置,其中所说的用于振动的部件包括用于以不超过约2.5cm的幅度进行振动的部件。
4.根据权利要求2的装置,其中所说的用于使所说的振动臂振动的部件包括用于在所说的第二方向上以至少约0.02cm的幅度进行振动的部件。
5.根据权利要求1的装置,其中所说的用于振动的部件包括用于使所说的容器沿总长度至少为约0.7cm的8字形路径进行振动的部件。
6.根据权利要求1的装置,其中由所说的弧形路径占据的角度不超过约9°。
7.根据权利要求1的装置,其中所说的弧形路径的曲率半径不超过约15cm。
8.根据权利要求1的装置,其中所说的用于振动的部件包括用于在频率至少为约2800RPM下进行振动的部件。
9.根据权利要求1的装置,其中所说的类脂为单层的形式。
10.根据前述任一项权利要求的装置,其中所说的泡囊包含脂质体。
11.根据权利要求10的装置,其中所说的脂质体包含磷脂。
12.根据权利要求1的装置,其中所说的气相开始占据所说容器体积的至少10%。
13.根据权利要求1的装置,其中所说的气相包含全氟化碳气体。
14.根据权利要求1的装置,其中所说的气相包含选自全氟丙烷、全氟丁烷、全氟戊烷、全氟己烷和六氟化硫的气体。
15.根据权利要求14的装置,其中所说的气相包含全氟戊烷。
16.根据权利要求14的装置,其中所说的气相包含六氟化硫。
17.根据权利要求14的装置,其中所说的气相包含全氟丙烷。
18.根据权利要求14的装置,其中所说的气相包含全氟己烷。
19.根据权利要求1的装置,其中所说的含水悬浮液相包含聚合物。
20.根据权利要求19的装置,其中所说的聚合物包含聚甲基丙烯酸酯。
21.根据权利要求19或20所说的装置,其中所说的气相包含空气。
22.根据权利要求1的装置,其中所说的含水悬浮液相包含多糖。
23.根据权利要求1的装置,其中所说的含水悬浮液相包含半乳糖。
24.根据权利要求23的装置,其中所说的气相包含氮气。
25.根据权利要求10的装置,其中所说的脂质体包含交联的脂质体或聚合的脂质体。
26.根据权利要求1的装置,其中所说的含水悬浮液相还包含聚乙二醇。
27.根据权利要求1的装置,其中所说类脂包含二棕榈酰基磷脂酰胆碱、二棕榈酰基磷脂酸和二棕榈酰基磷脂酰乙醇胺-PEG5000。
28.一种制备最佳尺寸的泡囊的方法,所说的方法包括如下步骤:
提供根据权利要求1-26任一项的装置,和
以超过约2,80RPM且不超过10,000RPM的频率将所说的容器振动足以在所说的容器中产生泡囊的时间。
29.根据权利要求28的方法,其中所说的振动产生的泡囊的95%小于10μm。
30.根据权利要求29的方法,其中所说的振动产生的泡囊平均尺寸小于2.5μm。
31.根据权利要求28的方法,其中所说的气相开始占据所说容器体积的至少10%。
32.根据权利要求29的方法,其中所说的振动的持续时间不超过约2分钟。
33.根据权利要求32的方法,其中所说的容器为注射器。
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1995
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101596322B (zh) * | 2007-06-06 | 2011-05-04 | 南方医院 | 气乳剂型超声造影剂微球及其制备方法 |
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EP0840570A2 (en) | 1998-05-13 |
US6039557A (en) | 2000-03-21 |
JP3645909B2 (ja) | 2005-05-11 |
HK1010127A1 (en) | 1999-06-17 |
CN1186419A (zh) | 1998-07-01 |
EP0840570B1 (en) | 2003-08-13 |
CA2218860A1 (en) | 1997-01-09 |
US5656211A (en) | 1997-08-12 |
CA2218860C (en) | 2006-12-05 |
ES2207687T3 (es) | 2004-06-01 |
EP0840570A4 (en) | 2001-05-30 |
BR9609343A (pt) | 1999-12-28 |
MX9709717A (es) | 1998-07-31 |
AR002310A1 (es) | 1998-03-11 |
WO1997000638A2 (en) | 1997-01-09 |
DE69629478D1 (de) | 2003-09-18 |
WO1997000638A3 (en) | 1997-02-20 |
JPH11507873A (ja) | 1999-07-13 |
ATE246956T1 (de) | 2003-08-15 |
AU7594796A (en) | 1997-01-22 |
AU703846B2 (en) | 1999-04-01 |
DE69629478T2 (de) | 2004-06-17 |
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