CN1199341A - 用于近红外诊断的含载有聚甲炔染料的胶体系统的造影剂 - Google Patents
用于近红外诊断的含载有聚甲炔染料的胶体系统的造影剂 Download PDFInfo
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- CN1199341A CN1199341A CN96197558A CN96197558A CN1199341A CN 1199341 A CN1199341 A CN 1199341A CN 96197558 A CN96197558 A CN 96197558A CN 96197558 A CN96197558 A CN 96197558A CN 1199341 A CN1199341 A CN 1199341A
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0078—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion microemulsion, nanoemulsion
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Nanotechnology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
本发明涉及加有聚甲炔染料并有适合的光物理性质和药理性质的胶体体系,它们在近红外区在荧光和透射诊断学中作为造影剂的应用,以及它们的制备方法。
Description
本发明涉及加有聚甲炔染料的胶体体系，它们在近红外光谱区、在荧光和透射诊断学中作为造影剂的应用，以及它们的制备方法。
由于生物组织对700-1000nm范围的长波光有相当高的穿透性，所以诊断医师除可使用先进的医学成象技术如X射线成象、核磁共振断层照相术或超声波诊断外，还可使用一种完全不同的组织成象方法。
可通过用透射成象的方法测定未吸收的射线部分以及通过将组织暴露到近红外区的光中发射出的荧光射线来得到该组织特异性信息。
使用近红外线的主要问题是产生非常宽的光散射，不管有清晰轮廓的物体的不同光物理性质以及所处的环境如何，这样的物体也只能得到模糊的影象。这一问题加大了距表面的距离，它被认为是透射和荧光照射检测的主要限制因素。
可在病兆组织(特别是肿瘤)中积累并显示特异性吸收和发射性质的适合荧光染料可有助于提高区别健康组织和有病兆的组织。测定了由染料吸收引起的照射(散射)光的变化或由射线激光引起的荧光的变化，并提供实际组织特异性信息。
到目前为止，用于光动力学治疗(PDT)的光敏剂(包括卟啉类、氯酞花青类、萘亚甲基花青类)已用于定位的和可见的肿瘤(Bonnett R.New photosensitizers for the photodynamic therapy of tumours.SPIEVol.2078，1994)。这里所列的各类化合物有这样一个缺点：它们在600-1200nm波长范围内一点也不吸收或只有很小程度的吸收。这些染料的光敏作用干扰希望没有其他影响的纯诊断应用。此外，这里所列的染料的光稳定性常常是十分低的。
与此相反，这类聚甲炔染料的吸收性质和荧光性质的特征是，在700-1000nm范围有高的吸收系数和有足够的荧光量子产量。聚甲炔染料的光敏作用可忽略，并且它们中的大多数是高度光稳定的。
可通过将荧光染料转变成胶体体系使其药物动力学性质产生明显变化。因此，用这种方法可使配方中的荧光染料达到组织或器官特异性积累或者定位特异性积累。
此外，染料必需对所用的水溶液是强亲水的，以致有足够数量用于成象的染料可用水溶液进入身体。
将染料转变成胶体体系可提高可应用的剂量是大家知道的。
本发明的一个目的是提供一种以高含量积累在要检查的组织中并可用近红外射线在所述组织中检测出的造影剂。
