CN1227029C - 转化酶抑制剂和利尿剂的组合在治疗微循环紊乱中的应用 - Google Patents
转化酶抑制剂和利尿剂的组合在治疗微循环紊乱中的应用 Download PDFInfo
- Publication number
- CN1227029C CN1227029C CNB988113163A CN98811316A CN1227029C CN 1227029 C CN1227029 C CN 1227029C CN B988113163 A CNB988113163 A CN B988113163A CN 98811316 A CN98811316 A CN 98811316A CN 1227029 C CN1227029 C CN 1227029C
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- Prior art keywords
- indapamide
- perindopril
- purposes
- diuretic
- pharmaceutical composition
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Abstract
本发明涉及血管紧张素转化酶抑制剂(CEI)和利尿剂的组合在制备用于治疗小动脉-毛细管微循环紊乱的药物组合物中的应用。
Description
本发明涉及血管紧张素转化酶抑制剂(CEI)和利尿剂的组合在制造用于治疗小动脉-毛细管微循环紊乱的药物组合物中的应用。
已知绝大多数变性血管疾病，如动脉高血压(N.M.Kaplan，“微血管稀疏化”《临床高血压》第6版，Baltimore，Wilkinson&Wikins，1994，86；A.S.Greene等，“高血压中的微血管稀疏化和组织血管耐受”，《美国生理学杂志》，1989，256(心脏循环生理，25)，H126-H31；A.S.Izzard等人，“高血压与脉管系统：小动脉和肌性反应”，《高血压杂志》1995，13，1-4；A-M.Heagerty等人“高血压中的小动脉结构”《高血压》1993，21，391-7)，以及某些代谢紊乱的血管并发症，如糖尿病(G.Reach等人的“微血管病和神经病的起因和机理-葡萄糖假说及其推论”，公开在G.Tchobroutsky，G.Slama，R.Assan，P.Freychet，Paris：Pradel，1990，448-57)或某些脂肪代谢障碍症(dyslipidemias)(J.F.Toole，“动脉粥样硬化”，脑血管疾病，New York，Raven Press，1984，199-213)都伴发有害的小动脉-毛细管微循环的解剖和/或功能的变化(J.C.M.L.Le Noble等的“对于自发性高血压幼鼠中睾提肌微循环的功能形态学研究”，《高血压杂志》1990，8，741-8；I.I.H.Chen等“自发性高血压大鼠睾提肌中的微血管稀疏化”《美国生理学杂志》1981，241，H306-10)。
小动脉-毛细管微循环中解剖和/或机能上的有害变化可以采取不同形式，例如：
-小动脉-毛细管稀疏化(P.Gasser，“通过视频显微镜检测的血压正常者和自发性高血压对象甲褶处的微循环”《高血压杂志》1992，1，83-6)。
-缺乏小动脉-毛细管恢复(B.W.Zweifach，“自发性高血压大鼠骨骼肌中微压和流速的关系”《高血压》1981，3，601-14)。
-和，更常见的是，对组织内血液分布的调节不良无法满足代谢需要，任何可能引起或永久造成绝对或相对组织灌注不足或局部缺血的有害变化(E.Vicaut，“高血压和微循环：实验研究简述”《高血压杂志》1992，10，补编.5，S59-S68)。
已知上述小动脉-毛细管微循环的不良解剖学和/或机能变化可以发生在例如动脉高血压血压值升高之前，导致某些真恶性循环(A.J.Zweifler等“边缘性高血压中指脉搏减弱：早期血管结构异常的迹象”《美国心脏学杂志》1982，104，812-15；J.M.Sullivan等“年轻高输出量临界高血压患者中微循环的衰退”《高血压》1983，5，844-51)。
最终，已知许多因素同时参与调节全身血液动力学(输出量，阻力，压力等)，并且根据前后关系(依赖于器官性质的等级化等)和瞬时代谢的需要(M.J.Mulvany，“特发性高血压中阻力脉管系统的结构”《高血压杂志》1987，5，129：H；H.A.J.Struijker-Boudier等“微循环和高血压”《高血压杂志》1992，10(补编7)S147-S156)参与调节或适当修正组织内的血液分布。
迄今为止已发现多种血管活性物质，特别是在近年来，譬如那些来源于或作用于平滑肌纤维和血管内皮的物质(S.Laurent等“动脉高血压中的动脉改变的生理病理学和药理学”《药理学家通讯》(theletter from the pharmacologist)，1977，11，146-54；Tabbei等，“高血压引起的人体内皮机能早发性老化”《高血压》1997，29，736-43)。
