JPH02243618A - 調剤用イオン交換樹脂組成物の製法 - Google Patents
調剤用イオン交換樹脂組成物の製法Info
- Publication number
- JPH02243618A JPH02243618A JP1290147A JP29014789A JPH02243618A JP H02243618 A JPH02243618 A JP H02243618A JP 1290147 A JP1290147 A JP 1290147A JP 29014789 A JP29014789 A JP 29014789A JP H02243618 A JPH02243618 A JP H02243618A
- Authority
- JP
- Japan
- Prior art keywords
- sugar
- weight
- alcohol
- water
- ion exchange
- 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
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- 239000004615 ingredient Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 229960001073 nomifensine Drugs 0.000 description 1
- XXPANQJNYNUNES-UHFFFAOYSA-N nomifensine Chemical compound C12=CC=CC(N)=C2CN(C)CC1C1=CC=CC=C1 XXPANQJNYNUNES-UHFFFAOYSA-N 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 150000004686 pentahydrates Chemical class 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229920001568 phenolic resin Polymers 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 239000011342 resin composition Substances 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
-
- A—HUMAN NECESSITIES
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
め要約のデータは記録されません。
Description
係わる。
を、造粒を容易にするのに充分な水、水性アルコールま
たはアルコールの存在において糖または糖アルコールと
共に粒状化することを特徴とする水に分散し易い調剤用
イオン交換樹脂組成物の製法を提供する。
がその重量の20倍の水と共に撹拌して10秒以内に分
散することを意味する。
させればよいが、生物学的半減期が8時間またはそれ以
下の活性成分を使用することが好ましい。
イン、ペンタゾシン、プロポキシフェンのような麻酔性
鎮痛剤、 ノルエフェドリン、プソイドエフェドリンのような交感
神経刺激剤、 1ii デキストロメトルファンのような鎮咳剤、i
v アスピリンのような鎮痛剤、 マ メトクロプラミドのような鎮咳剤、vi アトロ
ピン、臭化イブロアトロピン、スコポラミンのような抗
コリン作用剤、 マ11 シクロベンザプリン、パパベリンのような筋
肉弛緩剤、 viiiサルブタモール、テルブタリン、テオフィリン
のような気管支拡張剤、 i! アモキシシリン、アンピシリン、アズロシリン、
バカンピシリン、セファマンドール。
キシチン、セフトリアキラン。
のような抗うつ薬、 xi クロモリンのような抗ぜん息薬、xii\タモ
キシフェンのような抗腫瘍剤、xiiiパルプロイン酸
、フェニトインのような抗てんかん薬、 xiマ プロプラノロールのような心臓血管剤。
するものがあるなら、アルカリまたはアルカリ土類金属
塩が特に好適である。
(塩基性薬剤の場合なら)陽イオン交換樹脂または(酸
性薬剤の場合なら)陰イオン交換樹脂を利用できる。ア
クリル、メタクリル、フェノール・ホルムアルデヒドま
たはデクストラン系樹脂を母材とするイオン交換樹脂が
好適である。
ルベンゼンスルホン酸樹脂ゲル、例えば、Amberl
ile lit 120 (商標名)、Amberli
le XE 69(商標名) 、Dovex 5QW
(商標名)などであり、好ましい陰イオン交換樹脂は
スチレン−ジビニルベンゼン第4アンモニウム樹脂ゲル
、例えば、Dovex SBR(商標名) 、Dove
x !iAR(商標名)などである。
に使用される薬剤及び必要とされる薬剤放出速度に応じ
て異なるが、樹脂の粒度は0.045乃至1 mm、特
に0.045乃至0.5mn+であることが好ましい。
8乃至12%であることが好ましい。
脂に応じて異なるが、結合させる薬剤と樹脂の重量比は
1:3乃至2:1、特に2:3乃至3:2であることが
好ましい。
37号、英国特許第1218102号及び米国特許第2
99G332号に開示され、本願明細書でも例に基づい
て後述する公知の技術である。−船釣には、薬剤を樹脂
の水性懸濁液と混合し、この複合体(c。
濁流体の分析によって検出する。
150乃至370であることが好ましい。適当な糖/糖
アルコールはスクロース、デキストロース。
、ソルビトールまたはキシリトールなどであり、特にキ
シリトールが好ましい。糖/糖アルコールは微粒状であ
ることが好ましく、いずれの場合にもその粒度は600
ミクロンまたはそれ以下(30メツシユふるい)である
ことが好ましい。本発明の製法の特に好ましい実施例で
は、糖/糖アルコールの少なくとも90重量%の粒度が
250ミクロンまたはそれ以下(60メツシユふるい)
である。
コール濃度は組成物を水に分散し易くするのに充分なレ
ベルでなければならない。即ち、組成物をその重量の2
0倍の水と共に撹拌して(10秒以内に)分散させるの
に充分な量の糖/糖アルコールが存在しなければならな
い。−船釣には、組成物中に含有される糖/糖アルコー
ルの量は25乃至99重量%、好ましくは70乃至95
重量%である。
するのに充分な水、水性アルコールまたはアルコールの
存在において粒状化される。最適のアルコールは特に7
