ZA200202695B - Manufacture of polyglutamate-therapeutic agent conjugates. - Google Patents
Manufacture of polyglutamate-therapeutic agent conjugates. Download PDFInfo
- Publication number
- ZA200202695B ZA200202695B ZA200202695A ZA200202695A ZA200202695B ZA 200202695 B ZA200202695 B ZA 200202695B ZA 200202695 A ZA200202695 A ZA 200202695A ZA 200202695 A ZA200202695 A ZA 200202695A ZA 200202695 B ZA200202695 B ZA 200202695B
- Authority
- ZA
- South Africa
- Prior art keywords
- conjugate
- acid
- therapeutic agent
- poly
- polyglutamic acid
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 75
- 229940124597 therapeutic agent Drugs 0.000 title claims description 70
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- 229920002643 polyglutamic acid Polymers 0.000 claims description 89
- 239000000243 solution Substances 0.000 claims description 69
- 238000000034 method Methods 0.000 claims description 66
- 229960001592 paclitaxel Drugs 0.000 claims description 59
- 108010020346 Polyglutamic Acid Proteins 0.000 claims description 49
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- 239000007787 solid Substances 0.000 claims description 39
- 229920000642 polymer Polymers 0.000 claims description 37
- 230000008569 process Effects 0.000 claims description 36
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 27
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- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- GCSAXWHQFYOIFE-UHFFFAOYSA-N dipyridin-2-yl carbonate Chemical compound C=1C=CC=NC=1OC(=O)OC1=CC=CC=N1 GCSAXWHQFYOIFE-UHFFFAOYSA-N 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
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- 150000004820 halides Chemical class 0.000 description 1
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- 238000002513 implantation Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
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- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
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- 238000005007 materials handling Methods 0.000 description 1
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- HNEGQIOMVPPMNR-NSCUHMNNSA-N mesaconic acid Chemical compound OC(=O)C(/C)=C/C(O)=O HNEGQIOMVPPMNR-NSCUHMNNSA-N 0.000 description 1
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- 239000000178 monomer Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000000569 multi-angle light scattering Methods 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
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- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical class C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 239000000523 sample Substances 0.000 description 1
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 150000003754 zirconium Chemical class 0.000 description 1
Classifications
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Peptides Or Proteins (AREA)
- Polyamides (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15913599P | 1999-10-12 | 1999-10-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200202695B true ZA200202695B (en) | 2004-02-25 |