根据现今对这些不同调节作用的复杂性、参与因子的数量及其相互作用的深入了解，我们能够提供若干具有直接或间接血管活性药物的组合用于预防和治疗：
-一方面，当血压值升高到或甚至超过国际科学界所推荐的标准值时，用于临床发作，如动脉高血压，；
-另一方面，其对大/微循环紊乱中组织灌注起消肿作用，已知所述紊乱先于、维持和加重上述临床现象，例如(动脉高血压，如某些代谢性疾病的血管并发症等)(H.A.J.Struijker-Boudier等“对心血管疾病中的微循环评估”《临床科学》1996，91，131-9)。
所以，不同血管活性物质的作用通常彼此互补，而且在对变性血管疾病的基础治疗上或甚至在预防其所引起的发病率或意外伤害中具有改进的疗效。
已知一些CEI类药物对小动脉或冠状微循环具有有益作用，但有文献已经证明这些药物对小动脉和相邻毛细管代表的功能单元产生决无有益作用。
如今已知，作为本发明的主题，CEI和利尿剂的组合除了具备已知的性质以外，还令人惊奇地能够在小动脉和毛细管的水平校正微循环紊乱，但在现有出版物或专利中没有公开或请求保护关于这种组合，尤其是CEI的和利尿剂的组合的这种性质特性。
此类血管活性药物组合的新颖性除了上述事实以外，还特别在于该组合物的各组分通常以低剂量使用，该低剂量一般低于各组分在其第一适应症中的使用剂量。
所以，此类组合物的实用性在于适合用来制备用于治疗小动脉-毛细管微循环紊乱的药物组合物。因此，这些组合物对所有微循环紊乱参与其中的病变均有效，例如变性血管疾病、动脉高血压、心机能不全、大脑局部缺血、心脏病发作、下肢动脉炎；对II型糖尿病的心血管并发症、视网膜病、肾病等类似疾病的预防和治疗可以作为主要或次要治疗。
可用于上述组合物的CEI类药物是但不限于：哌道普利、卡托普利、依那普利、赖诺普利、地拉普利、福森普利、喹那普利、雷米普利、斯哌普利、咪哒普利、川多普利、贝那普利、西拉普利和替莫普利，及其与药物可接受酸或碱生成的加成盐。
优选的CEI类药物是哌道普利、卡托普利、依那普利、赖诺普利、贝那普利、喹那普利、和地拉普利及其盐，并且更优选哌道普利及其盐。
可用于上述组合物的利尿剂是但不限于：吲达帕胺、氢氯噻嗪、速尿、烯硫噻二嗪、三氯噻嗪、三氟噻嗪(Triflumethazide)、苄甲噻嗪、环己氯噻嗪、甲氯噻嗪、阿佐塞米、氯噻嗪、异丁噻嗪、苄氟噻嗪、环戊氯噻嗪、苄氯三噻嗪(Benzchlortriazide)、多噻嗪、氢氟噻嗪、苯硫噻嗪、乙噻嗪、戊氟噻嗪、氯哌酰胺、西氯奈德(Cicletanide)或苯吡磺苯酸，及其与药物可接受酸或碱生成的加成盐。
优选的利尿剂是吲达帕胺和氢氯噻嗪及其盐，并且更优选吲达帕胺及其盐。
所以，本发明更优选涉及转化酶抑制剂哌道普利或其一种与药物可接受碱生成的加成盐与利尿剂吲达帕胺的组合在制备用于治疗小动脉-毛细管微循环紊乱的药物组合物中的应用。
本发明所述的药物组合物将以适合于口服、非肠道且特别是静脉内或经皮、经鼻、直肠、经舌、经眼或经呼吸道给药的药物形式存在，并且更具体的如片剂、舌下片、胶囊(包括硬明胶胶囊)、glossette、锭剂、可注射制剂、气溶胶、滴眼剂或滴鼻剂、栓剂、霜剂、软膏、皮肤凝胶等。
优选的给药途径是口服途径以及能够瞬时或缓释活性成分的相应药物组合物。
片剂是优选的药物组合物。
在本发明的药物组合物中，CEI和利尿剂的含量是根据这些活性成分的性质进行调整，因此它们的相对配比随活性成分的不同而改变。
当CEI是哌道普利的叔丁胺盐形式且利尿剂是吲达帕胺时，它们的比例分别是65-85％(重量)和35-15％(重量)(以活性成分的总重量计)，并且优选该CEI为70-80％(重量)且该利尿剂为30-20％(重量)。
该组合的优选百分比是76％(重量)的哌道普利叔丁胺盐形式和24％(重量)的吲达帕胺。
本发明所述组合物除了含有活性成分以外，还含有一种或多种药物可接受载体或赋形剂。
在药物可接受赋形剂中，值得提及但不作为限定的是粘合剂、稀释剂、崩解剂、稳定剂、防腐剂、润滑剂、香料、矫味剂或甜味剂。
剂量将根据患者的年龄和体重、给药途径或被治疗适应症和有关治疗的性质而改变。按照CEI的性质剂量范围为1-50mg，按照利尿剂的性质剂量范围为0.5-25mg，每24小时摄取一次或数次。
本发明所述药物组合物的实施例。这些实施例不起限定作用。
实施例1：哌道普利/吲达帕胺片剂
| 组成 | 含量(mg) |
| 哌道普利的叔丁胺盐吲达帕胺疏水性胶体二氧化硅 | 20.6250.25 |
| 乳糖硬脂酸镁微晶纤维素 | 64.1750.4522.5 |
| 片剂最终为 | 90 |
实施例2：
| 组成 | 含量(mg) |
| 哌道普利的叔丁胺盐吲达帕胺疏水性胶体二氧化硅 | 41.250.25 |
| 乳糖硬脂酸镁微晶纤维素 | 61.550.4522.5 |
