CN1152686C - 稳定化药用组合物 - Google Patents
稳定化药用组合物 Download PDFInfo
- Publication number
- CN1152686C CN1152686C CNB988123738A CN98812373A CN1152686C CN 1152686 C CN1152686 C CN 1152686C CN B988123738 A CNB988123738 A CN B988123738A CN 98812373 A CN98812373 A CN 98812373A CN 1152686 C CN1152686 C CN 1152686C
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- acid
- pharmaceutical composition
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- lactose
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- 230000002378 acidificating effect Effects 0.000 claims abstract description 20
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 16
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 13
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Classifications
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/499—Spiro-condensed pyrazines or piperazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Obesity (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
(R)-2-4-溴′-2-氟苄基-1，2，3，4-四氢吡咯并〔1，2-a〕吡嗪-4-螺-3′-吡咯烷-1，2′，3，5′-四酮(称为AS-3201)的一种稳定的药用组合物，该组合物含有至少一种酸性物质作为稳定剂，此酸性物质具有比AS-3201更强的酸性，它们是例如抗坏血酸，柠檬酸，酒石酸，乳酸，马来酸，苹果酸或磷酸。
Description
技术领域
本发明是关于(R)-2-(4-溴-2-氟苄基)-1，2，3，4-四氢吡咯并〔1，2-a〕吡嗪-4-螺-3′-吡咯烷-1，2′，3，5′-四酮(此后被称为“AS-3201”)的稳定化药用组合物，此化合物具有强有力的醛糖还原酶抑制活性。
技术背景
AS-3201是如下结构式的化合物。在日本专利No.2516147(USP 5258382)的实施例22，JP-A-6-192222的参考实施例12(Chem.Abstr.，122，9860(1995))，以及JP-A-8-176105的实验(Chem.Abstr.125，221569(1996))中都描述了该化合物，它们还公开了该化合物强有力的醛糖还原酶抑制活性。
日本专利No.2516147(USP 5258382)的实施例28叙述了制备AS-3201片剂的具体方法。即，按常规方法将AS-3201(1g)，玉米淀粉(25g)，乳糖(58g)，结晶纤维素(11g)，羟丙基纤维素(3g)，轻质无水硅酸(1g)和硬脂酸镁(1g)混合，制成颗粒，并制成每片重100mg的片剂1000片。
在研究制备具有良好贮存稳定性的含有AS-3201的药用组合物方法的过程中，本发明者发现，AS-3201药物本身对热和湿度是稳定的，但是，当AS-3201与药用赋形剂或载体混合时，AS-3201表现出在较高湿度和较高温度下有增加其降解产物的趋势。
在这种情况下，本发明者作了进一步深入的研究，并发现，通过加入至少一种具有比AS-3201更强酸性的酸性物质体为稳定剂，可显著地改善含AS-3201药用组合物的稳定性，从而最后完成了本发明。
本发明的叙述
本发明提供了一种含AS-3201的药用组合物，它含有至少一种具有比AS-3201更强酸性的酸性物质作为稳定剂。
在本发明说明书中，术语“pKa1”是意指一种酸性物质在其无限稀释的溶液中，在25℃的酸离解指数。当一种酸性物质是多元酸时，它意指第一步离解的酸离解指数。术语“水溶解度”意指在100ml水中被溶解溶质的最大量。名词“大约”打算用于包含下述术语的数值。
