CN85101820A - 制备一种硝苯吡啶复合制剂的方法 - Google Patents
制备一种硝苯吡啶复合制剂的方法 Download PDFInfo
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- CN85101820A CN85101820A CN198585101820A CN85101820A CN85101820A CN 85101820 A CN85101820 A CN 85101820A CN 198585101820 A CN198585101820 A CN 198585101820A CN 85101820 A CN85101820 A CN 85101820A CN 85101820 A CN85101820 A CN 85101820A
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- compound formulation
- blocker
- nifedipine
- preparation
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Links
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- 238000000034 method Methods 0.000 title claims description 10
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- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 claims description 5
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- 235000019737 Animal fat Nutrition 0.000 description 1
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- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 1
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
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- 239000000049 pigment Substances 0.000 description 1
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- 229920002717 polyvinylpyridine Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical compound OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
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- 239000000600 sorbitol Substances 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及新的具有改善了生物利用率的固体复合制剂，按重量比该制剂含有1份硝苯吡啶和0.5-10份β-受体阻滞和惯用的辅助剂和赋形剂。
Description
本发明涉及新的具有改善了生物利用率的固态硝苯吡啶复合剂，该制剂含有硝苯吡啶和β-受体阻滞剂，并涉及其制备方法和作为药剂的使用。尤其可用作冠状动脉和血压的药剂。
已经公布了硝苯吡啶对血液循环具有很强的效应（参阅英国专利1173862）。由于硝苯吡啶的溶解度很小，在医药产品的药物制剂中引起许多困难，这在对这些活性化合物的专门配方的许多专利和专利申请中是明显的。例如美国专利3784684论及含有硝苯吡啶的专门吞食的明胶胶囊，用该胶囊能更有利地使用硝苯吡啶对冠状动脉血栓的作用。再者，英国专利1456618对同样说到确有好的硝苯吡啶生物利用率的固体药用制剂进行了描述，并提出了权利要求。而且DT-OS（德国公开说明书）2822882描述了固体剂型，讲到用某些加溶剂和表面活性补偿了该活性化合物的微溶性。此外，在欧洲公开说明书（1247）讲到用聚乙二醇和某些多孔载体改善二羟基吡啶的可吸收的能力。
同样，在文献中描述了各种方法以改善生物利用率，该利用率直接与改善溶介度有关。除了化学结构上的改变，例如引入改善溶解度的取代基，还描述了许多涉及改变活性化合物物理性质的方法。例如，提出了减少活性化合物的颗粒度，改变晶体结构，制成盐的形式，加入湿润剂，与其它物质络合，使用生物载体，形成固体分散体（共沉淀）或制备表面被吸收物〔参阅S·H·耶尔大学考夫斯基：药物和制药科学，（S·H·Yalkowskay，Drugs and the Phar-maceutical Science），12，135-180（1981），和J.波尔德门，配方和剂型的制备，埃尔西维亚/北荷兰：生物药物出版社，1977，215-219页，（J·Poldermann：Formulation and Preparation of dosage forms·Elsever/North-Holl-end·Biomedical press，1977，215-219）〕。