60mmHHにおいて沸点が100℃またはそれ以下の
C1Ca脂肪族アルコールである。好ましいアルコール
はエタノール及びイソプロパツールである。
量に対して1乃至20重量%、特に2乃至7重量%が好
ましい。本発明の製法の特に好ましい実施例では、糖/
糖アルコールの粒度が樹脂粒度と一致するまで混合物を
粒状化する。本願明細書中、 一致する”という場合は
糖/糖アルコールの少なくとも80重量%の粒度が薬剤
/樹脂複合体の平均粒度の0.5乃至1.5倍であるこ
とを意味する。薬剤/樹脂複合体及び糖/糖アルコール
を造粒したら、形成された顆粒を、好ましくはその水分
が(カール・フィッシャーの水分分析法で測定して)3
重量%以下となるまで乾燥させる。
ことを可能にする物質で顆粒をフィルム・コーティング
してもよい。
のが普通である。
ワックス、 (b) シェラツクまたはゼイン、 (C)非水溶性セルロース誘導体、特にエチル・セルロ
ース、 (d)ポリメタクリレート、特にEudrgil (
商標名)。
物であることが好ましい。非水溶性物質と水溶性物質の
比はとりわけ所期の放出速度及び選択される物質の可溶
度特性によって決定される。
ル、ポリエチレングリコール、ポリビニルピロリドン、
または好ましくは水溶性セルロース、例えばヒドロキシ
プロピルセルロース、特にヒドロキシプロピルメチルセ
ルロースが挙げられる。
な複合物質としてはシェラツク/ポリビニルピロリドン
、好ましくはエチルセルロース/ヒドロキシプロピルメ
チルセルロースが挙げられる。
式、例えばカプセルや薬袋のような服用形式を与える。
成される。
施例に基づいて以下に説明する。
P、 110g)に添加し、粉末全体が均等に湿潤する
まで混合した。混合を続けながら、モルフィン!f!、
濁液に陽イオン交換樹脂(約50重量%の水を含むDo
wex W 50X8−2H、60g )を添加した。
。次いで樹脂を精製水で洗浄し、流動層ドライヤーで乾
燥させた。
シリトールをモルフイン/樹脂複合体(4[1g )及
びザンサンゴム(20g )と共に造粒機中で混合した
。混合を続けながら、均等に湿潤した軽い顆粒が形成さ
れるまで混合物に精製水を添加した。
に対して2.0乃至5.0重量%とした。湿潤した顆粒
を、含水量が(カール・フィシャー法で測定して)約3
.0重量%となるまで流動層ドライヤー中で乾燥させた
。
リトール ザンサンゴム 例 2 例1の製法で下記組成を有する組成物を形成した。
シリトール ザンサンゴム 例 3 例1の製法で下記組成を有する組成物を形成した。
シリトール ザンサンゴム 例 4 例1の製法で下記組成を有する組成物を形成した。
ール ザンサンゴム た。
服用量を、絶えず混合しなからlOmQの水に加えた。
を形成したが、粉末状製品は水性媒中に分散して、樹脂
懸濁液を形成するのに数分間かかる湿潤塊を形成した。
している均質な製品であるのに対して、乾燥状態で混合
した粉末は不均質であり、薬剤は組成中に不均一に分布
していた。
乾燥状態のまま混合して湿潤顆粒ではなく粉末を形成す
ることを除いて例1の製法に従っ特許出願人 ユーロ
セルティク ソシエテ アノニム
Claims (9)
- (1)薬理学的活性成分を結合させたイオン交換樹脂を
、造粒を容易にするのに充分な水、水性アルコールまた
はアルコールの存在において糖または糖アルコールと共
に粒状化することを特徴とする水に分散し易い調剤用イ
オン交換樹脂組成物の製法。 - (2)糖または糖アルコールが、スクロース、デクスト
ロース、マルトース、フルクトース、ラクトース、マン
ニトール、ソルビトールまたはキシリトールであり、こ
れらのうち好ましくはキシリトールであることを特徴と
する請求項第(1)項に記載の製法。 - (3)糖または糖アルコールがいずれもその粒度が60
0ミクロンまたはそれ以下であることを特徴とする請求
項第(1)項または第(2)項に記載の製法。 - (4)糖または糖アルコールの少なくとも90重量%が
250ミクロンまたはそれ以下の粒度を有することを特
徴とする請求項第(3)項に記載の製法。 - (5)組成物が25乃至99重量%の、好ましくは70
乃至95重量%の糖または糖アルコールを含有すること
を特徴とする請求項第(1)項から第(4)項までのい
ずれかに記載の製法。 - (6)粒状化に使用される水、水性アルコールまたはア
ルコールの量が薬剤/樹脂複合体及び糖または糖アルコ
ールの総重量の1乃至20重量%、好ましくは2乃至7
重量%であることを特徴とする請求項第(1)項から第
(5)項までのいずれかに記載の製法。 - (7)糖または糖アルコールの粒度がイオン交換樹脂の
粒度と一致するまで造粒を続けることを特徴とする請求
項第(1)項から第(6)項までのいずれかに記載の製
法。 - (8)造粒に続いて、水分が3重量%以下になるまで顆
粒を乾燥させることを特徴とする請求項第(1)項から
第(7)項までのいずれかに記載の製法。 - (9)カプセルまたは袋に組成物を充填することを特徴
とする請求項第(1)項から第(8)項までのいずれか
に記載の製法。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB888826407A GB8826407D0 (en) | 1988-11-11 | 1988-11-11 | Pharmaceutical ion exchange resin composition |
GB888828592A GB8828592D0 (en) | 1988-12-07 | 1988-12-07 | Pharmaceutical ion exchange resin composition |
GB8828592.9 | 1988-12-07 | ||
GB8826407.2 | 1988-12-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH02243618A true JPH02243618A (ja) | 1990-09-27 |
JP2825202B2 JP2825202B2 (ja) | 1998-11-18 |
Family
ID=26294609
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1290147A Expired - Lifetime JP2825202B2 (ja) | 1988-11-11 | 1989-11-09 | 調剤用イオン交換樹脂組成物の製法 |