用于本发明药用组合物的稳定剂，包括具有比AS-3201更强酸性，即pKa＝5.6-5.8的任何药学上适用的酸性物质。这些物质的实例有：己二酸，抗坏血酸，天冬氨酸，谷氨酸，柠檬酸，琥珀酸，酒石酸，乳酸，富马酸，马来酸，苹果酸和磷酸。此外，优选具有pKa1小于大约4.5，以及在15℃-25℃水溶解度大于约10g/100ml的酸性物质。优选的酸性物质是例如，抗坏血酸，柠檬酸，酒石酸，乳酸，马来酸，苹果酸和磷酸。特别优选的酸性物质是，具有pKa1小于约3.3，以及在15℃-25℃水溶解度大于约50g/100ml的酸性物质，包括例如，柠檬酸，酒石酸，马来酸和磷酸，而在这些酸中，酒石酸是最优选的。
这些酸性物质的含量根据这些酸性物质的酸度或水溶解度和被组合的药用赋形剂或载体的种类而变化，但是，它通常是占药用组合物总重量的大约0.2％-10％的范围内，更优选在大约0.5％-大约2.5％重量的范围内。可单独加入一种酸性物质，或者加入二种或几种物质的混合物。
本发明的药用组合物可以是固体剂型，包括例如片剂，胶囊剂，颗粒剂和粉剂等。按常规的方法，通过将AS-3201同药用赋形剂或载体如稀释剂，崩解剂，粘合剂和润滑剂，以及作为稳定剂的酸性物质相混合，可制备这些药用组合物。取决于制备该组合物的方法，可加入此酸性物质本身，或者以该药用组合物制备过程中应用水或其它适合溶剂的溶液形式加入。还可对本发明的药用组合物任选进行包衣，或者本发明组合物还可以含有表面活性剂，着色剂和香味剂等。
除了显示与AS-3201具有不良配伍性的之外，可使用任何一种药用赋形剂或载体。稀释剂包括例如，乳糖，淀粉，结晶纤维素，D-甘露醇，蔗糖，葡萄糖，赤藓醇，木糖醇，D-山梨醇，二份无水磷酸钙和硫酸钙。崩解剂包括例如，淀粉，结晶纤维素，低取代的羟丙基纤维素，羧甲醚纤维素，羧甲醚纤维素钙，羧甲基淀粉钠，交联羧甲基纤维素钠，部分预先凝胶化的淀粉和羟丙基淀粉。粘合剂包括例如，阿拉伯胶，淀粉，羟丙基纤维素，羟丙基甲基纤维素，聚乙烯醇，聚麦芽三糖，明胶，乙基纤维素，甲基纤维素，羧甲醚纤维素钠，和糊精。润滑剂包括例如，硬脂酸镁，硬脂酸钙，硬脂酸，脂肪酸蔗糖酯，轻质无水硅酸，滑石粉，氢化油的聚乙二醇。
用于本发明药用组合物的表面活性剂包括例如，脱水山梨糖醇脂肪酸酯和聚山梨酸酯。着色剂包括例如焦油染料，焦糖和红色氧化铁。香味剂包括例如增甜剂和香料。
在本发明药用组合物中AS-3201的含量，通常占药用组合物总重量的大约0.5％-25％的范围内。其中AS-3201含量比较低的时候，作为稳定剂的酸性物质对改善药用组合物的稳定性特别有效。为了更稳定地贮存含有AS-3201的本发明药用组合物，如果有必要，可将本组合物包装在低湿气通透性材料的药瓶内，或者包装在防水的包装如热封的包装内。
实施本发明的最佳方式
通过实施例和比较实施例对本发明作更详细的说明，但是不应该认为本发明仅限于这些内容。顺便强调-点，将AS-3201制成微细粉末后再使用。
在实施例和比较实施例中，用高效液相色谱(HPLC)，测定含AS-3201的药用组合物中降解产物的含量。将待测样品溶解或分散于乙腈中，以相当于2μg AS-3201量的溶液加入HPLC柱。测定条件如下。
柱 ：Develosil ODS-5(日本Nomura化学公司制造)，
(φ5mm×150mm)
柱温度：40℃
流动相：0.1M磷酸缓冲液(pH3.3)/乙腈/四氢呋喃(3∶1∶1)
的混合液
流速 ：1.0ml/分钟。
波长 ：在220nm处紫外吸收。根据这些测定结果，通过下述等式可计算AS-3201降解百分数。
面积(总)：总的峰面积
(保留时间：2-30分钟)
面积(AS-3201)：AS-3201的峰面积
(保留时间：大约10分钟)
实施例1和比较实施例1
制备片剂：
实施例1 比较实施例1
AS-3201 10g 10g
酒石酸 10g -
乳糖 740g 750g
玉米淀粉 200g 200g
聚乙烯醇 20g 20g
硬脂酸镁 20g 20g
总量 1000g 1000g
将AS-3201，乳糖和玉米淀粉加入高剪切力制粒机中，将混合物与在10％聚乙烯醇水溶液中的酒石酸溶液一起制粒。将此颗粒干燥，并加入硬脂酸镁，在V型混合器内将此形成物混合。然后在旋转压片机上将此混合物压片，得到每片重100mg的片剂，每片含有AS-32011mg。
在比较实施例1中，其中以相同量的乳糖代替上述实施例配方中的酒石酸，然后以同样的方式制片并进行比较。
将实施例1和比较实施例1的片剂置于玻璃瓶内，用塞子封口，在50℃贮存1个月，或者在50℃和75％相对湿度(RH)下不加塞封口贮存1个月。测定AS-3201降解产物的量，并计算出降解百分数。结果显示在表1中。
表1
| 贮存条件 | AS-3201的降解百分数 |
| 实施例1 比较实施例1 | |
| 用塞子封口，50℃ 0.6％ 3.8％1个月不封口50℃-75％ RH， 0.8％ 14.1％1个月 | |
实施例2和比较实施例2
