CN1066977A - 诊断剂的制备 - Google Patents
诊断剂的制备 Download PDFInfo
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- CN1066977A CN1066977A CN92103376A CN92103376A CN1066977A CN 1066977 A CN1066977 A CN 1066977A CN 92103376 A CN92103376 A CN 92103376A CN 92103376 A CN92103376 A CN 92103376A CN 1066977 A CN1066977 A CN 1066977A
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Abstract
利用包括以下步骤的方法制备微囊:(i)喷雾-干
燥一种构成壁的物质的溶液或分散体以便获得中间
微囊和(ii)降低至少该中间微囊外侧的水溶性。
合适的构成壁的物质包括蛋白质,如白蛋白和凝
胶。
该微囊具有40到500纳米的壁厚并且在超声
成像中是有用的。控制中值大小,大小分布以及构成
壁的物质的不溶解度和交联度就可以制成要产生的
新型的微球体制品。
Description
本发明涉及诊断剂的制备,该诊断剂包括用于增强超声成像的空心蛋白质微胶囊。
知道人体内的气泡可以用于回波心动描记法这一事实已有一段时间了。为了这一目的,可将含有气泡的液体注入血流中〔见Ophir等人的(1980)“超声成像”2,66-77,他们将气泡稳定在胶原蛋白膜上,美国专利US-A-4,446,442(Schering)和欧洲专利EP-A-131,540(Schering)〕以及欧洲专利EP-A-224,943和EP-A-324,938公开了通过声波处理一种白蛋白溶液制备的气泡的应用。然而,气泡大小的分布显然是不可控制的,而且当气泡经受到由左心室产生的压力时会消失(Shapiro等人(1990)J.Am.Coll.Cardiology,16(7),1603-1607)。
EP-A-52575为同一目的公开了携带气体的固体颗粒,气体在血流中从颗粒中释放出来。
EP-A-458,745(Sintetica)公开了一种通过合成聚合物,如聚交酯和聚乙交酯的界面聚合反应制备充满空气或气体的微气泡的方法。WO 91/12823(Delta)公开了一种利用白蛋白的类似方法。Wheatley等人(1990)在Bioma-terials,11,713-717公开了藻酸盐的离子凝胶作用以形成直径大于30微米的微气泡。WO 91/09629公开了用作超声对比剂的脂质体。
我们现在已经发现了一种将微胶囊形成剂溶液雾化,然后降低所形成胶囊的可溶性的方法可产生一种改进的产品,Przyborowski等人(1982,Eur.J.NuCl.Med. 7,71-72)公开了通过喷雾干燥来进行放射标记的方法制备人类血清白蛋白(HSA)微球体以及随后在肺部闪烁扫描成像中的应用。微球体未被说成是空心的,且在反复制作中,我们只作出了固态微球体。除非颗粒是空心的,否则这些颗粒不适于回波心动图。此外,该微球体是采用一步法制备的,该方法不适于制备用于回波心动图的微胶囊,在已有方法中,必须从微球体中除去未变性的白蛋白(在我们的方法中不必这样做);并且显然所获得的微球体的尺寸范围宽,因为必须要进行进一步的筛选。因此,Przyborowski等人的方法不仅不是一个明显的可选择用于制备用于超声成像的微胶囊的方法,而且制成的颗粒不适于该目的。我们已发明了一种大大优于该已有方法的改进方法。
Przyborowski等人的文章提到了两种早些时候已公开的获得用于肺部闪烁扫描的白蛋白颗粒的方法。Aldrich和Johnston(1974)Int.J.Appl.Rad.Isot.25,15-18公开了利用一个旋转圆盘产生3-70微米直径的颗粒,然后将颗粒在热油中变性,除去油份并将颗粒用放射性同位素标记。Raju等人(1978)在Isotopenpraxis 14(2),57-61中利用同样的旋转圆盘技术,但采用简单加热颗粒使白蛋白变性。没有一种情况提到空心微胶囊,并且制成的颗粒都不适用于回波心动图。
本发明的一个方面是提供一种方法,包括第一步,为了获得微胶囊,将一种构成壁物质的溶液或分散体雾化。
优选地,由此获得的制品经过第二步,降低至少所述微胶囊外侧的水溶性。
所说的两个步骤可以作为一个单一的方法进行,或者收集第一步的中间产品,并在第二步骤中单独进行处理。这两种可能性在此后被称作一步法和二步法。
形成壁的物质和工艺条件应该这样选择以使得制品在使用条件下为充分地无毒的和非致免疫的,使用条件很清楚依赖于施用剂量和治疗时间。形成壁的物质可以是一种淀粉衍生物,一种合成聚合物,如聚谷氨酸叔丁基羰氧基甲基酯(美国专利第4,888,398号)或一种聚糖如聚葡萄糖。