Country Status (11)
Country | Link |
---|---|
US (1) | US5071646A (ja) |
EP (1) | EP0368682B1 (ja) |
JP (1) | JP2825202B2 (ja) |
AT (1) | ATE123218T1 (ja) |
AU (1) | AU621949B2 (ja) |
CA (1) | CA2002492A1 (ja) |
DE (1) | DE68922894T2 (ja) |
DK (1) | DK175154B1 (ja) |
ES (1) | ES2075061T3 (ja) |
GB (1) | GB2225941B (ja) |
IE (1) | IE893625L (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007504239A (ja) * | 2003-09-03 | 2007-03-01 | マリンクロッド・インコーポレイテッド | 顆粒状持続放出製剤およびその製造 |
Families Citing this family (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9003904D0 (sv) * | 1990-12-07 | 1990-12-07 | Astra Ab | Method for the manufacture of a pharmaceutical dosage form |
SE9003903D0 (sv) * | 1990-12-07 | 1990-12-07 | Astra Ab | New pharmaceutical formulations |
US5275820A (en) * | 1990-12-27 | 1994-01-04 | Allergan, Inc. | Stable suspension formulations of bioerodible polymer matrix microparticles incorporating drug loaded ion exchange resin particles |
US5840339A (en) * | 1991-07-30 | 1998-11-24 | Kunin; Robert | Blood cholesterol reducing pharmaceutical composition |
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-
1989
- 1989-11-08 CA CA002002492A patent/CA2002492A1/en not_active Abandoned
- 1989-11-09 AU AU44530/89A patent/AU621949B2/en not_active Expired
- 1989-11-09 JP JP1290147A patent/JP2825202B2/ja not_active Expired - Lifetime
- 1989-11-09 US US07/434,416 patent/US5071646A/en not_active Expired - Lifetime
- 1989-11-10 ES ES89311701T patent/ES2075061T3/es not_active Expired - Lifetime
- 1989-11-10 DK DK198905645A patent/DK175154B1/da not_active IP Right Cessation
- 1989-11-10 IE IE893625A patent/IE893625L/xx not_active IP Right Cessation
- 1989-11-10 DE DE68922894T patent/DE68922894T2/de not_active Expired - Lifetime
- 1989-11-10 AT AT89311701T patent/ATE123218T1/de not_active IP Right Cessation
- 1989-11-10 GB GB8925492A patent/GB2225941B/en not_active Revoked
- 1989-11-10 EP EP89311701A patent/EP0368682B1/en not_active Expired - Lifetime
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007504239A (ja) * | 2003-09-03 | 2007-03-01 | マリンクロッド・インコーポレイテッド | 顆粒状持続放出製剤およびその製造 |
Also Published As
Publication number | Publication date |
---|---|
AU621949B2 (en) | 1992-03-26 |
EP0368682B1 (en) | 1995-05-31 |
DK564589D0 (da) | 1989-11-10 |
DE68922894D1 (de) | 1995-07-06 |
EP0368682A1 (en) | 1990-05-16 |
CA2002492A1 (en) | 1990-05-11 |
GB2225941A (en) | 1990-06-20 |
GB2225941B (en) | 1992-12-09 |
GB8925492D0 (en) | 1989-12-28 |
ES2075061T3 (es) | 1995-10-01 |
AU4453089A (en) | 1990-05-17 |
IE893625L (en) | 1990-05-11 |
DK175154B1 (da) | 2004-06-21 |
DK564589A (da) | 1990-05-12 |
DE68922894T2 (de) | 1996-01-11 |
JP2825202B2 (ja) | 1998-11-18 |
ATE123218T1 (de) | 1995-06-15 |
US5071646A (en) | 1991-12-10 |
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