CN1125654C - 制备气体和气体前体填充的微球体的方法 - Google Patents
制备气体和气体前体填充的微球体的方法 Download PDFInfo
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- CN1125654C CN1125654C CN94192402A CN94192402A CN1125654C CN 1125654 C CN1125654 C CN 1125654C CN 94192402 A CN94192402 A CN 94192402A CN 94192402 A CN94192402 A CN 94192402A CN 1125654 C CN1125654 C CN 1125654C
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- liposome
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Abstract
描述了制备温度激活的气体前体填充的微球体的方法。设备和设备的制造方法,通过这些方法制备的气体前体填充的脂质体特别有用,例如,用于超声显像和治疗药物传送系统。
Description
相关申请
本申请是美国系列号为08/160,232和08/159,674,其中申请日皆为1993年11月30日的共同未决申请的部分继续,后两个申请是美国系列号为076,239,申请日为1993年6月11日的共同未决的申请的部分继续,后者是美国系列号为717,084和716,899的共同未决的申请的部分继续,后两个申请的申请日皆为1991年6月18日,它们依次又是美国系列号为569,828,申请日为1990年8月20日的申请的部分继续,后者依次是美国系列号为455,707,申请日为1989年12月22日申请的部分继续。每一申请的公开在此整体结合作为参考。
发明背景
发明领域
本发明涉及制备气体前体填充的脂质体的新的方法和设备。通过这些方法制备的脂质体特别有用,例如,用于超声显像和治疗剂传递系统。
发明背景
各种各样的技术已用于检查和诊断人和动物的疾病。X-射线是用于诊断显像的首要技术之一。通过此技术获得的影像反映了被显像物体的电子密度。在过去的年代里,对比剂,例如钡或碘已用于增强或阻断X-射线,结果增加了不同结构间的对比度。但是,已知X-射线有一定的危害性,因为在X-射线中产生的辐射正在电离,电离辐射的损害作用是可以累积的。
另一个重要的显像技术是磁共振显像(MRI)。然而这种技术有各种各样的缺陷,如花费高和不便于进行移动检查。此外,MRI在许多医疗中心不实用。
用于核医学的核素,提供了进一步的显像技术。使用此技术时,将核素,例如标记锝的化合物注射进患者体内,并从γ照相机中获得影像。然而,核医学技术受到空间小的限制并且使动物或患者暴露于辐射的损害作用之下。因此,核素的操作和处理成问题。
超声是另一种诊断显像技术,它不同于核医学和X-射线,因为它不使患者暴露于电离辐射的有害作用之下。而且,不象磁共振显像,超声相对廉价并可进行移动检查。使用超声技术,通过传感器声波可传入患者或动物体内。当声波传过身体时,在组织和组织液中界面,依赖于体内组织和组织液的声学特性,超声波部分或全部地反射或吸收。当声波通过界面反射时,可通过传感器中的接收器检测它们并处理形成影像。体内组织和组织液中声学特性决定了产生影像的对比度。
近年来,超声技术取得了进展。然而,尽管取得了各种各样的技术进步,在许多方面超声仍然是不完美的工具,特别是关于肝脾、肾、心血管疾病的检查和显像,包括测定血流量。检测这些区域的能力依赖于组织或组织液与周围的组织或组织液间的声学特性的差异。结果,找到了对比剂,它们可提高组织或组织液与周围的组织或组织液之间的声学特性的差异,以改善超声显像和疾病检查。
产生超声影像形成的原理指导研究者们探索气体对比剂。不同物质密度或声学阻抗大大不同导致在其界面上声学特性或声学阻抗的改变,特别是固体、液体和气体之间界面。当超声波遇此界面,在超声显像中声学阻抗的改变导致更强的声波反射和更强的信号。影响声效率或反射的另一个因素是反射界面的弹性。这种界面的弹性越大,声反射的效率越高。因此,鉴于上述原理,研究者们着重发展了基于气泡或含气剂体的超声对比剂及制备其有效方法。
Ryan等在美国专利4,544,545中,公开了有化学上修饰的胆固醇包被的磷酯脂质体。胆固醇包被可以是单层或双层。含水介质包含示踪物,治疗剂或细胞毒性剂,限定于脂质体内。脂质体直径为0.001微米至10微米,经搅拌和超声振动制备。
D′Arrigo在美国专利4,684,479和5,215,680中提出了一种含液包气乳化剂和从表面活性剂混合物中生产其方法。美国专利4,684,479公开了通过振荡在空气中液体介质中表面活性剂溶液的脂质体的生产。美国专利5,215,680旨在大量生产类脂包被的微气泡的方法,此方法包括振荡空气中液体介质中表面活性剂溶液或其它气体混合物和过滤灭菌产生的溶液。
WO 80/02365公开了含不活泼气体,如氮气或二氧化碳的微气泡的生产,不活泼气体包封于可凝胶化的膜中。脂质体可于低温保藏并在用于人体之前或期间加温。WO 82/01642叙述了微气泡前体及生产其方法。通过溶解固体材料在液体中形成微气泡。气体填充空隙,其中气体产生于:1)从固体前体聚集体微粒间空隙存在的气体中生产的;2)在前体颗粒的表面吸收的;3)前体颗粒内部结构的整合部分;4)当前体与液体发生化学反应时形成的;及5)溶于液体中的和前体溶入其中时释放的。
此外,Feinstein在美国专利4,718,433和4,774,958中提出了针对超声目的的白蛋白包被的微气泡的使用。
Widder在美国专利4,572,203和4,844,882中公开了一种超声显像方法和一种微气泡型超声显像剂。
Quay在WO93/05819中描述了形成了基于已知物理常数标准含特别挑选的气体的微气泡试剂的用途,物理常数包括1)气泡大小;2)气体密度;3)环境介质中气体的溶解性;4)气体进入介质的分散度。
Kaufman等在美国专利5,171,755中公开了一种乳化剂,包括高度氟化的有机化合物,基本上没有表面活性或水溶性的油和表面活性剂。Kaufman等也提供了在医疗上使用乳化剂的方法。
另一个致力于研究的重要领域是靶定位药物传送领域。靶传送装置是特别重要的,其中毒性是一个问题。特定的治疗剂传送方法有效地用于降低毒副作用为最低水平,降低要求的剂量,减少患者的花费。
根据本领域现有的方法和材料,引入遗传物质,例如进入活细胞受到限制而且无效。目前已发现几种不同的机理使遗传物质传送进活细胞。这些机理包括如磷酸钙沉淀和电穿孔、以阳离子聚合体和充水脂质体为载体的技术。这些方法在体内所有都相对无效,只限于用在培养细胞的转染。这些方法中无一有效于定点释放、传送和遗传物质整合于靶细胞。
传送治疗药物,例如遗传物质较好的方法,因需要用于治疗各种各样的人和动物疾病。在定性遗传疾病和理解蛋白转录方面已取得长足的进步,但为治疗人和动物疾病在传送遗传物质进入细胞方面进展很小。
主要的问题是传送遗传物质从细胞外空间进入细胞内空间或甚至有效地将遗传物质定位在选择的细胞膜表面。在体内已尝试了各种各样的技术,但没有大的成功。例如病素,如腺病素和逆转录病毒用作转送遗传物质进入细胞的载体。已用了整个病素,但能置入病毒囊内的遗传物质的量受到限制,并且有可能由活病毒引起相关的有害作用。可以分离病毒囊中的基本成分并用于携带遗传物质进入选择的细胞。然而在体内,不但传送载体必须识别某种细胞,而且也必须传送至这些细胞。尽管在病毒载体方面做了广泛的工作,但是在体内为传送遗传物质发展一种成功靶定位病毒介导的载体是困难的。
通常,含液体的脂质体用于传送遗传物质至培养的细胞内,但是在体内遗传物质的细胞传递基本上是无效的。例如阳离子脂质体转染技术在体内不能有效地发挥作用。需要更有效的方法改善治疗药物,如遗传物质的细胞传送。
本发明目的如前述,以及超声显像的对比剂和治疗剂有效靶定位传递领域的其它重要需求。
发明梗概
本发明提供了一种制备气体填充类脂微球体的方法,其包括,在存在液体温度激活气体前体时,摇荡含有类脂的水溶液,并且此后使得所述类脂微球体的温度升至高于所述温度激活气体前体的液-气相转变温度,其中所述温度激活气体前体为全氟化碳,其具有-100℃-70℃的液-气相转变温度。
本发明还提供了一种制备气体填充类脂微球体的方法,其包括,在存在气体或气体混合物时,摇荡含有类脂的水溶液,其中所述气体或气体混合物包括选自全氟化碳和六氟化硫的气体。
本发明提供了制备温度活化的气体前体填充的适用于作超声显像对比剂或药剂传送物的脂质体的方法和设备。本发明的方法提供的益处,如在制造温度活化的气体前体填充的脂质体过程中简单、费用很低。
制备温度活化的气体前体填充的脂质体的优选方法包括在温度活化的气体前体存在时,温度低于类脂的从凝胶态向液晶态相转变的温度,振荡含类脂的水溶液。
出乎意料之外,根据本发明方法制备的温度活化的气体前体填充的脂质体具有许多惊人的高效性。例如气体前体填充的脂质体,由于它们的生物相容性,当脂质体破裂后,有利于它携带的穿越细胞膜的脂溶性化合物释放出来。本发明的脂质体也表现出强烈的声回波特性,对压力的高度稳定性,和/或通常具有长的贮存寿命,或干燥或悬浮于液体介质中贮存。脂质体的回声性对根据本发明制造的脂质体的诊断和治疗应用是重要的。气体前体填充的脂质体也有如稳定的颗粒大小、低的毒性和柔软的膜的优点。据信气体前体填充的脂质体的柔软的膜可用于帮助这些脂质体聚集或打靶到组织,例如肿瘤上。
根据本发明如此制造的温度活化的气体前体填充的脂质体对超声对比显像有优越性。当在含水或组织介质内时,气体前体填充的脂质体对提高声的吸收产生界面。因此,气体前体填充的脂质体通常用于给患者显像,和/或诊断患者患病组织的存在及组织供热并促进药物的释放或活化。
除了超声以外,根据本发明制造的温度活化的气体前体填充的脂质体例如可用于磁显像和MRI对比剂。例如,气体前体填充的脂质体可含顺磁气体,例如大气,其中含痕量的氧17;顺磁离子如Mn+2、Gd+2、Fe+3、氧化铁或磁铁矿(Fe3O4),并因此可用作磁共振显像的敏感对比剂。此外,例如根据本发明制造的气体前体填充的脂质体可含有防辐射金属离子、如碘、钡、溴或钨,用作X-射线对比剂。
温度活化的气体前体填充的脂质体也特别用于作为药物载体。不象现有技术中的脂质体,具有只适用于包裹水溶性药物的液体内层,根据本发明制造的气体前体填充的脂质体特别适用于包裹脂溶性药物。而且,脂溶性药物的衍生物可以容易地掺入到液体层中,例如茂金属二卤化物的烷基化衍生物(Kuo等,J.Am.Chem.Soc.1991,113,9027-9045)。
附图简要说明
图1是根据本发明制备本发明气体前体填充的脂质体微球体体的优选设备部分图示。
图2显示过滤和/或分配含本发明治疗剂的气体前体填充的脂质体微球体体的优选设备。
图3显示过滤和/或分配含本发明治疗剂的气体前体填充的脂质体微球体的的优选设备。
图4是图3的设备部分分解图。
图5是在(A)过滤前和(B)过滤后,显示本发明气体前体填充的脂质体大小的显微照片。
图6图示的是(A)过滤前和(B)过滤后本发明气体前体填充的脂质体的大小分布。
图7是用过滤器(A)压出过滤前和(B)压出过滤后,类脂悬液的显微照片。
图8是继于过滤和压热类脂悬液形成的气体前体填充的脂质体的显微照片,在(A)通过过滤气体前体填充的脂质体筛分脂质体大小的步骤前和(B)通过过滤气体前体填充的脂质体筛分脂质体大小的步骤后拍下的显微照片。
图9是在温度活化之前,温度活化的气体前体填充的脂质体的图解。脂质体含有多层的膜。
图10是温度活化的液态气体前体填充的脂质体在液态到气态的活化温度后产生单层膜以及脂质体直径的膨胀的图解。
本发明详述
本发明目的在于制备温度活化的气体前体填充的脂质体的方法和设备。不象现有技术的方法,目的在于形成水溶性填充内层的脂质体,本发明的方法目的在于内部含气体前体和/或内部全部含气体的脂质体。
此处使用的短语“温度活化的气体前体”指一种化合物,在选择的活化或转变温度下,其从液态到气态相改变。活化或转变温度及其类似术语,是指气体前体的沸点,在此温度下,气体前体从液相向气相转变发生了。有用的气体前体是沸点在约-100℃到70℃的那些气体。活化温度对每种气体是特定的。此概念用图9和图10说明。对本发明的气体前体而言,优选的活化温度为37℃或人体温度。这样,在37℃液态气体前体就活化为气体。然而,气体前体可以液相或气相用于本发明的方法中。本发明的方法可在气体前体的沸点以下进行,以便液体掺和到微球体体中。此外,这些方法可以在气体前体的沸点进行,以便气体可掺入微球体体中。对具有低温沸点的气体前体而言,使用微液化器使液体前体冷却至低温而微乳化。使用液体介质中的溶剂,利用液体形式的前体也可降低沸点。作为选择,用集中高能的超声获得约70℃的上限。而且,可以实施此方法,在整个过程中,温度提高了,其中此过程以作为液态气体前体形式开始并以气体形式结束。
可以选择气体前体目的靶组织或组织液处形成气体,它是在进入患者或动物体内时,使用前,贮存期间或制造过程中。生产温度活化的气体前体填充的微球体体的方法可在低于气体前体的沸点温度下进行。在此实施方案中,气体前体包裹在微球体体内,以便在制造过程中不发生相改变。相反,气体前体填充的微球体用液相的气体前体制造。当允许温度超过前体的沸点时,任何时候都可以活化相的转变。而且,知道液滴状的液态气体前体的液体量,一旦产生气态时便可确定脂质体的大小。
作为选择,气体前体可用于产生在使用前形成的稳定的气体填充的微球体体。在此实施方案中,气体前体加到有悬浮和/或稳定介质的容器中,温度低于各自气体前体的液-气相转变温度。然后当温度提高时,在气体前体和液体溶液间形成乳液,气体前体从液态变成气态。由于此种供热和气体形成,气体代替了液态悬液上部空间的空气,以便形成气体填充的液体球,此球包裹气体前体的气体,环境气体(例如空气)或共包裹气态气体前体和环境空气。这种相转变可用于对比介质的最适混合及稳定。例如,气体前体,全氟丁烷,可包裹于脂质体中,而且当温度升高时,超过3℃(全氟丁烷的沸点),脂质体包裹的氟丁烷气体便产生了。另一个例子,气体前体氟丁烷可悬于含乳化和稳定剂例如丙三醇或丙二醇的液体悬液中并在购于市售的涡旋振荡器上涡旋。涡旋在足够低的温度下开始,气体前体在此温度下为液体,当样品的温度提高超过从液相向气相转变的温度时继续涡旋。这样做后,在微乳化过程中,前体转变成气态。在合适的稳定剂存在时,惊人稳定的气体填充的脂质体产生了。
因此,本发明的气体前体可经选择形成在体内气体填充的脂质体或设计产生现场气体填充的脂质体,此是在制造过程中,贮存时或先于使用的任何时候。
作为此发明的另一个实施实施,通过预先使气体前体的液态形成水溶性乳液并保持已知的大小,一旦实现了向气态的转变,通过使用理想气体定律可以估计最大微泡的大小。为了从气体前体制造气体微球体体,假定立即形成气相,在新形成的微泡中由于分散进了液体(通常本质上,含有水),没有气体排除掉。因此,从乳剂中的已知气体体积,我们实际上可预测气体脂质体大小的上限值。
根据本发明,限定大小含类脂气体前体液滴的乳液可以配制成,一达到特定的温度,气体前体的沸点,液滴就膨胀成限定大小的气体脂质体。限定大小代表实际大小的上限值,因为诸如气体分散进溶液、气体损失进入大气、和增长的压力的影响的因素是理想气体定律不考虑释的因素。
理想气体定律和计算从液态向气体转变的气泡体积增长的方程式如下:
理想气体定律假定如下:
PV=nRT
其中,
P=大气压
V=体积(升)
n=气体摩尔数
T=温度(K)
R=理想气体常数=22.4L大气压/deg mole
知道液体乳剂中液体的体积、密度和温度,液态前体的量(例如摩尔数)及液体前体的体积就可以计算,当其转变成气体时,它就可以膨胀成已知体积的脂质体。计算出的体积反映了气体脂质体大小的上限值,此是在假定立即膨胀成气体脂质体并在膨胀过程中忽略了气体的分散情况下得到的。
这样,乳液中液态前体的稳定,前体液滴成球状,通过方程式确定前体的体积。
体积(球体)=4/3πr3
其中,
r=球体的半径
因此,一旦预测了体积,并知道在理想温度下液体的密度,液滴中液体(气体前体)的量便可确定。用更富有描述性的方式,可用下列公式:
V气体=4/3π(r气体)3
结合理想定律
PV=nRT
代入后
V气体=nRT/P气体
或,
n=4/3[πr气体 3]P/RT
量n=4/3[πr气体 3P/RT]*MWn
转换成液体体积
(B)V液=[4/3{πr气体 3}P/RT]*MWn/D]
其中,D=前体的密度
求液滴的直径
(C)直径/2=[3/4π[4/3*[πr气体 3]P/RT]MWn/D]1/3
简化为
直径=2[[r气体 3]P/RT[MWn/D]]1/3
作为本发明的另一个实施方案,知道体积和特别地半径,合适选择大小的滤器筛分了针对合适半径球体为气体前体液滴的大小。
一个有代表性的气体前体可用于形成限定大小的微球体体,例如,直径为10μm。在此实施例中,微球体体在人类血流中形成,因此典型的温度是37℃或310K。在1大气压下并用方程式,(A),7.54×10-17摩尔的气体前体要求填充直径为10μm微球体体的体积。
使用上述计算的气体前体量和1-氟丁烷,1-氟丁烷分子量为76.11,沸点为32.5℃并且在20℃密度为6.7789grams/mL进一步计算预测到,5.74×10-15g此前体需要10μm的微球体体。进一步推断,并根据已知密度方程式(B),进一步预测到8.47×10-16mL液体前体必要地形成了上限值为10μm的微球体体。
最后,应用方程式(C),需要形成半径为0.0272μm或相应直径为0.00544μm的类脂液滴乳液,制造气体前体填充的微球体体,微球体体的上限值为10μm。
这种特定大小的乳液可通过使用合适的测定大小的滤器容易地获得。此外,如通过形成限定大小的气体前体液滴必需的滤器大小所见到的,滤器的大小也将有效地除去任何可能的细菌污染物并因此能用作灭菌过滤。
本发明的实施方案可用于各种通过温度活化的气体前体。实际上,溶剂体系凝固点的降低允许使用气体前体,此气体前体在低于0℃时进行液相至气相的转变。溶剂体系经选择提供一种用于气体前体悬液的介质。例如,20%的可溶于缓冲盐水中的丙二醇具有恰恰低于水的凝固点。经提高丙二醇的量或加入如氯化钠的物质凝固点可更加降低。
合适溶剂体系的选择也可通过物理方法解释。当物质,固体或液体,此处指溶质,溶于溶剂如以水为基础的缓冲液中时,例如,凝固点通过依赖于溶液组合物的量降低。因此,如Wall限定的,人们可通过下式表示溶剂凝固点的降低:
InXa=In(1-Xb)=ΔHfus/R(1/To-1/T)其中:
Xa=溶剂的摩尔组分
Xb=溶质的摩尔组分
ΔHfus=溶剂熔化热
To=溶剂正常凝固点
溶剂的正常凝固点产生了。如果Xb相对比Xa小,那么上述方程式可改写为:
Xb=ΔHfus/R[T-To/ToT]≈ΔHfus ΔT/R To2
上述方程式中假设温度的改变ΔT和比T2较小。假定溶质(每千克溶剂中的摩尔数)的浓度可用术语摩尔浓度m表示的话,上述方程式便可进一步简化。因此,
Xb=m/[m+1000/Ma]≈mMa/1000
其中,
Ma=溶剂的分子量,和
m=每千克(溶剂)中溶质的摩尔数
这样,代入组分Xb
ΔT=[MaRTo2/1000ΔHfus]m
Kf=MaTo2/1000ΔHfus
Kf称为摩尔凝固点而且等于在1大气压下,每单位摩尔浓度水1.86度。上述方程式可用于精确地测定本发明气体前体填充的微球体体溶液的摩尔凝固点。
因此,上面的方程式能用于估计凝固点降低和确定对降低溶剂凝固温度到合适的值必需的液体或固体溶质合适的浓度。
制备温度活化的气体前体填充的脂质体的方法包括:
涡旋(振荡)本发明气体前体填充的脂质体水溶性悬液;此方法的变化包括,在振荡前任意地压热,任意地加热气体前体和类脂的水溶性悬液,任意地给含悬液的容器开孔,任意地振荡或允许气体前体脂质体自然形成和冷却气体前体填充的脂质体悬液,任意地压出气体前体和类脂水溶性悬液通过约0.22μm的滤器,作为选择,过滤可在体内产生脂质体的用药过程中进行,以便使用约0.22μm的滤器;
一种微乳化方法,藉此,本发明的气体前体填充的脂质体含水悬液经搅拌被乳化并在患者用药前加热形成微球体体;和
通过加热、和/或搅拌在类脂悬液中形成气体前体,由此膨胀和取代容器中的其它微球体体及给容器开孔释放空气,较小密度的气体前体填充的微球体体漂浮在溶液的上层。
冷冻干燥对在振荡气体滴注法之前从类脂中除去水和有机物是有用的。干燥气体滴注法可用于从脂质体中除去水分。在温热后,经预先在干燥脂质体中(即在干燥之前)包裹气体前体,气体前体可膨胀填充脂质体。气体前体在真空干燥后,也可用于填充干燥脂质体。当干燥的脂质体保存在温度低于凝胶态到液晶态的温度时,干燥室内可缓冲地填充气态的气体前体,例如,全氟丁烷可用于填充干燥的脂质体,此脂质体由二棕榈酰磷脂酰胆碱(DPPC)组成,在温度为3℃(全氟丁烷的沸点)和低于40℃之间,此为类脂的相转变温度。这种情况下,最优选的是在约4℃至约5℃填充脂质体。
制备温度活化的气体前体填充的脂质体的优选方法包括在气体前体存在时,温度低于类脂从凝胶态向液晶态相转变的温度下振荡含类脂的水溶液。本发明也提供一种制备气体前体填充的脂质体的方法,此方法包括在气体前体存在时,振荡含类脂的水溶液,并分离产生的气体前体填充的脂质体用于诊断和治疗。通过上述方法制备的脂质体在此称为通过凝胶态振荡气体前体滴注方法制备的气体前体填充的脂质体。
通常,充水脂质体一般在高于类脂的相转变温度下形成,因为它们更柔和,并因此其液晶态用于生物体系。例如见Szoka和Papahadjopoulos,Proc.Natl.Acad.Sci.1978,75,4194-4198。相反,根据本发明方法的优选实施例制备的脂质体是气体前体填充的,它具有更大的柔韧性,因气体形成后,气体前体比水溶液更易压缩和柔和。这样,气体前体填充的脂质体当在温度低于类脂的相转变温度时,尽管凝胶相更坚硬,可用于生物体系。
本发明的方法提出,在温度活化的气体前体存在时,振荡含类脂的水溶液,此处所用的“振荡”一词,定义为搅拌水溶液以便使气体前体从现场周围环境进入水溶液的运动。任何类型搅拌水溶液和产生气体前体引入的运动都可用于振荡。振荡必须是充分有力的,以便一段时间后,允许泡沫生成。优选地,振荡充分有力以致于在短时间内形成泡沫,例如30分,优选为20分钟之内,更优选为10分钟之内。振荡可通过微乳化、微液化,例如涡旋振荡(如用旋涡振荡器),从一边向另一边或上下运动产生。在于液态加入气体前体的例子中,除了上述的振荡方法可用超声。而且,振荡可通过振荡含水溶性类脂溶液的容器产生或不振荡容器本身通过振荡容器内的水溶液产生。而且,振荡可通过手工或机器产生。可用的机械振荡器包括如振荡台,如VWR Scientific(Cerritos,CA)振荡台、微液化器,Wig-L-BugTM(Crescent DentalManufacturing,Inc.,Lyons,IL)和机械漆混合器及其它已知的机器。另一种产生振荡的方法包括在高速或高压下产生的气体前体的散射运动。也可理解,优选地,用大量水溶液,力的总量就相应增加了。剧烈的振荡限定为至少每分钟60次振动,而且是优选的。涡旋每分钟至少1000转,剧烈振荡的例子是更优选的。涡旋振荡每分钟为1800转为更优选的。
根据水溶液上层泡沫的存在可测定由振荡形成的气体前体填充的脂质体。一旦形成泡沫伴随着水溶液体积的降低。优选地,泡沫的最终体积至少约为水溶性类脂溶液初始体积的两倍。更优选地,泡沫的最终体积至少约为水溶液初始体积的3倍,更进一步优选地,泡沫的最终体积至少约为水溶液初始体积的4倍,并且最优选地,所有这些水溶性类脂溶液都变成泡沫。
可通过测定泡沫的形成确定持续振荡的时间。例如,在50ml离心管中的类脂溶液10ml,经涡旋振荡约15-20分钟或直至气体前体填充的脂质体的粘度变得相当厚,以致于在其旋转时,不再粘附于侧壁上。此时,泡沫可产生含气体前体填充的脂质体的溶液,达到30-35ml水平。
形成优选泡沫水平的要求的类脂浓度依赖于使用类脂的类型而改变,一旦有本说明书的公开,本领域的技术人员可容易地确定。例如,在优选的实施方案中,根据本发明的方法,用于形成气体前体填充的脂质体的1,2-二棕榈酰磷脂酰胆碱(DPPC)的浓度约为20mg/ml至30mg/ml盐水溶液。用于优选实施方案中的二硬脂酰磷脂酰胆碱(DSPC)的浓度约为5mg/ml至10mg/ml盐水溶液。
具体地说,浓度为20mg/ml至30mg/ml的DPPC,经振荡产生悬液和包裹的气体前体总体积比独自的悬液体积大4倍。浓度为10mg/ml的DSPC,经振荡,产生完全无任何液体悬液体积的总体积并全部包含泡沫。
一旦本说明书公开,本领域技术人员可以理解,在实施本发明的方法之前和以后可以熟练地使用类脂或脂质体。例如,类脂可被水合,然后冻干,通过冻融循环处理,或只水合。在优选的实施方案中,气体前体填充的脂质体形成之前,水合类脂,然后冻干,或水合,然后通过冻融循环处理并然后冻干。
根据本发明方法,存在的气体,如但不限于空气的存在,也可通过现场环境中大气提供。现场环境中大气可以是密闭容器中的大气或非封闭容器中的大气,可以是外部环境。作为选择,例如,可将气体注射或不然加入到有水溶性类脂的容器中或注射进水溶性类脂溶液本身,以提供气体而不是空气。不如空气重的气体可加到闭封容器中,而比空气重的气体可加到封闭或非封闭容器中。因此本发明包括和气体前体共同包裹空气和/或其它气体。
本发明优选的方法在温度低于使用的类脂凝胶态向液晶态相转变的温度下进行。所谓凝胶态向液晶态相转变的温度是指类脂双层从凝胶态转变成液晶态的温度。见,例如,Champman等.,J.Biol.Chem.1974,249 2512-2521。各种类脂的从凝胶态向液晶态相转变的温度对本领域的技术人员是显而易见的,例如,见Gregoriadis编的LiposomeTechnology,Vol.I,1-18(CRC Press,1984)和DerekMarch,CRC Handbook of Lipid Biolayers(CRC Press,BocaRaton,F1 1990),第139页。也可见下面表I。如果使用的类脂从凝胶态向液晶态相转变的温度高于室温,容器的温度可以调解,例如,通过提供制冷机冷却含有类脂溶液的容器。
既然气体前体(例如全氟丁烷)比其它气体,如空气不溶和分散,那么当包裹在脂质体中时,甚至脂质体由液晶状态的类脂组成时,它们趋于更稳定。由液晶类脂,如卵磷脂酰胆碱组成的小脂质体可用于包裹全氟丁烷的小滴。例如直径约为300nm至约50nm的类脂囊泡可用一包裹平均直径约25nm的全氟丁烷的小滴。温度活化转化后,前体填充的脂质体会产生直径约10nm的微球体体。在此情况下的类脂,用于通过小的脂质体限定微球体体大小的目的。类脂也用于稳定产生的微球体体的大小。在此情况下,诸如微乳化技术对形成包裹前体的小脂质体是优选的。微液化器(Microfluidics,Newton,MA)特别适用于制备包裹气体前体的小脂质体的乳化液。
表I饱和的二酰基-sn-甘油基-3-磷脂酰胆碱主链凝胶态向液晶态的相转变温度
酰基链中的碳# | 液晶态的相转变温度(℃) |
1,2-(12:0) | -1.0 |
1,2-(13:0) | 13.7 |
1,2-(14:0) | 23.5 |
1,2-(15:0) | 34.5 |
1,2-(16:0) | 41.4 |
1,2-(17:0) | 48.2 |
1,2-(18:0) | 55.1 |
1,2-(19:0) | 61.8 |
1,2-(20:0) | 64.5 |
1,2-(21:0) | 71.1 |
1,2-(22:0) | 74.0 |
1,2-(23:0) | 79.5 |
1,2-(24:0) | 80.1 |
通常,充气脂质体是在高于类脂的凝胶态向液晶的相转变温度的温度下常规地形成,由于其更有柔性,因此液晶态形式在生物体系中是有用的。参见,例如,Szoka和Papahadjopoulos,Proc.Natl.Acad.Sci.1978,75,4194-4198。相反,根据本发明方法的优选实施方案制得的脂质体是气体前体填充的,它给予更大的柔性,因为气体前体比液体溶液更可压缩和更柔顺。因而,当在低于类脂的相转变温度形成时,虽然凝胶态更硬,气体前体填充的脂质体可在生物体系中使用。
采用振荡凝胶态的气体前体滴注方法生产温度活化的气体前体填充的脂质体的优选设备示于图1中。将类脂和水介质的混合物批量或连续进料,在气体前体滴注过程中剧烈搅拌以生产气体前体填充的脂质体。参考图1,干燥类脂51由类脂供给容器50经导管59以连续流动或是间隙团块加入混合容器66中。如果采用批量方法,混合容器66可包含相对小的容器如注射器,试管,瓶或圆底烧瓶,或大容器。如果采用连续给料方法,混合容器优选大容器,如桶。
当气体前体填充的脂质体含治疗化合物时,治疗化合物可以,例如,上述类脂添加相似的方式在气体前体滴注过程前加入。另外,当脂质体用治疗化合物在外面涂敷时,治疗化合物可在气体前体滴注过程后加入。
除类脂类51外,水介质53,如盐水溶液,由水介质供给容器52经导管61也加入容器66中。类脂类51和水介质53组合形成类脂水溶液74。另外,干燥类脂类51可在被导入混合容器66前水合,这样,类脂类在水溶液中导入。制备脂质体方法的优选实施方案中,溶液74的最初装填量只占混合容器66容量的一部分。而且,在连续生产中,控制类脂水溶液74的加入速率和产生的气体前体填充的脂质体的移出速率不超过组合容器66容量的预定百分值。
振荡可以通过将加压气体前体的高速气流直接导入类脂水溶液74来完成。另外,振荡可以通过或是手动或是机械的机械振荡该水溶液来完成。这种机械振荡通过振荡组合容器66或不振荡混合容器本身而是直接振荡水溶液74也是有效的。如图1中所示的,在优选实施方案中,机械振荡器75与混合容器66相连。振荡应有足够的强度,这样,一段时间后,包含气体前体填充的脂质体的泡沫73在水溶液74的上面形成,如图1中所示的。检测泡73的形成可用作控制振荡时间长短的手段;即,不是预定振荡的时间,而是一直振荡直至预定量的泡沫产生。
图1的设备还含有控制温度的装置,这样,该设备可以保持制造脂质体方法的温度。例如,在优选实施方案中,制造脂质体的方法在低于气体前体的沸点下实施。在优选实施方案中,液态气体前体填充脂质体的内空间。此外,该设备可保持在气体前体的液态向气态转变温度的温度附近,这样,气体含在脂质体中。再则,设备的温度可贯穿制造脂质体的方法调节,这样,气体前体开始时为液体,然而,气体却并入所得脂质体中。在此实施方案中,设备的温度在制造脂质体的方法期间调节,这样,方法开始时温度低于相转变温度,并被调至在气体前体的相转变温度附近的温度。因此,容器可以紧闭和定时通风,或开向环境空气。
制造气体前体填充脂质体设备的优选实施方案中采用的类脂具有低于室温的凝胶向液晶相转变温度,为此提供一种冷却类脂水溶液74的方法。示于图1的实施方案中,冷却是通过为形成围绕混合容器66的环形通道而置于该容器周围的夹套64来完成的。如图1所示,迫使冷却液63由夹套进口和分别由出口62和63流经该环形通道。调节冷却液62的温度和流速,可将类脂水溶液74的温度保持在所需的温度。
如图1中所示,气体前体55,它可以是例如1-氟丁烷。与水溶液74一起导入混合容器66。空气可以使用未密封的混合容器导入,这样水溶液就连续地暴露于环境空气。在批量生产中,固定量的现场环境空气可以由密封该混合容器66来导入。如果采用重于空气的气体前体,容器无需密封。然而,导入不比空气重的气体前体时需要混合容器被密封。例如采用盖65,如图1中所示。气体前体55可以在混合容器66中加压,例如,通过将混合容器与加压气体供应罐54经导管57相连,如图1中所示。
振荡完毕后,含气体前体填充脂质体的泡沫73可从混合容器66提取。提取可以通过将注射器100的针头102(示于图2)插入泡沫73,并通过抽回柱塞106将定量的泡沫抽入套筒104。所下文进一步论述的,针头102的针尖在泡沫73中所置的位置可以用来控制吸取的气体前体填充脂质体的大小。
另外,提取可以通过将提取管67插入混合容器66来完成,如图1中所示。如果混合容器66是加压的,如前所述,气体前体55的压力可以用来迫使气体前体填充脂质体77由混合容器66经导管70导入提取容器76。混合容器66不加压的情况下,提取容器76可与真空源58(如真空泵)经导管78相连,这样产生足够的负压将泡沫73吸入提取容器76,如图1中所示。由提取容器76,气体前体填充的脂质体77被导入管形瓶82,于其中它们可以送往最终用户。加压气体前体56源可与提取容器76相连以帮助喷注气体前体填充的脂质体。由于负压会导致增加气体前体填充脂质体的大小,优选用正压移出气体前体填充的脂质体。