总体来讲,形成壁的物质可以从大部分亲水的,可生物降解的生理相容聚合物中选择。在这些聚合物中,可以列举出具有低水溶性的聚糖、聚交酯和聚乙交酯及其共聚物,交酯和内酯的共聚物,如ε-己内酯,δ-戊内酯,多肽和蛋白质,如凝胶、胶原蛋白、球蛋白和白蛋白。其它合适的聚合物包括:聚-(正)脂(见例如美国专利US-A-4,093,709;US-A-4,131,648;US-A-4,138,344;US-A-4,180,646);聚乳酸和聚乙二醇酸及其共聚物,例如DEXON(见J.Heller(1980)Biomaterials 1,51;聚(DL-交酯-CO-δ-己内酯),聚(DL-交酯-CO-δ-戊内酯);聚(DL-交酯-CO-g-丁内酯),聚腈基丙烯酸烷基酯;聚酰胺,聚羟基丁酸酯;聚二恶烷酮;聚-β-氨基酮(Polymer 23(1982);1693);多膦嗪(Science 193(1976),1214);及聚酐。有关生物降解聚合物的参考文献可见R.Langer等人(1983)在Macromol.Chem.Phys.C23,61-125的文章。聚氨基酸,如聚谷氨酸和聚天冬氨酸,以及它们的衍生物,即带有低级乙醇或乙二醇的部分脂也可被使用。这种聚合物的一个有用的例子是聚-(叔丁基-谷氨酸)。与其它氨基酸,如蛋氨酸、亮氨酸、缬氨酸、脯氨酸、甘氨酸、丙氨酸等的共聚物也是可能的。最近报道了一些新的具有可控制的生物可降解性的聚谷氨酸和聚天冬氨酸的衍生物(见收编于此作为参考的WO 87/03891;美国专利US4,888,398和EP130,935)。这些聚合物(以及 与其它氨基酸的共聚物)具有下列形式的分子式:
其中X表示一个氨基酸残基的侧链,A是一个由分子式-(CH2)nCOOR1R2OCOR(Ⅱ)组成的基团,其中R1和R2为H或低级烷基,R为烷基或芳基,或R和R1被一个取代的或非取代的连接节连在一起以形成一个5-或6-节环。
A也可以代表分子式基团:
以及
以及相应的酐。在所有这些分子式中,n,m和p为较低的整数(不超过5),且x和y也是整数,它们的选取使分子量不低于5000。
前面提到的聚合物适合于制作本发明的微球体,并依赖于取代基R、R1、R2和X的特性,壁的特性例如强度、弹性及生物可降解性是可以控制的。例如X可以是甲基(丙氨酸)、异丙基(缬氨酸)、异丁基(亮氨酸和异亮氨酸)或苯基(苯丙氨酸)。
优选地,形成壁的物质是蛋白质。例如,它可以是胶原蛋白、凝胶或(血清)白蛋白,在每种情况中,优选的是来源于人类(即取自人类或在结构上与人类蛋白质相一致)。最优选地,是从捐献血液中得到的人类血清白蛋白(HA)最理想的情况是,由已经转化或转染以表达HA的微生物(包括细胞系)发酵得到。
表达HA(该术语包括人类白蛋白的类似物和片段,例如欧洲专利EP-A-322094中的那些以及单体白蛋白的聚合物)的技术,已在例如欧洲专利EP-A-201239和EP-A-286424中作了公开,所有参考文献被收编于此作为参考。HA的“类似物和片段”包括所有这样一些肽:(ⅰ)能够在本发明的方法中形成微胶囊,并且(ⅱ)其中至少50%(最好至少75%、80%、90%和95%)的氨基酸序列的一段连续区域与至少50%(最好75%、80%、90%或95%)人类白蛋白的一段连续区域至少有80%是同系的(最好至少90%、95%或99%是同系的)。通过重组DNA技术产生的HA是特别优选的。因此,正如在本技术领域内已知的,可以通过在酵母或其它微生物中表达HA编码核苷酸序列并将生成物纯化的方法来产生HA。这种物质缺少与血清中得到的物质有关的脂肪酸。HA最好基本上不含脂肪酸;即它包含少于1%的由血清获得的物质的脂肪酸含量。最好脂肪酸在HA中是测不出来的。
在下面对优选实施例的描述中,使用了“蛋白质”一词,因为这是我们所优选的,但应该理解,如上面所讨论的,可以使用其它生物相容的形成壁的物质。
蛋白质溶液或分散液优选地是含0.1至50%重量/体积,更优选地为约5.0-25%的蛋白质,特别是当蛋白质是白蛋白时。约20%是最优选的。可以利用形成壁物质的混合物,在这种情况下,上面提到的百分比是指形成壁的物质的总含量。
要被雾化的制剂可包含除形成壁的物质和溶剂或液态载体以外的物质。因此,水相可含有重量1~20%的水溶性亲水化合物如糖及聚合物作为稳定剂,例如,聚乙烯醇(PVA)、聚乙烯吡咯烷酮(PVP)、聚乙二醇(PEG)、凝胶、聚谷氨酸及聚糖如淀粉、葡聚糖、琼脂、 黄原胶及类似物。一些类似的水相还可被用作成品微球体制品在使用前被悬浮于其中的液态载体。可以使用乳化剂(占重量的0.1~5%),包括大多数的生理学上可接受的乳化剂,如卵卵磷脂或大豆卵磷脂,或合成的卵磷脂如饱和的合成卵磷脂,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的合成卵磷脂,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,如游离脂肪酸,带有聚氧化烯化化合物,如聚氧丙烯乙二醇和聚氧乙烯乙二醇的脂肪酸脂;带有聚氧化烯乙二醇的脂肪醇醚;带有聚烷氧基化的脱水山梨醇的脂肪酸脂;皂;丙三醇-聚亚烷基硬脂酸;丙三醇-聚氧乙烯蓖麻醇酸酯;聚二醇的同系物和共聚物;聚乙氧基化的豆油和蓖麻油以及氢化的衍生物;蔗糖或其它带有脂肪酸、脂肪醇糖类的醚和酯,这些糖类也可以是聚烷氧基化的;饱和或未饱和脂肪酸的一-,二-和三甘油酯,甘油酯或豆油和蔗糖。
可以在微球体的壁中加入添加剂以提高其物理特性,如弥散性、弹性和透水性。
在有用的添加剂中,可列举出一些为降低透水性使壁“疏水化”的化合物,如脂肪、蜡及高分子量碳氢化合物。改进微球体在可注射液载体中的弥散性的添加剂是两亲化合物,如磷脂;它们还可增加透水性和生物降解率。
增加壁弹性的添加剂是增塑剂,如肉豆蔻异丙酯及其类似物。而且,非常有效的添加剂是由与壁本身类似的、但具有较低分子量的聚合物构成。例如,当使用聚交酯/聚乙交酯型共聚物作为构成壁的物质时,通过加入作为添加剂的低分子量(1000至15,000道尔顿)的聚乙交酯或聚交酯,可以使壁的特性有利地改善(提高柔软性和生物可降解性)。而且具有中等到低分子量的聚乙二醇(例如PEG2000)也是一种有效的柔软添加剂。
在壁中要加入的添加剂的数量是很不同的并按需要的不同而变化。在某些情况下根本就不用添加剂;在另外一些情况下添加剂的数量达到壁的重量的约20%也是可能的。