根据本发明，这一问题通过提供含有造影剂并加有染料的胶体体系来解决，所述胶体的尺寸为5nm至10μm，它含有在600-1200nm波长范围内能吸收光和/或产生荧光的最低一个染料。关于胶体的定义，参见Hunnius，Pharmazeutisches Worterbuch，6th edition，Berlin：deGruyter 1986，pp.589 f.，但是该说明在胶体体系的概念中包括其粒度高达10μm的粗分散体系。
令人吃惊的是，已发现加有染料的胶体体系在局部发炎或肿瘤区域积累。这一积累特别适用于用NIR诊断法诊断可见的肿瘤或炎症。
此外，令人吃惊地发现，本发明的造影剂在特异性细胞中，例如在肝的Kupfer细胞中可迅速分解，从而使血液中的胶体浓度迅速下降，同时已被目标组织吸收的胶体颗粒以很慢的速度分解。这样就降低了血液中造影剂浓度变化引起的背景噪音，从而提高了损伤的可见度和/或使它们可在早期发现。
因此，本发明涉及加有染料的胶体体系，它们含有其尺寸为5nm至10μm的胶体颗粒，而染料分子汇集在胶体颗粒中，或附着在胶体颗粒上，或被其壁和/或空腔包封。
所有这样的体系都是适用的，其中染料汇集在由与天然物质一样的可生物降解的部分合成材料组成的胶体颗粒中。制备适合的胶体颗粒的性质和方法已有描述，例如Boyett，J.B.，and Davis，C.W.，InjectableEmulsions and Suspensions；Liebermann，H.A.，M.M.Rieger，and G.S.Banker，eds.Pharmaceutical Dosage Forms：Disperse Svstems.Vol.2.New York：Marcel Dekker，1988，379-416。
特别适用的是这样一些体系，其中合成聚合物材料选自以下各类：聚-ε-己内酯、聚乳酸、聚乙醇酸、以及聚乳酸和聚乙醇得到的混合聚合物、聚羟基丁酸、聚羟基戊酸、以及聚羟基丁酸和聚羟基戊酸得到的混合聚合物、聚氨基酸、聚氰基丙烯酸烷基酯、聚酰胺、聚丙烯基葡聚糖、聚丙烯酸淀粉、聚丙烯基糖化物、聚丙烯酰胺、聚酯、酸(原酸)酯、多磷酸烯类(polyphosphorenes)以及乳酸和/或乙醇酸和聚氧乙烯的共聚物。优选的天然的或部分合成的可生物降解的聚合物材料主要包括蛋白质类，如清蛋白、胶原蛋白、明胶、血红蛋白或血纤维蛋白原；淀粉类；葡聚糖类、壳多糖和脱乙酰壳多糖。
将荧光染料包封在胶体颗粒中或与荧光染料一起形成胶体颗粒的两性物质也特别适用。优选的物质是磷脂类，脂肪酸类，脂肪醇类，胆甾醇，脂肪醇或脂肪醇与脂肪酸的酯类或醚类，脂肪酸或聚氧乙烯的糖衍生物，磷脂、脂肪酸、脂肪醇与聚氧乙烯的酯类或醚类，胆汁酸类，脱水山梨醇与聚氧乙烯或脂肪醇或脂肪酸的衍生物以及它们的组合物。
本发明优选的造影剂含有由蛋白质类，如清蛋白、胶原蛋白、明胶、血红蛋白或血纤维蛋白原；或淀粉类及其衍生物、葡聚糖类；壳多糖或脱乙酰壳多糖得到的胶体。
本发明另一优选的造影剂含有由以下物质得到的胶体：磷脂类；脂肪酸类；脂肪醇类；胆甾醇、脂肪醇和脂肪酸的酯类；脂肪醇和脂肪酸的醚类；含有脂肪酸或聚氧乙烯的糖衍生物；磷脂、脂肪酸或脂肪醇与聚氧乙烯的酯类或醚类；胆汁酸类；脱水山梨醇与聚氧乙烯、脂肪酸或脂肪醇的衍生物；以及所述物质的组合物。
本发明特别优选的是这样的造影剂，它们含有胶体形式的α-、β-、γ-或ε-羟基羧酸的聚酯类、聚氰基丙烯酸烷基酯类、聚氨基酸类、聚酰胺类、聚丙烯酸化的糖化物类或聚(原酸)酯类。
用于胶体近红外诊断剂的染料的特征是，它们在600-1200nm波长范围内吸收和产生荧光，其吸收系数为约100000l/mol.cm和更高，由于荧光是希望的，其荧光量子产量为5％以上。
所用的染料为选自如下的聚甲炔染料：花青染料、苯乙烯基型染料、部花青染料、斯夸苷染料(squaraine)和1，4，5，6-四氢-4，6-1，3，5-三嗪-2-醇(oxonol)染料。
这样一类花青染料是优选的：在700-1000nm之间有最大吸收值和荧光值，消光系数为约140000l/mol.cm和更大，带有一个或几个未取代的、支链的或非支链的、无环的或环状的和/或含有氧、硫、氮的碳-氢残基、或任选芳族碳-氢残基。
本发明的造影剂含有花青染料、苯乙烯基型染料、部花青染料、斯夸苷染料或1，4，5，6-四氢-4，6-1，3，5-三嗪-2-醇染料，或者所述染料的混合物。