Family
ID=22571222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200202695A ZA200202695B (en) | 1999-10-12 | 2002-04-05 | Manufacture of polyglutamate-therapeutic agent conjugates. |
Country Status (16)
| Country | Link |
|---|---|
| US (2) | US20020077279A1 (xx) |
| EP (2) | EP1225917A2 (xx) |
| JP (1) | JP2003511423A (xx) |
| KR (1) | KR100821437B1 (xx) |
| CN (2) | CN101507820A (xx) |
| AU (1) | AU781735B2 (xx) |
| BR (1) | BRPI0014652B1 (xx) |
| CA (1) | CA2387611C (xx) |
| HU (1) | HUP0203123A3 (xx) |
| MX (1) | MXPA02003719A (xx) |
| NO (1) | NO20021701L (xx) |
| NZ (1) | NZ529789A (xx) |
| PL (1) | PL354623A1 (xx) |
| SG (1) | SG147286A1 (xx) |
| WO (1) | WO2001026693A2 (xx) |
| ZA (1) | ZA200202695B (xx) |
Families Citing this family (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004510702A (ja) | 2000-06-14 | 2004-04-08 | メダレックス，インコーポレイティド | イソロイシンを有するプロドラッグ化合物 |
| US6872715B2 (en) | 2001-08-06 | 2005-03-29 | Kosan Biosciences, Inc. | Benzoquinone ansamycins |
| CN1777439A (zh) | 2003-04-22 | 2006-05-24 | 研究及应用科学协会股份有限公司 | 生长抑素的载体 |
| FR2855521B1 (fr) * | 2003-05-28 | 2005-08-05 | Flamel Tech Sa | Polyaminoacides fonctionnalises par au moins un groupement h ydrophobe et leurs applications notamment therapeutiques. |
| US7259156B2 (en) | 2004-05-20 | 2007-08-21 | Kosan Biosciences Incorporated | Geldanamycin compounds and method of use |
| US8614228B2 (en) | 2004-08-11 | 2013-12-24 | Arqule, Inc. | Quinone prodrug compositions and methods of use |
| WO2006020719A2 (en) | 2004-08-11 | 2006-02-23 | Arqule, Inc. | Aminoacid conjugates of beta - lapachone for tumor targeting |
| CN101023119B (zh) | 2004-09-22 | 2010-05-05 | 日本化药株式会社 | 新型嵌段共聚物，胶束制剂以及含胶束制剂为活性组分的抗癌剂 |
| JP5237821B2 (ja) | 2005-12-05 | 2013-07-17 | 日東電工株式会社 | ポリグルタミン酸−アミノ酸結合体および方法 |
| RU2008127309A (ru) * | 2005-12-06 | 2010-01-20 | Селл Терапьютикс, Инк. (Us) | Лечение эстроген-зависимого рака |
| US7462627B2 (en) * | 2006-02-09 | 2008-12-09 | Enzon Pharmaceuticals, Inc. | Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers |
| US7671067B2 (en) * | 2006-02-09 | 2010-03-02 | Enzon Pharmaceuticals, Inc. | Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin |
| KR20080106254A (ko) | 2006-03-28 | 2008-12-04 | 니폰 가야꾸 가부시끼가이샤 | 탁산류의 고분자 결합체 |
| WO2007135910A1 (ja) | 2006-05-18 | 2007-11-29 | Nippon Kayaku Kabushiki Kaisha | ポドフィロトキシン類の高分子結合体 |
| WO2008056596A1 (en) | 2006-11-06 | 2008-05-15 | Nippon Kayaku Kabushiki Kaisha | Polymeric derivative of nucleic acid metabolic antagonist |
| EP2090607B1 (en) | 2006-11-08 | 2015-05-20 | Nippon Kayaku Kabushiki Kaisha | Polymeric derivative of nucleic acid metabolic antagonist |
| CN101209350B (zh) * | 2006-12-30 | 2011-09-07 | 中国人民解放军军事医学科学院毒物药物研究所 | 以氨基酸为连接子的多聚谷氨酸-药物偶合物 |
| KR20090108082A (ko) * | 2007-02-09 | 2009-10-14 | 엔존 파마슈티컬즈, 인코포레이티드 | 7-에틸-10-하이드록시캄토테신 다분지형 고분자 접합체를 이용한 내성 또는 불응성 암의 치료방법 |
| CN104800856A (zh) * | 2007-04-10 | 2015-07-29 | 日东电工株式会社 | 多功能聚谷氨酸盐药物载体 |
| CN101687835B (zh) | 2007-04-30 | 2015-08-19 | 艾科尔公司 | 苯醌化合物的羟基磺酸盐和它们的应用 |
| WO2008141111A2 (en) * | 2007-05-09 | 2008-11-20 | Nitto Denko Corporation | Polymers conjugated with platinum drugs |