此后被称为“蛋白质制剂”的蛋白质溶液或分散液(最好是溶液)采用任何适当的技术被雾化并喷雾干燥,以产生直径在1.00-50.0微米之间的离散的微囊。这些数字代表至少90%的比例的微胶囊,用Coulter Master Sizer Ⅱ测量直径的。“微囊”一词意思是包含一个空间的空心颗粒,其中空间里充有一种气体或蒸气,但不带有任何固体物质。类似于在英国以“Maltesers”(注册商标)出售的蜜饯的蜂窝状颗粒未能形成。对于该空间来说不必是全部封闭的(尽管这是优选的),而且对于微囊来说,尽管他们通常是圆形的,但不必是精确的珠体。如果微囊不是珠形的,则上面所指的直径是和非珠形微囊具有相同质量并封闭相同体积的空间的相对应的珠形微囊的直径。
雾化包括:通过例如,由在压力下迫使蛋白制剂通过至少一个口或利用离心雾化器使该制剂进入热空气或其它惰性气体的腔室中,形成该蛋白质制剂的气悬体。腔室应足够大以使得最大的喷射液滴在干燥前不会碰撞腔壁。腔内的气体或蒸气是纯净的(即最好是消毒的并且无热原的)并在回波心动图中,伴随微胶囊的注入而以一定数量进入到血流中时,是无毒的。来自蛋白质制剂的液体的气化率应足够高以便形成空心微胶囊,但不能太高以至于弄破微胶囊。可以通过改变气体流速,在蛋白质制剂中的蛋白质浓度、液体载体的性质、溶液的送给速率,及最重要的是该气悬体所遇到气体的温度来控制气化率。在水中含15%-25%的白蛋白浓度的情况下,至少约为100℃,最好至少为110℃的进气温度一般足以保证形成空心体并且温度可以高至250℃而不会造成胶囊破裂。至少对于白蛋白来说,约为180~240℃,优选地约为210~230℃且更优选地约220℃是最佳的。在本发明的一步式方法中,温度可足以使至少部分的(通常为外侧)构成壁的物质,通常使基本上所有的构成壁的物质不溶解化。由于该气悬体所遇到的气体温度还依赖于气悬体的传输速率和蛋白质制剂的液体含量,可监测出口温度以保证腔室内适当的温度。已发现40~150℃的出口温度是合适的。但除此因素以外,控制流速尚未被发现像控制其它参数同样有效。
在两步法中,中间产生的微囊一般包括96-98%的单体HA并对于超声成像来说在体内具有有限的寿命。但它们可被用于超声成像,或者在进行两步法的第二步之前,可将它们存贮和输送。因此它们可构成了本发明的另一方面。
在方法的第二步中,在第一步中制备的中间微囊是凝固的并赋予它较低的水溶性以便持续更长时间,但又不是那样不可溶和惰性的以至于使它们不可生物降解。这一步骤还增加了微囊的强度以便它们能够更好地经受住剧烈的注射、血管切应力和心室压力。若微胶囊破裂,则它们的回波降低,Schneider等人(1992)在Invest.Radiol 27,134-139中指示已有技术中用声波处理过的白蛋白微气泡不具有这种强度,并且当经受标准左心室压力时会立即丧失其产生回波的特性。方法的第二步骤可采用加热(例如微波加热,辐射热或热空气,例如在普通的加热炉中),离子辐射(用例如,10.0-100.0KGy剂量的γ射线)或化学交联,例如,利用甲醛、戊二醛、氧化乙烯或其它交联蛋白质的试剂,并对由第一步形成的基本上干燥的中间微囊进行,或者对该微囊在一种液体中的悬浮液进行,在这种液体中,微囊是不溶的,例如一种适当的溶剂。在一步式方法中,交联剂如戊二醛可以喷入喷雾干燥腔中或可以就在喷雾装置的上游引入到蛋白质制剂中。作为另一种办法,腔内的温度要足够高使微囊不可溶解化。
如果希望的话,用与测量中间微囊同样的方式进行测量,最后的制品包含具有0.05至50.0微米直径的微胶囊,但是0.1至20.0微米范围的直径,且特别是0.1至8.0微米直径也可用本发明的方法得到的并优选将它们用于回波心动图。我们发现约0.5至3.0微米的范围特别适于低对比成像的产生,并适用于彩色多普勒成像,而约4.0至6.0微米的范围对于产生高对比度的成像来说效果更好。在确定由第一步骤产生的微囊尺寸时,人们需考虑这样一个事实,即第二步骤可以改变微囊的大小。
已发现,为获得所需特性的微球体,可以调整本发明的方法。因此,蛋白质溶液输送到喷嘴的压力是可以变化的,例如,从1.0至10.0×105帕,优选地为2.0-6.0×105帕,且最好是约5×105帕。如上面和下面所公开的,其它参数也是可变化的。以此方式,可得到新型的微球体。
本发明的另一个方面是提供一种空心微球体,其中多于30%,优选地,多于40%、50%或60%的微球体具有2微米范围内的直径,并且至少90%最好至少95%或99%的微球体具有1.0至8.0微米范围内的直径。
因此,四分位数的间距可以是2微米,并且有3.5、4.0、4.5、5.0、5.5、6.0或6.5微米的中值直径。
因此,至少30%、40%、50%或60%的微球体可具有1.5-3.5微米、2.0-4.0微米、3.0-5.0微米、4.0-6.0微米、5.0-7.0微米或6.0-8.0微米范围内的直径。最好所述百分比的微球体具有1.0微米间距范围内的直径,如1.5-2.5微米、2.0-3.0微米、3.0-4.0微米、4.0-5.0微米、5.0-6.0微米或6.0-7.0微米或7.0-8.0微米。