迄今，用特殊措施以补偿硝苯吡啶的低溶解度以及同时确保有好的生物利用率的一切尝试都有许多缺点。使用表面活性物质，加溶剂和某些具有特殊表面的载体，例如多孔性的，往往会导致该制剂相当大量的给药方式。为便于吞咽这种类型的片剂或胶囊往往要制成例如椭球形的特殊形式，但是在制剂重量大于400毫克时，也不是总能达到令人满意的结果。也不是更往常地服用较小的制剂能满意解决的。
关于药物制剂的要点是辅助剂和赋形剂的数和量都要保持尽可能的低。当比较两个药物的特长时，优先的终是那些，除了活性化合物外，含有尽可能少的辅助剂和添加物的药物制剂，主要是为了避免不必要的生物学的付反应。
本发明涉及新的具有改善生物利用率的固体复合制剂，该制剂按重量比，含有1分硝苯吡啶，0.5-10分β-受体阻滞剂和惯用的辅助剂和赋形剂。
最有兴趣的是按本发明的复合制剂含有一个β-受体阻滞剂，该β-受体阻滞剂包括醋丁酰心安，氯酰心安，纳多洛尔，心得安，心得乐或噻吗心安。
特别要提及的是醋丁酰心安和氯酰心安。
尤有兴趣的，是按本发明的复合制剂按重量比，含有1分硝苯吡啶和1-5分醋丁酰心安或氯酰心安。
按本发明的复合制剂量是由硝苯吡啶和β-受体阻滞剂的活性化合物与已知辅助剂和赋形剂一起，用湿润的成粒方法或干压法进行粒化而制备的，制剂中至少还有适量的片剂填料，将它们压制成片剂。
按本发明所使用的硝苯吡啶最好是先选用结构式Ⅱ
的叉化合物与通式Ⅲ
的烯胺化合物在具有1-4个碳原子的低级醇中，温度在40-100℃时反应而制备的。
一种可取的不同方法，是用共沸蒸馏法除去反应中的水。化合物Ⅱ和Ⅲ可以用等摩尔量的，也可以用稍过量的烯胺化合物Ⅲ。
叉的化合物Ⅱ是用等摩尔量的酮羧酯与0-硝基甲醛在有1-4个碳原子的低级醇作溶剂并有催化剂量的哌啶乙酸盐存在下，在温度为20和60℃之间时进行反应而制得的。化学式Ⅲ的烯胺化合物是由酮羧酸酯与氨在低级醇（1-4个碳原子），最好是异丙醇中，温度在0-40℃之间时反应而制得的。反应剂氨也能用水溶液状态的氨。
可以提及的辅助剂例有：崩解剂，诸如淀粉，改性淀粉，纤维素，纤维素衍生物，交链的聚乙烯基吡啶烷酮（PVPP），藻酸钠，和胶体二氧化硅;粘合剂，诸如明胶，黄胶，葡萄糖浆，淀粉糊，聚乙烯基吡咯烷酮（PVP），纤维素衍生物，分子量为1000-5000的聚乙二醇（PEG），和藻酸盐;润滑剂，诸如硬酯酸镁，硬脂酸钙，硬脂酸，石蜡，滑石，植物油或动物脂肪，油和蜡，分子量为1000-5000的聚乙二醇和硅酮。
可以提及的填料例有二硫酸钙，碳酸钙，磷酸二碱和三碱钙，碳酸镁，碱式碳酸镁，氯化钠，柠檬酸、酒石酸和琥珀酸的钠盐和钾盐，淀粉，改性淀粉，纤维素，粉状纤维素，糖，诸如乳糖，蔗糖或葡萄糖;和糖醇，诸如甘露醇和山梨醇。
对辅助剂和填料最有兴趣的包括淀粉，改性淀粉，诸如淀粉糊，纤维素，PVP，PVPP胶体二氧化硅，乳糖，碱式碳酸镁，硬脂酸镁和硬酯酸钙这类物质。
从现在有技术来看，十分意外的是，在将硝苯吡啶与提及的β-受体阻滞剂之一，一起粒化时，硝苯吡啶的释放可以大大提高，这样其生物利用率就得到有效的改善。这效果不取决于外加辅助剂的存在，按现有技术知识，该辅助剂例如配位剂，表面活性物质或水溶性聚合物增加释放的速率。
在释放试验中，在下列条件下使用美国药典的搅槽法进行（USPpaddle method）
900毫升0.1N盐酸
搅拌转动是100转/分
按本发明的复合制剂（例1的产品）在一小时后硝苯吡啶的释放速率达到85%。常惯的硝苯吡啶片剂相应的制剂，其中所用的硝苯吡啶是相同的晶体结构，并含有相同的辅助剂，一小时后释放率小于40%。从表1看到释放的改进是明显的。
表1.从含有硝苯吡啶药片的体外释放（美国药典搅槽法）
对照例：
100克硝苯吡啶，2080克玉米淀粉，1150克粉状纤维素和50克乳糖在行星式搅拌机中搅拌5分钟，用聚乙烯基吡咯烷酮/吐温80的水溶液（固体含量为200克/5克）粒化15分钟，潮湿的组合物加通过粗锉（内嵌有φ2.0毫米的筛网），并在流化床干燥器中干燥到最后水含量为5%。
干燥的颗粒过筛（1.0毫米筛孔的筛网）使之均匀，并与15克硬脂酸镁剧烈搅拌，然后将颗粒压成重360毫克的片剂。
实施例：
例1.
100克硝基吡啶，1508克盐酸醋丁酰心安，1372克玉米淀粉，100克乳糖和400克粉状纤维素在行星式搅拌机中搅拌5分钟，与聚乙烯基吡咯烷酮/吐温80的水溶液（固体含量为200克/5克）粒化15分钟。潮湿的组合物加压通过粗锉（内嵌有φ2.0毫米的筛网），并在流化体床干燥器中干燥到最后的水含量约为4.5%。干燥的颗粒过筛（1.0毫米筛孔的筛网）使之均匀，并与15克硬脂酸镁剧烈搅拌。然后将颗粒压制成重360毫克的片剂。片剂可用保护衣包裹。
例2
200克硝苯吡啶，2216克盐酸醋丁酰心安，2494克玉米淀粉，50克乳糖和90克粉状纤维素，在流化床成粒机（GlattWSG 5）中加热，先用十二烷基硫酸钠的水溶液（含量为10克）喷洒。然后粉末用羟基丙基甲基纤维素的水溶液（含有400克）粒化并干燥到最后水含量约为4.5%，过筛，（筛孔为φ0.8毫米）与20克硬脂酸镁在立方混合器中混合，将要压制的颗粒加工成重314.5毫克的片剂，并用不透明的胶膜在Accela包衣器中包衣。
例3.
