CN1151846C - 核磁共振断层扫描成像用造影剂的制备方法 - Google Patents
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Abstract
本发明涉及一种制备核磁共振断层扫描成像用造影剂的方法，借助于磁过滤器来过滤基于铁磁性、亚铁磁性、超顺磁性、或顺磁性颗粒的颗粒悬浮液，并除去所述铁磁性、亚铁磁性、超顺磁性、或顺磁性颗粒，且该悬浮液中颗粒的弛豫比r2/r1在过滤之前为大于3.2，而在分离之后为3.2或更低，其中r1为T1弛豫，而r2为T2弛豫。
Description
本发明涉及核磁共振断层扫描成像用造影剂的制备方法，用该方法制备的核磁共振断层扫描成像用造影剂以及该造影剂的应用。
在药物制剂中，利用金属工具或在金属容器中或采用注射装置进行的生产操作可导致以金属颗粒状杂质形式存在的杂质颗粒。为保护病人，对于不经肠道给药的药物制剂，特别是输注用药剂中的多种杂质颗粒，根据其粒径加权重药典中规定了其最高限。这些杂质颗粒常为铁磁性、亚铁磁性、超顺磁性或顺磁性化合物。
可依据第4,119,700号美国专利中描述的方法分离起始物质中天然的铁磁性杂质。该发明借助一磁场将铁磁性杂质分离。从被公开的专利说明书WO 90/07380和WO 83/02405中可以得到生物材料磁性分离的方法。公开的专利说明书WO 90/07380中描述了一种装置，其中分离室被一个永磁体所环绕，并且该装置具有一个进口和一个出口。欧洲专利申请EP 670 185描述了一种类似的装置，用该装置可分离磁性标记的细胞。
对于药物制剂，利用吸附性过滤或膜过滤将杂质颗粒的数目尽可能减少。特别是对于由使用者的行为，如将药剂喷到输注容器中所产生的杂质，由于相应的微孔膜过滤器常常仅当添加机械压力时方可工作，故降低杂质颗粒的数目是困难的。在大多数情况下，输注装置中的过滤插件的孔径为几毫米，对于杂质颗粒其保留率并不令人满意。对于含有颗粒的药物制剂，如长效剂量形式的非胃肠道给药的脂肪乳剂或晶体混悬液，一般来说采用膜或吸附性过滤分离杂质颗粒是完全不可能的。
第3,817,389号美国专利描述了一种可结合在注射装置中的过滤器。该过滤器不是磁性的，而且不包括任何磁性颗粒。
本发明开发出一种核磁共振断层扫描成像用造影剂的制备方法，在该方法中借助于磁过滤器来过滤基于铁磁性、亚铁磁性、超顺磁性、或顺磁性颗粒的颗粒悬浮液，并除去所述铁磁性、亚铁磁性、超顺磁性、或顺磁性颗粒，且该悬浮液中颗粒的弛豫比r2/r1在过滤之前为大于3.2，而在分离之后为3.2或更低，其中r1为T1弛豫，而r2为T2弛豫。
所述磁过滤器使所有铁磁性、亚铁磁性、超顺磁性、或顺磁性化合物的分离成为可能。
用于分离的梯度磁场必须明显强于天然磁场的梯度。依赖于所分离物质的磁矩选择适当的梯度磁场。为将顺磁性化合物从反磁性药物制剂中分离出来，则需要高的梯度磁场。
为分离不期望有的磁性化合物，将各药物制剂或其起始或中间产物由装置中通过并因而通过一梯度磁场。梯度磁场的磁场梯度越高，对顺磁性、亚铁磁性、超顺磁性、或铁磁性杂质的作用力就越强。一般来说药剂和药物辅料(如水)为反磁性的，因此与顺磁性、亚铁磁性、超顺磁性、或铁磁性杂质相比，所受的作用力非常小。而且，所述作用力不仅不会使它们沿梯度方向运动，而且还会排斥它们。因此，为从反磁性制剂中分离磁性物质，与通过微孔过滤器过滤(如0.22μm膜过滤器)相反，依据本发明操作中一般不需在梯度磁场中施加特殊的压力；一般来说重力或液体静压力就足够了。
利用本发明的磁过滤器，借助于流动过程即可进行不期望有的磁性颗粒的分离。对于流动方法，与静止方法相反，流速必须与待分离的铁磁性、亚铁磁性或超顺磁性物质的磁矩以及所采用磁场梯度相匹配。
本发明的磁过滤器可以是无菌的。
本发明磁过滤器的实施方案可以多种方式实行。例如可通过一个安装于分离室外部的永磁体或电磁体在该分离室上产生梯度磁场。为增加磁场的局部有效梯度，分离室由顺磁性或软磁材料构成和/或包括顺磁体或优选的软磁材料是非常有用的。
该分离室具有一入口和一出口，而且其中存在磁场。
分离室中的梯度磁场也可由构成分离室或处于分离室之中的永磁性物质产生。
此外，分离室中的梯度磁场也可由带电的导体产生，该导体要么位于分离室之中，要么围绕分离室。在上述两种情况中，分离室由顺磁性或软磁性物质构成和/或包括顺磁性或优选的软磁性物质同样是非常有用的。
软磁性物质优选为软磁性的铁或钢，特别是以细颗粒(如直径几微米的球)或玻璃料形式存在的，或以线(如钢丝绒、网或筛网)形式存在的。
