CN1243435A - 注入堆积密度为0.28～0.38g/ml的含福莫特罗的吸入用新配方 - Google Patents
注入堆积密度为0.28～0.38g/ml的含福莫特罗的吸入用新配方 Download PDFInfo
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- 239000000203 mixture Substances 0.000 title claims abstract description 25
- 229960002848 formoterol Drugs 0.000 title claims abstract description 6
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 238000009472 formulation Methods 0.000 title abstract description 4
- 239000000843 powder Substances 0.000 claims abstract description 16
- 208000023504 respiratory system disease Diseases 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 15
- 239000013543 active substance Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- RATSWNOMCHFQGJ-TUYNVFRMSA-N (e)-but-2-enedioic acid;n-[2-hydroxy-5-[(1s)-1-hydroxy-2-[[(2s)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide;dihydrate Chemical compound O.O.OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1 RATSWNOMCHFQGJ-TUYNVFRMSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229960003610 formoterol fumarate dihydrate Drugs 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 3
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- QWIZNVHXZXRPDR-UHFFFAOYSA-N D-melezitose Natural products O1C(CO)C(O)C(O)C(O)C1OC1C(O)C(CO)OC1(CO)OC1OC(CO)C(O)C(O)C1O QWIZNVHXZXRPDR-UHFFFAOYSA-N 0.000 description 1
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- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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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- 239000002253 acid Substances 0.000 description 1
- -1 and wherein Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000004683 dihydrates Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
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- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960000193 formoterol fumarate Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- QWIZNVHXZXRPDR-WSCXOGSTSA-N melezitose Chemical compound O([C@@]1(O[C@@H]([C@H]([C@@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O)CO)CO)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QWIZNVHXZXRPDR-WSCXOGSTSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- KQTIIICEAUMSDG-UHFFFAOYSA-N tricarballylic acid Chemical class OC(=O)CC(C(O)=O)CC(O)=O KQTIIICEAUMSDG-UHFFFAOYSA-N 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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Abstract
一种干粉剂组合物,其中包含福莫特罗和载体物质,这两种物质都呈微细形式,其中该配方的注入堆积密度为0.28—0.38g/ml。这种干粉剂组合物在治疗呼吸系统疾病方面是有用的。
Description
发明领域
本发明提供一种新药物配方、其制备及其用途。
发明背景
吸入法给药用的强效药因其制备精确剂量的问题，一般是与乳糖等载体相缔合来配制的。当这样的药物稀释时，配方重量的差异导致与它们未被稀释时比较更小的药物剂量差异。这些配方一般由载体的粗大颗粒和药物的微细颗粒组成，这种组合一般称为订做的混合物。
本发明提供一种改进的配方，在为模仿吸入而设计的系统中，已发现该配方能改善药物的分散。
本发明说明
按照本发明，提供的是一种干粉剂组合物，其中包含一种活性物质，即福莫特罗，其药物上可接受的盐或溶剂化物，或这种盐的溶剂化物，和一种载体物质，这两种物质都呈微细形式，其中该配方的注入堆积密度为0.28～0.38g/mL，较好为0.30～0.36g/mL。
按照本发明的注入堆积密度是用已知技术测定的，例如＂粉末测试指南：散装粉末物理性能测定方法＂L.Svarovsky，ElsevierApplied Science 1987，pp 84-86中描述的那些。