| EP2155255B1 (en) | 2007-05-09 | 2013-08-14 | Nitto Denko Corporation | Compositions that include a hydrophobic compound and a polyamino acid conjugate |
| JP2010526917A (ja) * | 2007-05-09 | 2010-08-05 | 日東電工株式会社 | 複数種の薬物を有するポリグルタミン酸塩複合体及びポリグルタミン酸塩−アミノ酸複合体 |
| WO2009041570A1 (ja) | 2007-09-28 | 2009-04-02 | Nippon Kayaku Kabushiki Kaisha | ステロイド類の高分子結合体 |
| WO2009111271A1 (en) * | 2008-03-06 | 2009-09-11 | Nitto Denko Corporation | Polymer paclitaxel conjugates and methods for treating cancer |
| CN101977631A (zh) | 2008-03-18 | 2011-02-16 | 日本化药株式会社 | 生理活性物质的高分子量偶联物 |
| WO2009136572A1 (ja) | 2008-05-08 | 2009-11-12 | 日本化薬株式会社 | 葉酸若しくは葉酸誘導体の高分子結合体 |
| WO2010025337A1 (en) * | 2008-08-29 | 2010-03-04 | Enzon Pharmaceuticals, Inc. | Method of treating ras associated cancer |
| AU2009302387B2 (en) * | 2008-10-07 | 2014-12-04 | Rexahn Pharmaceuticals, Inc | HPMA - docetaxel or gemcitabine conjugates and uses therefore |
| EP2358396A2 (en) * | 2008-10-15 | 2011-08-24 | Nitto Denko Corporation | Method of preparing polyglutamate conjugates |
| WO2010048018A1 (en) * | 2008-10-21 | 2010-04-29 | Enzon Pharmaceuticals, Inc. | Treatment of neuroblastoma with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin |
| DE102008060549A1 (de) * | 2008-12-04 | 2010-06-10 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Wirkstoff-Peptid-Konstrukt zur extrazellulären Anreicherung |
| US8808749B2 (en) | 2009-05-15 | 2014-08-19 | Nippon Kayaku Kabushiki Kaisha | Polymer conjugate of bioactive substance having hydroxy group |
| US8846110B2 (en) | 2009-10-13 | 2014-09-30 | Rexahn Pharmaceuticals, Inc. | Polymeric systems for the delivery of anticancer drugs |
| CN102811742A (zh) * | 2010-03-11 | 2012-12-05 | 日东电工株式会社 | 碳水化合物-聚氨基酸-药物轭合物 |
| EP2641605B1 (en) | 2010-11-17 | 2018-03-07 | Nippon Kayaku Kabushiki Kaisha | Polymer derivative of cytidine metabolism antagonist |
| CN102649810A (zh) * | 2011-05-19 | 2012-08-29 | 东北林业大学 | 喜树碱衍生物、其制备方法和用途 |
| US8691284B2 (en) | 2011-07-07 | 2014-04-08 | Empire Technology Development Llc | Fluorinated block co-polymers |
| RU2623426C2 (ru) | 2011-09-11 | 2017-06-26 | Ниппон Каяку Кабусики Кайся | Способ получения блок-сополимера |
| US8383093B1 (en) | 2011-11-01 | 2013-02-26 | Serina Therapeutics, Inc. | Subcutaneous delivery of poly(oxazoline) conjugates |
| US8907045B2 (en) | 2012-04-03 | 2014-12-09 | Empire Technology Development Llc | Biocompatible adhesive polymers |
| WO2014175899A1 (en) * | 2013-04-26 | 2014-10-30 | Nitto Denko Corporation | Reduction of endotoxins from polyanionic polymer conjugates |
| KR101507119B1 (ko) * | 2013-05-31 | 2015-03-30 | 주식회사 바이오리더스 | 점막 점착성 폴리감마글루탐산 나노마이셀 및 이를 이용한 약물 전달체 |
| CN106267227A (zh) * | 2016-08-12 | 2017-01-04 | 北京蓝贝望生物医药科技股份有限公司 | 抗肿瘤药物 |
| CN106750272B (zh) * | 2016-12-05 | 2019-05-28 | 福建卫生职业技术学院 | 一种水溶性蛇葡萄素聚合物 |
| CN110123748A (zh) * | 2019-04-22 | 2019-08-16 | 南京师范大学 | 一种叶酸介导的靶向双载药聚合物胶束及其制备方法和应用 |
| CN113773282A (zh) * | 2021-09-22 | 2021-12-10 | 无锡紫杉药业有限公司 | 一种10-乙酰紫杉醇的制备方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4356166A (en) * | 1978-12-08 | 1982-10-26 | University Of Utah | Time-release chemical delivery system |
