CN88100555A - 无水的，5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-碳酰胺的纳盐结晶 - Google Patents
无水的，5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-碳酰胺的纳盐结晶 Download PDFInfo
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- 159000000000 sodium salts Chemical class 0.000 title claims abstract description 10
- IZSFDUMVCVVWKW-UHFFFAOYSA-N chembl1097558 Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(O)=C1C(=O)C1=CC=CS1 IZSFDUMVCVVWKW-UHFFFAOYSA-N 0.000 title abstract 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 239000013078 crystal Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 abstract description 6
- 239000000730 antalgic agent Substances 0.000 abstract description 3
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 3
- 229940035676 analgesics Drugs 0.000 abstract 1
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract 1
- 238000009472 formulation Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 230000036571 hydration Effects 0.000 description 5
- 238000006703 hydration reaction Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
对于止痛剂或消炎剂的配方具有有利的性质的无水5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-碳酰胺的钠盐结晶。
Description
本发明的目的在于具有对止痛药或消炎药药物配方有利的性质的5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-碳酰胺的钠盐无水结晶。
Kadin，美国专利4，556，672号已公开了具有下面所示的化学式的上述5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-碳酰胺。
（或可做药用的盐）作为一种用作止痛或消炎药的特别优选的化合物。在此公开的专利文献中的式（Ⅰ）化合物的钠盐是以半水合物或水合物离析出来的。进一步的干燥就使一水合物变成无水的化合物。我们现在已确定所形成的几种水合物通常都是具有多种形态（例如无定形的和针状的结晶）的混合物。这些不同的水合型通常具有造成配方困难的流动性质和静电性质。我们也已确定在升温和/或减压下初步干燥所得的无水产物是无定形的和吸湿的。因此很希望发现一种可克服配方困难的结晶型钠盐。
我们现在已发现一种无水的、结晶型的5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-碳酰胺的钠盐，它具有有价值而不显而易见的性质。因此这种盐易于处理及调配成剂量形式如胶囊剂。它不吸湿甚至在相对湿度达90%时仍保持稳定的剂量形式。当将它压成片剂时它比水合的盐溶解得更快。
根据上面引用的、本文作为参考资料的、早先由Kadin公开的专利，通常是将这种有利的结晶盐配制成并用作一种止痛药。
意外的是，在室温时通过搅拌在乙腈中的水合型的钠盐可简单地制备出本发明的化合物。已经观察到这种转变是在室温时没有任何其他溶剂存在下进行的，不过在回流的甲苯中亦可以慢慢地进行。
一旦发现，本发明是易于实行的。在此方法中式（Ⅰ）的化合物的钠盐最好首先离析成它的水合物的形式，然后在乙腈中简单地搅拌以得到本发明的有用的、无水的、不吸湿的结晶钠盐。在乙腈中这一转变的温度并不是关键性的，但在室温时易于进行，免去加热或冷冻所需的能量费用。另一方面这种转变可在甲苯的回流温度用迪安-斯达克榻分水器（Dean-Stark trap）共沸除水的情况下在甲苯中进行，但是并不易于进行。由于在此方法中低沸点的苯并不很有效，通常生产的是无定形的无水产物，因此可以认为当应用除乙腈以外的溶剂时，较高的温度对于无水结晶的形成是关键性的。
本发明的结晶盐其特征在于它的如下文所示的特殊物理性质。在上文引用了由Kadin早先公开的这种盐通常的配制和应用。下文举例说明了一种特殊的、稳定的并于临床有用的包括本发明的盐的胶囊剂配方。
下面的例子是用于说明本发明而不能被解释为对本发明的限制，在这个范围与其精神内可以有许多的变化。
制备法1
5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-碳酰胺的钠盐水合物
根据Kadin，美国专利4，556，672号的实例10制备标题的水合物。用另一种方法，将5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-碳酰胺（上述Kadin的实例8;51.2g，0.16mol）在40℃悬浮于400ml乙腈中，同时将碳酸氢钠（14.1g.，0.168mol）溶于200ml水中并热至40℃。在20分钟内将此温热的水溶液加到该温热的乙腈悬浮液中，在此期间有少量泡沫出现。在40℃搅拌所得到的溶液，用5g活性碳脱色，在25℃搅拌30分钟并过滤再用50ml的乙腈：水（1∶1）洗涤。将合并的滤液与洗液在真空下通过蒸气浴浓缩，当用200ml水置换乙腈至最终体积约为500ml时，冷却至25℃通过过滤回收第一批产物。用50ml水洗涤该固体。将合并的母液和洗液气提至400ml生成第二批产品，在空气下干燥后，第一批产品重35.76g（含水6.4%）和第二批产品重16.77g（含水6.2%）经含水量校正产量为90%。计算一水合物的含水量为5.0%，用差示扫描量热法测定这两批产品显示出4条吸热线（约在110，150，237和255）。
实例1
无水的5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-碳酰胺的钠盐结晶。
将水合的5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-碳酰胺的钠盐（52.5g根据制备法1的另一种方法制备）在52.5ml的乙腈中于室温下搅拌，经过滤回收标题产物，用50ml乙腈洗涤;并在真空中于55℃干燥而得到46.7g（95%）的标题产物;在偏振光显微镜下的结晶体;在50-300℃的范围内用差示扫描量热法测定，显示在255±2℃处有一条单独的清晰的吸热线。