为防止不良的化学反应如腐蚀，分离室壁以及在分离室之内的软磁性或顺磁性物质和带电导体也可具有适当的保护性涂层。这些保护性涂层可为材料科学已知的材料。适用的有，如铬镀层、由稳定氧化物(如氧化铝)构成的保护性涂层、或塑料涂层(如PVC、聚苯己烯、聚乙烯)。当带电导体被放在分离室内产生梯度磁场时，任何情况下均必须用已知的绝缘材料进行绝缘(如涂层形式的塑料)。
图1中显示出作为附加过滤器的本发明磁过滤器可能实施方案的实施例。本发明的磁过滤器也可结合到注射或输注装置中。图2和3显示出结合到输注装置中用于磁性分离的磁过滤器实施方案。图4中显示出结合到注射装置中的磁过滤器的另一实施方案。图1所示的不同实施方案，如永磁性球或带电导体的使用，均可用于在所有结合进输注或注射装置中的本发明装置中进行磁性分离。
图5显示另一具体实施方案。分离室中包括软磁性盘，该盘含有孔洞并在分离过程中被磁化，被分离液体或悬浮液或溶液流经该孔洞。大量细孔径孔洞可获得非常高的供所分离液体接触的磁性表面。这样的盘或圆柱体优选用如药物生产过程使用的高标号钢制成。它们可被结合到管线系统中或适用于有特别纯度要求的药物生产过程中。相对于破坏性药剂成份，适用的高标号钢盘在大的pH范围中不被腐蚀。此外，它们易于清洗，另外可用于常规加热消毒法中。用位于分离室之外的环形磁体或带电线圈对软磁铁盘进行磁化，因此不需对环形磁体或带电线圈进行纯化。
调节钢盘的直径、孔洞的数量和相当于盘或圆柱体高度的长度，由此可调节所分离液体的流速、其保留时间或所分离液体与磁化体之间的比例，这样可获得最佳的分离度。此外，如果分离时将几个钢盘或圆柱体叠放在一起，且所述盘或圆柱体上的孔洞相互偏离，在钢盘或圆柱体上的流速可被减慢。
如果在分离室上部的钢盘不能被磁化或含有非磁化材料，而通过外部环状磁体或带电线圈将分离室中较低部位的盘磁化，这又得到另一个具体实施方案。这保证了磁性颗粒仅在分离室的较低部位被分离。
在本发明的药物制剂磁性分离过滤器中，特别有利的是后者可用简单的方法进行消毒，如热处理、膨胀水蒸汽的高压蒸煮、和通过环氧乙烷气体。此外，所述装置较常规膜或带孔过滤器更为稳定。本发明的磁过滤器也特别适用作预过滤器，在常规过滤操作，如灭菌过滤前降低杂质的数目。
本发明的另一方面涉及药剂、特别是造影剂的制备，它们可借助本发明的磁过滤器制得。本发明的磁过滤器适用于从药物制剂中选出某些基于顺磁性、超顺磁性、铁磁性或亚铁磁性颗粒的颗粒。
这可通过改变磁场强度获得。因此，具有特别高磁矩的颗粒可从含有不同磁性颗粒混合物的药物制剂中分离出来(如，一种用于核磁共振成像的、含磁铁矿的悬浮液)。
含有磁性颗粒的药剂，例如可用在核自旋断层照相中作造影剂。该领域中使用基料为超顺磁磁铁矿的悬浮液。令人十分吃惊的是根据其磁矩，利用梯度场强度可分离颗粒混合物，即本发明的方法可被控制成不完全沉降磁性颗粒，而是选择性分离，特别是保留具有高磁矩的颗粒。
为进行诊断，令人十分吃惊的是与原颗粒悬浮液相比，由此所得的药剂具有明显更优越的性能。因此可制得用途十分新颖的药剂，如用于核磁共振血管造影术或核磁共振淋巴造影术中的造影剂。
因此，借助于本发明的磁过滤装置，可对所得药剂的弛豫行为产生影响，并因此强化MRT技术中的造影效果。对于具体的医学诊断设备或诊断问题，优选的是改变与所给药超顺磁性颗粒相靠近的生理学分子中氢原子的T1弛豫，而在其它情况下改变T2弛豫(或适当改变两者)，可用于诊断或诊断成像。通过磁分离，如以下实施例所述也可对这些参数起作用。
借助该磁过滤器，也可能制备出与现有药剂相比具有改变磁性能的药物制剂。由于非经胃肠道给药的颗粒吸收进入人或动物网状内皮组织(RES)时需依靠于其尺寸，磁分离也可能影响药物制剂在体内的药代动力学性能。现今已知的控制粒径分布的方法尚不理想。后一方法是基于在药剂物质生产或过滤过程中难于控制的、昂贵的沉淀法。后者如上所述具有固有的缺陷。
考虑到材料加工或其它不适当的原因，如药剂或其配方不太稳定，通过离心或沉降法将不需要的、较大的超顺磁颗粒从胶体药剂中分离出来是十分昂贵的。
本发明的磁过滤器还可用于从顺磁性药物制剂，如用于治疗缺铁性贫血的铁盐溶液或胶体葡萄糖铁(如葡萄糖铁注射液，USP XXV)中分离出铁磁性或亚铁磁性颗粒。
以下实施例用于进一步描述本发明的主题，而并不对本发明起定界作用。
实施例1
将约100mg铁屑悬浮于10ml含4.69g轧喷酸、dimeglumine盐的水溶液中。用一环形磁体(RL 19，IBS Magnet Berlin，外径19mm，内径6.5mm，高10mm)制成如图1e所示的磁过滤器，其分离室位于环形磁体的内体积中。分离室由塑料制成的壁构成并充填有钢丝绒。不采用其它作用力而仅依靠静压力使悬浮液由磁过滤器中滤过。经过磁过滤后，显微学研究表明铁屑被过滤器从照影剂溶液中分离出来。