适用的生理上可接受的福莫特罗的盐包括从无机酸和有机酸衍生的酸加成盐，例如氯化物、溴化物、硫酸盐、磷酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、4-甲氧基苯甲酸盐、2-或4-羟基苯甲酸盐、4-氯苯甲酸盐、对甲苯磺酸盐、甲磺酸盐、抗坏血酸盐、乙酸盐、琥珀酸盐、乳酸盐、戊二酸盐、葡糖酸盐、丙三羧酸盐、羟基萘羧酸盐或油酸盐或其溶剂化物。活性物质最好是福莫特罗富马酸盐，尤其二水合物形式。
载体物质较好的是一种单糖、二糖或多糖，一种糖醇或一种多醇。适用的载体是诸如乳糖、葡萄糖、棉子糖、松三糖、乳糖醇、麦牙糖醇、茧蜜糖、蔗糖、甘露糖，和淀粉。乳糖是特别好，特别是其一水合物形式。
按照本发明的配方的各组分必须均呈微细形式，即它们的质量中值直径一般应当小于10mm，较好的是1～7mm，是用激光衍射仪或coulter计数器测定的。这些组分可以用有本门技术技能的人员已知的方法例如研磨、微粉化或直接沉淀，以所希望的粒度产生。
按照本发明的组合物配制成包含，优选5～250nmol，更优选15～120nmol的活性物质作为日剂量。当活性物质是福莫特罗富马酸盐二水合物时，该组合物配制成能提供优选3～96μg，更优选3～48μg，最优选3～24μg的福莫特罗富马酸盐二水合物的日剂量。更优选地，该组合物配制成能提供3、4.5、6、9或12μg福莫特罗富马酸盐二水合物的单元剂量。该组合物配制成每单元剂量包含优选50μg～25mg，更优选50μg～10mg，最优选100～4000μg的载体物质。
按照本发明，进一步提供的是按照本发明的一种组合物的制备方法，包括
(a)使活性物质和载体物质微粉化；
(b)任选地调理该产品；和
(c)球形化直至得到所希望的堆积密度。
本工艺在步骤(b)之后较好进一步包含一个低能量再微粉化步骤。
按照本发明的配方可以用本身已知的常用技术制作。这样的生产工艺一般包括使这些组分微粉化成所需要的粒度，用诸如WO92/18110或WO 95/05805中所述的方法除去所得到颗粒上的任何无定形区域，然后将所得到的粉末造粒、球形化和过筛。所得到团粒的粒度较好在100～2000mm的范围内，更好的是在100～800mm。所生产配方的堆积密度可以根据经验通过改变成分和工艺来调节，例如，可以通过延长颗粒在球形化装置中翻滚的时间来提高堆积密度。
在固-固混合中，最重要的特色之一是确保含量均匀。微细粉末的粉末混合中遇到的主要问题是混合机不能使粉末团粒破碎。已经发现，微细粉末调理步骤之后用低能量输入的再微粉化步骤是有利的。它一般应当用足以使粉末团粒破碎的能量进行，但不要用如此多的能量，以致影响颗粒本身的粒度。这样一个步骤给出一种组合物，其中，活性物质和载体物质大体上均匀分布，例如相对标准偏差小于3％(较好小于1％)，且不影响微细颗粒的结晶性。
按照本发明的配方可用任何已知干粉吸入器给药，例如该吸入器可以是单剂量或多剂量吸入器，还可以是一种呼吸驱动干粉吸入器，例如Turbuhaler(商品名)。本发明进一步提供按照本发明的组合物在制造用于治疗的药物方面的用途。按照本发明的组合物在治疗呼吸系统疾病，特别是气喘病方面是有用的。本发明也提供治疗受呼吸系统疾病困扰的病人的方法，该方法包括对患者施用治疗有效量的按照本发明的组合物。
下列实例说明，但不限制本发明。
实例1
0.0315份福莫特罗富马酸盐二水合物和2.969份乳糖一水合物在转鼓混合机(Turbula)中混合成均匀分布的混合物，然后以某一压力和适合于获得小于3mm粒度(用coulter计数计测得的质量平均直径)的进料速率将混合物送入螺旋喷射磨中进行微粉化。然后用WO95/05805中所公开的方法对微粉化后的颗粒进行处理，以除去其晶体结构中的非晶区域。然后将该粉末喂入双螺杆进料机(K-Tron)中使粉末聚集，在振动筛(0.5mm目径)中过筛，在圆周速度0.5m/s的旋转盘中进行球形化4分钟，然后再用同样的筛子过筛，随后再球形化6分钟，最后再过筛(目径1.0mm)，得到堆积密度为0.32g/ml的粉末。
实例2
重复实例1，但粉末在微粉化之后在螺旋喷射磨中在低压(约1巴)下再次进行微粉化，并作如下调整，即无需按WO 95/05805中所述方法处理颗粒这一步骤，得到堆积密度为0.32g/ml的粉末。
Claims (9)
1.一种干粉剂组合物，其中包含一种活性物质，即福莫特罗，其药物上可接受的盐或溶剂化物，或这种盐的溶剂化物，和一种载体物质，这两种物质都呈微细形式，其中该配方的注入堆积密度为0.28～0.38g/ml。
2.按照权利要求1的组合物，其中所述活性物质是和福莫特罗富马酸盐二水合物。
3.按照权利要求1或2的组合物，其中所述堆积密度是0.30～0.36g/ml。
4.按照权利要求1、2或3的组合物，其中所述活性物质和载体物质实际上是均匀分布的。
5.用于治疗呼吸系统疾病的按照权利要求1-4中任何一项的组合物。
6.制备按照权利要求1的组合物的方法，该方法包括：
(a)使活性物质和载体物质微粉化；
(b)任选地调理该产品；和
(c)球形化直至得到所希望的堆积密度。
7.按照权利要求6的方法，该方法还包括在步骤(b)之后的低能量再微粉化步骤。
8.按照权利要求1-4中任何一项的组合物在制造用于治疗的药物方面的用途。
9.一种治疗受呼吸系统疾病困扰的病人的方法，该方法包括对患者施用治疗有效量的按照权利要求1-4中任何一项的组合物。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9700134A SE9700134D0 (sv) | 1997-01-20 | 1997-01-20 | New formulation |
| SE97001341 | 1997-01-20 |
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| CN1243435A true CN1243435A (zh) | 2000-02-02 |
| CN1213741C CN1213741C (zh) | 2005-08-10 |
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| CNB988018993A Expired - Lifetime CN1213741C (zh) | 1997-01-20 | 1998-01-13 | 注入堆积密度为0.28～0.38g/ml的含福莫特罗的吸入用新配方 |
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| JP (2) | JP4512203B2 (zh) |
| KR (1) | KR100528417B1 (zh) |
| CN (1) | CN1213741C (zh) |
| AT (1) | ATE257699T1 (zh) |
| AU (1) | AU728835B2 (zh) |
| BE (1) | BE1011401A3 (zh) |
| BR (1) | BR9806895A (zh) |
| CA (1) | CA2277890C (zh) |