1000克氯酰心安，400克硝基吡啶，600克粉状纤维素，1200克重碳酸镁和40克十二烷基硫酸钠在搅拌成粒机（例如LOEdige MGT 30）中搅拌1分钟，用淀粉糊（淀粉含量为200克）在成粒机中粒化5分钟，转子的速度为200转/分。用Ⅱ型切碎机装置（chopper setting Ⅱ）得到约为200-300微米的平均粒度。颗粒通过粗锉（内嵌有筛网φ2.0毫米）并在流化床干燥器中（例如Glatt WST 5）干燥到最后水含量约为4.0%。干燥的颗粒与100克硬脂酸镁在混合器中混合10分钟，然后压成具有平均直径9毫米，重约237毫克的片剂。
生产的片剂可以再用不透明的胶膜层包衣，该膜层含有，例如红色氧化铁作光保护层。
例4.
500克氯酰心安，200克硝苯吡啶，450克粉状纤维素，400克玉米淀粉，650克碳酸钙，25克吐温80和50克硬脂酸镁在立方混合器中混合。然后干压（Alexander WP 50磨;压榨压力为35巴），片状物先压碎，再用1.25毫米的筛网使颗粒均匀，并与25克硬脂酸镁和200克玉米淀粉混合均匀。制成的颗粒压成重250毫克并具有直径9毫米的片剂。
得到的片剂能直接使用，也可以外包一层保护衣，该保护衣由羟基甲基丙基纤维素，聚乙二醇和氧化铁或其他生理上允许的色素或有色胶膜组成。
例5.
750克氯酰心安，300克硝苯吡啶，855克玉米淀粉，975克碱式碳酸镁，150克预先转化成糊状的玉米淀粉和600克粉状纤维素在行星式搅拌机（Collette MP 20）中搅拌8分钟，在继续加入250毫升2.0%浓度的十二烷基硫酸钠水溶液后，随着搅拌速度的增大粒化15分钟。湿润的组合物进行磨锉，在流化床干燥到最后水含量约3.8%，并过筛（筛孔为1.0毫米）使之均匀。在75克硬脂酸镁中混合得到最后的混合物，压制成重247毫克的片剂。
所得片剂可以包上不透日光的包衣，当然这种颗粒也能装入硬的明胶胶囊中。
Claims (9)
1、制备一种具有改良了生物利用率的固体复合产品的方法，其特征在于，按重量比1份硝苯吡啶和0.5-10份β-受体阻滞剂与适量的辅助剂和赋形剂一起粒化，这些颗粒进一步加工成惯用的型式。
2、按权利要求1的复合制剂制备方法，其中含有如醋丁酰心安，氯酰心安，纳多洛尔，心得安，心得乐和噻吗心安中一个β-受体阻滞剂。
3、按权利要求1-2的复合制剂，其中含有醋丁酰心安作为β体阻滞剂。
4、按权利要求1-2的复合制剂制备方法，其中含有氯酰心安作为β-受体阻滞剂。
5、按权利要求1-4的复合制剂制备方法，其中按重量比含有1份硝酸吡啶和1-5份β-受体阻滞剂。
6、按权利要求1-5的复合制剂制备方法，其中制成颗粒剂，片剂，包衣片或薄膜片的型式。
7、按权利要求6的方法，其特征在于，按重量比，1份硝苯吡啶和1-5份β-受体阻滞剂与淀粉，纤维素和适量的其它惯用辅助剂在成粒机中进行水相粒化，生产的颗粒也加工成惯用的型式。
8、按权利要求1的复合制剂的制备方法，其特征在于，结构式Ⅱ
的叉化合物与结构式Ⅲ
的烯胺化合物在有低级醇（1-4个碳原子），最好是在异丙醇作溶剂，和在0-40℃温度时，进行反应，制得的硝苯吡啶按权利要求7加工成合适的服用型式。
9、按权利要求1所制备的复合制剂，可作为防治血液循环失调的用途。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843419130 DE3419130A1 (de) | 1984-05-23 | 1984-05-23 | Nifedipinkombinationspraeparate und verfahren zu ihrer herstellung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN85101820A true CN85101820A (zh) | 1987-01-10 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN198585101820A Pending CN85101820A (zh) | 1984-05-23 | 1985-04-01 | 制备一种硝苯吡啶复合制剂的方法 |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0165450A3 (zh) |
| JP (1) | JPS60255724A (zh) |
| KR (1) | KR850008619A (zh) |
| CN (1) | CN85101820A (zh) |
| AU (1) | AU4280785A (zh) |
| DD (1) | DD237114A5 (zh) |
| DE (1) | DE3419130A1 (zh) |
| DK (1) | DK228085A (zh) |
| ES (1) | ES8607725A1 (zh) |
| GR (1) | GR851218B (zh) |
| HU (1) | HUT38252A (zh) |
| IL (1) | IL75244A0 (zh) |
| PT (1) | PT80500B (zh) |
| ZA (1) | ZA853878B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3427402A1 (de) * | 1984-07-25 | 1986-01-30 | Bayer Ag, 5090 Leverkusen | Neues kombinationspraeparat, verfahren zu seiner herstellung und seine verwendung als arzneimittel |
| FR2577802B1 (fr) * | 1985-02-26 | 1987-07-24 | Synthelabo | Compositions pharmaceutiques a base de betaxolol et de nifedipine |
| DE3610037A1 (de) * | 1986-03-21 | 1987-09-24 | Schering Ag | Nifedipinkombinationspraeparat |
