JP2003073304A - 生体内薬物徐放材料 - Google Patents
生体内薬物徐放材料Info
- Publication number
- JP2003073304A JP2003073304A JP2001262476A JP2001262476A JP2003073304A JP 2003073304 A JP2003073304 A JP 2003073304A JP 2001262476 A JP2001262476 A JP 2001262476A JP 2001262476 A JP2001262476 A JP 2001262476A JP 2003073304 A JP2003073304 A JP 2003073304A
- Authority
- JP
- Japan
- Prior art keywords
- collagen
- hydroxyapatite
- hap
- release material
- col
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- A61K47/54—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 an organic compound
- A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- 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
- A61K47/6435—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 the peptide or protein in the drug conjugate being a connective tissue peptide, e.g. collagen, fibronectin or gelatin
-
- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
-
- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Nanotechnology (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
シアパタイトは薬剤の徐放担体としては実用的ではな
い。 【構成】 共沈物として合成され、比表面積50〜30
0m2/gのハイドロキシアパタイト(HAp)結晶が
コラーゲン(Col)線維の周りにC軸方向に配向して
複合化したHAp/Colナノ複合体のハイドロキシア
パタイト表面、コラーゲン表面および両者の水和水中に
増殖因子、DNA酵素等の生理活性物質、薬剤を保持し
たことを特徴とする生体吸収性のカプセルまたは生体内
に注射的な投与が可能で注入後ゲル化する生体内薬物徐
放材料。
Description
タイトとコラーゲン(HAp/Col)ナノ複合体から
なる生体内薬物徐放材料に関する。
ものは、例えば、1)コラーゲンのように水分を保持す
る能力の高い材質に、薬剤を保持させ、それが生体内に
移植されることにより、拡散し放出されるといったも
の、2)ポリ乳酸等の生体分解性の生体材料に製造過程
において薬剤を混合し、その生体材料の分解とともに放
出されるといったもの等、が一般的である。
的な投与が可能な長期徐放性製剤が知られている(特公
平5−12328号公報、特公平5−71566号公
報、特公平6−94418号公報、特開平8−3474
7号公報)。また、歯周組織における組織再生膜(GT
R膜)、止血剤、骨補填剤、軟骨補填剤、硬組織細胞の
三次元培養基材として用いられるコラーゲンリン酸カル
シウム複合材料も知られている(特開平6−30424
2公報)。
ウム化合物をリン酸カルシウム溶液中で反応させた複合
物を乾燥させて得られる。また、リン酸カルシウムとコ
ラーゲンの共沈を行った後、得られた沈殿物を加圧成形
することによって配向性の優れた人工骨等として用いら
れる複合材料の製造方法(特開平11−199209号
公報)も知られている。
能力が高く、多量の薬剤溶液を保持したまま、生体内に
移植でき、さまざまなサイトカイン、増殖因子等の担体
として実験等に使用されてきた。しかし、コラーゲンや
ゼラチン等の含水性ゲル状物質を用いた増殖因子の担体
は、移植後の薬剤放出速度が早く比較的短期間しかその
効果を発揮できないため、それら単独の担体では多量の
増殖因子を使用しなければならない。
性が高い生体材料として広く利用され、骨充填材を増殖
因子の担体として使用する試みが数多くなされている。
また、ハイドロキシアパタイトは非常に極性の強い結晶
構造をとっておりタンパクやDNAと電気酌に親和性が
高く、その結晶の表面に吸着することが知られており、
生化学の分野では微結晶のハイドロキシアパタイトがク
ロマトグラフィーの材料として使用されてきた。
ような微結晶では生体材料として使用するには粉末状で
あり、実用的ではない。そのため、焼結体等が生体材料
として使用されているが、これでは薬剤が吸着する面積
が極端に減少してしまうため、薬剤の担体としては実用
的ではない。
は、ハイドロキシアパタイトの微結晶とコラ一ゲンから
なる複合体であり、増殖因子の吸着に有効なハイドロキ
シアパタイトの比表面積が約50〜300m2/g程度
と非常に大きく、かつ水分保持能力の高いコラーゲンを
含んでいるため、多量の増殖因子を保持しうる。
イトと増殖因子は強く結合するため、増殖因子の放出速
度が遅く、生体内で長期的かつ局所的に増殖効果を持続
できる。増殖因子以外に薬剤、DNA等の電気的に極性
を持つ物質であれば表面吸着能が高くその徐放性担体と
しても利用できる。
カルシウム溶液及びコラーゲン溶液を一定の条件で反応
させることにより共沈物として合成され、比表面積50
〜300m2/gのハイドロキシアパタイト(HAp)
結晶がコラーゲン(Col)線維の周りにC軸方向に配
向して複合化したHAp/Colナノ複合体のハイドロ
キシアパタイト表面、コラーゲン表面および両者の水和
水中に増殖因子、DNA酵素等の生理活性物質、薬剤を
保持したことを特徴とする生体内薬物徐放材料である。
ノグリカン(ヒアルロン酸・コンドロイチン硫酸・ケラ
タン硫酸等)またはハイドロゲルなどを複合化すること
により増殖因子を封入した生体吸収性のカプセルとなる
ことを特徴とする上記の生体内薬物徐放材料である。
可能で注入後ゲル化することを特徴とする上記の生体内
薬物徐放材料である。
イドロキシアパタイトとコラーゲンを複合することによ
り得られた生体材料である。このHAp/Col複合体
は、水酸化カルシウムの懸濁液とコラーゲンを含んだリ
ン酸水溶液を蒸留水に同時滴下し共沈させ、共沈物を加
圧脱水して成形することにより合成される。