制备片剂：
实施例2 比较实施例2
AS-3201 1g 1g
富马酸 5g -
D-甘露醇 70g 75g
羧甲基淀粉钠 20g 20g
羟丙基纤维素 2g 2g
硬脂酸镁 2g 2g
总量 100g 100g
在V型混合器内将AS-3201，富马酸，D-甘露醇，羧甲基淀粉钠和羟丙基纤维素混合均匀，并加入硬脂酸镁，再将此形成物混合均匀。在单冲制片机上将混合物压片，得到每片重100mg的片剂，每片含AS-3201 1mg。
在比较实施例2中，其中以相同量的D-甘露醇代替了上述实施例配方中的富马酸，然后制片并进行比较。
将实施例2和比较实施例2的片剂置于玻璃瓶内，将该瓶用塞子封口，在50℃贮存1个月，或者在50℃和75％RH下不加塞封口贮存1个月。测定AS-3201降解产物的含量，并计算降解百分数。结果显示在表2中。
表2
| 贮存条件 | AS-3201的降解百分数 |
| 实施例2 比较实施例2 | |
| 用塞子封口，50℃ 1.6％ 6.4％1个月不封口50℃-75％RH 9.0％ 27.0％1个月 | |
实施例3和比较实施例3
制备胶囊剂：
实施例3 比较实施例3
AS-3201 1g 1g
乳酸 1g -
乳糖(用于直接制片) 75g 76g
羧甲醚纤维素钙 20g 20g
羟丙基甲基纤维素2910 2g 2g
硬脂酸镁 1g 1g
总量 100g 100g
将AS-3201，钙和乳酸在研钵内研磨混匀，然后使此混合物通过30目筛子过筛。向混合物中加入乳糖和羟丙基甲基纤维素2910，将所形成的混合物在V型混合机内混合。加入硬脂酸镁，再进一步将混合物混合均匀。将混合物装入3号胶囊，每粒胶囊含180mg，得到每粒含有AS-3201 1.8mg的胶囊。
在比较实施例3，其中用相同量的乳糖代替了上述实施例配方中的乳酸，然后制备胶囊剂并进行比较。
将实施例3和比较实施例3的胶囊剂置于玻璃瓶内，用塞子封口在50℃贮存1个月，或者不加塞封口在50℃和75％RH下贮存1个月。测定AS-3201降解产物的含量，并计算降解百分数。结果显示在表3中。
表3
| 贮存条件 | AS-3201的降解百分数 |
| 实施例3 比较实施例3 | |
| 用塞子封口，50℃ 0.8％ 2.0％1个月不加塞封口50℃-75％(RH) 1.0％ 4.7％1个月 | |
实施例4和比较实施例4
制备粉剂：
实施例4 比较实施例4
AS-3201 10g 10g
柠檬酸 30g -
乳糖 740g 770g
低取代的羟丙基纤维素 200g 200g
羟丙基纤维素 20g 20g
总量 1000g 1000g
将AS-3201，乳糖和低取代的羟丙基纤维素装入流化床制粒机和干燥器，通过对其喷雾5％羟丙基纤维素水溶液中的柠檬酸溶液，将此混合物制成颗粒。干燥之后，使形成物通过30目筛子过筛。得到含有1％AS-3201的粉剂。
在比较实施例4中，以相同量的乳糖代替上述实施例配方中的柠檬酸制备粉剂，并进行比较。
将实施例4和比较实施例4的粉剂置于玻璃瓶内，将该瓶加塞封口在50℃贮存1个月，或者将该瓶敞口在50℃和75％RH下贮存1个月，测定AS-3201降解产物的含量，并计算降解百分数，结果显示在表4中。
表4
| 贮存条件 | AS-3201的降解百分数 |
| 实施例4 比较实施例4 | |
| 加塞封口，50℃ 0.1％ 4.8％1个月敞口，50℃-75％RH 1.3％ 19.8％1个月 | |
实施例5和比较实施例5
制备片剂：
实施例5 比较实施例5
AS-3201 10g 10g
磷酸 10g -
乳糖 740g 750g
低取代的羟丙基纤维素 200g 200g
羟丙基纤维素 20g 20g
硬脂酸镁 20g 20g
总量 1000g 1000g
将AS-3201，乳糖和低取代的羟丙基纤维素装入流化床制粒机和干燥器，通过对其喷雾5％羟丙基纤维素水溶液的磷酸溶液，将混合物制成颗粒。使颗粒干燥，然后加入硬脂酸镁，将形成物在V型混合器内混合均匀。将混合物在旋转制片机上压片，得到每片重100mg的片剂，每片含AS-3201 1mg。
在比较实施例5中，以相同量的乳糖代替上述实施例配方中的磷酸制备片剂，并进行比较。
将实施例5和比较实施例5的片剂置于玻璃瓶内，将该瓶用塞子封口在50℃贮存1个月，或者敞口在50℃和75％RH下贮存1个月。测定AS-3201降解产物的含量，并计算降解百分数。结果显示在表5中。
表5
| 贮存条件 | AS-3201的降解百分数 |
| 实施例5 比较实施例5 | |
| 加塞封口，50℃， 0.1％ 4.8％1个月敞口，50℃-75％RH， 0.5％ 19.8％1个月 | |
实施例6
制备片剂：
AS-3201 20g
酒石酸 8g
乳糖 732g
低取代的羟丙基纤维素 200g
羟丙基纤维素 20g
硬脂酸镁 20g
总量 1000g