| US5629433A (en) * | 1994-07-18 | 1997-05-13 | Hauser, Inc. | Selective process for the deacylation and deacetylation of taxol and taxanes |
| CA2192725C (en) * | 1995-12-28 | 2004-04-20 | Kenji Tsujihara | Camptothecin derivatives |
| JP3737518B2 (ja) * | 1996-03-12 | 2006-01-18 | ピージー−ティーエックスエル カンパニー， エル．ピー． | 水溶性パクリタキセルプロドラッグ |
| US6441025B2 (en) * | 1996-03-12 | 2002-08-27 | Pg-Txl Company, L.P. | Water soluble paclitaxel derivatives |
| CZ20023330A3 (cs) * | 2000-03-17 | 2003-02-12 | Cell Therapeutics, Inc. | Konjugáty kamptotecinu a polyglutamové kyseliny a způsoby přípravy |
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2000
- 2000-10-12 CN CNA2009101276554A patent/CN101507820A/zh active Pending
- 2000-10-12 EP EP00972079A patent/EP1225917A2/en not_active Withdrawn
- 2000-10-12 EP EP04013703A patent/EP1466627A1/en not_active Withdrawn
- 2000-10-12 KR KR1020027004640A patent/KR100821437B1/ko not_active IP Right Cessation
- 2000-10-12 SG SG200401981-6A patent/SG147286A1/en unknown
- 2000-10-12 CA CA2387611A patent/CA2387611C/en not_active Expired - Fee Related
- 2000-10-12 MX MXPA02003719A patent/MXPA02003719A/es active IP Right Grant
- 2000-10-12 BR BRPI0014652A patent/BRPI0014652B1/pt not_active IP Right Cessation
- 2000-10-12 CN CNA008170290A patent/CN1607962A/zh active Pending
- 2000-10-12 JP JP2001529754A patent/JP2003511423A/ja active Pending
- 2000-10-12 AU AU10793/01A patent/AU781735B2/en not_active Ceased
- 2000-10-12 HU HU0203123A patent/HUP0203123A3/hu unknown
- 2000-10-12 WO PCT/US2000/028109 patent/WO2001026693A2/en active IP Right Grant
- 2000-10-12 PL PL00354623A patent/PL354623A1/xx not_active IP Right Cessation
- 2000-10-12 NZ NZ529789A patent/NZ529789A/en not_active IP Right Cessation
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2001
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2002
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- 2002-04-11 NO NO20021701A patent/NO20021701L/no not_active Application Discontinuation
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2003
- 2003-04-02 US US10/404,152 patent/US7399860B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| SG147286A1 (en) | 2008-11-28 |
| JP2003511423A (ja) | 2003-03-25 |
| EP1225917A2 (en) | 2002-07-31 |
| WO2001026693A3 (en) | 2001-12-27 |
| US7399860B2 (en) | 2008-07-15 |
| KR20020059616A (ko) | 2002-07-13 |
| NO20021701D0 (no) | 2002-04-11 |
| US20020077279A1 (en) | 2002-06-20 |
| HUP0203123A3 (en) | 2004-12-28 |
| NZ529789A (en) | 2005-04-29 |
| CA2387611A1 (en) | 2001-04-19 |
| BRPI0014652B1 (pt) | 2016-08-09 |
| AU781735B2 (en) | 2005-06-09 |
| BR0014652A (pt) | 2003-06-10 |
| PL354623A1 (en) | 2004-02-09 |
| CN1607962A (zh) | 2005-04-20 |
| NO20021701L (no) | 2002-05-23 |
| MXPA02003719A (es) | 2002-08-30 |
| AU1079301A (en) | 2001-04-23 |
| HUP0203123A2 (hu) | 2003-01-28 |
| US20030224971A1 (en) | 2003-12-04 |
| EP1466627A1 (en) | 2004-10-13 |
| CA2387611C (en) | 2011-03-29 |
| KR100821437B1 (ko) | 2008-04-10 |
| WO2001026693A2 (en) | 2001-04-19 |
| CN101507820A (zh) | 2009-08-19 |
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