实施例2
用一环形磁体(NE 1556，IBS Magnet Berlin，外径15mm，内径5mm，高6mm)制成如图1a所示的磁过滤器，其分离室位于环形磁体的内体积中。分离室由塑料制成的壁构成并充填有微铁球(直径约0.3mm)。在静压力作用将0.8毫升氧化铁微粒(按US 4,101,435之实施例7中的方法制造)的超顺磁胶体溶液由磁过滤器中滤过，其中胶体溶液铁含量为500mmol/l，T2弛豫(r2)约为160l/(mmol s)。
对于弛豫比r2/r1，未处理溶液测得为7.4，而滤液测得为3.2。
使用A 3D FLASH技术(10/2，6/40°)，用实验室MRT仪(SISCOSIS 85，2.0特斯拉)记录所有核磁共振血管造影图。
采用麻醉(Rompun/Ketavet，1∶1混合物)鼠(Han.Wistar；体重200g)作为实验动物。
对两只鼠分别用“未过滤”起始物和依据本发明“过滤”制剂处理，首先记录各自照影前图像，再记录静脉给药各照影剂1、15或30分钟后的图像。所采用的剂量为约100μmol铁/kg体重。
图6显示“未过滤”铁磁体悬浮液的MR血管造影图。给药1分钟或15分钟后所得的照影效果没有多少诊断价值。
图7显示“过滤”铁磁体悬浮液的MR血管造影图[(a)照影前，(b)注射后1分钟，(c)注射后30分钟]。甚至在给药1分钟后，即可清晰地检测出大量血管；给药照影剂30分钟后其作用大大增强。与未处理物相比，依据本发明所制得的照影剂制剂特别适用于核磁共振血管造影术。
实施例3
用一环形磁体(NE 2016 IBS Magnet Berlin，外径20mm，内径10mm，高6mm)制成如图1a所示的磁过滤器，其分离室位于环形磁体的内体积中。分离室由塑料制成的壁构成并充填有微铁球(直径约0.3mm)。在静压力作用下将0.8ml氧化铁微粒(按US 4,101,435，实施例7中的方法制造)的超顺磁胶体溶液由磁过滤器中滤过，其中胶体溶液铁含量为500mmol/l，T2弛豫(r2)约为160l/(mmol s)。滤液的弛豫比r2/r1为2.1。
图8显示用此制剂所得的血管造影图，甚至在给药1分钟以后即可检测出血管差别，而采用实施例2所制得的制剂则需要较长的时间方可达到此效果。
Claims (15)
1、一种制备核磁共振断层扫描成像用造影剂的方法，其特征在于，借助于磁过滤器来过滤基于铁磁性、亚铁磁性、超顺磁性、或顺磁性颗粒的颗粒悬浮液，并除去所述铁磁性、亚铁磁性、超顺磁性、或顺磁性颗粒，且该悬浮液中颗粒的弛豫比r2/r1在过滤之前为大于3.2，而在分离之后为3.2或更低，其中r1为T1弛豫，而r2为T2弛豫。
2、如权利要求1所述的方法，其特征在于，所述颗粒悬浮液是基于超顺磁性颗粒的悬浮液。
3、如权利要求1所述的方法，其特征在于，所述磁过滤器包括分离室，该分离室具有一入口和一出口，而且其中存在磁场。
4、如权利要求1或3所述的方法，其特征在于，所述磁过滤器结合在注射装置或输注装置中。
5、如权利要求3所述的方法，其特征在于，所述分离室中的梯度磁场由安装于该分离室外部上的永磁体或电磁体产生。
6、如权利要求3或5所述的方法，其特征在于，所述分离室由顺磁性或软磁材料构成和/或包括顺磁体或软磁材料。
7、如权利要求3所述的方法，其特征在于，所述分离室中的梯度磁场由构成分离室或处于分离室之中的永磁性材料产生。
8、如权利要求3所述的方法，其特征在于，所述分离室中的梯度磁场由带电的导体产生，该导体位于所述分离室之中或者围绕所述分离室。
9、如权利要求7或8所述的方法，其特征在于，所述分离室还包括顺磁性或软磁材料。
10、如权利要求1所述的方法，其特征在于，所述磁过滤器是无菌的。
11、如权利要求3所述的方法，其特征在于，所述分离室包括一个或多个在分离过程中被磁化的软磁性盘，该盘含有孔洞，而待分离液体流经该孔洞。
12、如权利要求11所述的方法，其特征在于，在所述分离室中几个盘被叠放在一起，且所述盘上的所述孔洞相互偏离。
13、如权利要求11或12所述的方法，其特征在于，所述分离室上部的盘不能被磁化或由非磁化材料构成，而通过外部环状磁体或带电线圈将分离室中较低部位的盘磁化。
14、如权利要求11或12所述的方法，其特征在于，所述软磁性盘由高标号钢制成。
15、一种核磁共振断层扫描成像用造影剂，其特征在于，其是根据如权利要求1所述的方法制备的。
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| DE10137515A1 (de) * | 2001-07-26 | 2003-02-13 | Diagnostikforschung Inst | Verfahren zur Herstellung pharmazeutischer Zubereitungen |