本发明的另一方面是提供具有蛋白质壁的微球体,其中至少90%,最好至少95%或99%的微球体具有1.0-8.0微米范围内的直径;至少90%,最好至少95%或99%的微球体具有40-500纳米,最好100-500纳米的壁厚;且至少50%的微球体壁中的蛋白质是交联的。最好至少75%、90%、95%、98.0%、98.5%或99%的蛋白质是充分交联的以至于能忍受用1%的HCl溶液的两分钟萃取。被萃取的蛋白质采用Bradford的Coomassie Blue蛋白质分析法检测。交联度通过改变蛋白质的加热、辐射或化学处理来进行调节。在交联过程中,就像用凝胶渗透HPLC(高压液相色谱)或凝胶电泳测试到的那样,蛋白质单体被交联,并且很快就变成不能在简单的溶解过程中被取得,如下面实例8中所示。连续处理可导致已交联物质的进一步交联,以致在上述HCl萃取中成为不可得到的。在以175℃加热过程中,本发明的rHA微球体在20分钟内失去约99%的HCl-可萃取的蛋白质,而在150℃时,20分钟的加热仅除去约5%的HCl可萃取的蛋白质,30分钟的加热除去47.5%,40分钟除去83%,60分钟除去93%,80分钟除去97%和100分钟除去97.8%的HCl-可萃取的蛋白质。因此,为获得良好的交联度,微球体可在175℃下加热至少17-20分钟,在150℃下加热至少80分钟并在其它温度下加热一段相应更长或更短的时间。
本发明的另一方面是提供直径主要在1.0-10.0微米的空心微球体,当悬浮在水中时,至少10%的微球体能够在施加0.25秒的2.66×104帕压力下保存下来而不会破裂,塌陷或进水。人类左心室中的最大瞬时压力为200毫米汞柱(2.66×106帕)。最好当如上述测试时,在0.25秒的2.66×106帕压力下,有50%、75%、90%或100%保存下来,即保留产生回波。在体内,最好在一次通过心脏两个心室过程中有同样百分比的微球体保留产生回波的特性。
本发明可注入的微球体,在含或不含添加剂的情况下可保存在干燥处以便改善存贮并防止融合。作为添加剂,人们可选择重量的0.1%至25%水溶性的生理上可接受的化合物,如甘露糖醇,半乳糖、乳糖或蔗糖,或亲水性聚合物如葡萄糖、Xanthan、琼脂、淀粉、PVP、聚谷氨酸、聚乙烯醇(PVA)及凝胶。微球体在可注入的液态载体相中的有效寿命,即观察到有效的回波信号的时间,可按需要调整从几分钟延长到几个月,这可通过调整气隙率、溶解性或壁的交联度来完成。可以通过适当地选择构成壁的物质及添加剂,并通过调节气化率及喷露干燥腔中的温度来调整这些参数。
为了将微囊的凝聚作用降到最低限度,可采用装有0.5毫米筛子的Fritsch离心针形研磨机或Glen Creston气体冲击式喷气研磨机,将适当的惰性赋形剂与微囊一起研磨,适当赋形剂是惰性的并适于静脉内使用的磨得很细的粉末,如乳糖、葡萄糖、甘露糖醇、山梨醇、半乳糖、麦芽糖或氯化钠。一旦研磨,微囊/赋形剂混合物可悬浮在液态介质中以便于除去不起作用的/损坏的微囊。当在液相中重组后时,希望包括微量的表面活性剂以防止凝聚。适于该目的的阳离子、阴离子和非离子表面活性剂包括poloxamers,山梨醇酯,多乙氧基醚和卵磷脂。
然后让微囊悬浮物浮起来,或可被离心以沉淀出任何表面有破损,进而在应用中导致液体进入并不再有回波特性的损破的颗粒。
然后,将微囊悬浮液重新混合以保证均匀的颗粒分布,并在适于静脉注射的缓冲液,如0.15摩尔NaCl,0.01毫摩尔缓血酸胺PH7.0中清洗和重组。悬浮液可被等分,作冷冻干燥并随后用例如,γ辐射、干燥加热或氧化乙烯进行灭菌。
降低不溶解或凝固微囊的凝聚作用的另一种方法是将微囊直接悬浮在水性介质中,该水性介质中包含选自poloxa mers、山梨醇酯、多乙氧基醚和卵磷脂的表面活性剂。利用一种适当的均化器可得到凝聚作用的降低。
然后可让微囊悬浮物漂浮起来或被离心以沉淀出损坏的颗粒,如上所述,并如上进一步处理。
尽管本发明的微囊可以以干燥状态进行销售,特别是当设计成注入后具有有限寿命时,但是希望微囊还以现成制剂方式销售,即准备注射的在水性液体载体中的微囊悬浮物。
然而,制品通常以干燥粉末的形式供应和储存,并仅仅在注入之前悬浮在一种适当灭菌的、无致热原的液体中。悬浮液通常以注射方式向适当的静脉内,如肘静脉或其它血管内注入约1.0-10.0毫升。具有约1.0×105至1.0×1012颗粒/毫升的微囊浓度是合适的,最好约为5.0×105至5.0×109。
尽管超声成像可应用于各种动物和人体器官系统,其主要应用之一是获得心肌组织和灌注或血流方式的图象。
该技术利用了由扫描器和成像装置组成的超声扫描设备。该设备产生了预定区域的可见图像,在这种情况下,预定区域是人体心脏区域。一般地,变送器直接放置在要成像区域上方的皮肤上。扫描器装有包括超声变送器在内的各种电子部件。变送器产生对心脏区域施行扇形扫描的超声波。超声波被心脏区域的各部分反射,并被接收变送器所接收,并根据本技术领域内已知的脉冲-回波法进行处理。处理之后,信号被送到成像装置(也是本技术领域内已知的)供观察。
在本发明的方法中,在患者“准备好”并且扫描器就位后,将微囊悬浮液例如通过一个臂静脉,注入。对比剂通过静脉流入心脏的右侧静脉,通过主肺动脉,流向肺部,穿过肺部,通过毛细管进入肺静脉并最后进入心脏的左心房和左心室腔。
利用本发明的微囊,可以观察和诊断血液流过肺部所需时间,血流方式,左心房大小,二间瓣(分隔左心房和左心室)能力,左心室腔的大小及室壁运动的异常。根据从左心室射出的对比剂,还可分析主动脉瓣的能力,同时还可分析从左心室射出的体积的量或百分比。最后,组织中的对比图形将表示哪些区域,如果存在的话,没有充分灌注。
总而言之,这样一种成像方式会有助于诊断异常的心脏血流特性,瓣膜活性,腔体大小,及室壁运动,并提供一种心肌灌注的潜在的表征。
这种微囊可允许从静脉注入获得左心成像。当注入外周静脉时,白蛋白微囊能够穿过肺部通道。这样就导致了左心室(LV)腔及心肌组织回波心动图的不透光性。