为获得基本上均一大小的气体前体填充的脂质体,可以进行过滤。在某些优选实施方案中,过滤装配含有多于一个过滤器,且优选,过滤器不是紧密地相互连接,如图4中所示。过滤前,气体前体填充脂质体大小范围从约1微米至大于60微米(图5A和6A)。经单个过滤器过滤后,气体前体填充的脂质体通常小于10微米但仍存在大到25微米的颗粒。经二个过滤器(10微米接着8微米过滤器)过滤后,几乎所有的脂质体小于10微米,且大多数为5至7微米(图5B和6B)。
如图1中所示,过滤可以通过将过滤器元件72直接并入提取管67的末端来完成,这样就只有低于预定大小的气体前体填充脂质体从组合容器66中提取。另外,或除提取管过滤器72外,气体前体填充脂质体筛分可以通过将过滤器80并入将气体前体填充脂质体77由提取容器76导入管形瓶82的导管79来完成,如图1中所示。过滤器80可含有阶式过滤器装配124,如图4中所示的。示于图4中阶式过滤装配124包含二个连续过滤器116和120,过滤器120置于过滤器116上游。优选实施方案中,上游过滤器120是-“NUCLEPORE”10μm过滤器,下游过滤器116是-“NUCLEPORE”8μm过滤器。二个0.15mm金属网盘115最好安置在过滤器116的两面。优选实施方案中,过滤器116和120由特氟隆TMO型圈118分隔最小150μm。
除过滤外,筛分也可以利用气体前体填充脂质体浮力对大小的依赖来完成。气体前体填充脂质体具有适宜的低于水的密度,因此会浮于混合容器66的顶部。由于最大的脂质体具有最小的密度,它们将最快浮到顶部。最小的脂质体通常最后升至顶部,而非气体前体填充脂质体将沉至底部。该现象可以利用来通过经由不同浮力的过程将气体前体填充脂质体从混合容器66移出来筛分之。因而,提取管67在混合容器66中垂直位置的设定可以控制提取的气体前体填充脂质体大小;管越高,提取的气体前体脂质体越大。然而,通过定时或不断调节提取管67在混合容器66中的垂直位置,提取的气体前体填充脂质体的大小可以在不断进行的基础上控制。这种提取可由并入装置68而方便化,装置68是与连在提取管67上的螺纹套管72匹配的螺纹箍71,这使得提取管67在提取容器66中的垂直位置得以准确调节。
凝胶态振荡气体前体注入过程本身也可用来气体前体填充类脂基微球体体的筛分。通常,振荡能量的强度越高,所得的气体前体填充脂质体的大小就越小。
本发明也包括制备分发给最终用户的含药物气体前体填充脂质体的新方法。一旦气体前体填充的脂质体形成了,其通常不可以在会引起破裂的温度下加热灭菌。因此,希望由灭菌成分形成气体前体填充脂质体,且随后的操作尽可能的少,以避免污染的危险。根据本发明可以如下完成,例如,在振荡前将含类脂和水溶液的混合容器灭菌,并将气体前体填充脂质体由混合容器66,经提取容器76,直接分发入消毒注射器100的注射套管104,示于图2中,而无进一步加工或处理;即,无随后灭菌。装有气体前体填充脂质体77并适当包装的注射器100可以分发给最终用户。之后产品无需进一步操作。只需从包装中取出注射器并从注射器针102取下保护罩(未示出)并将针插入患者体内或导管,就可将气体前体填充脂质体施于患者。而且,注射器柱塞106挤压入注射管104时产生的压力会引起最大的气体前体填充脂质体破碎,由此得到筛分的程度,无需过滤。
使用时如需要过滤气体前体填充脂质体,例如因为它们从提取容器76移出时未过滤或需要进一步过滤,注射器100可以装有自己的过滤器118,如图2中所示。当气体前体填充脂质体注射时,由柱塞106的作用造成它们挤过过滤器108,这样导致气体前体填充脂质体被筛分。因而,气体前体脂质体筛分和注入患者可以一步完成。
为了适应在注射器中心盒中的单或双过滤器的使用,需要非标准的带中心盒的注射器。如图3中所示,装过滤器的壳尺寸,直径近1cm至近2cm,长约1.0cm至约3.0cm,带有装过滤器的内经约0.8cm。中心中过滤器盒的异常大尺寸是为适应微球体穿过有足够表面积的中心,以减少需要施于注射器柱塞的压力。这样,当注射时微球体就不会受到异常的大压力源,此压力会引起微球体破裂。
如图3中所示的,阶式过滤器盒110可直接装在注射器112上,由此在使用时可阶式过滤。如图4中所示的,过滤器盒110由并入带阳螺纹的下层凸缘112和带阴螺蚊的阴箍凹形槽114间的阶式过滤器装配124装配。下层凸缘112配有Luer锁,使其易于固定到注射器112上,上层凹形槽114配有针头102。
优选实施方案中,类脂溶液压出过滤器且类脂溶液在振荡前高温灭菌过。一旦气体前体填充脂质体形成,其可以如前所述过滤筛分。形成气体前体填充脂质体前的这些步骤提供不少优点,例如,减少未水合类脂的量并由此提供明显较高的气体前体填充脂质体产率,以及提供可直接施于患者的灭菌气体前体填充脂质体。例如,混合容器如管瓶或注射器可以装有过滤的类脂悬浮液,然后该溶液可在组合容器内灭菌,例如,通过压垫灭菌。气体前体可以注入类脂悬浮液,通过振荡灭菌容器形成气体前体填充脂质体。优选灭菌容器装配有置入的过滤器,这样,气体前体填充脂质体在接触患者前穿过过滤器。
此优选方法的第一步,将类脂溶液压过过滤器,通过裂解干类脂和更大表面积的水合作用减少了未水合类脂的量。优选,过滤器具有孔径约0.1至约5μm,更优选约0.1至约4μm,甚至更优选,约0.1至约2μm,且甚至更优选,约1μm,最优选0.22μm。如图7中所示,当类脂悬浮液过滤时(图7B),与未先过滤的类脂悬浮液相比(图7A),未水合的类脂量减少。未水合类脂表现为不均一大小的无形块,是不希望的。
第二步,灭菌,提供可易于施于患者的组合物。优选,灭菌通过热灭菌来完成,优选,将溶液在至少约100℃高压灭菌,且更优选,在约100℃至约130℃高压灭菌,甚至更优选,约110℃至约130℃,甚至更优选,约120℃至约130℃,且最优选130℃。优选加热进行至少约1分钟,更优选,约1至约30分钟,甚至更优选,约10至约20分钟,且最优选,约15分钟。
当灭菌以不引起气体前体填充脂质体破裂温度下的热灭菌的方法进行时,灭菌可以在形成气体前体填充脂质体之后进行,且是优选的。例如,γ射线可以采用在气体前体填充脂质体形成前和/或后。
气体前体的灭菌可以通过穿过0.22μm过滤器或更小的过滤器,在水介质中乳化之前完成。经内含物的灭菌过滤直接入含有预定量的灭菌的和灭菌填充的含水载体的管瓶,这点可很容易地完成。
图8说明气体前体填充脂质体在130℃高压灭菌15分钟,接着涡旋10分钟后成功形成的能力。再则,压出和灭菌程序后,振荡步骤产生气体前体脂质体,极少至无残留无水类脂相。图8A显示高压灭菌后但在过滤前产生的气体前体填充脂质体,结果是许多气体前体填充脂质体具有大小10μm的大小。图8B显示经10μm“NUCLEPORE”过滤器过滤后的气体前体填充脂质体,结果得到10μm左右的均一大小。
制备气体前体填充类脂微球体可以采纳用的材料包括任一种本领域熟练技术人员已知的适合于脂质体制备的材料或其组合物。在其沸点经历由液态向气态相转变的气体前体可用于本发明。所用的类脂可以是天然或合成来源。选用特定的类脂以适合所需属性,最大血清稳定性的短血浆半衰期与长血浆半衰期。某些类脂对特定的应用会更有效,当气体前体填充类脂微球体破裂时,含有的治疗化合物被释放。
气体前体填充脂质体中的类脂可以是单个双层或多片双层的形式,且优选多片的。
可被温度活化的气体前体在本发明中是有用的。表II列出在接近正常体温(37℃)经历由液态向气态相转变的气体前体和需要形成具有10μm大小的微球体的乳化滴大小。表列由潜在的气体前体组成,它们可以用来形成限定大小的温度活化的含气体前体的脂质体。该表列无论如何不构成限定,而只用为本发明方法的可能性。
表II
气体前体的物理特性和形成10μm微球体体的乳化滴直径
化合物 | 分子量 | 沸点(℃) | 密度 | 形成10微米微球体体的乳化滴在径(μm) |
1-氟丁烷 | 76.11 | 32.5 | 6.7789 | 1.2 |
2-甲基丁烷(异戊烷) | 72.15 | 27.8 | 0.6201 | 2.6 |
2-甲基-1-丁烷 | 70.13 | 31.2 | 0.6504 | 2.5 |
2-甲基-2-丁烷 | 70.13 | 38.6 | 0.6623 | 2.5 |
3-甲基-1-丁烯-3-炔 | 66.10 | 34.0 | 0.6801 | 2.4 |
3-甲基-1-丁炔 | 68.12 | 29.5 | 0.6660 | 2.5 |
全氟甲烷 | 88.00 | -129 | 3.034 | 3.3 |
全氟乙烷 | 138.01 | -79 | 1.590 | 1.0 |
全氟丁烷 | 238.03 | 3.96 | 1.6484 | 2.8 |
全氟戊烷 | 288.04 | 57.73 | 1.7326 | 2.9 |
八氟环丁烷 | 200.04 | -5.8 | 1.48 | 2.8 |
十氟丁烷 | 238.04 | -2 | 1.517 | 3.0 |
六氟乙烷 | 138.01 | -78.1 | 1.607 | 2.7 |
十氟戊烷 | 288.05 | 29.5 | 1.664 | 2.9 |
八氟-2-丁烯 | 200.04 | 1.2 | 1.5297 | 2.8 |
全氟环丁烷 | 200.04 | -5.8 | 1.48 | 2.8 |
八氟环戊烯 | 212.05 | 27 | 1.58 | 2.7 |
全氟环丁烯 | 162 | 5 | 1.602 | 2.5 |
*来源:Chemical Rubber Company Handbook of Chemistryand Physics Robert C.Weaot和Devid R.Lide编,CRC Press,Inc.Boca Raton,Florida(1989-1990)。
气体前体的实例决不限于表II。事实上,对于各种不同的应用,实际上只要经过适宜的活化温度能经受至气相的相转变,任何液体都可以用作气体前体。可以使用的气体前体的实例包括,但决不限于: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-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;1-丁烯;2-丁烯;2-甲基-丁烯;3-甲基-1-丁烯;全氟-1-丁烯;全氟-2-丁烯;1,4-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;全氟环丁烯;3-氯-环丁烯;全氟乙烷;全氟丙烷;全氟丁烷,全氟戊烷;全氟己烷;环丙烷;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;二乙炔;3-乙基-3-甲基二氮丙啶;1,1,1-三氟重氮基乙烷;二甲胺;六氟二甲胺;二甲基乙胺;双-(二甲基膦)胺;2,3-二甲基-2-降冰片烷;全氟二甲胺;氯化二甲基氧鎓;1,3-二氧戊烷-2-酮;全氟化碳如却不限于4-甲基-1,1,1,2-四氟乙烷;1,1,1-三氟乙烷;1,1,2,2-四氟乙烷;1,1-二氯乙烷;1,1-二氯-1,2,2,2-四氟乙烷;1,1,2-三氯-1,2,2-三氟乙烷;1,1-二氟乙烷;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;二氯三氟乙烷;氟代乙烷;六氟乙烷;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;三氟甲基磺酰氯;三氟甲亚磺酰氟;(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;disilano甲烷;氟甲烷;碘甲烷;碘三氟甲烷;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;二甲硫醚;甲基乙烯醚;氩;新戊烷;氮气(N2);氧氧化氮;1,2,3-十九烷三羧基-2-羟基三甲基酯;1-壬烯-3-炔;氧气(O2);1,4-戊二烯;正戊烷;全氟戊烷;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;四氯邻苯二甲酸;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;乙烯醚;氙;氮气;空气和其它环境气体。
本发明优选的气体为全氟化碳,氟气,全氟甲烷;全氟乙烷,全氟丁烷,全氟戊烷,全氟己烷;更优选全氟乙烷,全氟丙烷和全氟丁烷;最优选全氟丙烷和全氟丁烷,由于全氟化气体越是惰性就越无毒性。
本发明的微球体体包括但不限于脂质体,类脂包衣物,乳液和聚合物。
用来制造类脂微球体体的类脂类包括但不限于:类脂类如脂肪酸,溶类脂类,带饱和和非饱和类脂的磷脂酰胆碱包括二油酰磷脂酰胆碱;二肉豆蔻酰磷脂酰胆碱;双十五酰磷脂酰胆碱;二月桂酰磷脂酰胆碱;二棕榈酰磷脂酰胆碱;二硬脂酰磷脂酰胆碱;磷脂酰乙醇胺如二油酰磷脂酰乙醇胺;磷脂酰丝氨酸;磷脂酰甘油;磷脂酰肌醇;鞘脂类如鞘磷酯;糖脂如神经节苷脂GM1和GM2;糖脂(glucolipids);硫苷脂;糖基鞘脂;磷脂酸;棕榈酸;硬脂酸;花生四烯酸;油酸;承载聚合物如聚乙二醇,几丁质,透明质酸或聚乙烯吡咯烷酮的类脂类;承载类脂的磺化单、双、寡或聚糖的类脂类;胆甾醇,胆甾醇硫酸酯和胆甾醇半琥珀酸酯;生育酚半琥珀酸酯,带醚和酯连接脂肪酸的类脂类,聚合的类脂类,二乙酰基磷酸酯,硬脂胺,心磷脂,带6-8个碳长度的短链脂肪酸的磷脂,带不对称酰链的合成磷脂(例如,带一个6个碳的酰链和另一个12个碳的酰链),6-(5-胆甾烯-3β-基氧)-1-硫代-β-D-吡喃半乳糖苷;二半乳糖二甘油酯;6-(5-胆甾烯-3β-基氧)己基-6-氨基-6-去氧-1-硫代-β-D-吡喃半乳糖苷,6-(5-胆甾烯-3β-基氧)己基-6-氨基-6-去氧-1-硫代-α-D-吡喃甘露糖苷,12-(((7′-二乙基氨基香豆素-3-基)羰基)甲基氨基)-十八酸;N-[12-(((7′-二乙基氨基香豆素-3-基)羰基)甲氨基)十八酰基)]-2-氨基棕榈酸;4′-三甲铵丁酸胆甾烯酯;N-琥珀酰二油酰磷脂酰乙醇胺;1,2-二油酰-Sn-甘油;1,2-二棕榈酰-Sn-3-琥珀酰甘油;1,3-二棕榈酰-2-琥珀酰甘油;1-十六基-2-棕榈酰甘油磷酰乙醇胺;和棕榈酰高半胱氨酸;和/或其组合物。脂质体可以形成单层或双层和可有或没有包衣。
承载类脂的亲水聚合物如聚乙二醇(PEG),包括但不限于PEG,2000MW,5,000MW,和PEG,8,000MW,对改善气体前体填充脂质体的稳定性和大小分布特别有用。PEG化的类脂的各种不同的摩尔比,例如承载二棕榈酰磷脂酰乙醇胺(DPPE)的PEG,5000MW也是有用的;优选8个摩尔百分数的DPPE。对包入气体前体非常有用的优选产品含有83个摩尔百分数的DPPC,8个摩尔百分数的DPPE-PEG5,000MW和5个摩尔百分数的二棕榈酰磷脂酸。
此外,用来制造混合体系的化合物的实例包括,但决不限于,溴化月桂基三甲基铵(十二基-),溴化鲸蜡基三甲基铵(十六基-),溴化肉豆蔻基三甲基铵(十四基-),氯化烷基二甲基苄基铵(烷基=C12,C14,C16),溴化/氯化苄基二甲基十二烷基铵,溴化/氯化苄基二甲基十六烷基铵,溴化/氯化苄基二甲基十四基铵,溴化/氯化鲸蜡基吡啶鎓。同样,全氟化碳类如五氟十八基碘,全氟辛基溴(PFOB),全氟萘烷,全氟dodecalin,全氟辛基碘,全氟三丙胺,和全氟三丁胺。全氟化碳类可以包埋在脂质体或稳定于乳液中,如本领域所熟知的,如美国专利4,865,836。类脂意浮液的上述实施也可以通过压热而灭菌却不明显改变悬浮液的大小。