用Single Truck Jet Mill(SEISHIN ENTERPRISE公司制造)，以6kgf/cm2的压缩空气压力将AS-3201制成微细粉末，然后将AS-3201微细粉末、乳糖和低取代的羟丙基纤维素一起装入流化床制粒机和干燥器。通过对其喷雾5％羟丙基纤维素水溶液的酒石酸溶液，将混合物制成颗粒。使颗粒干燥后，加入硬脂酸镁，然后将形成物在V型混合器内混合均匀。在旋转制片机上将混合物压片，得到每片重125mg的片剂，每片含AS-3201 2.5mg。
以加塞封口或敞口的瓶将制得的片剂在50℃-75％RH下贮存1个月之后，其降解百分数分别为0.1％和0.8％。
实施例7
制备片剂：
AS-3201 160g
酒石酸 8g
乳糖 492g
低取代的羟丙基纤维素 300g
羟丙基纤维素 20g
硬脂酸镁 20g
总量 1000g
按照与实施例6相同的方式制片，得到每片重125mg的片剂，每片含AS-3201 20mg。以加塞封口或敞口的瓶将制得的片剂在50℃-75％RH下贮存1个月之后，其降解百分数分别为0.1％和0.2％。
产业适用性
如上面所阐述，本发明含AS-3201的药用组合物具有极好的稳定性。特别是含有低含量AS-3201的药用组合物，其稳定性有显著的改善。
Claims (5)
1.一种药物组合物，该组合物含有(R)-2-(4-溴-2-氟苄基)-1，2，3，4-四氢吡咯并〔1，2-a〕吡嗪-4-螺-3′-吡咯烷-1，2′，3，5′-四酮作为有效成分，并含有至少一种选自抗坏血酸、柠檬酸、酒石酸、乳酸、马来酸、苹果酸、磷酸和富马酸的酸性物质作为稳定剂。
2.权利要求1所述的药物组合物，其中所述酸性物质是选自柠檬酸、马来酸和磷酸中的一个或多个。
3.权利要求1所述的药物组合物，其中所述酸性物质是酒石酸。
4.权利要求1-3中任何之一所述的药物组合物，其所述酸性物质的含量为所述药物组合物总重量的0.2％-10％。
5.权利要求4所述的药物组合物，其中所述酸性物质的含量为所述药物组合物总重量的0.5％-2.5％。
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| NZ503796A (en) * | 1997-10-20 | 2001-11-30 | Dainippon Pharmaceutical Co | Fast-dissolving pharmaceutical composition comprising micronised (R)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (AS-3201) |
| EP2206702B1 (en) | 2001-08-08 | 2011-12-28 | Tobira Therapeutics, Inc. | Bicyclic compound, production and use thereof |
| ZA200409537B (en) * | 2003-01-31 | 2006-10-25 | Yamanouchi Pharma Co Ltd | Stable solid medicinal composition for oral administration |
| WO2004112773A1 (fr) * | 2003-04-24 | 2004-12-29 | Shin-Jen Shiao | Compositions pharmaceutiques utilisees pour le traitement de maladie immune et amelioration |
| JP2009504767A (ja) * | 2005-08-17 | 2009-02-05 | フレミング・アンド・カンパニー・ファーマシューティカルズ | ビタミンｂ１２鼻用スプレーおよび使用方法 |
| CN102186474A (zh) | 2008-08-14 | 2011-09-14 | 杏林制药株式会社 | 稳定的医药组合物 |
| WO2014186581A1 (en) * | 2013-05-15 | 2014-11-20 | Tobira Therapeutics, Inc. | Cenicriviroc compositions and methods of making and using the same |
| CA2958239A1 (en) | 2014-09-11 | 2016-03-17 | Sumitomo Dainippon Pharma Co., Ltd. | Ophthalmic suspension formulation |