除了如上简要描述的扫描器外,还存在其它的超声扫描装置,其实例在美国专利Nos.4.134,554及4,315,435中作了公开,这些公开文献被收编于此作为参考。从本质上讲,这些专利是关于包括动态剖面回波图(DCE)在内的各种技术,借助一个以足以能够动态显示运动器官的帧速率的超声能量,来生成动物或人类解剖学剖面切片的接续二维图像。用于DCE中的各类装置一般被称为DCE扫描器,它们以窄射束或射线的形式发送和接收短的声脉冲。反射的信号强度是时间的函数,而时间又可以利用普通声速被转化为一个位置,反射信号以有些类似于雷达或声纳定位显示的方式显示在阴极射线管或其它适当的装置上。虽然DCE可被用于包括肝脏、胆囊、胰腺及肾脏在内的许多器官系统的成像,但它常被用于显示心脏组织及心脏主要血管的图像。
该微囊可被用于大范围区域的成像,即使当在外周静脉点注射时。那些区域包括(并非限制):(1)通往心脏的静脉导液系统;(2)在实施踏旋器试验或类似试验过程中的心肌组织及灌注特性;以及(3)在口服或静脉注射意在增加到达心肌组织的血流量的药物之后的心肌组织。此外,该微囊在显示由于如下情况的干预而发生心肌组织灌注的变化方面是有用的,(1)冠状动脉静脉搭桥;(2)冠状动脉的血管成形术(变窄动脉的球囊扩张);(3)应用溶解血栓的试剂(如链球菌激酶)以溶解冠状动脉内的血块;或(4)由于近期心脏病发作而产生的灌注缺陷或改变。
而且,在冠状血管造影期间(或数字减法血管造影),注入微囊可提供有关组织灌注特性方面的信息,它扩大和补充了从仅能表示血管解剖特性的血管造影过程中获得的信息。
通过使用本发明的微胶囊,其它的用超声技术即刻成像的包括肝脏、脾脏及肾脏等心脏器官系统可适用于增强这种现在可获得的图像,和/或产生新的显示灌注和流动特性的图像,利用已有的超声成像技术的成像对灌注和流动特性是不敏感的。
现在将以实例的方式并参考附图对本发明优选的方面进行描述:
图1是用于本发明方法的第一阶段中适当的喷雾干燥装置从前和侧面得到的部分剖开的透视图,
图2是一个曲线图,表示如何通过改变该方法第二步骤中的温度和加热时间来调整微球壁(在该情况下为白蛋白)的凝固程度,和
图3是一个曲线图,表示如何通过改变该方法第二步骤中的加热时间长短来改变微球体的耐压性。
实施例1.
一种合适的喷雾干燥器(图1)可由丹麦Soeborg的A/S Niro Atomizer得到,商品名为“Mobile Minor”。它包括一个由空气涡轮以最小4巴至最大6巴的气压驱动的离心雾化器(M-20/B Minor型),在6巴压力下,雾化器轮速达到约33,000转/秒。通过安装在操纵盘上的一个阀装置接通或关闭通往雾化器的压缩空气。通往雾化器的压缩空气的最大消耗量在6巴的压力下是17标准立方米/小时。所有与液体输送和粉末接触的部件都是由不锈钢AISI316制成的,除了由不锈钢AISI329制成的泵输送管和雾化器轮以能抵抗强大的离心力。
干燥腔有一个由不锈钢AISI316制成的内侧,用Rockwool很好地保温,外侧复盖层是低碳钢薄板。干燥腔装有一个侧光源,和一个在操作过程中供观察用的观察窗。干燥腔顶部内侧由不锈钢AISI316制成,而外侧由不锈钢AISI304制成。
为获得最佳可能的干燥效果,使用一个由不锈钢AISI304制成的空气分散器以便在干燥腔中进行空气的分配。由不锈钢AISI316制成的空气管提供了消耗的空气和粉末到旋流器的横向传送,旋流器由不锈钢AISI316制成,并设计成将粉末和空气相隔离。
也是由不锈钢AISI316制成的,并具有一个硅橡胶垫圈的一个蝶阀型的封闭阀被用于在旋流器的帮助下,将粉末排放到靠一个弹簧装置紧挨着旋流器下面放置的粉末收集玻璃容器内。
一个由铝硅合金制成的,与0.25千瓦三相鼠笼式电动机,和带有皮带保护罩的三角皮带传动装置构成一体的风扇通过干燥腔和旋流器将空气和粉末吸入。
一个空气加热器利用电能(总消耗量为7.5千瓦小时/小时,可无级变化的)将干燥空气加热,并且能达到高至约350℃的内部空气温度,尽管这一温度通常对于本发明微囊的制备来说太高了。
可以加入两流体喷嘴式雾化的设备,它由不锈钢AISI316制成,并包括带有喷嘴支座和喷嘴的输入管,放置在干燥腔的顶板上。该设备包括一个油/水分离器,减压阀和用于到达两流体喷嘴的压缩空气的压力表。压缩空气的消耗量:在0.5-2.0巴(0.5-2.0×105帕)的压力下为8-15公斤/小时。
合适的,用于将构成壁的制剂传送给雾化装置的输送泵是蠕动泵。该泵装有一个电动机(1×220伏,50赫兹,0.18千瓦)和一个用于手动调节的连续可变的齿轮。一个由硅胶皮管制成的输送管由供给箱(当地料源)中引出,通过输入泵,接到雾化装置上。
一个独立的空气过滤器,包括预过滤器,不锈钢的过滤器体和独立的空气过滤器,被用于处理进入的干燥空气,以使其变得十分纯净。
在无致热原的水(适于注射)中的灭菌无致热原的rHA的20%的溶液被泵入到装在上述市售喷雾干燥装置内的一个两流体喷嘴式雾化器的喷嘴中。蠕动泵的速度被保持在约10毫升/分的速率,以便对于220℃的入口空气温度,出口空气温度能保持在95℃。
压缩空气以2.0-6.0巴(2.0-6.0×105帕)的压力供给到两流体雾化喷嘴。在该压力范围内,可得到具有平均大小为4.25-6.2微米的微囊。
一般地,平均颗粒大小的增加(通过降低雾化压力)会导致超过10微米大小的微囊数量的增加(见表1)。
表 1 雾化压力对直径超过10微米的微囊出现率的影响
雾化压力(1×105 帕)6.05.03.52.52.0 | 大于10微米的%出现率0.80.36.08.613.1 |
在该方法的第二步中,利用一个Gallenkamp风扇型加热炉,将5克微囊放在一个玻璃烧杯中加热。在175℃的温度下加热一小时足以得到由HPLC测定为100%凝固的微囊。这种加热凝固效应将在试管内的回波半寿命从几秒钟提高到超过30分钟。通过改变加热温度和保温时间,有可能使凝固度在5%至100%之间变化。改变温度的加热凝固曲线的例子表示在图2中。