如果需要,可采用阴离子或阳离子类脂来结合阴离子或阳离子药物。阳离子类脂可用来结合DNA和RNA类似物于气体前体填充脂质体的表面内或上。可采用各种类脂如DOTMA,N-[1-(2,3-二油酰氧)丙基]-N,N,N-三甲基铵氯化物;DOTAP,1,2-二油酰氧-3-(三甲基铵)丙烷;和DOTB,1,2-二油酰-3-(4′-三甲基铵)丁酰-Sn-甘油。通常,脂质体中阳离子类脂与非阳离子类脂的摩尔比可以是,例如,1∶1000,1∶100,优选,2∶1至1∶10间,更优选在1∶1至1∶2.5的范围内,且最优选1∶1(阳离子类脂的摩尔量与非阳离子,如DPPC摩尔量的比)。当阳离子类脂用来构建微球体时,品种繁多的类脂可包含非阳离子类脂。优选,此非阳离子类脂是二棕榈酰磷脂酰胆碱,二棕榈酰磷脂酰乙醇胺或二油酰磷脂酰乙醇胺。如上所述作为阳离子的替代,承载类脂的阳离子聚合物如聚丝氨酸或聚精氨酸也可用来构建微球体,并提供负电荷治疗剂如遗传物质与微球体外部的结合。此外,负电荷类脂可用来,例如,结合正电荷治疗化合物。磷脂酸,一种负电荷类脂,也可用来配合DNA。这是非常令人惊奇的,因为在这之前,通常认为需要正电荷类脂来结合遗传物质于脂质体上。脂质体中5至10个摩尔百分数的磷脂酸改善气体前体填充脂质体的稳定性和大小分布。
本发明还包含与本发明实质一致的对本领域熟练技术人员而言是显而易见的其它有用类脂类或其组合物。例如,承载碳水化合物的类脂可用于体内靶定闰,如美国专利4,310,505中所述的,其公开全部并入本文作为参考。
最优选类脂为磷脂,优选DPPC和DSPC,且最优选DPPC。
可用来产生气体前体填充微球体的饱和和不饱和脂肪酸优选包括,但不限于具有12个碳原子到22个碳原子间的直链或支链形式的分子。可以采用的饱和脂肪酸的实例包括,但不限于,月桂酸,肉豆蔻酸,棕榈酸,和硬脂酸。可以采用的不饱和脂肪酸的实例包括,但不限于月桂烯酸,肉豆蔻脑酸,抹香鲸酸,棕榈油酸,岩芹酸和油酸。可采用的支链脂肪酸的实例包括,但不限于,异月桂酸,异肉豆蔻酸,异棕榈酸,和异硬脂酸和类异戊二烯。
通过用作将阳离子聚合物固定入包围气体前体的类脂层的一个或多个烷基或甾醇基,阳离子聚合物可以结合到类脂层。可以这种方式使用的阳离子聚合物包括,但不限于,聚丝氨酸和聚精氨酸及其类似物如聚高精氨酸或聚高丝氨酸。阳离子类脂和阳离子聚合物,或承载全氟烷基化基团的阳离子的正电荷基团,例如,可用来配合负电荷分子如遗传物质的磷酸糖类,因而将此物质结合到气体前体填充脂质体球的表面。例如,可采用双亲全氟烷基化二吡啶的阳离子类似物,如Garelli和Vierling在Biochim、Biophys、Acta,1992,1127,41-48中所描述的,其公开全部并入本文作为参考。另外,例如,负电荷分子可通过酯,酰胺,醚,二硫或硫脂键直接结合到类脂的首基。
生物活性材料,如肽或蛋白质,可以掺入类脂层,假定肽具有充分的亲脂性或可以用烷基或甾醇基衍生而连接于类脂层。负电荷肽可用上述阳离子类脂或聚合物相连。
一种或多种乳化或稳定剂可与气体前体一块包括以配制成温度活化的气体前体填充微球体。这些乳化/稳定剂的目的是双重的。首先,这些试剂帮助保持气体前体填充微球体的大小。如上面提到的,这些微球体的大小通常影响结果充气微球体的大小。其次,乳化和稳定剂可用来包衣或稳定由前体得的微球体。稳定含对照试剂微球体是使体内对照效果最大所需的。虽然稳定微球体是优选的,但这不是绝对需要的。因为由这些气体前体得到的充气微球体比空气稳定,它们仍可以设计来提供增强有用的对照;例如,外围静脉注射后它们穿过肺循环,即使未由一或多种包衣或乳化剂特别地稳定。一或多种包衣或稳定剂优选是柔性材料。用聚糖,神经节苷脂和聚合物稳定的气体微球体比用清蛋白和其它蛋白稳定的更有效。用脂族化合物制备的脂质体是优选的,因为用这些化合物稳定的微球体对压力变化更有柔性和更稳定。
类脂溶液或气体前体填充脂质体可以例如添加品种繁多的粘度改善剂来稳定。粘度改善剂包括,但不限于碳水化合物及其磷酰化和磺化衍生物;聚醚类,优选分子量范围为400与8000之间;二和三羟基烷烃及其聚合物,优选分子量范围为800和8000之间。甘油,丙二醇,聚乙二醇,聚乙烯吡咯烷酮,和聚乙烯醇也可用作本发明的稳定剂。多孔或半固体颗粒如羟磷灰石,金属氧化物和凝胶的共沉淀物如透明质酸与钙也可以用来配制芯或胞窝来稳定气体前体。
乳化和/或稳定剂也可用来与类脂或脂质体结合。这些试剂包括,但不限于阿拉伯胶,胆甾醇,二乙醇胺,甘油单硬脂酸酯,羊毛脂醇,卵磷脂,单和双甘油酯,单乙醇胺,油酸,油醇,泊拉沙姆,聚氧乙烯50硬脂酸酯,聚氧乙烯蓖麻油,聚氧乙烯10油基醚,聚氧乙烯20鲸蜡基硬脂基醚,聚氧乙烯40硬脂酸酯,聚山梨酸酯20,聚山梨酸酯40,聚山梨酸酯60,聚山梨酸酯80,丙二醇二乙酸酯,丙二醇单硬脂酸酯,月桂基硫酸钠,硬脂酸钠,失水山梨醇单月桂酸酯,失水山梨醇单油酸酯,失水山梨醇单棕榈酸酯,失水山梨醇单硬脂酸酯,硬脂酸,三乙醇胺,和乳化蜡。所有的带全氟脂肪酸的类脂作为类脂成分可用来替代植物或动物来源类脂中的饱和或饱和烃脂肪酸。可与类脂或脂质体溶液一起使用的悬浮和/或增粘剂包括但不限于,阿拉伯胶,琼脂,藻酸,单硬脂酸钻,膨润土,糖糊,carbomer 934P,羟甲基纤维素,钙和钠和钠12,甘油,鹿角胶,纤维素,糊精,白明胶,瓜尔胶,羟乙基纤维素,羟丙基甲基纤维素,硅酸镁铝,甲基纤维素,果胶,聚环氧乙烷,聚乙烯醇,聚乙烯吡咯烷酮,聚丙二醇,藻酸酯,二氧化硅,藻酸钠,黄蓍胶,和黄原胶。本发明优选产品以8∶1∶1或9∶1∶1比率的生理盐水∶甘油∶丙二醇混合溶剂体系掺入类脂。
本发明的气体前体填充脂质体优选包含不渗透材料。不渗透材料定义为在典型贮存条件下不允许大量脂质体内含物通过的材料。大量定义为大于约50%的内含物,内含物为包囊于脂质体内部的气体和其它成分,如治疗剂。在贮存期间和施用于患者前,优选,不大于约25%的气体被释放,更优选,大不于约10%的气体被释放,最优选不大于约1%的气体被释放。
业已发现,气体前体填充脂质体的气体不透性至少部分地与凝胶态向液晶态相转变温度有关。通常认为,在给定的温度下,凝胶态向液晶态相转变温度越高,脂质体就越是气体不渗。饱和二酰基-Sn-甘油-3-磷酰胆碱的主要链熔解转变,参见上表I和Derek Marsh,CRC Handbook of LiguidBilayers(CRC Press,Boca Raton,F1 1990)的第139页。然而,应当指出,通常可用较少的能量,就可将治疗化合物从由有较低凝胶态向液晶态相转变温度类脂组成的气体前体填充脂质体中释放出来。
在某些优选实施方案中,类脂的相转变温度高于类脂要施于的患者的体温。例如,对于施于人体,优选具有相转变温度高于37℃的类脂。通常,微球体具有凝胶态向液态相转变温度高于约20℃就足够了,且优选带有相转变温度高于约37℃的那些。
优选的实施方案中,由本发明方法制备的脂质体是稳定的。稳定性定义为对由形成直至超声应用时破裂的抗性。为稳定可选用用来构建微球体的类脂。例如,由DSPC(二硬脂酰磷脂酰胆碱)组成的气体前体填充脂质体比由DPPC(二棕榈酰磷脂酰胆碱)组成的气体前体填充脂质体稳定,而它们转而又比由蛋磷脂酰胆碱(EPC)组成的气体前体填充脂质体更稳定。优选,由形成直至超声应用时不大于约50%的脂质体破裂,更优选不大于约25%的脂质体破裂,甚至更优,不大于约10%的脂质体,且最优选,不大于约1%的脂质体。
主题脂质体在贮存期比由已知方法如压力法或其它技术生产的其它充气脂质体具有更大的气体不渗透性和稳定性。形成72小时后,例如,常规制备的脂质体通常基本上没有气体,气体扩散出脂质体和/或脂质体破裂和/或融合,导致反射性的伴随损失。与之相比,保存在水溶液中的本发明气体前体填充脂质体通常具有长于约三个星期的贮存期稳定性,优先长于约四星期的贮存期稳定性,更优选长于约五星期的贮存期稳定性,甚至更优选长于约三个月的贮存期稳定性,且通常贮存期稳定性甚至更长,如长于六个月,十二个月,或甚至二年。
此外,业已发现本发明的气体前体填充脂质体可以用共价连于聚乙二醇的聚合物的类脂(通常称作PEG化的类脂)来稳定。还发现将至少小量的负电荷类脂掺入任何脂质体膜,虽然不是必需的,但有利于提供不趋向于由聚合而破裂的脂质体。至少小量是指占总类脂量的约1至约10个摩尔百分比。适合的负电荷类脂,或含净负电荷的类脂,对本领域熟练技术人员是显而易见的,且包括,例如,磷脂酰丝氨酸,磷脂酰甘油,磷脂酸,和脂肪酸。由二棕榈酰磷脂酰胆碱制备的脂质体是最优选的,因为除其释放期稳定性外,它们是为其共振频率超声,射频能,(例如,微波)和/或致回波性应用时破裂的能力而选择的。
再则,本发明脂质体优选在血管系统中足够稳定,这样它们就可以承受再循环。气体前体填充脂质体可以包衣,这样被网状内皮组织吸收减至最小。有用的包衣物包括,例如,神经节苷,葡糖苷酸,半乳糖醛酸,葡糖醛酸,聚乙二醇,聚丙二醇,聚乙烯吡咯烷酮,聚乙烯醇,糊精,淀粉,磷酰化和磺化单、双、三寡和聚糖和白蛋白。脂质体也可为如避免被免疫系统识别的目的而包衣。
所用的类脂也优选最柔性的。柔性,如气体前体填充脂质体的上下文中定义的,是结构改变其形态,例如,以穿过大小小于脂质体的开孔的能力。
假定脂质体的循环半衰期足够长,当流经人体时,脂质体通常将流经靶组织。因此,通过将声波集中于要治疗的选择组织时,治疗剂会在靶组织当地释放。为进一步帮助击中靶标抗体,碳水化合物,肽、糖肽、糖脂,外源凝集素,和合成和天然聚合物也可以掺入脂质体的表面。其它的用于击中目标的帮助包括聚合物如聚乙烯醇,聚乙烯吡咯烷酮,和聚乙烯醇,其可以由磷脂的烷基化,酰化,甾醇基或衍化首基掺入表面。磷脂如二油酰磷脂酰二乙醇胺(DOPE),二棕榈酰磷脂酰乙醇胺,或二硬脂酰磷脂酰乙醇胺(DSPE)。肽、抗体,外源凝集素,糖肽,寡核苷酸,和糖共轭物也可掺入气体前体填充类脂球的表面。
在某些优选实施方案中,作为对气体前体注入方法以及保持气体前体填充脂质体稳定性的帮助,例如,可加乳化剂于类脂中。乳化剂实施例包括,但不限于,甘油,鲸蜡醇,山梨醇,聚乙烯醇,聚丙二醇,丙二醇,乙醇,月桂基硫酸钠,Laureth 23,聚山梨醇酸酯(所有单体),所有饱和和不饱和脂肪酸,三乙醇胺,吐温20,吐温40,吐温60,吐温80,聚山梨醇酸20,聚山梨酸酯40,聚山梨酸酯60,和聚山梨酸酯80。
对于使用前的贮藏,本发明脂质体可以悬浮于水溶液中,如盐水(例如,磷酸盐缓冲的盐水溶液),或单是水,且优选贮存在约2℃至约10℃间的温度下,优选约4℃下。优选,水是经灭菌的。
典型的贮存条件是,例如,未除气的0.9%NaCl水溶液在4℃下保存48小时。贮存温度优选低于形成脂质体材料的凝胶态向液晶态的相转变温度。
最优选,脂质体贮存在等渗盐水溶液,虽然如果需要,盐水溶液可以是低渗的(例如,约0.3至约0.5%NaCl)。如果需要,溶液也可以缓冲以提供约pH7的pH范围。适合的缓冲物包括,但不限于,乙酸盐,柠檬酸盐,磷酸盐,碳酸氢盐,和磷酸盐缓冲的盐水,5%葡萄糖,和生理盐水(通常)。
抑菌剂也可与脂质体一起包括以防止贮存期的细菌降解。适合的抑菌剂包括但不限于,苯扎氯铵,苄索氯铵,苯甲酸,苯甲醇,羟苯丁酯,氯化十六基吡啶鎓,氯丁醇,氯甲酚,羟苯甲酯,苯酚,苯甲酸钾,山梨酸钾,苯甲酸钠和山梨酸。
本文中用的“充气”是指脂质体具有至少约10%气体的内体积,优选至少约25%气体,更优选至少50%气体,甚至更优选至少约75%气体,最优选至少约90%气体。本领域熟练技术人员可以理解。一旦得到本公开,也可以使用气体前体,接着激活以形成气体。
各种生物相容的气体可以用于本发明的充气脂质体中。这些气体包括空气,氮气,二氧化碳,氧气,氩,氟,氙,氦,或其任何和所有组合物。一旦得到本公开,其它适合气体对本领域熟练技术人员是显而易见的。例如,在含有环境气体(如空气)的封闭环境中,在气体前体向气体转变期间,两种气体可以混合,并且当搅拌和形成微球体时,微球体的气体内含物导致两种或多种气体的混合物,取决于混合气体的密度。
本发明脂质体的大小取决于预定的目的。较小的脂质体的共振频率超声通常会比较大的脂质体高。筛分也可用作调整所得脂质体生物分布和消除。除过滤外,如需要,脂质体的大小可以本领域已知的方法调节,如挤压,声处理,匀浆,导入液体不互混鞘的液体芯的层流的使用。参见,例如,美国专利4,728,578;英国专利4,737,323,US4,728,575;US4,737,323;国际专利申请PCT/US85/01161;Mayer等,Biochimica et Biophysica Acta 1986,858,161-168,Hope等,Biochimica et Biophysica Acta 1985,812,55-65;美国专利4,533,254;Mayhew等,Methods in Enzymology 1987,149,64-77;Mayhew等,Biochimica et Biophysica Acta 1984,755;169-74;Cheng等,Investigative Radiology 1987,22,47-55;PCT/US 89/05040;美国专利4,162,282,美国专利4,310,505;美国专利4,921,706;和Liposomes Technology,Gregoriadis,G.编,Vol.I.29-37,51-67和79-108dmu(CRC Press Inc.Boca Raton,FL.1984)。上述专利,文件和专利申请的各个公开均全部并入本文作为参考。压力下经给定大小的孔的压出是调节脂质体大小的优选方法。
由于脂质体大小影响生物分布,不同大小的脂质体可以选作不同的目的。例如,血管内使用,优选的大小范围是平均外径在约30纳米和约10微米间,优选的平均外径为约5微米。
更具体地说,对于静脉使用,脂质体的大小优选平均外径约10μm或更小,且优选小于约7μm,更优选不小于平均外径5纳米。优选脂质体平均外径不小于约30纳米。
为提供治疗剂传递至器官如肝和使肺瘤与正常细胞不同,优选较小的在约30纳米剂约100纳米平均外径间的脂质体。
为柱塞组织如肾或肺,脂质体优选小于约200微米平均外径。
对于鼻内、直肠内或表面施药,微球体优选小于约100微米平均外径。
大的脂质体,例如,大小在1和10微米间的,通常限于血管空间,直至它们被衬在血管内的吞噬细胞单元清除,如衬于毛细胞窦状腺的巨噬细胞和Kappfer细胞。为通达至窦状隙外的细胞,可以采用较小的脂质体,例如小于约300纳米的大小。
脂质体的给药途径依预期的使用而定。正如本领域熟练技术人员能认识的,本发明治疗剂传递系统施药可以各种方式进行,如血管内,淋巴内,非肠道,皮下,肌内,鼻内,直肠内,腹膜内,间质,经雾化器入气道,高压、经口、局部,或肿瘤内。使用各种剂量形式。优选的给药途径是静脉内,对于血管内使用,治疗剂传递系统通常静脉内注射,但也可动脉内注射。本发明脂质体也可以间质注射或注入任何体腔。
采用超声由本发明脂质体释放治疗剂特别适合于具有超声能传送良好声窗的组织。体内的大多数组织均是这种情况,如肌肉,心脏,肝和大多数其它主要结构。脑中,为引导超声能穿过颅骨,需要一外科手术孔。对于无声窗的身体部分,例如骨,优选射频能或微波能。
此外,本发明特别有用于将治疗剂传递于患者的肺。本发明的气体前体脂质体比例如常规的液体填充脂质体轻,后者常沉淀在中心近侧气道而不是抵达肺的本末梢区域。因此认为本发明的气体前体填充脂质体可改善治疗化合物向肺的末梢区域包括末端气道和肺泡的释放。对于施于肺,气体前体填充脂质体可由例如雾化使用。
截留2CC空气的脂质体(类脂=83%DPPC/8%DPPE-PEG5,000/5%DPPA)空气装入雾化器中并雾化。雾化后的所得脂质体,大小为1至2微米左右并显现出漂浮于空气中。这样大小的颗粒对于远距离传递药物,肽、遗传物质和其它治疗化合物入肺(即末端气道和肺泡)是理想的。因为充气脂质体几乎与空气一样轻,比常规水填充脂质体轻得多,它们在空气中漂浮较长,且由此更好地释放化合物入末端肺。当DNA加入这些脂质体时,它易于吸收或结合到脂质体上。因而,被气体和气体前体填充的脂质体和微球体对于肺药物释放具有巨大的潜力。
在如以肺作靶体的使用中,肺用类脂衬上随着类脂衬于靶组织,气体前体填充的脂质体聚集,治疗剂可以被释放。此外,不使用超声,给药后气体前体填充脂质体也可以进裂。因此,上面类型的给药中无需使用超声来释放药物。
再则,本发明的气体前体填充脂质体对在水介质中或暴露于氧和/或大气时降解的治疗剂特别有用。例如,脂质体可以用惰性气体如氮气或氩气填充,与不稳定的治疗化合物一起使用。此外,气体前体填充脂质体可用惰性气体填充并用来包囊不稳定治疗剂,用于通常会造成治疗剂暴露于大气的患者的部位,如皮肤和眼科使用。