は、HAp結晶がCol線維の周りにC軸方向に配向し
複合化したナノ複合体である。ハイドロキシアパタイト
のBET法による比表面積が非常に大きく、約50〜3
00m2 /gである。また、HAp/Col複合体れに
含まれるハイドロキシアパタイトは結晶が小さい(クロ
マトグラフィーに使用されるものと同等、もしくはそれ
以下)ため多量の薬剤をその表面に吸着することがで
き、かつコラーゲンに含まれた薬剤をも引き寄せ、その
場にとどめる効果をもたらすことができる。
高い材料を組み合わせることにより、薬剤の放出速度を
遅くすることができ、増殖因子を生体内で長期的にかつ
局所的に徐放できる。本発明の薬物徐放材料は2種類の
材料を複合させることにより薬剤担体としての問題点を
補い合い、長所を引き出し合っているといえる。
て、細胞の増殖・分化を制御する増殖因子と細胞の増殖
の場を提供する組織再生足場材料として利用できる。ま
た、再生医学において、骨再生を促進する増殖因子・薬
剤等を含んだ骨充填材料としての用途も有する。
タイト/コラーゲン複合体(以下:「HAp/Col」
と記載)プレートを用いた。HAp/Colプレートを
リン酸バッファー溶液中で37℃、24時間静置した。
続いてFGF2(−)群とFGF2(+)群の2群に分
け、それぞれ下記のバッファー溶液1こ4℃、72時間
浸漬した。
液(血小板系免疫グロブリン検査用緩衝溶液)に浸漬。
FGF2(+)群・・・5mlのTyrode+bFGF
(20ng/ml)混合溶液に浸漬。各溶液からHAp
/Colプレートを取り出し、純粋なTyrode溶液で3回
洗浄して表面に存在するFGF2を除去した(3回目は
45分間)。
olプレートを置き、その細胞浮遊液(細胞:5×10
3 個/ml)を播種した。24時間後、10cm径の培
養容器(1個につきl枚)に移し培地の量を20mlと
して培養を行った。以降2日ごとに培地交換を行った。
細胞播種後5日目に、細胞をプロピルヨードで染色し、
共焦点顕微鏡で観察した。その結果、増殖因子を含まな
いFGF2(−)群では、細胞がほとんど増殖しなかっ
た。
群では、細胞の旺盛な増殖が認められた。本複合体はF
GF2の徐放担体として優れた特性を示すことが明らか
になった。
Claims (3)
- 【請求項1】 共沈物として合成され、比表面積50〜
300m2/gのハイドロキシアパタイト(HAp)結
晶がコラーゲン(Col)線維の周りにC軸方向に配向
して複合化したHAp/Colナノ複合体のハイドロキ
シアパタイト表面、コラーゲン表面および両者の水和水
中に増殖因子、DNA酵素等の生理活性物質、薬剤を保
持したことを特徴とする生体内薬物徐放材料。 - 【請求項2】 含水性の高いグリコサミノグリカンまた
はハイドロゲルを複合化することにより増殖因子を封入
した生体吸収性のカプセルとなることを特徴とする請求
項1記載の生体内薬物徐放材料。 - 【請求項3】 生体内に注射的な投与が可能で注入後ゲ
ル化することを特徴とする請求項1記載の生体内薬物徐
放材料。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001262476A JP4204772B2 (ja) | 2001-08-30 | 2001-08-30 | 生体内薬物徐放材料の製造方法 |
EP02760639A EP1421954A4 (en) | 2001-08-30 | 2002-08-14 | SLOW DRUG DELIVERY MATERIALS I IN VIVO / I |
US10/487,706 US20050031698A1 (en) | 2001-08-30 | 2002-08-14 | Materials sustainedly releasing drug in vivo |
PCT/JP2002/008282 WO2003020316A1 (fr) | 2001-08-30 | 2002-08-14 | Matieres a liberation lente de medicament in vivo |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001262476A JP4204772B2 (ja) | 2001-08-30 | 2001-08-30 | 生体内薬物徐放材料の製造方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2003073304A true JP2003073304A (ja) | 2003-03-12 |
JP4204772B2 JP4204772B2 (ja) | 2009-01-07 |
Family
ID=19089370
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2001262476A Expired - Lifetime JP4204772B2 (ja) | 2001-08-30 | 2001-08-30 | 生体内薬物徐放材料の製造方法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20050031698A1 (ja) |
EP (1) | EP1421954A4 (ja) |
JP (1) | JP4204772B2 (ja) |
WO (1) | WO2003020316A1 (ja) |
Cited By (1)
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KR100795345B1 (ko) | 2006-09-15 | 2008-01-17 | 전북대학교산학협력단 | 하이드록시아파타이트 나노복합체의 제조방법 |
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SE527610C2 (sv) * | 2004-06-15 | 2006-04-25 | Promimic Ab | Förfarande för framställning av syntetiskt, kristallint kalciumfosfat i nanostorlek |
EP2148887B1 (en) | 2007-04-19 | 2014-04-30 | Fibralign Corporation | Oriented collagen-based materials, films and methods of making same |
US8513382B2 (en) | 2008-08-11 | 2013-08-20 | Fibralign Corporation | Biocomposites and methods of making the same |