随着加热凝固,微囊被解凝聚,并以两种方式之一分散到水中,方法1包括首先将加热凝固的球体与等重量的磨细的乳糖(平均直径5微米)混合。然后让混合物通过一个带有0.5毫米筛板和12齿转子的Fritsch离心研磨机。研磨过的球体被收集并第二次通过研磨机以确保已充分混合。然后研磨过的粉末重新悬浮在含有一毫克。毫升-1pluronic F68的水中。一般将10克的微囊和乳糖加入100毫升的水和pluronic F68中。解凝聚的方法2包括在100毫升含有100毫克的pluronic F68的水中加入5克加热凝固的微囊。利用Silverson均化器(型号为L4R具有一个2.54厘米的管形均化头和一个高剪切筛板)将微囊分散并均化60秒钟。
利用漂浮技术将重新悬浮的球体分离成完整的(含气体的)和破裂的球体。一小时以后可见含气体的球体漂浮在表面并通过倾注将其与不含所需气体而下沉的微粒分离。可采用离心法加速分离过程。在5000倍的重力加速度下,离心30秒钟作用足以将两种微粒分离。
随着分离作用,完整的微囊在有乳糖和pluronic F68存在的情况下被冷冻干燥。冷冻干燥的最佳条件包括让50毫克的微囊重新悬浮在含有50毫克乳糖和5毫克pluronic F68的5毫升水中。冷冻干燥的微胶囊可被重新分散到一种液体(例如水、盐水)中以获得单分散的分布状态。
实例2
重复实例1中的过程,但在第一步中存在下列区别:利用一个离心雾化器替代两流体喷嘴;入口温度为150℃(让出口空气温度仍维持在105℃);并以1.0-6.0×105帕的压力将压缩空气供给喷嘴。轮子以20-40,000转/分钟的速度旋转并甩出液滴,随后得到平均直径数值在1.0-8.0微米范围内的微囊。
实例3
在实例1或2方法的第二步中有如下改变:一小部分的微囊(0.5克)在一个微波炉上被加热,以使其在2500兆赫的频率下获得300-350瓦小时的微波热量。由此得到的90%-95%的单体rHA是不可溶解的微囊(由凝胶渗透色谱法测定的)并且做为这种加热凝固的结果是它们在试管内的产生回波的半寿命从几秒钟增加到超过30分钟。
实例4
在实例1或2的方法的第二步中有如下改变:一小部分的微囊(0.5克)在氩气作用下被密封在一个玻璃管内。玻璃管被冷却到4℃,然后用一个钴60γ射线源给它15.0KGy剂量的γ射线照射。这种照射导致形成了其中有10-15%的单体白蛋白是不可溶解的微囊。
实例5
在实例1或2的方法的第二步中有如下改变:一小部分的微囊(0.5克)在氩气作用下被密封在一个玻璃管内。玻璃管被冷却到4℃,然后用一个钴60γ射线源给予50.0KGy剂量的γ射线照射。照射之后微囊在氧气内维持50℃保温6小时。这种照射导致形成了其中有50-60%的单体rHA是不可溶解的微囊。
实例6
在实例1或2的方法的第二步中有如下改变:将一小部分的微囊(0.5克)悬浮在5毫升的乙醇、三氯甲烷或二氯甲烷中,其中包含a)1.5%的戊二醛,b)2.0%的氯化二邻苯二甲酰或c)5.0%的甲醛。微囊被搅拌10分钟到3小时不等。然后通过过滤提取微囊并在含有5%乙醇胺的原始有机缓冲液中充分清洗以便除去多余的交联剂。最后在有机溶剂中清洗微囊,并真空干燥以除去残留的溶剂。由这种方法造成的不溶解的程度可在5-100%的范围内变化,导致试管内的致回波的半寿命从1-2分钟延长到超过一小时。
实例7
微囊形成和使外壳的不溶解化的两个独立的步骤可以组合成为一个单一的过程。在该实例中微囊的形成和聚合物质的不溶解化是通过喷雾干燥过程同时获得的。
rHA溶液通过蠕动泵送到一个小反应腔中同时用一个分开的输送线供给含5%的适当的交联剂溶液,例如戊二醛,氧化二邻苯二甲酰或甲醛。在反应腔内停留的时间使得在交联剂和蛋白质之间开始形成加合物但不会产生蛋白质之间的交联。反应容器出口被直接接到装在一个特别采用的喷雾干燥装置的两流体喷嘴雾化器上,并能处理易挥发的溶剂。雾化干燥的条件如在实例1中所列。微囊在室温下恒温干燥以允许形成蛋白质之间的交联,然后悬浮在含5%乙醇胺的乙醇中以抑制任何残留的交联剂。充分清洗微囊,最后微囊被真空干燥以除去残余的溶剂。
实例8:微囊中游离的单体rHA的测定
在20毫升玻璃瓶内的100毫克的微囊中加入1毫升体积的乙醇,并用声波处理30秒钟。再向该悬浮液中加入19毫升的水。
将混合物在一个台式微量离心机(Gilson)中离心20秒钟,并对澄清的组分进行测定。通过将50毫升这种组分自动装在Shimadzu LC6A HPLC上,并用磷酸钠缓冲液(PH7.0)在TSK凝胶渗透柱上以1毫升/分的流速作色谱分析来进行测定。
代表rHA单体的峰值高度被记录下来,并利用1到10毫克/毫升单体rHA之间的标准曲线来确定单体浓度。
通过测量凝固的微囊中的单体浓度来计算游离单体rHA的百分比,并以未凝固微囊的百分比单体浓度表示该值。结果在图2中给出。
在加热炉(如实例1所述)内加热喷雾干燥的微囊导致了可被测得的单体数量上的减少(见图2)。这种可测得的单体rHA的减少是由于单体rHA的变性和交联成为不可溶解的聚合物的缘故,不可溶解聚合物用前面提到的HPLC法无法测得。
利用HPLC法估测rHA单体值,由图2很清楚地看出,在15分钟的保温之后,在rHA微囊中不存在游离的单体rHA。然而,通过加热更长一段时间,rHA微囊仍有可能进一步交联。
长时间加热会导致微囊交联度的增加,从而使微囊相应的耐压强度增加。
通过认真控制保温的温度和时间,有可能生成具有可控的交联范围(及耐压性)的微囊。
实例9:在175℃下的保温时间对于rHA微囊耐压性的影响
将一批rHA微囊分为5克一份的等分试样,并在175℃下烘烤如图3所示的不同的时间长度。