气体前体填充的脂质体对经皮传递如膏药传递体系,也特别有用。破裂超声的使用可增加治疗化合物的经皮传递。再则,器械可用来监视和调整药物传递。例如,诊断超声可用来可视监控气体前体填充脂质体的进裂和调整药物传递和/或水听器可用来监察气体前体填充脂质体的进裂和调整药物传递。
在优选实施方案中,充气脂质体是以单个颗粒的赋形剂给药,与包埋入聚合物基质用于控释的目的正好相反。
对于体外使用,如细胞培养使用,气体前体填充脂质体可以加到培养物的细胞中,然后培养。随后声能、微波或热能(例如简单加热)可以用于含细胞和脂质体的培养基。
通常,本发明的治疗剂传递系统以水悬浮液的形式给药,水悬浮液如水的或盐水溶液(例如磷酸盐缓冲的盐水)的悬浮液。优选,水是经灭菌的。也优选盐水溶液是等渗盐水溶液,虽然如果需要,盐水溶液可以是低渗的(例如,约0.3至约0.5%NaCl)。如果需要,盐水溶液也可以是缓冲的以提供约pH5至约pH7.4的pH范围。此外,葡萄糖最好包括在培养基中。可用于施用气体前体填充脂质体的其它溶液包括,但不限于,杏仁油,玉米油,棉籽油,油酸乙酯,肉豆蔻酸异丙酯,棕榈酸异丙酯,矿物油,肉豆蔻醇,辛基十二醇,橄榄油,花生油,桃仁油,芝麻油,大豆油,角鲨烯,肉豆蔻基油酸酯,鲸蜡基油酸酯,肉豆蔻基棕榈酸酯,以及其它酯化于烷基链脂肪酸(C=2-22)的饱和和不饱和烷链醇(C=2-22)。
施用的气体前体填充微球体的有用剂量和施用方式取决于年龄,体重,和要治疗的哺乳动物,和预定的具体应用(治疗/诊断)。典型地,剂量以较低量开始并增加直至取得所需治疗效果。
对于超声成像使用,本发明脂质体优选有大于2dB的反射率,更优选约4dB和约20dB间。在此范围内,本发明脂质体最高的反射率是由较大脂质体,较高的脂质体浓度,和/或当较高超声频率采用时显现的。
对于治疗药物传递,脂质体给药于或通过它种方式抵达患者所需治疗的区域后,向该区域使用某种频率的超声,本发明含治疗剂的脂质体的破裂令人惊奇地容易进行。具体地说,业已令人意外地发现,当超声以相应于含治疗剂的气体前体填充脂质体的峰共振频率使用时,脂质体将破裂并释放其内含物。
峰共振频率可以在体内或体外,优选在体内,采用常规方法如下测定:通过将脂质体暴露于超声,收集反射的共振频率信号并分析收集的用来测定峰的信号的图谱。该峰,如以上测定的,相应于峰共振频率(或第二谐波,如有时称谓的)。
优选,本发明脂质体具有约0.5mHz到约10mHz间的峰共振频率。当然,本发明的气体前体填充脂质体的峰共振频率将依外径和,在某种程度上,依脂质体的弹性或柔性而不同。与较小的和更小弹性或柔性的脂质体相比,较大的和更有弹性或柔性的脂质体具有较低的共振频率。
当暴露于与更高强度(瓦数)和更长持续期(时间)组合的非峰共振频率时,含治疗剂的气体前体填充的脂质体也会破裂。然而,这种更高的能量导致大量地增加热量,这或许是不希望的。通过调节能量的频率以匹配峰共振频率,破裂的效率和治疗释放得以改善,适宜的组织加热通常不发生(通常温度不增高约2℃),且需要较少的综合能量。因而,以峰共振频率使用超声,虽然不是必须的,是最优选的。
对于诊断或治疗超声,本发明应用中,任何一种类型的诊断超声图像设备都可以使用,设备的具体的类型式型号对本发明的方法来说不重要。设计来施用超声烘烤的设备也是适合的,这类设备如美国专利4,620,546,4,658,828和4,586,512中所描述的,各专利公开全文并入本文作为参考。优选,设备采用共振频率(RF)谱分析仪。转换器探头可外部或植入使用。超声通常以较低强度和较短持续期开始,然后,强度,时间,和/或共振频率增加直至脂质体在超声上可见(诊断超声应用)或破裂(治疗超声应用)。
虽然各种原理的应用对本领域熟练技术人员是显而易见的,一旦得到本公开,经一般性的引导,对于外径约1.5至约10微米的气体前体填充脂质体来说,共振频率通常在约1至约10兆赫兹范围内。随着气体前体填充脂质体在靶组织内的累积,通过调节聚集区于靶组织(例如肿瘤)的中心,脂质体在真时超声下可视。以使用7.5兆赫曲线排列转换器为例,调节释放于转换器的能量至最大,并调节聚集区于组织内,则空间峰暂时平均(Spatial peak temporal average)(SPTA)能量在水中为最大值,接近5.31mW/cm2。此能量会造成治疗剂从气体前体填充脂质体部分释放,但更大量的释放可以通过使用更强能量来完成。
将转换器开到多普勒方式,可实现更高的能量输出,由同一转换器可达2.5瓦/cm2。转换器以多普勒方式操作,能量可释放至靶组织的选择聚集区且可使气体前体脂质体释放其治疗剂。选择转换器以匹配气体前体填充脂质体的共振频率这种治疗剂释放方法更有效。
对于较大直径的气体前体填充脂质体,例如,大于3微米平均外径,在完成治疗剂释放上,较低频率的转换器会更有效。例如,3.5兆赫的较低频率转换器(20mm曲线排列型)可选用来与气体前体填充脂质体的共振频率一致。采用这种转换器,101.6毫瓦/cm2可以释放到聚集点,且开到多普勒方式,可增加功率输出(SPTA)至1.02瓦/cm2。
对使用气蚀现象来释放和/或活化气体前体填充脂质体内的药物/前药,可以使用较低频率能,由于气蚀在较低频率下更有效地出现。采用由较高电压(高达300伏)驱动的0.757兆赫转换器,气体前体填充脂质体溶液的气蚀在约5.2大气压的阀值下出现。
表III在通常使用的仪器上由诊断超声传送到组织的能量范围,仪器如Piconics Inc.(Tyngsboro,MA)生产的带接收器脉冲1966型661的Portascan通用目的扫描仪;Picker(Cleveland,OH)生产的包括80C System的Echoview 8LScanner或Medisonics(Mountain View,CA)生产的Model D-9 Versatone Bidirectional Dopeler。通常,脉冲重复中采用的能量范围对诊断和监控充气脂质体是有用的,但对于破裂本发明充气脂质体是不够的。
表III
由诊断设备产生的能量和强度*
*数值来源于Carson等的Ultrasound in Med.&Biol.1978,3,341-350-文,其公开全部并入本文作为参考。
脉冲重复率 | 总超声能输出 | 转换器表面的平均强度 |
520 | 4.2 | 32 |
676 | 9.4 | 71 |
806 | 6.8 | 24 |
1000 | 14.4 | 51 |
1538 | 2.4 | 8.5 |
更高能量超声如治疗超声设备中常用的,对于活化含治疗剂的气体前体脂质体是优选的。通常,依据由超声加热的组织区域,治疗超声设备采用多达50%至100%的占空因数(duty cycle)。大量肌肉块的区域(即,背,股)和高度血管化组织如心脏需要较大的空因数,例如100%。
在超声诊断中,要使用一种或多种声波脉冲而且该机器从脉冲到接受反射的声音信号之间要暂停。超声诊断中使用的有限数量的脉冲限制了传递到被成像组织的有效能量。
在超声治疗中,使用连续的超声波来传递高水平的能量。使用本发明的脂质体,声波能量可以是脉冲的,但优选连续的超声波。如果使用脉冲,声波优选一次以至少约8个回声序列长度脉冲,并且优选至少20个脉冲。
可以使用固定的频率或调制的频率。将固定的频率定义为声波的频率在时间段内是恒定的。调制频率则是声波的频率在时间段内是变化的,例如由高到低(PRICH)或电低到高(CHIRP)。例如,声能的起始频率为10MHz的PRICH脉冲偏到1MHz且能量从1增加到5瓦特。总而言之,调制的频率,高的超声能量可在脂质体范围内增加局部体膨胀的速度使其破裂而提供治疗剂的局部释放。
所使用的声波频率可在约0.025到约100兆赫之间变化。优选的频率范围约0.75-3兆赫,最优选的频率范围为约1-2兆赫。通常治疗时可使用约0.75到约1.5兆赫的频率。通常也可使用约3到7.5兆赫的诊断频率。对于很小的质脂体,如低于0.5微米的平均外径,由于这些较小的脂质体在较高的声波频率时更有效地吸收声能,因此优选较高频率的声波。当使用很高的频率时,如超过10兆赫,声能通常会限制渗透到液体和组织的深度。外用可优选皮肤和其它表面组织,但由于深结构,可优选通过组织间隙探针或血管内超声导管来使用声能。
用气体前体填充的脂质体来使递治疗剂时,可将被传递的治疗化合物按需嵌入脂质体的壁中,包囊在脂质体中和/或吸附到脂质体上。本文所使用的与治疗化合物的部位有关的短语“吸附”或其变化形成的意思是指治疗化合物以某种方式连接到微球体的壁的内部和/或外部,如通过共价或离子键或其它化学或电化学键的方式或相互作用的方式连结。本文所使用的与治疗化合物的部位有关的短语“包囊”或其变化形式是指治疗化合物位于微球体内的空隙中。本文所使用的与治疗化合物的部位有关的短语“嵌入”或其变化形式是指治疗化合物位于微球体内壁。短语“含有治疗剂”指以各种形式使治疗剂置于微球体中。因此,治疗剂的位置是可变的,例如,包裹在气体前体填充的微球体内的空隙中,位于气体前体和气体前体填充的微球体内壁之间,结合在气体前体填充的微球体的外表面和/或网在微球体结构本身中。
任何一种治疗剂都可包囊在脂质体中。本文所使用的治疗剂意指对病人具有有益效果的试剂。本文所使用的术语治疗剂与术语对比剂和/或药物是同义的。
可用气体前体填充脂质体传递的药物的实例可包含以传递药物为目的,但不局限于此,激素产品如加压素和催产素及其衍生物,胰高血糖素,和甲状腺剂如碘产品和抗早状腺剂;心血管产品如螯合剂和汞利尿剂和强心甙;呼吸产品如黄嘌呤衍生物(茶碱和氨茶碱);抗感染剂如氨基糖甙,抗真菌剂(二性霉素),青霉素和头孢菌素抗生素,抗病毒剂如合多夫定,利巴韦材,金刚烷胺,阿糖腺苷和阿昔洛韦,抗蠕虫剂(anti-helmintics),抗疟剂和抗结核药物;生物产品如免疫血清,抗毒素和抗蛇毒血清,狂犬病预防产品,细菌疫苗,病毒疫苗,类毒素;抗肿瘤剂如硝基脲nitrosureas,氮芥,抗代谢物(氟尿嘧啶,激素如Progesings和雌激素和抗雌激素);抗生素如放线菌素;有丝分裂抑制剂如依托泊甙和长春生物碱(the vinca alkaloids),放射药物如放射活性碘和磷产品;以及干扰素,羟基脲,甲基苄肼,氮烯咪胺,米托坦,天冬酰胺酶和环孢子菌素。
在气体前体滴注方法中,可将遗传和生物活性物质混入这些脂质体气体前体填充空间内或混入这些颗粒的脂质膜内或脂质膜上。优选结合在这些颗粒的表面上。可将具有高的辛醇/水分配系数的遗传物质和生物活性物质直接混入包裹气体前体的脂质层中但优选结合在气体前体填充脂质体球的表面上。要达到这样的目的,通常需将能结合遗传物质或生物活性物质的基团结合在这些物质的脂质层中。在使用遗传物质(DNA,RNA,单股和双股和反义和有意低聚核苷酸)时,通过使用可混合到干燥类脂起始物质中的阳离子类脂或阳离子聚合物,很容易达到这个目的。
用磷脂酸,例如,用超过5摩尔%和优选约10摩尔%量的二棕榈酰磷脂酸制得的气体填充和气体前体填充脂质体可作为遗传物质高效结合剂而起作用,这是本发明意外的发现。此脂质体强烈地结合DNA。因为在此之前,带正电荷的脂质体被认为是与DNA结合中最有用的。具有5摩尔%到10摩尔%DPPA的脂质体起到高效的保留气体和气体前体结构的作用。结合有磷脂酸的组合对超声诊断是非常强烈的而且对运载DNA以及其它药物是有用的。
据信,某些前体的纤粒、微粒及乳剂在局部缺血组织和疾病组织中的积累是特别有效的。此前体可用于超声检测局部缺血组织和疾病组织,也可用于将药物释放到这些组织中。用含气体前体的乳剂或纤粒包裹药物,所述药物能传递到疾病组织。例如,可用六氟化硫、hesafluoropropylene、溴氯氟甲烷、八氟丙烷、1,1-二氯氟乙烷、六氟乙烷、hesaftuoro-2-butyne、全氟戊烷、全氟丁烷、八氟-2-丁烯或六氟-1,3-丁二烯或八氟环戊烯(27℃)将药物如强心甙、生成血管因子和作用于血管的化合物传递到心肌局部缺血区。类似地,也可用上述前体乳剂将反义DNA或化学治疗剂传递到肿瘤中。要求温度、PH和氧压的微小变化引起疾病组织和局部缺血组织优先积累某些前体。这些前体可用作传递载体或在超声中传递药物。
合适的治疗剂包括但不局限于顺磁气体如空气,它含有痕量的氧17;顺磁离子如Mn+2、Gd+2、FeiO4;氧化铁或磁铁矿(Fe304)并因此可用作磁共振影象(MRI)的敏感性对比剂,不透射线的金属离子如碘、钡、溴或钨(可用作X-射线对比剂)、四极核的气体(gases from quadrupolar nuclei),可具有用作磁共振对比剂的潜力,抗肿瘤剂如铂化合物(如,螺铂、顺铂和卡铂)、氨甲喋呤、氟尿嘧啶、阿霉素、紫杉酚、丝裂霉素、ansamitocin、博来霉素、阿糖胞苷、阿糖腺苷、巯基聚细胞溶素、长春新碱、马利兰、苯丁酸氮芥、苯丙酸氮芥(如,PAM、L-PAM或苯丙氨酸芥子)、疏基嘌呤、米托坦、盐酸丙卡巴肼、放射菌素D(actinmycin D)、盐酸柔红霉素、盐酸阿霉素、丝裂霉素、普卡霉素(mithramycin)、氨鲁米特、雌莫司汀磷酸钠、氟他胺、乙酸亮丙端林、乙酸甲地孕酮、柠檬酸他莫昔芬、睾内酯、曲洛司坦、安吖啶(M-AMSA)、门冬酰胺酶(L-asparaginase)Erwina aspovaginase依托泊甙(VP-16)、干扰素α-2a、干扰素α-2b、替尼泊甙(VM-26)、硫酸博来霉素、氨甲喋呤、阿霉素、和arabinosyl、羟基脲、丙卡巴肼和达卡巴嗪;有丝分裂抑制剂如依托泊甙和长春生物碱(thevinca alkaloids),放射性药物和放射性碘和磷产品;激素如黄体制剂,雌激素和抗雌激素;抗蠕虫剂(anti-helmintics)、抗疟剂和抗结核药;生物制品如免疫血清、抗毒素和抗蛇毒血清,狂犬病预防产品;细菌疫苗;病毒疫苗;氨基糖甙类;呼吸产品如黄嘌呤衍生物荼碱和氨茶碱;甲状腺剂如碘产品和抗甲状腺剂;心血管产品包括螯合剂和汞利尿剂和强心甙;高血糖素;血液产品如非肠道铁剂、氯化血红素、血卟啉及其衍生物;生物应答改良剂如胞壁酰二肽、胞壁酰三肽、微生物细胞壁成分、淋巴细胞活素(如,细胞内毒素如脂多糖、巨噬细胞激活因子)、细菌亚单位(如分枝杆菌、棒状杆菌)、合成的二肽N-乙酰-胞壁酰-L-丙氨酰-D-异谷氨酰胺;抗真菌剂如酮康唑、制霉菌素、灰黄霉素、氟胞嘧啶(5-FC)、咪康唑、两性霉素B、蓖麻素、环孢子菌素和β-内酰胺抗生素(如,sulfazecin);激素如生长激素、促黑素细胞激素、雌二醇、二丙酸氯地米松、倍他米松、醋酸倍他米松和倍他米松磷酸钠、Vetamethasone disodium phosphate、Vetumethasone Sodiumphosphate、醋酸可的松、地塞米松、醋酸地塞米松、地塞米松磷酸钠、9-去氟肤轻松(flunsolide)、氢化可的松、醋酸氢化可的松、氢化可的松环戊丙酸酯、磷酸氢化可的松钠、琥珀酸氢化可的松钠、甲泼尼、泼尼松龙醋酸泼尼松龙、醋酸甲泼泥龙、琥珀酸甲泼尼龙钠、醋酸帕拉米松龙、磷酸泼尼松龙钠、氢化泼尼松特丁酸醋、泼尼松、曲安西龙、曲安奈德、二乙酸曲安西龙、己曲安奈德和醋酸氟氢可的松、缩宫素、加压素及其衍生物;维生素如Cyanocobalamin neinoicacid、retinoids及衍生物如维生素A棕榈酸酯和α-生育酚;肽如超氧化锰二变位酶(manganese Super oxide dimutase);酶如碱性磷酸酯酶;抗过敏剂如amelexanox;抗凝剂如苯丙香豆素和肝素;循环系统药物如心得安;代谢增强剂如谷胱甘肽;抗结核剂如对氨基水杨酸、异烟肼、硫酸缠霉素、环丝氨酸、盐酸乙胺丁醇、乙硫异烟胺、吡嗪酰胺、利福平和硫酸链毒素;抗病毒剂如阿昔洛韦、金刚烷胺、齐多夫定(AZT或azidothgmidine)、利巴韦林和阿糖腺苷一水合物(adenine arabinoside,ara-A);抗心绞痛剂如地尔硫草、硝苯地平、维拉帕米、丁四硝酯、硝酸异山利酯、三硝酸甘油(glyceryl trinitrate)和戊四硝酯;抗凝剂如苯丙香豆素、肝素;抗生素如氨苯砜、氯霉素、新霉素、头孢克洛、头孢羟氨苄、头孢氨苄、头孢拉啶、红霉素、克林霉素、林肯霉素、阿莫西林、氨苄西林、巴安西林、羟苄西林、双氯西林、氨环己西林、picloxaeillin、海他西林、甲氧西林、萘夫西林、苯唑西林、青霉素,包括青霉素G、青霉素V、替卡西林、利福平和四环素;消炎剂如二氟尼柳、布洛芬、吲哚美辛、甲氯芬那盐、甲芬那酸、萘普生、羟布宗、保泰松、吡罗昔康、舒林酸、托美丁、阿斯匹林和水杨酸盐;抗原生动物剂如氯喹、羟基氯喹、甲硝唑、奎宁和锑酸葡甲胺(meglumineantimonate);抗风湿药如青霉胺;麻醉药如复方樟脑酊;鸦片制剂如可待因、海洛因、美沙酮、吗啡和鸦片;强心甙如去乙酰毛花甙、洋地黄毒甙、地高辛、洋地黄甙和洋地黄;神经肌肉阻断剂如阿曲库铵苯磺酸盐、加拉碘铵、乙芴溴铵、碘二甲箭毒、泮库溴铵、氯琥珀胆碱(succinylchaline chloride)、氯化筒箭毒碱和维库溴铵;镇静药(催眠药)如异戊巴比妥、异戊巴比妥钠、阿普比妥、仲丁比妥钠、水合氯醛、乙氯维诺、炔己蚁胺、盐酸氟西泮、格鲁米特、盐酸左美丙嗪、甲乙哌酮、盐酸咪达唑仑、副醛、戊巴比妥、戊巴比妥钠、苯巴比妥钠、司可巴比妥钠、他布比妥、替马西泮和三唑仑;局麻药如盐酸卡因、盐酸氯普鲁卡因、盐酸依替卡因、盐酸利多卡因、盐酸甲哌卡因、盐酸普鲁卡因和盐酸丁卡因;全身麻醉药如氟哌利多、依托咪酯、柠檬酸芬太尼与氟哌利多、盐酸氯胺酮、美索比妥钠和硫喷妥钢;以及放射性粒子或离子如锶、碘化物、铼和钇。