| 最终的片剂为 | 90 |
实施例3：
| 组成 | 含量(mg) |
| 卡托普利氢氯噻嗪 | 5025 |
实施例4：
| 组成 | 含量(mg) |
| 马来酸依那普利氢氯噻嗪 | 2012.5 |
实施例5：
| 组成 | 含量(mg) |
| 赖诺普利氢氯噻嗪 | 2012.5 |
实施例6：
| 组成 | 含量(mg) |
| 贝那普利盐酸盐氢氯噻嗪 | 1012.5 |
实施例7：
| 组成 | 含量(mg) |
| 喹那普利盐酸盐氢氯噻嗪 | 2012.5 |
实施例8：
| 组成 | 含量(mg) |
| 哌道普利叔丁胺盐氢氯噻嗪 | 212.5 |
实施例9：
| 组成 | 含量(mg) |
| 哌道普利叔丁胺盐氢氯噻嗪 | 425 |
实施例10：
| 组成 | 含量(mg) |
| 卡托普利吲达帕胺 | 501.25 |
实施例11：
| 组成 | 含量(mg) |
| 马来酸依那普利吲达帕胺 | 201.25 |
实施例12：
| 组成 | 含量(mg) |
| 赖诺普利吲达帕胺 | 201.25 |
实施例13：
| 组成 | 含量(mg) |
| 贝那普利盐酸盐吲达帕胺 | 101.25 |
实施例14：
| 组成 | 含量(mg) |
| 喹那普利盐酸盐吲达帕胺 | 201.25 |
实施例15：
| 组成 | 含量(mg) |
| 哌道普利叔丁胺盐苄氟噻嗪 | 45 |
实施例16：
| 组成 | 含量(mg) |
| 卡托普利苄氟噻嗪 | 505 |
实施例17：
| 组成 | 含量(mg) |
| 地拉普利盐酸盐吲达帕胺 | 302.5 |
实施例18：
| 组成 | 含量(mg) |
| 地拉普利盐酸盐氢氯噻嗪 | 3025 |
实施例19：
| 组成 | 含量(mg) |
| 福森普利氢氯噻嗪 | 1025 |
本发明组合物的药理学研究
哌道普利的叔丁胺盐(0.76mg/kg/d，PO)+吲达帕胺(0.24mg/kg/d，PO)的组合物对1R-1C肾血管高血压大鼠的作用：对心内膜下小动脉-毛细管密度的血液动力学研究。
首先将8周龄的Wistar大鼠(n＝56；体重＝200g)的左肾动脉用小夹子(直径0.2mm)定位，四天后实施对侧肾切除术。对一系列相同大鼠(n＝13)进行同样的干预(麻醉+手术)，但不实施肾动脉狭窄或肾切除术(NT对照组)。1R-1C Goldblatt大鼠接受：
-正常饲料：HT对照组；
-或含有哌道普利的叔丁胺盐(0.76mg/kg/天)和吲达帕胺(0.24mg/kg/天)的饲料：HT组+组合。
鉴于各组的具体死亡率，对各组的数量进行调整，以确保在处理4周后每组至少有9只动物存活用于分析。
| 被处理的数量 | 被测数量(存活动物) | |
| NT对照组 | 13 | 13 |
| HT对照组 | 21 | 9 |
| HT+哌道普利-吲达帕胺组合 | 18 | 10 |
处理4周后，在麻醉条件下记录血液动力学参数(表I)，随后取出心脏用于定量组织形态学分析。哌道普利盐-吲达帕胺组合显著降低了动脉血压(p＜0.01)。上述处理没有改变对心脏输出量和心律。相对于HT对照组比较，左心室肥大的程度(LV的重量/体重)有明显降低(p＜0.001)。
表I
| NT对照组 | HT对照组 | HT+组合 | |
| 收缩期动脉压(mmHg)舒张期动脉压(mmHg)心输出量(ml/min)心率(/min) | 138±5110±559±4486±10 | 209±12146±1145±4455±19 | 110±1979±1263±7496±11 |
| LV重量/体重(mg/g) | 2.1±0.1 | 3.7±0.2 | 2.2±0.2 |
左心室壁中的心内膜下毛细管的密度
在与NT对照组比较时，HT对照组的毛细管密度明显降低(p＜0.05)，但用哌道普利盐-吲达帕胺组合可以使之正常化。
左心室壁中的心内膜下小动脉的密度
在HT对照组中每平方毫米心内膜下表面的小动脉数量明显增加(p＜0.05)，而在哌道普利盐-吲达帕胺联合给药组中正常。
结果如表II所示：
| NT对照组 | HT对照组 | HT+组合 | |
| 心内膜下毛细管密度心内膜下小动脉密度 | 1030±428.25±0.46 | 916±3910.51±0.41 | 1076±418.96±0.63 |
上述数据解释如下：
-经证实，在绝大多数变性血管疾病中，本例是在动脉高血压中，存在对小动脉-毛细管微循环有害的解剖学和/或功能改变。
-在上述实验中，最显著的异常涉及毛细管密度，该密度在高血压对象中明显降低，但通过上述两种活性成分的组合的“治疗”下可以正常化。
-由于实验所采用的条件，难以确定组合中的各组分各自对小动脉和毛细管所具有的分别作用。但是，似乎各组分对于微循环功能单元中的小动脉部分和毛细管部分都有影响。
所以，此处所研究的哌道普利盐和吲达帕胺以76/24％的比例组合使心内膜下毛细管和小动脉密度正常化的事实是为了举例说明本发明。