| WO2006107288A2 (en) | 2004-02-17 | 2006-10-12 | E.I.Dupont De Nemours And Company | Magnetic field enhanced cake-filtration solid-liquid separations |
| CA2577038A1 (en) * | 2004-09-09 | 2006-03-16 | Bell, Glenda Fay | Separation of plastic and elastomers for food and pharmaceutical products |
| US8066877B2 (en) | 2005-02-17 | 2011-11-29 | E. I. Du Pont De Nemours And Company | Apparatus for magnetic field and magnetic gradient enhanced filtration |
| US8075771B2 (en) * | 2005-02-17 | 2011-12-13 | E. I. Du Pont De Nemours And Company | Apparatus for magnetic field gradient enhanced centrifugation |
| EP1738774A1 (de) * | 2005-06-29 | 2007-01-03 | Schering AG | Magnetische Eisenoxidpartikel enthaltende Zusammensetzungen und deren Verwendung in bildgebenden Verfahren |
| EP1738773A1 (de) * | 2005-06-29 | 2007-01-03 | Schering AG | Magnetische Eisenoxidpartikel enthaltende Zusammensetzung und deren Vervendung in bildgebenden Verfahren |
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| DK0915738T3 (da) | 2002-05-06 |
| IL128057A (en) | 2001-08-26 |
| US20030108613A1 (en) | 2003-06-12 |
| JP2000516131A (ja) | 2000-12-05 |
| CA2262685A1 (en) | 1998-02-12 |
| NO990523D0 (no) | 1999-02-04 |
| US6517813B1 (en) | 2003-02-11 |
| AU3941597A (en) | 1998-02-25 |
| KR100502881B1 (ko) | 2005-07-25 |
| EP0915738A1 (de) | 1999-05-19 |
| DE29713847U1 (de) | 1997-12-18 |
| CN1230136A (zh) | 1999-09-29 |
| ES2171985T3 (es) | 2002-09-16 |
| IL128057A0 (en) | 1999-11-30 |
| AR008817A1 (es) | 2000-02-23 |
| KR20000029821A (ko) | 2000-05-25 |
| WO1998005430A1 (de) | 1998-02-12 |
| HUP0001608A1 (hu) | 2000-09-28 |
| DE59706019D1 (de) | 2002-02-21 |
| HUP0001608A3 (en) | 2001-01-29 |
| PT915738E (pt) | 2002-07-31 |
| AU727764B2 (en) | 2000-12-21 |
| NZ333962A (en) | 2000-07-28 |
| NO990523L (no) | 1999-03-30 |
| ATE211950T1 (de) | 2002-02-15 |
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