在某些优选的实施方案中,治疗剂为单克隆抗体,如能够与黑素瘤抗原结合的单克隆抗体。
其它优选的治疗剂包括遗传物质如核酸、RNA和DNA,它们是天然或合成得到的,包括重组RNA和DNA及反义RNA和DNA。可使用的遗传物质的类型包括例如载于表达载体上的基因如质粒、噬菌体质粒(phagemids)、装配型质粒、酵母人工染色体(YAC)和缺陷性病毒或“辅助”病素,抗原核酸,单股和双股RNA和DNA及基类似物,如硫代磷酸酯和硫化磷酸酯低聚核苷酸。另外,可将遗传物质与例如蛋白质或其它聚合物混合。
可由于本发明脂质体中的基因治疗剂的例子包括至少编码一部分HLA基因的DNA、至少编码一部分营养不良素(dystrophin)的DNA、至少编码一部分CFTR的DNA、至少编码一部分IL-2的DNA、至少编码一部分TNF的DNA、能与至少编码一部分Ras的DNA结合的反义低聚核苷酸。
编码某些蛋白质的DNA可用于治疗许多不同类型的疾病。例如,可用腺嘌呤核苷脱氨酶治疗ADA缺乏症;可用肿瘤坏死因子和/或白细胞介素-2治疗晚期癌;可用HDL受体治疗肝脏疾病;可用胸苷激酶治疗卵巢癌、脑肿瘤或HIV感染;可用HLA-B,治疗恶性黑素瘤、可用白细胞介素-2治疗成神经细胞瘤、恶性黑素瘤、或肾癌;可用白细胞介素-4治疗癌症;可用HIVenv治疗HIV感染;可用反义ras/p53治疗肺癌;以及可用凝血因子VII治疗血友病B。例如,参见Thompson,L.,Science,1992,258,744-746。
如果需要,可将多种治疗剂置于脂质体中。例如,单个脂质体中可含有多种治疗剂或者可一起给予含有不同治疗剂的脂质体。作为实例,可同时给予能与黑素瘤抗原结合的单克隆抗体和至少编码一部分IL-2的低聚核苷酸。本文中所使用的短语“至少一部分”意思是指低聚核苷酸不需要代表整个基团,只要其所表示的那部分基因能有效地阻断基因的表达。
类似地,可将药物前体包囊在脂质体中,并且药物前体被包含在本文所使用的术语治疗剂的范围之内。本技术领域中,药物前体是熟知的,包括未激活的药物前体,当暴露在高温、代谢酶、气蚀和/或压力下,在氧或其它物质存在下,或当从脂质体中释出时,这些药物前体将形成活性药物。在本发明的方法中,当超声或射频微波能使用含药物前体的脂质体时,在气蚀、加热,加压和/或从脂质体中释放时,这些药物前体能从气体填充类脂物球中激活或释放出来。合适的药物前体对本专业技术人员是显而易见的,例如在Sinkula等J.Pharm.Sci.1975,64,181-210中进行了描述,由该文所公开的全部都引入本文供参考。
例如,药物前体可包括活性药物的未激活形式,其中药物前体上存在有延缓活化和/或改变药物的溶解性或其它特性的化学基团。在这种形式时,通常药物前体是未活化的,但是当通过加热、气蚀、加压和/或通过周围环境中的酶或其它物质从药物前体中除去该化学基团时,即可产生活性药物。本技术领域中详细描述了这些药物前体,并且包括各种各样通过键与化学基团结合的药物,如与短、中等或长链脂肪族碳酸形成的碳酸酯、有机磷酸的半酯、焦磷酸酯、硫酸酯、酰胺、氨基酸、偶氮键、氨基甲酸酯、磷酰胺、葡糖苷酸、N-乙酰葡糖苷胺和β-葡糖苷。
具有母体分子和可逆修饰或连接的药物的实例如下:具有酮缩醇的铃兰毒甙、具有烷基酯的乙内酰脲、具有甘油或丙氨酸酯的氯苯甘油醚、具有咖啡因复合物的扑热息痛、具有THAM盐的乙酰水杨酸、具有乙酰氨基酚酯的乙酰水杨酸、具有硫酸酯的纳洛酮、具有甲基酯的15-甲基前列腺素F2α、具有聚乙二醇的普鲁卡因、具有烷基酯的红霉素、具有烷基酯或磷酸酯的氯洁霉素、具有甜菜碱盐的四环素、具有环取代的酰氧基苄基酯的7-酰基氨基头孢菌素、具有苯基丙酸癸酸酯的诺龙、具有烯醇醚乙缩醛的雌二醇、具有乙酸酯的甲基强的松龙、具有n-乙酰氨基葡糖苷葡糖苷酸(三甲硅烷基)醚的睾丸酮、具有21-磷的酯的可的松或强的松龙或地塞米松。
药物前体也可以设计为可逆的药物衍生物并用作修饰剂来增强药物转运到特定部位的组织。具有可逆修饰或连续以使药物转运到特定部位组织并增强治疗效果的母体分子的实例包括具有卤代烷基亚硝基脲的异氰酸酯、具有丙酸酯的睾丸酮、具有二烷基酯的氨甲喋呤(3-5′-二氯氨甲喋呤)、具有5′-酰化的阿糖胞苷、氮芥(2、2′)-二氯-N-甲基二2基脲、具有氨基甲基四环素的氮芥、具有胆甾醇或雌二醇或脱氢异雄酮酯的氮芥和具有偶氮苯的氮芥。
作为一个本领域的技术人员会意识到,可选择一个特定的修饰所给出的药物的化学基团来影响药物在脂质体膜中或空间中的分配。可选择能选择性地连结化学基团与药物的键来产生理想的代谢速度,如,在酯键情况下,从气体前体填充的脂质体中释出后,在血清酯酶存在下的水解速度。另外,可选择特定的化学基团来影响本发明气体前体填充的运载药物脂质体中所用的药物的生物分布。如具有环磷酰胺的N,N-二(2-氯乙基)-二氨基磷酸分布到卵巢腺癌中。
另外,可设计气体前体填充脂质体中所用的药物前体含有可逆的衍生物,它用来改良活性产生的期限、延长或贮存作用效果。例如,可用葡聚糖和羧甲基葡聚糖酯修饰烟酸,用藻酸盐修饰莲霉素、用双羟萘酸盐修饰二氢链霉素、用5′-adamantoate酯修饰阿糖胞甙(ara-C),用5-棕榈酸和5′-苯甲酸酯修饰阿糖腺苷(ara-A)、用甲基酯修饰两性霉素B、用17-β-烷基酯修饰睾丸酮、用甲酸酯修饰雌二醇、用2-(4-咪唑基)乙胺盐修饰前列腺素、用氨基酸酰胺修饰多巴胺、用单和双(三甲基硅烷基)醚修饰氯霉素、和用双羟萘酸修饰环氯胍。在这种形式时,长期作用的药物贮存库可在体内从气体前体填充的载有药物前体的脂质体中释放出来。
另外,可使用通常热不稳定的化合物来产生无毒基团化合物。优选高温分解的具有偶氮键,过氧化物和二硫键的化合物。在这种形式的药物前体下,由高能量的声波与气体前体填充的脂质体相互作用引起的气蚀和/或温度增加激活化合物中的偶氮,过氧化物和二硫键而由这些包裹在其中的药物前体产生串联的游离基。多种药物或化学物质都可构成这些药物前体,如偶氮化合物,通式为R-N=N-R的化合物,其中R为烃链,两个氮原子之间双键可在体内反应产生游离基产物。
可用来产生游离基产物的药物或化合物的实例包括含偶氮的化合物的偶氮苯、2,2′-偶氮二异丁腈、偶氮二酰胺、石蕊精、氮霉素、azosemide、偶氮磺酰胺、氧化偶氮苯、axtreonam、苏丹亚、磺胺柯衣定、磺氨基柯衣定和碘胺水杨嗪,含二硫键的化合物如sulbentine、二硫胺,硫藤黄菌素、二硫化四甲秋兰姆,含过氧化物的化合物如过氧化氢和过氧化苯甲酰、2,2′-偶氮二异丁腈、2,2′-偶氮二(2-酰氨基丙烷)二盐酸盐和2,2′-偶氮二(2,4-二甲基戊腈)。
用氧气填充的气体前体填充脂质体会产生气蚀的广泛的游离基。而且过渡金属离子,特别是锰、铁和铜能增加由氧形成活性氧中间体的速度。在脂质体中包裹金属离子,可增加体内游离基的形成。可将这些金属离子以游离盐、复合物如与EDTA、DTPA、DOTA或desferrioxamine或以金属离子氧化物的形式混入脂质体中。另外,衍生的金属离子复合物可结合到类脂物的首基,或离子的亲脂复合物例如可结合到类脂物双层中。当热刺激时,如气蚀,这些金属离子将增加形成活性氧中间体的速度。而且,可将放射敏感剂如2-甲基-5-硝基-1-咪唑基-乙醇和misonidazole混合在气体前体填充的脂质体中来在热刺激下产生游离基。
作为使用药物前体的例子,可通过易于在体内被血清活性酶清除的酯键,将酰化的化学基团与药物结合。该酰化的药物前体被混合在本发明气体前体填充的脂质体中。除烃烷基和取代的烃烷基外,其衍生物也可由卤素取代和全卤取代基如全氟烷基组成。全氟烷基应该具有稳定乳浊液的能力。当用超声所产生的声波脉冲来冲击气体前体填充的脂质体时,由脂质体包裹的药物前体将暴露于血清中。血清中的酯酶消除酯键,因此产生药物。
类似地,超声不仅可用来破裂气体前体填充的脂质体,而且可产生热效应,它可增加化学清除的速度并由药物前体释放活性药物。
脂质体也可以设计,以便使药物在脂质体的内部和外面具有对称或不对称的分布。
可选择或修饰特定化学结构的治疗剂来达到所需的溶解性,这样治疗剂可被包裹在脂质体气体前体填充空间内,吸附在脂质体上或网在脂质体中。表面结合的治疗剂可携带一种或多种酰基链,这样,当经气蚀而冲击或加热或裂开气泡时,酰化的治疗剂离开表面和/或治疗剂可从酰基链化学基团中被除去。类似地,可将其它治疗剂配制芳香族或甾族结构的疏水基团来使其结合到脂质体的表面。
下列实施例更进一步地描述本发明,这些实施例说明制备和试验气体前体填充的脂质体。实施例1-5和22-24是实际的;实施例6-21是预测的。下列实施例不会对附加的权利要求的范围构成限制。实施例1:用全氟丁烷制备气体填充脂质球
如下用全氟丁烷(Pfaltz and Bauer,Waterbury,CT)制备含气体前体的脂质体:将5ml以5mg/ml量溶于8∶1∶1生理盐水∶甘油∶丙二醇中的类脂溶液(类脂=87摩尔%DPPC,8%摩尔%DPPE-PEG 5,000,5摩尔%二棕榈酰磷脂酸)(所有的类脂都从Avanti Polar Lipids,Alabastr,AL得到)放在具有橡皮塞的玻璃瓶中(瓶子的体积=15.8ml)。用真空泵Model Welch 2-Stage DirecTorr Pump(VWRScientific,Cerritos,CA),通过穿透橡皮塞的18号针头将软管接到瓶中来抽掉其中的空气。真空除掉气体后,经过连接在全氟丁烷罐的管子上的另一个18号针头,将全氟丁烷加入塞住的瓶中。重复该过程5次,以便除去塞住口的瓶中的痕量空气并且类脂溶液上方的空间完全充满了全氟丁烷。在从瓶塞上拔掉18号针头之前,让该18号针头与外界通气1或2分钟,由此便得玻璃瓶内的压力与外界环境压力平衡。用全氟丁烷充满瓶子后,用橡皮带扎牢瓶子并将其固定在Wig-L-BugTM(Crescent Dental Mfg.Co.,Lyons,IL)的支架上。然后通过Wig-L-BugTM将瓶子振荡60秒。多泡的悬浮液泡沫产生并且可以看到泡沫层与瓶底澄清溶液的明显分离只需几分钟时间。振摇后,物质的体积从5CC增到约12CC,揭示脂质体捕获了约7CC的全氟化碳气体前体。用Accusizer(Model 770,Particle Sizing System,Santa.Barbara,CA)来筛分物质的大小并且也用偏振光显微镜(Nikon TMS,Nikon)以150倍放大率来测定。脂质体显示为相当大的球形结构,其平均直径约为20到50μm。然后,将部分脂质体经过注射器注射通过具有8μm大小孔的Costar滤器(Syrfil800938,Costar,Pleasanton,CA)。用光学显微镜和AccusizerSystem再测定脂质体。其大小约为3μm容重约为7μg。大于99.9%的脂质体,其大小小于11μm。上述实施表明:通过振荡和过滤的方法,用气体前体的气体,全氟丁烷,可制得合乎需要大小的脂质体。
基本地重复上述实施,除了,在室温用全氟丁烷充满瓶子后,将瓶子移至冰冻器中并使原料的温度为-20℃。在此温度下,全氟丁烷度成液体。因为甘油和丙二醇的存在,类脂溶液不结冰。将瓶子迅速移至Wig-L-BugTM振荡引起能量的传递,使得第二次振荡时的瓶子摸上去略热些。涡旋后,又可以看到与上述类似的较大体积的泡沫。用光学显微镜和Accusizer再研究产生的脂质体。将部分脂质体经过以上所述8μm滤器过滤筛分大小,再通过显微镜和Accusizer来研究。筛选的结果与用上述气体前体产生的结果完全相同。
用体重约3.5kg的新西兰白兔进行成像。用兔子调制食品(二甲苯10mg/ml;氯胺酮100mg/ml和乙酰丙嗪20mg/ml)给兔子服镇静剂并用Acoustic Imaging,Model No.7200,临床超声仪扫描,用具有7.5MHz调频器的彩色多普勒扫描肾脏。扫描兔子肾脏的同时,也用另一台具有7.5MHz调频器,用于心脏黑白刻度成像的Acostic Imaging超声仪,moden.5200扫描兔子的心脏。用安装了8μm过滤器(如上)的注射器,经耳静脉注射全氟丁烷填充的脂质体。注0.5CC(0.15cc/kg)的含气体前体全氟丁烷的脂质体后,可观察到肾脏戏剧性和持久性的增强作用达30分钟以上。由于在肾弓状动脉和微循环内反射增强的信号,所以该增强作用以鲜明的色彩在肾实质内显示出来。同时成像的心脏表明,在最初几分钟覆盖阴影,它妨碍了心脏的显现即反射光太强,使得超声波已被完全反射和吸收。然而,几分钟后,可观察到鲜明和持久的心室和血流强作用,该作用也持续50分钟以上。用黑白刻度超声仪也可以得到肝的像。这些显示了在心脏和血流增强作用的同时,实质和血管的增强作用。
简要地说,本实验表明怎样用脂质体来捕获气体前体并产生很稳定的确定的和理想大小脂质体。本发明作为超声造影剂和用于药物释放具有巨大的潜力。由于脂质体如此稳定,所以它们将经过血液循环到达靶组织(例如肿瘤)。然后可利用超声,微波射频或磁场将能量集中在靶组织上来进裂脂质体并实现药物的局部释放。实施例2:经过微观流化作用来制备气体前体
除了加入气体前体后,在Microfluidics微观流化器上(Microfluidics Ine.,Newton,MA)将所含内容物微观流化六次之外,如实施例1制备气体前体填充的类脂双层。冲程压范围在10,000和20,000psi之间。接着用该制剂按照实施例1来制备用气体前体包裹的气体填充脂质双层。实施例3:用磷脂酸和二棕榈酰磷酰酰胆碱制备气体填充的
类脂双层
除了将DPPC与5摩尔%磷脂酸(Avanti Polar Lipids,Alabastar,AL)结合之外,按实施例1所述来制备气体填充类脂双层。与类脂颗粒在下层水性媒介物中的量减小相比,制备气体填充脂质双层引起溶解度的增加。产物经筛分大小显示,与单独使用DPPC相比,总的平均大小减小到大小40μm。实施例4:用磷脂酸,二棕榈酰磷脂酰乙醇胺-PEG5,000和
二棕榈酰磷脂酰胆碱制备气体填充的磷脂双层
除了类脂的配方为在含8∶1∶1(V∶V∶V)生理盐水∶丙二醇∶甘油的媒介物中含82摩尔%二棕榈酰磷脂酰胆碱,10摩尔%二棕榈酰磷脂酸和8摩尔%二棕榈酰磷脂酰乙醇胺-PEG5,000(Avanti Polar Lipids,Alabaster,AL)之外,按实施3所讨论的制备全氟丁烷包裹的类脂双层,得到泡沫和主要不含任何颗粒的媒介物下层。改变该媒介物澄清度变化的媒介物下层。同样按实施例3配制配方得到含全氟丁烷的气体填充类脂双层。先过滤,再用Particle SizingSystems Model 770光学粒度仪(Optical Sizer)(Particle SizingSystems,Santu Barbara,CA)测定气体填充微球体的大小。粒度分析结果为99%的颗粒低于34μm。然后通过8μm滤器过滤得到的产品,得到相同大小的微球体。后来的微球体进行粒度分析。结果为99.5%的颗粒低于10μm。该产品用于实施例1的体内实验。