分析计算 C14H8ClN2O3SNa：
C，49.06;H，2.35;N，8.18;S，9.35;Cl，10.34;
硫酸盐灰分，20.72;H2O，O;在100℃于真空中干燥损失，O。
实测值
C，48.85;H，2.39;N，8.22;S，9.54;Cl，10.43;
硫酸盐灰分，20.58;H2O，0.07;在100℃于真空中干燥损失，0.07。
和水合物型形成明显的对照，水合物型是橙色的，而现在的无水钠盐是黄色。
将水合物型的样品（制备法1）和现时的无水型的标题化合物碎成细小颗粒并以2000磅的终压力，在直径为 1/2 英寸的模中压成小片。每次压片时，使冲压机移开并用石蜡覆盖压模的底部，以便于对已知的表面区域的单平面进行溶解速率试验。将含有受压药物的模子放入一个带有浆叶的美国药典溶解烧瓶的底部，使浆叶处于药片曝露面的之上2.5cm处，在水和0.5M硼酸盐缓冲液（pH9.0）两者之中，就内部的溶解速率（对口服剂型的药效来说这是一个重要的因素）而言，无水型的要比水合物快约三倍。
无水型显示出变为水合物的轻微倾向。甚至在应用水湿制粒法中亦低于在优选的胶囊制剂中，不会形成水合物（由没有由黄色变为橙色的颜色改变得到证明）
实例2
含有无水的5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-碳酰胺钠盐的口服胶囊剂量型
将下列成份拌合，用875ml水湿粒化，最后用Karl Fischer干燥至含水分5%;
5-氯-3-（2-噻吩甲酰）
-2-羟基吲哚-1-碳
酰胺 600.00g
（561.52g.A＊）
微晶纤维素
（Avicel PH101） 885.75g.
水合的玉米淀粉 236.25g.
Povidone（PVC-30） 105.00g.
（＊A是指游离酸的活度当量）
然后将干的、湿的颗粒粉剂进一步与下列成份拌合，
羟基乙酸淀粉钠
（Explotab） 210.00g.
硬脂酸镁 42.00g.
十二烷基硫酸钠 21.00g.
应用充分拌合好约375mg.的填充重量，在一通常使用的胶囊填充机上制备含有100mg.A的软凝胶胶囊。当给狗口服投药时，与以口服溶液投药比较由血液水平显示有89%的高生物利用度，因此这类胶囊表现出有极优良的生物利用度。
Claims (1)
1、一种用于制备无水的5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-碳酰胺的钠盐结晶的方法，该方法包括将一种相应的水合物型与乙腈一起搅拌。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1987/000201 WO1988005656A1 (en) | 1987-02-02 | 1987-02-02 | Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide |
| USPCT/US87/00201 | 1987-02-02 | ||
| USPCT/US87/000201 | 1987-02-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN88100555A true CN88100555A (zh) | 1988-08-17 |
| CN1022324C CN1022324C (zh) | 1993-10-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN88100555A Expired - Fee Related CN1022324C (zh) | 1987-02-02 | 1988-02-02 | 制备无水、结晶型的5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺的钠盐的方法 |
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| US (1) | US5036099A (zh) |
| EP (1) | EP0277738B1 (zh) |
| JP (1) | JPS63201184A (zh) |
| KR (1) | KR900001422B1 (zh) |
| CN (1) | CN1022324C (zh) |
| AP (1) | AP52A (zh) |
| AR (1) | AR243182A1 (zh) |
| AT (1) | ATE73800T1 (zh) |
| AU (1) | AU587736B2 (zh) |
| BG (1) | BG51042A3 (zh) |
| CA (1) | CA1335590C (zh) |
| CS (2) | CS265250B2 (zh) |
| CY (1) | CY1775A (zh) |
| DD (1) | DD267490A5 (zh) |
| DE (1) | DE3869149D1 (zh) |
| DK (1) | DK44888A (zh) |
| EC (1) | ECSP941082A (zh) |
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| FI (1) | FI89598C (zh) |
| GR (1) | GR3004200T3 (zh) |
| HK (1) | HK132695A (zh) |
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| SG (1) | SG27994G (zh) |
| SI (1) | SI8810183A8 (zh) |
| UA (1) | UA25898A1 (zh) |
| WO (1) | WO1988005656A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4861794A (en) * | 1988-04-13 | 1989-08-29 | Pfizer Inc. | 3-substituted-2-oxindole-1-carboxamides as inhibitors of interleukin-1 biosynthesis |
| US4853409A (en) * | 1988-04-13 | 1989-08-01 | Pfizer Inc. | 3-substituted-2-oxindole-1-carboxamides for suppressing T-cell function |
| EP0365194B1 (en) * | 1988-10-18 | 1995-08-02 | Pfizer Inc. | Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides |
| HU208421B (en) * | 1988-10-18 | 1993-10-28 | Pfizer | Process for producing starting materials for producing 3-acyl-2-oxindol-carboxamides ofantiphlogistic activity |