| CA3017102A1 (en) | 2016-03-10 | 2017-09-14 | Sumitomo Dainippon Pharma Co., Ltd. | Composition comprising fine particle and process thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW202450B (zh) * | 1991-06-26 | 1993-03-21 | Dainippon Pharmaceutical Co | |
| JP3158128B2 (ja) * | 1992-12-25 | 2001-04-23 | 大日本製薬株式会社 | コハク酸イミド誘導体 |
| JPH08176105A (ja) * | 1994-12-27 | 1996-07-09 | Dainippon Pharmaceut Co Ltd | ２−カルボキシコハク酸イミド誘導体 |
-
1998
- 1998-10-15 WO PCT/JP1998/004657 patent/WO1999020276A1/ja active IP Right Grant
- 1998-10-15 AU AU94618/98A patent/AU9461898A/en not_active Abandoned
- 1998-10-15 JP JP2000516673A patent/JP3995414B2/ja not_active Expired - Fee Related
- 1998-10-15 ES ES98947882T patent/ES2224436T3/es not_active Expired - Lifetime
- 1998-10-15 EP EP98947882A patent/EP1038525B1/en not_active Expired - Lifetime
- 1998-10-15 KR KR1020007004190A patent/KR100571613B1/ko not_active IP Right Cessation
- 1998-10-15 PT PT98947882T patent/PT1038525E/pt unknown
- 1998-10-15 DK DK98947882T patent/DK1038525T3/da active
- 1998-10-15 DE DE69824971T patent/DE69824971T2/de not_active Expired - Lifetime
- 1998-10-15 US US09/529,719 patent/US6297244B1/en not_active Expired - Lifetime
- 1998-10-15 AT AT98947882T patent/ATE270552T1/de active
- 1998-10-15 CN CNB988123738A patent/CN1152686C/zh not_active Expired - Fee Related
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2001
- 2001-01-29 HK HK01100616A patent/HK1029921A1/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CN1282247A (zh) | 2001-01-31 |
| PT1038525E (pt) | 2004-11-30 |
| HK1029921A1 (en) | 2001-04-20 |
| AU9461898A (en) | 1999-05-10 |
| DE69824971D1 (de) | 2004-08-12 |
| ATE270552T1 (de) | 2004-07-15 |
| US6297244B1 (en) | 2001-10-02 |
| JP3995414B2 (ja) | 2007-10-24 |
| WO1999020276A1 (fr) | 1999-04-29 |
| DE69824971T2 (de) | 2004-12-23 |
| EP1038525A1 (en) | 2000-09-27 |
| EP1038525B1 (en) | 2004-07-07 |
| EP1038525A4 (en) | 2003-03-26 |
| ES2224436T3 (es) | 2005-03-01 |
| KR20010015780A (ko) | 2001-02-26 |
| KR100571613B1 (ko) | 2006-04-17 |
| DK1038525T3 (da) | 2004-08-02 |
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