Claims (11)
1.血管紧张素转化酶抑制剂和利尿剂的组合在制备用于治疗小动脉-毛细管微循环紊乱的药物组合物中的用途。
2.如权利要求1所示的用途，其中所述转化酶抑制剂是哌道普利、卡托普利、依那普利、赖诺普利、地拉普利、福森普利、喹那普利、雷米普利、斯哌普利、咪哒普利、川多普利、贝那普利、西拉普利或替莫普利，和其中所述利尿剂是吲达帕胺、氢氯噻嗪、速尿、烯硫噻二嗪、三氯噻嗪、三氟噻嗪、苄甲噻嗪、环己氯噻嗪、甲氯噻嗪、阿佐塞米、氯噻嗪、异丁噻嗪、苄氟噻嗪、环戊氯噻嗪、苄氯三噻嗪、多噻嗪、氢氟噻嗪、苯硫噻嗪、乙噻嗪、戊氟噻嗪、氯哌酰胺、西氯奈德或苯吡磺苯酸，及这些化合物与药物可接受酸或碱生成的加成盐。
3.如权利要求2所述的用途，其中所述转化酶抑制剂是哌道普利、卡托普利、依那普利、赖诺普利、贝那普利、喹那普利、地拉普利，和其中所述利尿剂是吲达帕胺和氢氯噻嗪，和这些化合物与药物可接受酸或碱生成的加成盐。
4.转化酶抑制剂哌道普利或其一种与药物可接受碱生成的加成盐与利尿剂吲达帕胺的组合在获得用于治疗小动脉-毛细管微循环紊乱的药物组合物中的用途。
5.如权利要求4所述的用途，其中所述转化酶抑制剂是哌道普利的叔丁胺盐并且其中所述利尿剂是吲达帕胺。
6.如权利要求4所述的用途，其中所述药物组合物中的哌道普利叔丁胺盐和吲达帕胺的含量分别是65-85％(重量)和35-15％(重量)，以活性成分的总重量计。
7.如权利要求6所述的用途，其中所述含量是76％(重量)的哌道普利叔丁胺盐和24％(重量)的吲达帕胺。
8.如权利要求1所述的用途，其中所述药物组合物为片剂剂型。
9.如权利要求4所述的用途，其中所述药物组合物为片剂剂型。
10.一种适用于权利要求9所述应用的药物组合物，其中该片剂中含有2mg的哌道普利叔丁胺盐和0.625mg的吲达帕胺，以及药物可接受、无毒、惰性的赋形剂或载体。
11.一种适用于权利要求9所述应用的药物组合物，其中该片剂中含有4mg的哌道普利叔丁胺盐和1.25mg的吲达帕胺，以及药物可接受、无毒、惰性的赋形剂或载体。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9714485A FR2771010B1 (fr) | 1997-11-19 | 1997-11-19 | Utilisation d'une combinaison d'un inhibiteur de l'enzyme de conversion de l'angiotensine et d'un diuretique pour le traitement des desordres microcirculatoires |
| FR97/14485 | 1997-11-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1279615A CN1279615A (zh) | 2001-01-10 |
| CN1227029C true CN1227029C (zh) | 2005-11-16 |
Family
ID=9513523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988113163A Expired - Lifetime CN1227029C (zh) | 1997-11-19 | 1998-03-03 | 转化酶抑制剂和利尿剂的组合在治疗微循环紊乱中的应用 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6653336B1 (zh) |
| EP (1) | EP1032414B1 (zh) |
| JP (1) | JP2001523646A (zh) |
| CN (1) | CN1227029C (zh) |
| AT (1) | ATE239500T1 (zh) |
| AU (1) | AU740748B2 (zh) |
| BR (1) | BR9814885A (zh) |
| CA (1) | CA2310136C (zh) |
| DE (1) | DE69814444T2 (zh) |
| DK (1) | DK1032414T3 (zh) |
| EA (1) | EA002968B1 (zh) |
| ES (1) | ES2198708T3 (zh) |
| FR (1) | FR2771010B1 (zh) |
| HK (1) | HK1033096A1 (zh) |
| HU (1) | HU226022B1 (zh) |
| NO (1) | NO20002479L (zh) |
| NZ (1) | NZ504220A (zh) |
| PL (1) | PL340561A1 (zh) |
| PT (1) | PT1032414E (zh) |