可以看到,用其它粘滞度的调节剂和变化比例的增溶剂来改变媒介物,结果增大或减小澄清度和粒度。在大量类脂物和联合使用的类脂类似物中,可以发现,采用DPPE-PEG脂质可明显改善粒子大小分布和气体填充类脂双层的稳定性。实施例4A:用气体填充类脂双层结合DNA
用含磷脂酸和气体前体的脂质体和含脂质体的气体结合DNA。在50℃,将7mM二硬脂酰-Sn-甘油磷酸盐(DSPA)(Avamti Polar Lipids,Alabaster,AL)悬浮在生理盐水中并涡旋。让原料冷却至室温。将40mgPBR322质粒DNA(International Biotcehnoeogies,Inc.,New Haven,CT)加到来类脂溶液中并轻轻振药。然后用Beckman TJ-6离心机(Beckman,Fullerton,CA)将溶液离心10分钟。用Hoefer Tko-100 DNA荧光计(Hoefer,San Francisco,CA)来分析上清液和沉淀中DNA含量。该方法只检测双股DNA,因为它使用了DNA特效添加染料Hoechst 33258。可以发现用磷脂酸制备的带负电荷的脂质体,或带将负电荷的类脂物意外地结合了DNA。用含DPPC的脂质体作对照重复该实验。在DPPC脂质体上未发现有明显量的DNA。用87∶8∶5摩尔%的DPPC:DPPE-PEG 500:DPPA的类脂类微球体混合物制备的气体填充脂质体来重复该实施,DNA又结合到含二棕榈酰磷脂酸的气体填充脂质上。实施例5:前体的微乳化作用
将Microfluidizer(Microfluidics,Newton,MA)放在-20℃的冷冻室中。将液面上空含35CC全氟丁烷和含25CC类脂溶渗液的带塞玻璃烧瓶置于冷冻室中。类脂溶液为在8∶1∶1磷酸缓冲液(PH7.4)∶甘油∶丙二醇中含83∶8∶5摩尔比的DPPC:DPPE+PEG 5,000:DPPA。在冷冻室中溶液不结冰,但全氟丁烷变为液体。
将类脂和液态气体前体的悬浮液放入Microfluidizer的流化室内并在16,000psi下流化20回。得到具有约20nm到50nm大小的限定大小的囊泡。当升温至室温时,得到约10μm的稳定的微球体。实施例6:制备气体前体填充脂质体
将50mg的1,2-二棕榈酰-Sn-甘油基-3-胆碱磷酸(分子量734.05,粉末,批号.160PC-183)(Avanti-PolarLipids,Alabaster,AL)称重并在离心管中,用5.0ml盐溶液(0.9%NaCl)或磷酸盐缓冲盐(0.8%氯化钠,0.02%氯化钾,0.115%磷酸氢二钠和0.02%磷酸二氢钾,PH调至7.4)来水合。向该悬浮液中加入165μl/ml的2-甲基-2-丁烯。将水合的悬浮液在涡旋器(Scientffic Industries,Bohemia,NY)上,在仪器沉降为6.5的位置,振荡10分钟。可见总体积为12ml。预计盐溶液5.0ml减小到约4ml。
经过该新方法制得的气体前体填充脂质体用光学显微镜进行粒度分析。测量最大的脂质体粒度范围从约50到约60μm并且可见的最小粒度为约8μm。平均粒度范围从约15至约200μm。
用Swin-Lok Filter Holder(Nuclepor Filtrcetion Produets,Costar Corp.,Cambridge,MA)和20cc注射器(BectonDickinsion & Co.,Rutherforel,NJ)将气体前体填充脂质体通过10或12μm“核微孔”膜过滤。该膜为10或12μm的“核微孔”膜(Nucleporo Fittration Produets,Costar Corp.,Cambridge,MA)将10.0μm滤器放在Swin-Lok Filter Holder中并且将盖子牢牢拧紧。将脂质体溶液摇匀并经过18号针头转移到20cc注射器中。将大约12ml的脂质体溶液移入注射器中,并将注射器拧紧在Swin-Lok Filter Holder上。将注射器和滤器架的安装倒置,以便于较大的气体前体填充脂质体囊泡可以开到顶部。将注射器轻轻上推并用此方法,将气体前体填充脂质体过滤。
通过10.0μm滤器挤压后气体前体填充脂质体的残留率(挤压过程后,残留气体前体填充脂质体的量),约为83-92%。用手挤压前,泡沫的体积约为12ml并且水溶液的体积约为4ml。用手压出后,泡沫的体积约为10-11ml,水溶液的体积约为4ml。
用光学显微镜再测定挤压过的气体前体填充脂质体的粒度分布。测得最大脂质体粒度范围从约25到约30μm并且可见的最小粒度为约5μm。平均粒度范围从约8至15μm。实施例7:用冻干法制备气体前体填充脂质体
将50mg的1,2-二棕榈酰-Sn-甘油基-3-胆碱磷酸(分子量:73405,粉末)(Avanti-Polar Lipids Alabaster,AL)称重并放到离心管中。用5.0ml盐溶液(0.9%NaCl)水合类脂。向该悬浮液中加入165μL/ml的2-甲基-2-丁烯。在仪器沉降为6.5处将类脂涡旋10分钟。涡旋后,将整个溶液在液氮中冷冻。然后将样品放在冻干器上冷冻干燥。将干燥的类脂从冻干器上取下并用5ml盐溶液再水合并在6.5沉降处涡旋10分钟。用移液管取少量该溶液的样品滴到载玻片并在微镜下观察溶液。然后测定气体前体填充脂质体的粒度。测量最大的脂质体粒度为约60μm并且可见的最小粒度为约20μm。平均粒度范围从约30到约40μm。实施例8:制备超过类脂相转变温度的气体前体填充脂质体
的实例
将50mg的1,2-二棕榈酰-Sn-甘油基-3-胆碱磷酸(分子量:734.05,粉末)(Avanfi-Polar Lipids,Alabaster,AL)称重并放入离心管中。向该悬浮液中加入165μL/ml的2-甲基-2-丁烯。用大约2英尺的乳胶管(内径0.25英寸)象线圈一样缠绕在锥形离心管周围。用电线将乳胶管固定在离心管上。然后将乳胶管接到恒温循环水浴上(VWRScientific Model 1131)。将水浴温度调在60℃并使循环水高速循环通过管子。将温度计放到类脂溶液中并可以看到在42℃和52℃之间。
在涡旋仪沉降为6.5档处,将类脂溶液涡旋10分钟。可以看到有很小量的成泡类脂(相变温度=41℃),并且悬浮液不能明显形成气体前体填充脂质体。光学显微镜显示溶液中的大类脂颗粒。在该温度下形成的气体前体填充脂质体的数量少于在低于相变温度的温度下形成的数量的3%。将溶液静置15分钟直到溶液的温度平衡到室温(25℃)。然后将溶液涡流10分钟。10分钟后,可以看到气体前体填充脂质体形成。实施例9:用冰冻-融化法制备气体前体填充脂质体
将50mg的1,2-二棕榈酰-Sn-甘油基-3-胆碱磷酸(分子量:734.05,粉末)(Avanti-Polar Lipids,Alabaster,AL)称重并放入离心管中。然后加5.0ml 0.9%NaCl来水合类脂。向该悬浮液中加入165μL/ml 2-甲基-2-丁烯。在仪器沉降为6.5处,将水性类脂溶液涡旋10分钟。涡旋后,将整个溶液在液氮中冰冻。然后将整个溶液在室温下(25℃)的水浴中融化。冰冻-融化法重复8次。在仪器沉降为6.5处,将水合的悬浮液涡旋10分钟。可以看到如实施例6所述的气体前体填充脂质体。实施例10:用乳化剂(十二烷基硫酸钠)制备气体前体填充
脂质体
准备两支离心管,每支含50mgDPPPC。将1摩尔%(约0.2mg Duponol C批号2832)的十二烷基硫酸钠加到一个离心管中,另一离心管中加10摩尔%(2.0mg Duponol C批号2832)。将5ml 0.9%NaCl分别加到两支离心管中。分别加入165μL/ml 2-甲基-2-丁烯。将两支离心管在液氮中冰冻并冷冻干燥约16小时。从冻干器上取下两样品并分别入5ml盐水。在6.5处分别涡旋10分钟。
测得加1摩尔%十二烷基硫酸钠的气体前体填充脂质体的最大粒度为约75μm并且可见的最小粒度为约6μm。平均粒度范围从约15到40μm。测得加10摩尔%十二烷基硫酸钠的气体前体填充脂质体的最大粒度为约90μm并且可见的最小粒度为约6μm。平均粒度范围为从约15到35μm。
在含1摩尔%十二烷基硫酸钠的气体前体填充脂质体溶液中,泡沫的体积约为15ml并且水溶液的体积为3-4ml。在含10摩尔%十二烷基硫酸钠的气体前体填充脂质体中,泡沫的体积也约为15ml并且水溶液的体积约为3-4ml。实施例11:测定是否可通过声处理来产生气体前体填充脂
质体
将50mg类脂,1,2-二棕榈酰-Sn-甘油基-3-胆碱磷酸(Avanti-Polar Lipids,Alabaster,AL)称重并用5ml0.9%NaCl水合。向该悬浮液中加入165μL/ml2-甲基-2-丁烯。代替涡旋,将该水溶液用Heat Systems SonicatorUltrasonic Processor XL(Heat Systems,Inc.,Farmingdale,NY)Model XL 2020声处理。将频率为20KHz的声处理仪在其旋扭4处产生连续波。在4℃下,用微型管尖声处理10分钟。声处理后,将温度升到40℃并在光学显微镜下观察溶液。可见有气体前体填充脂质体已经产生的迹象。
接着,在50℃下进行声处理重复上述过程并加入165μL/ml 2-甲基-2-丁烯。除去声处理仪的微型管尖并用声处理仪提供的管端盖板代替。制备另一溶液(每5ml盐水中含50mg类脂)并用该管尖声处理。10分钟后,在显微镜下观察溶液。在上述气体转变温度下,用声处理制备的气体填充脂质合格产生较低产率的气体填充脂质球。实施例12:测定浓度对气体前体填充脂质体制备的作用
该实施例测定低浓度限的类脂是否会阻止气体前体填充脂质体的产生。将10mg的1,2-二棕榈酰-Sn-甘油基-3-胆碱磷酸(Avanti-Polar Lipids,Alabaster,AL)加到10ml盐水中。向该悬浮液中加入165μL/ml的2-甲基-2-丁烯。在6.5处,将类脂质/盐水/气体前体溶液涡旋10分钟。在显微镜下观察溶液进行粒度分析。测得最大脂质体粒度范围从约30到45μm并且可见的最小粒度约为7μm,平均粒度范围从约30到45μm。
可见当气体前体填充脂质体的产生比前面所述的更快时,它们也更易碎。因此可见,类脂的浓度是影响气体前体填充脂质体产生和稳定性的因素。实施例13:阶式过滤
将未过滤的气体前体填充脂质体吸到50ml注射器中并通过最小间隔150μm的阶式“核微孔”10μm滤器和8μm滤器(图3和4)。或者,例如,可以将样品通过彼此紧密连接的10μm和8μm滤器过滤。气体前体填充脂质体以使流速为2.0ml/min的压力通过滤器。接着测定过滤后的气体前体填充脂质体中气体前体填充脂质体的产率,结果其体积为未过滤体积的80-90%。
用四种不同的方法对产生的气体前体填充脂质体行粒度分析来测定其粒度和分布。在Particl Sizing Systcms Model770 Optizing unit,一种安装有Universal Imaging生产的成像方法软件的Zeiss Axioplan光学显微镜和Coulter Counter(Coulter Electronics Limited,Luton,Beds,England)上进行粒度分析。如图5和6所示,与未过滤的气体前体填充脂质体相比,该气体前体填充脂质体的粒度更均匀地分布在8-10μm附近。因此,可以看出,过滤后的气体前体填充脂质体的粒度更均匀。实施例14:制备过滤的DPPC悬浮液
将250mg DPPC(二棕榈酰磷脂酰胆碱)和10ml 0.9%NaCl加到50mlFalcon离心管中(Belton-Dickinson,LincolnPark,NJ)并保持在室温(约20℃)。向该悬浮液中加入165μL/ml2-甲基-2-丁烯。在氮气压力下,将悬浮液挤压通过1μm Nuclepore(Costar,Pleasanton,CA)聚碳酸酯膜。产生的悬浮液用Particle Sizing Systems(Sunta Barbara,CA)Model 370激光散射粒度分析仪进行粒度分析。所有液体颗粒平均外径为1μm或更小。
另外,在18,000 p.s.i.下,将同样量的DPPC/气体前体悬浮液5次通过MicrofluidicsTM(Microfluidics Corporation,Newton,MA)微量流化仪。将产生的变稀薄的悬浮液在Paotick Sizing Systems(Santa Barbara,CA)Sub Micron PartickSizer Model 370激光散射粒度分析仪上进行粒度分析,可见粒度均匀地小于1μm。已知经微观流化的悬浮液的颗粒大小可稳定保持六个月。实施例15:制备过滤的DSPC悬浮液
将100mg DSPC(二硬脂酰磷脂酰胆碱)和10ml 0.9%NaCl加到500ml Falcon离心管中(BecTon-Dickinson,Lincoln Park,NJ)。向该悬浮液中加入165μL/ml的2-甲基-2-丁烯。在氮气压力下,在300-800p.s.i下,将悬浮液挤压通过1μm“核微孔”(Costar,Pkasanton,CA)聚碳酸酯膜。将产生的悬浮液在Partick Sizing Systems(Santa Barbara,CA)Sub Micron Partick Sizer Model 370激光散射粒度分析仪上进行粒度分析。可见所有颗粒粒度为1μm或更小。
另外,在18,000p.s.i下将同样量的DPPC/气体前体悬浮液5次通过MicrofluidicsTM(Mierofluidics Corporation,Newton,MA)微现流化仪。将产生的变稀薄的悬浮液在SubMicron Partick Sizer Systcms Model 270激光散射度分析仪上进行粒度分析并且可见粒度均匀地小于1μm。实施例16:通过压热器处理来灭菌过滤的类脂悬浮液
用Barnstcd Model C56835压热器(Barnstcel/Thermolyne,Dubuque,IA)将前面实施例9和10经过粒度分析的DPPPC/气体前体和DSPC/气体前体悬浮液进行压热器处理然后振荡。过滤步骤也可在使用前通过管状(inline)滤器进行。气体前体也可在粒度分析和振荡前进行压热器处理。
平衡至室温后(约20℃),灭菌悬浮液用于气体前体滴注。实施例17:经涡旋,将气体前体滴注到过滤并压热器处理的
类脂物中
将前面已挤压通过1μm滤器并热器处理20分钟,以15mg/ml量溶解在0.9%NaCl中的10ml 1,2-二棕榈酰-磷脂酰胆碱加到Falcon 50ml离心管中(Becton-Dickinson,Lincoen Park,New Jersey)。向该悬浮液中加入165μL/ml的2-甲基-2-丁烯,类脂悬浮液平衡到室温后(约20℃),将液体在VWR Genie-2(120v,0.5安培,60Hz)(ScientificInelustries,Inc.,Bohemia,NY)上涡旋10分钟或直到气体前体填充脂质体的总体积至少为原水性类脂溶液体积的二倍或三倍。离心管底部的溶液中几乎完全没有无水颗粒状类脂,并全产生较大体积的含气体前体填充脂质体的泡沫。因此,预先压热处理并不影响类脂悬浮液形成气体前体填充脂质体的能力。压热处理不改变脂质体的粒度,并且不减小类脂悬浮液形成气体前体填充脂质体的能力。实施例18:经过振荡器的振荡,将气体前体滴注到过滤并经
压热处理过的类脂物中。
将前面已挤压通过1μm滤器并经压热器处理20分钟,以25mg/ml量溶于0.9%NaCl中的10ml 1,2-二棕榈酰磷脂酰胆碱加到Falcon Soml离心管中(Becton-Dickinson,Lincoln Park,NJ)。向该悬浮液中加入165μL/ml的全氟戊烷(PCRResearch Chemicals,Gainesville,FL)。类脂悬浮液平衡到室温后(约20℃),将离心管垂直放入VWR ScientificOrbital振荡器中(VWR Scientific,Cerritos,CA),并以300r.p.m的速度振荡30分钟。在振荡器上的振荡产生气体前体填充的脂质体。实施例18A:
可用下列物质替代全氟戊烷来进行上面的实验:六氟化硫、六氟丙烯、溴氯氟甲烷、八氟丙烷、1,1-二氯氟乙烷、六氟乙烷、六氟-2-丁炔、全氟戊烷、全氟丁烷、八氟-2-丁烯或六氟-1,3-丁二烯或八氟环戊烯,他们都可产生气体前体填充的脂质体。实施例19:经过涂料混合器振荡,将气体前体滴注到过滤并