含有花青染料或斯夸苷染料的本发明造影剂是优选的。
本发明这样的造影剂也是优选的，其中染料带有一个或几个另外的、支链的或非支链的、环状的或多环的烷基、链烯基、聚链烯基、炔基、聚炔基、芳基、烷芳基或芳烷基残基，它们都含有至多60个碳原子，以及任选带有另外的卤素原子、羟基、羧基、氨基羰基、烷氧基羰基、氨基、醛基、氧代、氧基或含有至多20个碳原子的烷氧基、和/或它们可被一个或几个杂原子O、N、S或P间隔或取代的。
含有通式I、II或III中至少一种染料的本发明造影剂是特别优选的 
式中，R1、R2、R3、R4、R7、R8、R9和R10为相同的或不同的，它们可各自独立为-COOE1、-CONE1E2、-NHCOE1、-NHCONHE1、-NE1E2、-OE1、-SO3E1、-SO2E1、-SO2NE1E2、-E1残基、氟、氯、溴或碘原子或硝基，或其中5～6元环分别与每对相邻的残基R1、R2、R3或R4，R7、R8、R9或R10稠合，这取决于位于其间的碳原子，所述的环为饱和的或不饱和的或芳族的环，任选带有另外的-COOE1、-CONE1E2、-NHCOE1、-NHCONHE1、-NE1E2、-OE1、-SO3E1、-SO2E1、-SO2NE1E2残基，
式中，E1和E2为相同的或不同的，各自独立为氢原子；饱和的或不饱和的、支链的或非支链的C1-C50烷基链，所述的链或其中的一部分任选形成环状C5-C6单元或双环C10单元，它们可被氧原子、硫原子、氮原子间隔和/或取代；羧酸酯；羧酸酰胺；脲；硫脲；氨基甲酸酯或醚基；或者它们为羟基聚氧乙烯链或甲氧基聚氧乙烯链，或被1-19个氟原子取代的支链的或非支链的C1-C10烷基链，
R5和R6各自独立为-E1残基或C1-C4磺基烷基链，其中E1规定如上。Q为以下片段
式中，R11为氢、氟、氯、溴或碘原子、-NE1E2、-OE1或-E1残基或硝基，R12为氢原子或-E1残基，b为0、2或3中的一个数，
式中，E1和E2规定如上，X和Y为相同的或不同的，各自独立为O、S、-CH＝CH-或为以下片段
式中，R13和R14各自独立为氢；饱和的或不饱和的、支链的或非支链的C1-C15烷基链，其中R13和R14可通过形成5元环或6元环相互连接，所述的环中原子可被氧原子和/或羟基间隔和/或取代；含有至多6个碳原子的烷氧基；羧酸酯单元和/或羧酸酰胺单元，或含有上述染料带生理上可允许的无机阳离子或有机阳离子的羧酸盐和/或磺酰盐的本发明造影剂是特别优选的。
钠、钾、钙、镁、钆以及赖氨酸、谷氨酰胺和甲基谷氨酰胺可作为阳离子出现。
带正的总电荷的染料优选为碘化物、溴化物或高氯酸盐。
此外，本发明的造影剂还含有两种有不同光物理性质和/或药理性质的少量染料。
此外，本发明的造影剂还可含有常用于盖仑制剂的辅助剂、底物和稀释剂。
使用由相关文献已知的方法来制备染料，例如Hamer，F.M.TheCyanine Dyes and Related Compounds.New York：John Wiley andSons，1964；Bioconjugate Chem.4(1993)，105-11；Anal.Biochem.217(1994)，197-204；Tetrahedron 45(1989)，4845-66；Anal.Chim.Acta 282(1993)，633-641；Dves Pigm 21(1993)，227-234；EP 0591820A1。
本发明的另一目的是本发明的造影剂在近红外区在体内荧光和吸收诊断中的应用。
在使用本发明造影剂在体内诊断中，优选在该物质的静脉给药后，通过用600-1200nm波长范围的单色光照射并进行非吸收射线和/或荧光射线的位置相关检测来进行。在得到的数据的基础上产生合成影象。
本发明的诊断剂用类似于在相关文献中所述的生产胶体颗粒的方法来制备，其中将一种或几种染料加到反应混合物中。通过将反应体系设定到另一染料浓度可改变负载比(charging ratio)。
优选的方法是将上述有机材料与一种或多种染料一起溶于不能与水混合的一种或几种有机溶剂中，任选加入其他溶剂后将它们乳化，可任选将乳化剂加到乳液中。随后可过滤生成的胶体体系，并通过干燥如冻干使它稳定。