| CZ (1) | CZ295682B6 (zh) |
| DE (1) | DE69821119T2 (zh) |
| DK (1) | DK1009394T3 (zh) |
| EE (1) | EE04038B1 (zh) |
| ES (2) | ES2212262T3 (zh) |
| FR (1) | FR2759907B1 (zh) |
| GR (1) | GR980100022A (zh) |
| HU (1) | HU228682B1 (zh) |
| ID (1) | ID21917A (zh) |
| IE (1) | IE980025A1 (zh) |
| IL (1) | IL130837A0 (zh) |
| IS (1) | IS2243B (zh) |
| NL (1) | NL1008021C2 (zh) |
| NO (1) | NO327457B1 (zh) |
| NZ (1) | NZ336593A (zh) |
| PL (1) | PL189552B1 (zh) |
| PT (1) | PT1009394E (zh) |
| RU (1) | RU2180220C2 (zh) |
| SE (1) | SE9700134D0 (zh) |
| SK (1) | SK283949B6 (zh) |
| TR (1) | TR199901692T2 (zh) |
| UA (1) | UA57763C2 (zh) |
| WO (1) | WO1998031351A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SE9703407D0 (sv) | 1997-09-19 | 1997-09-19 | Astra Ab | New use |
| SE9802073D0 (sv) | 1998-06-11 | 1998-06-11 | Astra Ab | New use |
| ITMI991582A1 (it) | 1999-07-16 | 2001-01-16 | Chiesi Farma Spa | Polveri costituite da particelle aventi la superficie perfettamente levigata da utilizzare come veicoli per la preparazione di miscele inala |
| GB9928311D0 (en) * | 1999-11-30 | 2000-01-26 | Novartis Ag | Organic compounds |
| PE20011227A1 (es) | 2000-04-17 | 2002-01-07 | Chiesi Farma Spa | Formulaciones farmaceuticas para inhaladores de polvo seco en la forma de aglomerados duros |
| GB0009469D0 (en) | 2000-04-17 | 2000-06-07 | Vectura Ltd | Improvements in or relating to formalities for use in inhaler devices |
| GB0012261D0 (en) * | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel process |
| GB0012260D0 (en) | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel composition |
| ITMI20010428A1 (it) * | 2001-03-02 | 2002-09-02 | Chemo Breath S A | Composizioni ad uso inalatorio a base di formoterolo |
| US6667344B2 (en) | 2001-04-17 | 2003-12-23 | Dey, L.P. | Bronchodilating compositions and methods |
| US20030055026A1 (en) | 2001-04-17 | 2003-03-20 | Dey L.P. | Formoterol/steroid bronchodilating compositions and methods of use thereof |
| SE0200657D0 (sv) * | 2002-03-04 | 2002-03-04 | Astrazeneca Ab | Novel Formulation |
| GB0312148D0 (en) | 2003-05-28 | 2003-07-02 | Aventis Pharma Ltd | Stabilized pharmaceutical products |
| GB0315889D0 (en) | 2003-07-08 | 2003-08-13 | Aventis Pharma Ltd | Stable pharmaceutical products |
| TWI359675B (en) | 2003-07-10 | 2012-03-11 | Dey L P | Bronchodilating β-agonist compositions |
| DE102007049931A1 (de) | 2007-10-18 | 2009-04-23 | Pharmatech Gmbh | Vorrichtung und Verfahren zur kontinuierlichen Herstellung von sphärischen Pulveragglomeraten |
| WO2011110852A1 (en) | 2010-03-10 | 2011-09-15 | Astrazeneca Ab | Polymorphic forms of 6- [2- (4 -cyanophenyl) - 2h - pyrazol - 3 - yl] - 5 -methyl - 3 - oxo - 4 - (trifluoromethyl - phenyl) 3,4-dihydropyrazine-2-carboxylic acid ethylamide |
| EP2821061B1 (en) | 2013-07-01 | 2017-12-20 | Arven Ilac Sanayi Ve Ticaret A.S. | Novel inhalation formulations |