| WO (1) | WO1999025374A1 (zh) |
| ZA (1) | ZA986673B (zh) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2811318B1 (fr) * | 2000-07-06 | 2002-08-23 | Adir | Nouvelle forme cristalline gamma du sel de tert-butylamine du perindopril, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| FR2811320B1 (fr) * | 2000-07-06 | 2002-08-23 | Adir | Nouvelle forme cristalline alpha du sel de tert-butylamine du perindopril, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| FR2811319B1 (fr) * | 2000-07-06 | 2002-08-23 | Adir | Nouvelle forme cristalline beta du sel de tert-butylamine du perindopril, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| US20040156903A1 (en) * | 2002-05-22 | 2004-08-12 | Abrams Andrew L.. | Metering and packaging of controlled release medication |
| AU2002303840A1 (en) * | 2001-05-31 | 2002-12-09 | Microdose Technologies, Inc. | Metering and packaging of controlled release medication |
| FR2841140B1 (fr) * | 2002-06-24 | 2004-10-01 | Servier Lab | Microcapsules pour la liberation retardee et controlee du perindopril |
| WO2005021039A1 (en) * | 2003-08-29 | 2005-03-10 | Cotherix, Inc. | Combination of cicletanine and an oral antidiabetic and/or blood lipid-lowering agent for treating diabetes and metabolic syndrome |
| CN1292747C (zh) * | 2003-09-16 | 2007-01-03 | 广东省心血管病研究所 | 一种用于治疗高血压的复方制剂 |
| DE102004019845A1 (de) * | 2004-03-29 | 2005-10-20 | Krka Tovarna Zdravil D D | Verfahren zur Herstellung einer festen pharmazeutischen Zusammensetzung |
| WO2005094793A1 (en) * | 2004-03-29 | 2005-10-13 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing a solid pharmaceutical composition |
| SI21800A (sl) * | 2004-05-14 | 2005-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Nov postopek sinteze perindoprila |
| DE102004062257A1 (de) * | 2004-12-23 | 2006-07-06 | Merckle Gmbh | Direkt verpresste Indapamid-Tabletten mit verzögerter Wirkstofffreisetzung |
| MY138209A (en) * | 2005-03-11 | 2009-05-29 | Servier Lab | New (y) crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it. |