这些造影剂也可按熟悉本专业的技术人员已知的方法来制备，这些方法可包括使用常用的辅助剂和/或稀释剂等。它们包括生理上允许的电解质、缓冲剂、洗涤剂、乳化剂，以及用于调节造影剂的渗透性或提高造影剂的稳定性和溶解性的物质，如环状葡聚糖。制备过程中制剂的消毒，特别当它们应用时的消毒要用需用的制药措施来确保。
以下实施例将更详细地说明本发明。
实施例1
含有1，1′，3，3，3′，3′-六甲基-靛三炭花青碘化物的颗粒悬浮液的制备
将7.6mg六甲基靛三炭花青碘化物和0.2g其分子量为约15000g/mol的乳酸和乙醇酸的共聚物溶于2.5ml二氯甲烷中。在剧烈搅拌下，将该溶液加到20ml 2％明胶溶液中，明胶溶液已在高压锅中、在121℃下蒸煮15分钟。将混合物再搅拌45分钟。将如此制得的悬浮液按5ml一份装入20ml玻璃容器中，并用液氨直接冷冻。随后，将冷冻的悬浮液冻干。一份用5ml 0.9％的食盐溶液再次悬浮后，每毫升悬浮液含有约1010个含有六甲基靛三炭(indotricarbo)花青碘化物的颗粒，其粒度为约1至10μm。
实施例2
实施例1制剂的应用
施用200μl包封有六甲基靛三炭花青碘化物(0.6μmol/ml)的聚(1-丙交酯-乙交酯)颗粒悬浮液(1010个颗粒/ml)后，用CCD相机给有LS 174T肿瘤的裸鼠荧光成象，得到24小时后荧光主要在肿瘤组织的影象(图1)。
Claims (11)
1.一种含有加染料的胶体体系的近红外诊断用的造影剂，其特征在于，胶体颗粒的尺寸为5μm至10μm，以及它们含有至少一种在600-1200nm波长范围内吸收光和/或产生荧光的染料。
2.根据权利要求1的造影剂，其特征在于，胶体含有α-、β-、γ-或ε-羟基羧酸的聚酯类、聚氰基丙烯酸烷基酯类、聚氨基酸类、聚酰胺类、聚丙烯酸化的糖化物类或聚(原酸)酯类。
3.根据权利要求1的造影剂，其特征在于，胶体含有蛋白类、如清蛋白、胶原蛋白、明胶、血红蛋白、血纤维蛋白原；或淀粉类；葡萄聚糖类、壳多糖和脱乙酰壳多糖。
4.根据权利要求1的造影剂，其特征在于，胶体含有磷脂类，脂肪酸类，脂肪醇类，胆甾醇，脂肪醇和脂肪酸的酯类，脂肪醇的醚类，脂肪酸或聚氧乙烯的糖衍生物，磷脂、脂肪酸或脂肪醇与聚氧乙烯的酯类或醚类，胆汁酸，脱水山梨醇与聚氧乙烯、脂肪酸或脂肪醇的衍生物，以及所述物质的组合物。
5.根据权利要求1-4中至少一项的造影剂，其特征在于，它含有花青染料、苯乙烯基型染料、部花青染料、斯夸苷染料、1，4，5，6-四氢-4，6-1，3，5-三嗪-2-醇染料或所述染料的混合物作为其染料组合。
6.根据权利要求1-4中至少一项的造影剂，其特征在于，它含有花青染料或斯夸苷染料中至少一种染料。
7.根据权利要求6的造影剂，其特征在于，所述的染料带有一个或几个另外的未分支的、支链的、环状的或多环的烷基、链烯基、聚链烯基、炔基、聚炔基、芳基、烷芳基或芳烷基残基、每一个残基含有至多60个碳原子，它们可任选带有另外的卤素原子、羟基、羧基、氨基羰基、烷氧基羰基、氨基、醛基、氧代或含有至多20个碳原子的烷氧基、和/或它们任选被一个或几个另外的杂原子O、N、S或P间隔和/或取代。
8.根据权利要求7的造影剂，其特征在于，它含有通式I、II或III中至少一种染料中至少一种染料
式中，R1、R2、R3、R4、R7、R8、R9和R10为相同的或不同的，它们各自独立为-COOE1、-CONE1E2、-NHCOE1、-NHCONHE1、-NE1E2、-OE1、-SO3E1、-SO2E1、-SO2NE1E2、-E1残基、氟、氯、溴或碘原子或硝基、或其中5-6个元环分别与每对相邻的残基R1、R2、R3或R4，R7、R8、R9或R10anellated，取决于位于其间的碳原子，所述的环为饱和的或不饱和的或芳族的环，任选带有另外的-COOE1、-CONE1E2、-NHCOE1、-NHCONHE1、-NE1E2、-OE1、-SO3E1、-SO2E1、-SO2NE1E2残基，