| US5059693A (en) * | 1989-10-06 | 1991-10-22 | Pfizer Inc. | Process for making 3-aroyl-2-oxindole-1-carboxamides |
| US5006547A (en) * | 1990-03-19 | 1991-04-09 | Pfizer Inc. | Tenidap as an inhibitor of the release of elastase by neutrophils |
| US5008283A (en) * | 1990-03-19 | 1991-04-16 | Pfizer Inc. | Use of tenidap to inhibit activation of collagenase and to inhibit the activity of myeloperoxidase |
| US5122534A (en) * | 1991-02-08 | 1992-06-16 | Pfizer Inc. | Use of tenidap to reduce total serum cholesterol, ldl cholesterol and triglycerides |
| DE4111305C2 (de) * | 1991-04-08 | 1994-12-01 | Mack Chem Pharm | Pharmazeutische Zubereitung zur rektalen Applikation, die ein 2-Oxindol-l-carboxamid-derivat enthält |
| WO1997022605A1 (en) * | 1995-12-19 | 1997-06-26 | Pfizer Inc. | Stable, long acting salts of indole derivatives for the treatment of joint diseases |
| EP0826685A1 (en) * | 1996-08-21 | 1998-03-04 | Pfizer Inc. | Stable, long acting salts of carboxamides for the treatment of joint disease |
| DE19854355A1 (de) * | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation B von 8-Cyan-1-cyclopropyl-7-(1S, 6S-2,8-diazabicyclo-/4.3.O/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| US7407195B2 (en) * | 2004-04-14 | 2008-08-05 | William Berson | Label for receiving indicia having variable spectral emissivity values |
| US7651031B2 (en) | 2004-10-25 | 2010-01-26 | William Berson | Systems and methods for reading indicium |
| US7728726B2 (en) * | 2005-01-14 | 2010-06-01 | William Berson | Radio frequency identification labels |
| US7619520B2 (en) * | 2005-01-14 | 2009-11-17 | William Berson | Radio frequency identification labels and systems and methods for making the same |
| US7931413B2 (en) * | 2005-01-14 | 2011-04-26 | William Berson | Printing system ribbon including print transferable circuitry and elements |
| US7621451B2 (en) * | 2005-01-14 | 2009-11-24 | William Berson | Radio frequency identification labels and systems and methods for making the same |
| WO2019087191A1 (en) | 2017-11-02 | 2019-05-09 | Accurate Medical Therapeutics Ltd. | Embolization catheter with integral filter |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3767653A (en) * | 1971-06-28 | 1973-10-23 | Squibb & Sons Inc | Thiazines |
| GB1532413A (en) * | 1974-12-23 | 1978-11-15 | Union International Co Ltd | Chenodeoxycholic acid |
| DE2613346C3 (de) * | 1976-03-29 | 1981-07-23 | Diamalt AG, 8000 München | Monoklin kristalline Chenodesoxycholsäure und Verfahren zu ihrer Herstellung |
| GR850310B (zh) * | 1984-02-07 | 1985-06-05 | Pfizer | |
| US4556672A (en) * | 1984-03-19 | 1985-12-03 | Pfizer Inc. | 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents |
| DE3579716D1 (de) * | 1984-03-19 | 1990-10-25 | Pfizer | Verfahren zur herstellung von 2-oxindole-1-carboxamiden und deren zwischenprodukte. |
| US4569942A (en) * | 1984-05-04 | 1986-02-11 | Pfizer Inc. | N,3-Disubstituted 2-oxindole-1-carboxamides as analgesic and antiinflammatory agents |
-
1987
- 1987-02-02 RO RO140907A patent/RO105052B1/ro unknown