随着加热凝固,如实例8所述测定游离单体的数量。对于每一种图中显示的保温情况,不存在可测出的单体rHA。
利用Fritsch离心研磨机(如上所述)使加热凝固的微囊去除聚集,并通过前面提到的漂浮技术回收完整的,含空气的微囊。将被回收的微囊以0.5×108个囊/毫升的浓度悬浮在含Pluronic F68(1毫克/毫升)的水中。
在将该悬浮液装在一个封闭容器(25毫升聚苯乙烯容器)中的同时,用一只50毫升注射器施加压力,使重新悬浮的,含空气的微囊经受增加的大气压力。
对于每一个被评估的压力,将各个微囊悬浮液加压至所选择的压力并在释放压力之前将该压力保持5秒钟。对于每一份被分析的悬浮液,压力增加要进行3次。用RS手持式流体压力计测量该封闭容器中的压力。
随着加压过程,用光显微镜和图象来评估微囊,以及被评估微囊的含空气和不含空气的微囊的百分比。进行这种分析是因为只有含有空气的微囊在增强超声回波对比度方面起作用。
如可在图3中看出,如实例1中所述的,在175℃下凝固60分钟的微囊在该实验中所经受的所有压力下都是稳定的。
通过仔细控制在该特定温度(175℃)下的保温时间,有可能生成一批具有不同交联度,进而可耐受不同压力增加程度的微囊。
通过调节保温时间长短及温度来仔细控制交联,有可能生成一批专门设计成能耐受特定压力增加的含空气的微囊。
如同保温时间长短一样,用于使微囊交联的温度可以有无数的变化。
实例10:微囊的分类
本发明方法的一个优点就是它能够使微囊的中心大小及大小分布成为可控制的。但是,如需要,人们可以,例如采用漂浮法,进一步选择所希望的尺寸大小。在微囊的均化分散体中,较大的颗粒由于其较低密度(包容更多的空气)比较小的颗粒升到表面的速度要快。因此,通过让该分散体放着,在溶液任何高度层上的颗粒大小的分布随时间都将发生变化。
微囊被分散到一个具有约165毫米高液柱的玻璃瓶内的2000毫升的水溶液中,该溶液含6%重量/体积比氯化钠和0.1%重量/体积比的Pluronic F68。一个取样管被放置在该液体上表面以下50毫米处以便能够以定时的时间间隔上取样。
通过改变放置时间和氯化钠浓度,有可能生成各种颗粒大小分布,最小可分离出2微米的微囊。
其他湿式分选技术包括水压色谱法和区域漂浮分馏法。利用淘洗原理和交叉流动分离的“干式”技术,可以Microsplit (British Rem)Zig-zag(Alpine)和Turbo(Nissiun)分选器的形式由市场买到。由Nitettsu Mining公司生产的直角形喷射分选器利用一种不同的原理(Coanda 效应)也可以获得微囊分类的良好结果。
附图1说明:
A-送给装置
B-顶部空气扩散器保证了空气流动方式的有效控制,涡流空气直接围绕在有叶片的圆盘式雾化器周围。
C-旋转雾化器或喷嘴雾化器
D-不锈钢连接管系统可以很容易地拆下供清洗,
E-通向腔室顶部入口的踏板。
F-当腔盖上升时,用于驱动气压提升装置的空气阀
G-为增加装置灵活性的橡胶脚轮
H-粉末和排出的干燥空气在一个高效不锈钢旋流器内分离。
I-粉末在一个玻璃容器内被回收。
K-位于中心的操纵台
L-带有三相电动机的离心排风扇
M-用于空气流动控制的气流调节器
N-由空气加热器提供了高达350℃的干燥空气温度。干燥空气温度可通过一个百分比定时开关连续调节最大能量消耗为75千瓦。
电源:该装置只能在三相电源(50或60赫兹)上以交流电压440、415、400、380、220、200V进行工作。
所有与液体或产品接触的部件都是由耐酸的,不锈钢AISI316制成的
Claims (18)
1、一种方法,包括将一种在一液态载体中的构成壁的物质的溶液或分散体雾化到一种气体中,以便通过该液态载体的气化获得中空微囊的步骤。
2、根据权利要求1所述的方法,其特征在于由此获得的产品要经过另一个降低至少微囊外侧水溶性的步骤。
3、根据权利要求1或2所述的方法,其特征在于该构成壁的物质是一种蛋白质。
4、根据权利要求3所述的方法,其特征在于该蛋白质是胶原蛋白,凝胶或血清白蛋白。
5、根据权利要求4所述的方法,其特征在于该蛋白质是人类血清白蛋白,或利用DNA重组技术制备的一种类似物或其片段。
6、根据权利要求3到6中的任何一个所述的方法,其特征在于该蛋白质溶液或分散体包括10.0-30.0%的蛋白质。
7、根据权利要求3到6中的任何一个所述的方法,其特征在于在权利要求1的该步骤中,该蛋白质溶液或分散体如所述那样被雾化形成离散的0.01-50.0微米直径的微囊。
8、一种根据权利要求3到7中的任何一种所述的方法,其特征在于权利要求1中方法的产品包含有96-98%的单体蛋白质。
9、一种根据权利要求3到8中的任何一种从属于权利要求2时的方法,其特征在于该权利要求2步骤中的产品包含有不超过5%的单体蛋白质。
10、一种根据权利要求2到7中的任何一种所述的方法,其特征在于该权利要求1步骤的条件能基本上同时实现权利要求2的步骤。
11、利用根据权利要求1到10中任何一种方法得到的微囊。
12、利用根据权利要求1到10中的任何一种方法所可能获得的微囊。
13、空心微球体,其特征在于大于30%的微球体具有2微米范围内的直径并且至少有90%具有1.0到8.0微米范围内的直径。
14、空心微球体,其特征在于直径的四分位数间距是2微米或更小且中值直径在2.0微米到8.0微米之间并包括这两个值。
15、具有蛋白质壁的空心微球体,其特征在于至少90%的微球体具有1.0到8.0微米范围内的直径;至少90%的微球体具有40到500纳米范围内的壁厚且至少50%的微球体壁中的蛋白质被交联成使该蛋白质在1%的HCl中持续2分钟不会被萃取。
16、根据权利要求15所述的空心微球体,其特征在于至少95%的蛋白质是如所述那样地被交联的。