式中，E1和E2为相同的或不同的，各自独立为氢原子；饱和的或不饱和的、支链的或非支链的C1-C50烷基链，所述的链或其中的一部分任选形成环状C5-C6单元或双环C10单元，它们可被氧原子、硫原子、氮原子间隔和1或取代；羧酸酯；羧酸酰胺；脲；硫脲；氨基甲酸酯或醚基；或者它们为羟基聚氧乙烯链或甲氧基聚氧乙烯链，或被1-19个氟原子取代的支链的或非支链的C1-C10烷基链，R5和R6各自独立为-E1残基或C1-C4磺基烷基链，其中E1规定如上，Q为以下片段
式中，R11为氢、氟、氯、溴或碘原子、-NE1E2、-OE1或-E1残基或硝基，R12为氢原子或-E1残基，b为0、2或3中的一个数，
式中，E1和E2规定如上，X和Y为相同的或不同的，各自独立为O、S、-CH＝CH-或为以下片段
式中，R13和R14各自独立为氢；饱和的或不饱和的、支链的或非支链的C1-C15烷基链，其中R13和R14可通过形成5元环或6元环相互连接，所述的环中原子可被氧原子和/或羟基间隔和/或取代；含有至多6个碳原子的烷氧基；羧酸酯单元和/或羧酸酰胺单元，或它含有上述染料带生理上可允许的无机阳离子或有机阳离子的羧酸盐和/或磺酸盐。
9.根据权利要求1-8中至少一项的造影剂，其特征在于，它含有两种有不同光物理性质和/或药理性质的少量染料。
10.根据权利要求1-9中至少一项的造影剂，其特征在于，它还含有常用于盖仑制剂的辅助剂、底物和稀释剂。
11.根据权利要求1-10中至少一项的造影剂在近红外区用于体内荧光检查和吸收诊断的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19539409.7 | 1995-10-11 | ||
| DE19539409A DE19539409C2 (de) | 1995-10-11 | 1995-10-11 | Kontrastmittel für die Nahinfrarot-Diagnostik |
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| Publication Number | Publication Date |
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| CN1199341A true CN1199341A (zh) | 1998-11-18 |
| CN1075951C CN1075951C (zh) | 2001-12-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN96197558A Expired - Fee Related CN1075951C (zh) | 1995-10-11 | 1996-09-26 | 用于近红外诊断的含载有聚甲炔染料的胶体系统的造影剂 |
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| Country | Link |
|---|---|
| US (2) | US6319488B1 (zh) |
| EP (1) | EP0854732A2 (zh) |
| JP (1) | JPH11504656A (zh) |
| KR (1) | KR100290240B1 (zh) |
| CN (1) | CN1075951C (zh) |
| AU (1) | AU711266B2 (zh) |
| CA (1) | CA2233995A1 (zh) |
| DE (1) | DE19539409C2 (zh) |
| HU (1) | HUP9900458A3 (zh) |
| IL (1) | IL119365A (zh) |
| NO (1) | NO981586D0 (zh) |
| WO (1) | WO1997013490A2 (zh) |
| ZA (1) | ZA968229B (zh) |
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-
1995