| WO2015060743A1 (ru) * | 2013-10-21 | 2015-04-30 | Шолекс Девелопмент Гмбх | Ингаляционный препарат для лечения болезней органов дыхания, содержащий в качестве активных веществ микронизированный салметерол ксинофоат и микронизированный флутиказона пропионат и способ его получения |
| KR20220066906A (ko) | 2019-09-24 | 2022-05-24 | 키에시 파르마슈티시 엣스. 피. 에이. | 흡입용 건조 분말 제제를 위한 신규 담체 입자 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE17441T1 (de) * | 1981-07-24 | 1986-02-15 | Fisons Plc | Inhalierbare arzneimittel, verfahren zu deren herstellung und pharmazeutische formulierungen diese enthaltend. |
| EP0072046B1 (en) * | 1981-07-24 | 1986-01-15 | FISONS plc | Inhalation drugs, methods for their production and pharmaceutical formulations containing them |
| SE9302777D0 (sv) * | 1993-08-27 | 1993-08-27 | Astra Ab | Process for conditioning substances |
| SK282826B6 (sk) * | 1991-12-18 | 2002-12-03 | Aktiebolaget Astra | Farmaceutická kompozícia na podávanie inhaláciou s obsahom formoterolu a budesonidu a jej použitie |
| IS1736B (is) * | 1993-10-01 | 1999-12-30 | Astra Ab | Aðferð og tæki sem stuðla að aukinni samloðun agna |
| BR9407686A (pt) * | 1993-10-01 | 1997-02-04 | Astra Ab | Processo e aparelho para o tratamento de um medicamento em pó finamente dividido uso do aparelho e aglomerados |
| SE9603669D0 (sv) * | 1996-10-08 | 1996-10-08 | Astra Ab | New combination |
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1997
- 1997-01-20 SE SE9700134A patent/SE9700134D0/xx unknown
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1998
- 1998-01-13 AT AT98901617T patent/ATE257699T1/de active
- 1998-01-13 CA CA002277890A patent/CA2277890C/en not_active Expired - Lifetime
- 1998-01-13 EP EP98901617A patent/EP1009394B1/en not_active Expired - Lifetime
- 1998-01-13 KR KR10-1999-7006413A patent/KR100528417B1/ko active IP Right Grant
- 1998-01-13 IL IL13083798A patent/IL130837A0/xx not_active IP Right Cessation
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- 1998-01-13 BR BR9806895-4A patent/BR9806895A/pt not_active Application Discontinuation
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- 1998-01-13 RU RU99118588/14A patent/RU2180220C2/ru active
- 1998-01-13 DK DK98901617T patent/DK1009394T3/da active
- 1998-01-13 AU AU57858/98A patent/AU728835B2/en not_active Expired
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- 1998-01-13 DE DE69821119T patent/DE69821119T2/de not_active Expired - Lifetime
- 1998-01-13 SK SK958-99A patent/SK283949B6/sk not_active IP Right Cessation
- 1998-01-13 WO PCT/SE1998/000039 patent/WO1998031351A1/en active IP Right Grant
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- 1998-01-13 CN CNB988018993A patent/CN1213741C/zh not_active Expired - Lifetime
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- 1998-01-13 NL NL1008021A patent/NL1008021C2/nl not_active IP Right Cessation
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- 1998-01-15 BE BE9800031A patent/BE1011401A3/fr not_active IP Right Cessation
- 1998-01-16 ES ES009800079A patent/ES2149082B1/es not_active Expired - Fee Related
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