US10086079B2 (en) | 2008-08-11 | 2018-10-02 | Fibralign Corporation | Biocomposites and methods of making the same |
US10065046B2 (en) | 2010-07-15 | 2018-09-04 | Fibralign Corporation | Conductive biopolymer implant for enhancing tissue repair and regeneration using electromagnetic fields |
US9724308B2 (en) | 2010-09-10 | 2017-08-08 | Fibralign Corporation | Biodegradable multilayer constructs |
US10238769B2 (en) | 2011-10-11 | 2019-03-26 | Fibralign Corporation | Graft for directed vascular and lymphatic regeneration and methods to guide endothelial cell assembly |
US20150024043A1 (en) * | 2013-07-18 | 2015-01-22 | Sachin Patel | Medi-Cap (Bio-Absorbable Capsules) |
US11273235B2 (en) | 2013-10-10 | 2022-03-15 | Fibralign Corporation | Method and device for lymphedema treatment |
CN109551845B (zh) * | 2018-12-29 | 2020-06-12 | 泉州维林森体育用品有限公司 | 一种含胶原蛋白的水柔针织面料 |
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CA2071912C (en) * | 1990-11-30 | 2002-10-15 | Hanne Bentz | Use of a bone morphogenetic protein in synergistic combination with tgf-beta for bone repair |
US5942496A (en) * | 1994-02-18 | 1999-08-24 | The Regent Of The University Of Michigan | Methods and compositions for multiple gene transfer into bone cells |
WO1996029030A1 (en) * | 1995-03-17 | 1996-09-26 | Smith & Nephew Richards Inc. | Medical implants |
FR2734118B1 (fr) * | 1995-05-12 | 1997-07-11 | Duranton Rene | Dispositif pour la commande et la surveillance a distance d'une lampe a decharge |
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US5702449A (en) * | 1995-06-07 | 1997-12-30 | Danek Medical, Inc. | Reinforced porous spinal implants |
US6777001B1 (en) * | 1996-11-25 | 2004-08-17 | Kabushiki Kaisya Advance | Method of production of ceramics |
US5771975A (en) | 1997-02-14 | 1998-06-30 | Northrop Grumman Corporation | Composite cylinder termination |
US6344209B1 (en) | 1997-04-24 | 2002-02-05 | Takeda Chemical Industries, Ltd. | Apatite-coated solid composition |
US5972368A (en) * | 1997-06-11 | 1999-10-26 | Sdgi Holdings, Inc. | Bone graft composites and spacers |
EP1155704A1 (en) * | 2000-01-13 | 2001-11-21 | Chih-I Lin | Orthopedic filling material and method of use thereof |
CN1106861C (zh) * | 2000-05-19 | 2003-04-30 | 清华大学 | 纳米相钙磷盐/胶原/聚乳酸骨复合多孔材料的制备方法 |
-
2001
- 2001-08-30 JP JP2001262476A patent/JP4204772B2/ja not_active Expired - Lifetime
-
2002
- 2002-08-14 US US10/487,706 patent/US20050031698A1/en not_active Abandoned
- 2002-08-14 EP EP02760639A patent/EP1421954A4/en not_active Withdrawn
- 2002-08-14 WO PCT/JP2002/008282 patent/WO2003020316A1/ja active Application Filing
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100795345B1 (ko) | 2006-09-15 | 2008-01-17 | 전북대학교산학협력단 | 하이드록시아파타이트 나노복합체의 제조방법 |
Also Published As
Publication number | Publication date |
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JP4204772B2 (ja) | 2009-01-07 |
US20050031698A1 (en) | 2005-02-10 |
EP1421954A1 (en) | 2004-05-26 |
WO2003020316A1 (fr) | 2003-03-13 |
EP1421954A4 (en) | 2010-01-06 |
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