| DE3829398A1 (de) * | 1988-08-30 | 1990-03-08 | Rentschler Arzneimittel | Fixe arzneimittelkombination mit verzoegerter freisetzung |
| WO1993000081A1 (en) * | 1991-06-28 | 1993-01-07 | Sepracor, Inc. | Optically pure s(-) nadolol for treatment of cardiovascular disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE1670827C3 (de) * | 1967-03-20 | 1974-10-24 | Bayer Ag, 5090 Leverkusen | 4-(2'-Nitrophenyl)-2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridin |
| SU432703A3 (zh) * | 1971-08-24 | 1974-06-15 | Фридрих Боссерт, Вульф Фатер, Курт Бауер | |
| DE2400819C2 (de) * | 1974-01-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Verfahren zur Herstellung fester Zubereitungen von schwerlöslichen Arzneimittelwirkstoffen in feinster Verteilung |
| GB1579818A (en) * | 1977-06-07 | 1980-11-26 | Yamanouchi Pharma Co Ltd | Nifedipine-containing solid preparation composition |
| EP0001247A1 (en) * | 1977-09-14 | 1979-04-04 | Kanebo, Ltd. | Pharmaceutical preparation containing nifedipine and a method for producing the same. |
-
1984
- 1984-05-23 DE DE19843419130 patent/DE3419130A1/de not_active Ceased
-
1985
- 1985-04-01 CN CN198585101820A patent/CN85101820A/zh active Pending
- 1985-05-11 EP EP85105796A patent/EP0165450A3/de not_active Withdrawn
- 1985-05-20 GR GR851218A patent/GR851218B/el unknown
- 1985-05-20 IL IL75244A patent/IL75244A0/xx unknown
- 1985-05-20 JP JP60106213A patent/JPS60255724A/ja active Pending
- 1985-05-21 PT PT80500A patent/PT80500B/pt unknown
- 1985-05-21 DD DD85276559A patent/DD237114A5/de unknown
- 1985-05-22 ZA ZA853878A patent/ZA853878B/xx unknown
- 1985-05-22 DK DK228085A patent/DK228085A/da not_active Application Discontinuation
- 1985-05-22 KR KR1019850003501A patent/KR850008619A/ko not_active IP Right Cessation
- 1985-05-22 ES ES543389A patent/ES8607725A1/es not_active Expired
- 1985-05-23 AU AU42807/85A patent/AU4280785A/en not_active Abandoned
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Also Published As
| Publication number | Publication date |
|---|---|
| HUT38252A (en) | 1986-05-28 |
| KR850008619A (ko) | 1985-12-21 |
| DK228085A (da) | 1985-11-24 |
| DD237114A5 (de) | 1986-07-02 |
| ES8607725A1 (es) | 1986-06-01 |
| ES543389A0 (es) | 1986-06-01 |
| PT80500B (en) | 1987-04-21 |
| AU4280785A (en) | 1985-11-28 |
| GR851218B (zh) | 1985-11-25 |
| JPS60255724A (ja) | 1985-12-17 |
| PT80500A (en) | 1985-06-01 |
| EP0165450A2 (de) | 1985-12-27 |
| IL75244A0 (en) | 1985-09-29 |
| EP0165450A3 (de) | 1986-03-12 |
| DK228085D0 (da) | 1985-05-22 |
| ZA853878B (en) | 1986-01-29 |
| DE3419130A1 (de) | 1985-11-28 |
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