- 1995-10-11 DE DE19539409A patent/DE19539409C2/de not_active Expired - Lifetime
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- 1996-09-26 CN CN96197558A patent/CN1075951C/zh not_active Expired - Fee Related
- 1996-09-26 AU AU15892/97A patent/AU711266B2/en not_active Ceased
- 1996-09-26 CA CA002233995A patent/CA2233995A1/en not_active Abandoned
- 1996-09-26 US US09/051,511 patent/US6319488B1/en not_active Expired - Fee Related
- 1996-09-26 JP JP9514616A patent/JPH11504656A/ja active Pending
- 1996-09-26 KR KR1019980701830A patent/KR100290240B1/ko not_active IP Right Cessation
- 1996-09-26 WO PCT/DE1996/001878 patent/WO1997013490A2/de not_active Application Discontinuation
- 1996-09-26 HU HU9900458A patent/HUP9900458A3/hu unknown
- 1996-09-30 ZA ZA968229A patent/ZA968229B/xx unknown
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102115456B (zh) * | 2009-12-30 | 2014-08-20 | 深圳迈瑞生物医疗电子股份有限公司 | 花菁类化合物，包含所述化合物的组合物及其在细胞检测中的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| US6319488B1 (en) | 2001-11-20 |
| WO1997013490A2 (de) | 1997-04-17 |
| AU1589297A (en) | 1997-04-30 |
| ZA968229B (en) | 1997-05-14 |
| EP0854732A2 (de) | 1998-07-29 |
| CA2233995A1 (en) | 1997-04-17 |
| NO981586L (no) | 1998-04-07 |
| AU711266B2 (en) | 1999-10-07 |
| HUP9900458A3 (en) | 1999-11-29 |
| IL119365A0 (en) | 1997-01-10 |
| CN1075951C (zh) | 2001-12-12 |
| NO981586D0 (no) | 1998-04-07 |
| DE19539409C2 (de) | 1999-02-18 |
| HUP9900458A2 (hu) | 1999-06-28 |
| IL119365A (en) | 2000-07-26 |
| JPH11504656A (ja) | 1999-04-27 |
| KR100290240B1 (ko) | 2001-05-15 |
| DE19539409A1 (de) | 1997-04-17 |
| US20020022004A1 (en) | 2002-02-21 |
| WO1997013490A3 (de) | 1997-10-23 |
| KR19990044581A (ko) | 1999-06-25 |
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