| BRPI0615607A2 (pt) * | 2005-08-30 | 2011-05-24 | Lek Pharmaceuticals | composição farmacêutica compreendendo perindopril ou seus sais |
| DE102005058166A1 (de) * | 2005-12-05 | 2007-06-06 | Hexal Ag | Matrixkontrolliertes transdermales System mit Amin-Salzen der ACE-Hemmer-Dicarbonsäuren |
| WO2008068577A2 (en) * | 2006-12-01 | 2008-06-12 | Glenmark Pharmaceuticals Limited | Pharmaceutical compositions |
| SI22543A (sl) | 2007-06-27 | 2008-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Nove soli perindoprila |
| CN107496899A (zh) | 2011-09-29 | 2017-12-22 | 梅约医学教育与研究基金会 | 芳族阳离子肽和使用它们的方法 |
| RU2618471C2 (ru) * | 2012-12-03 | 2017-05-03 | Закрытое Акционерное Общество "Вертекс" | Пероральная фармацевтическая композиция диуретика и ингибитора АПФ в микронизированной форме, лекарственное средство и его применение |
| CA3126333A1 (en) * | 2019-01-09 | 2020-07-16 | Ken-ichi YAMADA | Pharmaceutical composition for intraocular or oral administration for treatment of retinal diseases |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK9200258U4 (da) * | 1992-03-11 | 1993-07-23 | Merck & Co Inc | Farmaceutisk præparat indeholdende enalapril til brug mod hypertension |
| PT804229E (pt) * | 1995-03-16 | 2003-06-30 | Pfizer | Utilizacao de amlodipina de um dos seus sais ou defelodipina em combinacao com um inibidor da en zima de conversao da angiotensina (ace) para no fabrico de um medicamento destinado ao tratamento da insuficiencia cardiaca congestiva nao isquemica |
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1997
- 1997-11-19 FR FR9714485A patent/FR2771010B1/fr not_active Expired - Fee Related
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1998
- 1998-03-03 EP EP98913813A patent/EP1032414B1/fr not_active Expired - Lifetime
- 1998-03-03 PL PL98340561A patent/PL340561A1/xx unknown
- 1998-03-03 AU AU68377/98A patent/AU740748B2/en not_active Revoked
- 1998-03-03 CN CNB988113163A patent/CN1227029C/zh not_active Expired - Lifetime
- 1998-03-03 US US09/554,715 patent/US6653336B1/en not_active Expired - Lifetime
- 1998-03-03 PT PT98913813T patent/PT1032414E/pt unknown