- 1987-02-02 UA UA4614718A patent/UA25898A1/uk unknown
- 1987-02-02 WO PCT/US1987/000201 patent/WO1988005656A1/en active IP Right Grant
- 1987-02-02 US US07/460,137 patent/US5036099A/en not_active Expired - Lifetime
-
1988
- 1988-01-25 DE DE8888300561T patent/DE3869149D1/de not_active Expired - Fee Related
- 1988-01-25 ES ES88300561T patent/ES2032955T3/es not_active Expired - Lifetime
- 1988-01-25 EP EP88300561A patent/EP0277738B1/en not_active Expired - Lifetime
- 1988-01-25 AT AT88300561T patent/ATE73800T1/de not_active IP Right Cessation
- 1988-01-27 IN IN67/DEL/88A patent/IN171799B/en unknown
- 1988-01-28 AP APAP/P/1988/000081A patent/AP52A/en active
- 1988-01-29 CA CA000557662A patent/CA1335590C/en not_active Expired - Fee Related
- 1988-01-29 DK DK044888A patent/DK44888A/da not_active Application Discontinuation
- 1988-02-01 NZ NZ223373A patent/NZ223373A/xx unknown
- 1988-02-01 YU YU18388A patent/YU46766B/sh unknown
- 1988-02-01 AR AR88309983A patent/AR243182A1/es active
- 1988-02-01 PT PT86675A patent/PT86675B/pt not_active IP Right Cessation
- 1988-02-01 DD DD88312599A patent/DD267490A5/de not_active IP Right Cessation
- 1988-02-01 ZA ZA88679A patent/ZA88679B/xx unknown
- 1988-02-01 PH PH36441A patent/PH26545A/en unknown
- 1988-02-01 IL IL8527788A patent/IL85277A/en not_active IP Right Cessation
- 1988-02-01 SI SI8810183A patent/SI8810183A8/sl not_active IP Right Cessation
- 1988-02-01 OA OA59273A patent/OA08710A/xx unknown
- 1988-02-01 BG BG82816A patent/BG51042A3/xx unknown
- 1988-02-01 PL PL1988270415A patent/PL149550B1/pl unknown
- 1988-02-01 AU AU11160/88A patent/AU587736B2/en not_active Ceased
- 1988-02-01 KR KR1019880000876A patent/KR900001422B1/ko not_active IP Right Cessation
- 1988-02-01 MA MA21408A patent/MA21171A1/fr unknown
- 1988-02-02 CS CS88648A patent/CS265250B2/cs unknown
- 1988-02-02 IS IS3309A patent/IS1533B/is unknown
- 1988-02-02 CN CN88100555A patent/CN1022324C/zh not_active Expired - Fee Related
- 1988-02-02 JP JP63022675A patent/JPS63201184A/ja active Granted
- 1988-02-02 MY MYPI88000091A patent/MY102737A/en unknown
- 1988-09-29 NO NO88884329A patent/NO170581C/no not_active IP Right Cessation
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1989
- 1989-07-18 IE IE26988A patent/IE60000B1/en not_active IP Right Cessation
- 1989-08-01 RU SU894614718A patent/RU2011381C1/ru not_active IP Right Cessation
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-
1991
- 1991-11-22 CS CS913541A patent/CS354191A3/cs unknown
-
1992
- 1992-03-31 GR GR920400571T patent/GR3004200T3/el unknown
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1993
- 1993-11-15 LV LVP-93-1225A patent/LV10252B/xx unknown
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1994
- 1994-02-22 SG SG27994A patent/SG27994G/en unknown
- 1994-05-05 EC EC1994001082A patent/ECSP941082A/es unknown
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1995
- 1995-08-24 HK HK132695A patent/HK132695A/xx not_active IP Right Cessation
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1996
- 1996-04-05 CY CY177596A patent/CY1775A/xx unknown
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