经压热器处理的类脂物中
将前面已挤压通过1μm滤器并经压热器处理20分钟,以25mg/ml的量溶于0.9%NaCl中的10ml1,2-二棕榈酰磷脂酰胆碱加入Falcon 50ml离心管中(Becton-Dckinson,Lincaln Park,NJ)。向该悬浮液中加入165μL/ml的2-甲基-2-丁烯。类脂悬浮液平衡到室温后(约20℃),用手用力振荡离心管10分钟。当停止振荡时,气体前体填充脂质体形成。实施例21:经阶式或块状滤器分级过滤压热器处理的气体
前体填充脂质体
如实施例17所述,用DPPC制备气体前体填充脂质体。将产生的未过滤脂质体抽到50ml注射器中并通过由最小间隔为150μm的“核微孔”(Costar,Pleasanton,CA)10μm滤器和8μm滤器组成阶式滤器系统。另外,另一份样品用彼此紧紧连接的10μm和8μm滤器块过滤。将气体前体脂质体以使其滤速为2.0ml/min的压力通过滤器。过滤气体前体填充脂质体的体积为未过滤体积的80-90%。
通过四种不同的方法将产生的气体前体填充脂质体进行粒度分析来测定其大小和分布。Particle Sizing Systems(Santa Barbara,CA)Model 770 Optical Sizing unit和安装有成像方法软件(Universul Imaging,West Chester,PA)的Ieiss(Oberkochen,Germany)Axiopean光学显微镜和CoulterCounter(Coulter Electronics Limited,Luton,Beds,England)进行粒度分析。如图8所示,与未过滤的气体前体填充脂相比,该气体前体填充脂质体的粒度更均匀地分布8-10μm周围。
除了使用的振荡器为Crescent″Wig-L-Bug″(CrescentManufacturing Dentul Co.,Lyons,IL)外,按实施例6相同的方法进行。然后将制剂振荡60秒来代替所述的通常为5分钟到10分钟。气体填充脂质球产生。实施例23:
将10μL全氟戊烷(bp29.5℃,PCR Research Chemicals,Gainesville,FL)加到5mg/ml类脂悬浮液中并在室温下,在机器沉降为6.5挡处,在Genie II混合器上(ScientificIndustries,Inc.Bohemia,NY)涡旋。然后用Richmar(RichmarIndustries,Inola,KO),1MHz的治疗超声仪进行高温处理,将温度升高到用温度计测量时在42℃以上。当到达相变温度时,可以看到气体微球体。同时用诊断超声仪(AcousticImaging,Phoenix,AZ)进行扫描。在临床诊断超声仪上也可见来自气体微球体的Acoustic信号。
用八氟环戊烷(bp27℃,PCR Research Chemicals,Gainesville,FL)进行同样的实验。实施例24:
进行与实施23相同的实验,其中,将悬浮液治进行涡旋并注射到体重300克的Harlan-Sprague Dawleg鼠中且该鼠事先在左大腿区域注射了C5A肿瘤细胞系。然后将Ridnmar1MHz的治疗超声置于肿瘤区域,并静脉注射与类脂悬浮液混合的阿霉素。将治疗超声置于连续波(100%工作期)并使肿瘤加热。在左大腿区域存在有C5A肿瘤细胞系的第二只鼠被给予相同的剂量的阿霉素乳剂,但不在该动物上使用超声。在三周的期间内注意到,与未使用超声的对照组相比较,肿瘤明显地小。
除本文所显示和描述的内容之外,在本文基础上,对本发明进行各种改进,这对本领域技术人员来说是显而易见的。这些改进也将落在附加权利要求的范围之内。
Claims (25)
1.一种制备气体填充类脂微球体的方法,其包括,在存在液体温度活化气体前体时,振荡含有类脂的水溶液,并且此后使得所述类脂微球体的温度升至高于所述温度活化气体前体的液-气相转变温度,其特征在于:所述温度活化气体前体为全氟化碳,其具有-100℃-70℃的液-气相转变温度。
2.一种制备气体填充类脂微球体的方法,其包括,在存在气体或气体混合物时,振荡含有类脂的水溶液,其特征在于:所述气体或气体混合物包括选自全氟化碳和六氟化硫的气体。
3.权利要求1或2的方法,其中,所述振荡是在所述水溶液在温度低于所述类脂的凝胶态向液晶态相转变温度时进行的。
4.权利要求1的方法,其中,所述温度活化气体前体在激活为气体后占所述类脂微球体内部容积的至少约50%。
5.前述权利要求中任一的方法,其中,所述类脂包括脂族化合物,其具有含2-30个碳的烷基。
6.前述权利要求中任一的方法,其中,所述类脂包括磷脂。
7.权利要求6的方法,其中,所述磷脂选自二油酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、双十五酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二油酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、磷脂酰乙醇胺、二棕榈酰磷脂酸、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇以及磷脂酸。
8.前述权利要求中任一的方法,其中,类脂微球体进一步包括聚乙二醇。
9.权利要求8的方法,其中,所述类脂微球体包括共价结合于聚乙二醇的二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酸以及二棕榈酰磷脂酰乙醇胺。
10.前述权利要求中任一的方法,进一步包括分离步骤,分离所产生的用于诊断或治疗的气体或温度活化气体前体填充类脂微球体。
11.前述权利要求中任一的方法,其中所述振荡是在加压的条件下进行的。
12.权利要求1的方法,其中所述温度活化气体前体具有约37℃的液一气相转变温度。
13.前述权利要求中任一的方法,其中,所述全氟化碳选自全氟甲烷、全氟乙烷、全氟丙烷、全氟丁烷、全氟戊烷、全氟己烷以及全氟环丁烷。
14.权利要求13的方法,其中,所述全氟化碳选自全氟丙烷、全氟环丁烷以及全氟丁烷。
15.权利要求14的方法,其中,所述全氟化碳为全氟丙烷。
16.前述权利要求任一的方法,其中,在所述类脂微球体中的类脂呈单层形式。
17.前述权利要求任一的方法,其中,在所述类脂微球体中的类脂呈双层形式。
18.前述权利要求1-17中任一的方法制得的气体填充类脂微球体。
19.权利要求18的气体填充类脂微球体,其包括气体选自全氟化碳和六氟化硫,由类脂单层包封。
20.权利要求18的气体填充类脂微球体,其包括气体选自全氟化碳和六氟化硫,由类脂双层包封。
21.权利要求19或20的气体填充类脂微球体,其中,所述微球体进一步包括来自大气环境的其它气体。
22.权利要求21的气体填充类脂微球体,其中,所述其它气体为空气。
23.权利要求21的气体填充类脂微球体,其中,所述其它气体为氮气。
24.权利要求18-23中任一所述的气体填充类脂微球体在产生超声影象的方法中的用途。
25.权利要求18-23中任一所述的气体填充类脂微球体在制备用于产生超声影象的方法的药物中的用途。
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US08/076,239 US5469854A (en) | 1989-12-22 | 1993-06-11 | Methods of preparing gas-filled liposomes |
US08/076,239 | 1993-06-11 | ||
US15967493A | 1993-11-30 | 1993-11-30 | |
US08/160,232 US5542935A (en) | 1989-12-22 | 1993-11-30 | Therapeutic delivery systems related applications |
US08/159,687 | 1993-11-30 | ||
US08/159,674 | 1993-11-30 | ||
US08/159,687 US5585112A (en) | 1989-12-22 | 1993-11-30 | Method of preparing gas and gaseous precursor-filled microspheres |
US08/160,232 | 1993-11-30 |
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EP (2) | EP0712293B1 (zh) |
JP (2) | JP4274387B2 (zh) |
CN (1) | CN1125654C (zh) |
AT (1) | ATE233574T1 (zh) |
AU (1) | AU683900B2 (zh) |
CA (1) | CA2164845C (zh) |
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LU (1) | LU91325I2 (zh) |
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- 1993-11-30 US US08/159,687 patent/US5585112A/en not_active Expired - Lifetime
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- 1994-05-20 CN CN94192402A patent/CN1125654C/zh not_active Expired - Lifetime
- 1994-05-20 DE DE122007000024C patent/DE122007000024I2/de active Active
- 1994-05-20 EP EP94919208A patent/EP0712293B1/en not_active Expired - Lifetime
- 1994-05-20 AU AU70431/94A patent/AU683900B2/en not_active Ceased
- 1994-05-20 WO PCT/US1994/005792 patent/WO1994028780A2/en active IP Right Grant
- 1994-05-20 CA CA002164845A patent/CA2164845C/en not_active Expired - Lifetime
- 1994-05-20 ES ES94919208T patent/ES2193161T3/es not_active Expired - Lifetime
- 1994-05-20 EP EP02078168A patent/EP1252885A3/en not_active Withdrawn
- 1994-05-20 DK DK94919208T patent/DK0712293T3/da active
- 1994-05-20 DE DE69432219T patent/DE69432219T2/de not_active Expired - Lifetime
- 1994-05-20 PT PT94919208T patent/PT712293E/pt unknown
- 1994-05-20 JP JP50183995A patent/JP4274387B2/ja not_active Expired - Lifetime
- 1994-05-20 AT AT94919208T patent/ATE233574T1/de active
-
1995
- 1995-06-06 US US08/487,230 patent/US5853752A/en not_active Expired - Lifetime
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1997
- 1997-10-02 US US08/942,862 patent/US6071495A/en not_active Expired - Fee Related
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1998
- 1998-07-17 US US09/118,329 patent/US6479034B1/en not_active Expired - Fee Related
-
2007
- 2007-03-13 NL NL300267C patent/NL300267I2/nl unknown
- 2007-03-16 LU LU91325C patent/LU91325I2/fr unknown
- 2007-07-23 JP JP2007190697A patent/JP4916969B2/ja not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US4900540A (en) * | 1983-06-20 | 1990-02-13 | Trustees Of The University Of Massachusetts | Lipisomes containing gas for ultrasound detection |
Also Published As
Publication number | Publication date |
---|---|
US5585112A (en) | 1996-12-17 |
US6479034B1 (en) | 2002-11-12 |
DE69432219T2 (de) | 2003-12-04 |
EP0712293A1 (en) | 1996-05-22 |
JP4916969B2 (ja) | 2012-04-18 |
AU683900B2 (en) | 1997-11-27 |
PT712293E (pt) | 2003-07-31 |
ES2193161T3 (es) | 2003-11-01 |
DK0712293T3 (da) | 2003-06-30 |
LU91325I2 (fr) | 2007-05-16 |
US6071495A (en) | 2000-06-06 |
NL300267I2 (nl) | 2007-10-01 |
CA2164845C (en) | 2008-04-29 |
JP4274387B2 (ja) | 2009-06-03 |
EP1252885A2 (en) | 2002-10-30 |
EP0712293B1 (en) | 2003-03-05 |
DE122007000024I2 (de) | 2011-06-16 |
WO1994028780A3 (en) | 1995-02-02 |
US5853752A (en) | 1998-12-29 |
AU7043194A (en) | 1995-01-03 |
CN1125389A (zh) | 1996-06-26 |
NL300267I1 (nl) | 2007-05-01 |
JP2007314559A (ja) | 2007-12-06 |
JPH08511526A (ja) | 1996-12-03 |
ATE233574T1 (de) | 2003-03-15 |
WO1994028780A2 (en) | 1994-12-22 |
DE122007000024I1 (de) | 2007-10-04 |
EP1252885A3 (en) | 2003-04-16 |
CA2164845A1 (en) | 1994-12-22 |
DE69432219D1 (de) | 2003-04-10 |
EP0712293A4 (en) | 1998-05-06 |
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