- 1998-03-03 ES ES98913813T patent/ES2198708T3/es not_active Expired - Lifetime
- 1998-03-03 WO PCT/FR1998/000411 patent/WO1999025374A1/fr active IP Right Grant
- 1998-03-03 DE DE69814444T patent/DE69814444T2/de not_active Expired - Lifetime
- 1998-03-03 BR BR9814885-0A patent/BR9814885A/pt not_active Application Discontinuation
- 1998-03-03 DK DK98913813T patent/DK1032414T3/da active
- 1998-03-03 CA CA002310136A patent/CA2310136C/fr not_active Expired - Lifetime
- 1998-03-03 EA EA200000536A patent/EA002968B1/ru not_active IP Right Cessation
- 1998-03-03 NZ NZ504220A patent/NZ504220A/en not_active IP Right Cessation
- 1998-03-03 JP JP2000520807A patent/JP2001523646A/ja active Pending
- 1998-03-03 HU HU0004544A patent/HU226022B1/hu unknown
- 1998-03-03 AT AT98913813T patent/ATE239500T1/de active
- 1998-07-27 ZA ZA986673A patent/ZA986673B/xx unknown
-
2000
- 2000-05-12 NO NO20002479A patent/NO20002479L/no not_active Application Discontinuation
-
2001
- 2001-06-04 HK HK01103825A patent/HK1033096A1/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ZA986673B (en) | 1999-02-04 |
| PL340561A1 (en) | 2001-02-12 |
| EA002968B1 (ru) | 2002-12-26 |
| WO1999025374A1 (fr) | 1999-05-27 |
| HUP0004544A3 (en) | 2001-07-30 |
| DK1032414T3 (da) | 2003-09-01 |
| NO20002479D0 (no) | 2000-05-12 |
| HU226022B1 (en) | 2008-03-28 |
| DE69814444T2 (de) | 2004-03-18 |
| PT1032414E (pt) | 2003-08-29 |
| HUP0004544A2 (hu) | 2001-06-28 |
| AU740748B2 (en) | 2001-11-15 |
| ES2198708T3 (es) | 2004-02-01 |
| EA200000536A1 (ru) | 2000-10-30 |
| NZ504220A (en) | 2003-05-30 |
| BR9814885A (pt) | 2000-10-03 |
| US6653336B1 (en) | 2003-11-25 |
| FR2771010B1 (fr) | 2003-08-15 |
| DE69814444D1 (de) | 2003-06-12 |
| NO20002479L (no) | 2000-05-12 |
| EP1032414B1 (fr) | 2003-05-07 |
| HK1033096A1 (en) | 2001-08-17 |
| FR2771010A1 (fr) | 1999-05-21 |
| AU6837798A (en) | 1999-06-07 |
| CA2310136C (fr) | 2004-04-20 |
| EP1032414A1 (fr) | 2000-09-06 |
| ATE239500T1 (de) | 2003-05-15 |
| JP2001523646A (ja) | 2001-11-27 |
| CN1279615A (zh) | 2001-01-10 |
| CA2310136A1 (fr) | 1999-05-27 |
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