17、直径主要在1.0到10.0微米的空心微球体,当悬浮在水中时至少10%的微球体能够在施加0.25秒的2.66×104帕的压力下保存下来而不会破裂,塌陷或进水。
18、一种产生用于随后观察诊断的图象的方法,其特征在于包括a)向哺乳动物体内注入权利要求11到17的任何一种微囊,b)让哺乳动物或其某部位经受适当的超声辐射以及c)检测反射,透射,共振的超声辐射或由所说微囊所调制的频率。
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- 1992-04-10 DK DK95110723T patent/DK0681843T3/da active
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- 1992-04-10 AU AU15891/92A patent/AU655016B2/en not_active Ceased
- 1992-04-10 AT AT99203198T patent/ATE290405T1/de not_active IP Right Cessation
- 1992-04-10 WO PCT/GB1992/000643 patent/WO1992018164A1/en not_active Application Discontinuation
- 1992-04-10 US US07/956,875 patent/US5518709A/en not_active Expired - Lifetime
- 1992-04-10 EP EP92908598A patent/EP0533886A1/en active Pending
- 1992-04-10 NZ NZ242328A patent/NZ242328A/en not_active IP Right Cessation
- 1992-04-10 DK DK92303236T patent/DK0512693T3/da active
- 1992-04-10 PT PT95110723T patent/PT681843E/pt unknown
- 1992-04-10 CN CN92103376A patent/CN1066977A/zh active Pending
- 1992-04-10 DE DE69233148T patent/DE69233148T2/de not_active Expired - Fee Related
- 1992-04-10 ZA ZA922636A patent/ZA922636B/xx unknown
- 1992-04-10 PT PT92303236T patent/PT512693E/pt unknown
- 1992-04-10 ES ES95110723T patent/ES2203626T3/es not_active Expired - Lifetime
- 1992-10-29 RU RU92016571A patent/RU2109521C1/ru active
- 1992-12-09 FI FI925600A patent/FI925600A0/fi unknown
- 1992-12-09 GB GB9225716A patent/GB2260745B/en not_active Expired - Fee Related
-
1994
- 1994-10-07 AU AU74483/94A patent/AU691196B2/en not_active Ceased
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1995
- 1995-08-22 US US08/517,590 patent/US6022525A/en not_active Expired - Fee Related
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1998
- 1998-01-23 IL IL12303898A patent/IL123038A0/xx unknown
- 1998-06-17 HK HK98105577A patent/HK1006538A1/xx not_active IP Right Cessation
- 1998-08-19 JP JP10233181A patent/JPH11128232A/ja active Pending
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1999
- 1999-09-28 US US09/407,370 patent/US6569405B1/en not_active Expired - Fee Related
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2000
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1072966C (zh) * | 1994-11-19 | 2001-10-17 | 安达里斯有限公司 | 中空微胶囊的制备 |
CN101585892B (zh) * | 2008-05-22 | 2010-09-29 | 中国科学院化学研究所 | 一种制备聚合物微球的方法 |
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