JP4049810B2 - 固体の作用物質製剤 - Google Patents
固体の作用物質製剤 Download PDFInfo
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- JP4049810B2 JP4049810B2 JP52461596A JP52461596A JP4049810B2 JP 4049810 B2 JP4049810 B2 JP 4049810B2 JP 52461596 A JP52461596 A JP 52461596A JP 52461596 A JP52461596 A JP 52461596A JP 4049810 B2 JP4049810 B2 JP 4049810B2
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- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
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- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
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- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
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- 229960001722 verapamil Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
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- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
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- 229940046009 vitamin E Drugs 0.000 description 1
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Description
A)1種または数種の作用物質、
B)次のものからなる混合物:
B1)少なくとも1種の、熱可塑的に加工できる水溶性ポリマー10〜90重量%、
B2)低置換の水不溶性ヒドロキシプロピルセルロース10〜90重量%、および
C)製剤の全量に対して、1種または数種の製剤学的補助物質0〜50重量%、
の複合溶融押出により得られる、固体製剤に関する。
さらに本発明は該製剤の製造方法ならびに薬剤としてのその使用に関する。
溶融押出により製造され、作用物質を含有する製剤は周知である。
作用物質を含有する、水溶性ポリマーの溶融物、有利にはビニルピロリドンのコポリマーの押出は、欧州特許出願公開第240904号明細書、および欧州特許出願公開第240906号明細書に記載されている。
特開昭58−192817号公報および特開昭58−79915号公報から、結合剤として熱可塑性ポリマー、例えばヒドロキシプロピルセルロースをベースとした、作用物質を含有する製剤の溶融押出が公知である。
セルロースをプロピレンオキシドで部分的にエーテル化することにより製造される、低置換ヒドロキシプロピルセルロース(L−HPC)は水不溶性であるが、しかし水と接触すると膨潤する。このような膨潤挙動のためL−HPCは崩壊剤として錠剤の崩壊促進のために使用される。L−HPCはまた、錠剤の硬度を向上するために錠剤の結合剤として使用することもできる。
カワシマ等(Chem. Pharm. Bull. 41(1933), 1827-31)は、錠剤化のために顆粒中でL−HPCを使用する際に、一方ではL−HPCの粒子の大きさにより大きく影響を受け、他方では作用物質の放出プロフィールが決定的に圧縮の際のプレス力により影響されることを記載している。
しかし置換度の高いヒドロキシプロピルセルロースに対して、L−HPCは熱可塑的な加工性を有していない。
本発明の課題は、ポリマー−作用物質−溶融押出により製造でき、かつ作用物質の放出を調整できるような作用物質製剤を見出すことである。
これに応じて冒頭で規定した製剤、該製剤の製造方法、ならびに薬剤としての該製剤の使用が判明した。
成分A)としては溶融押出の際の加工条件下で分解しない作用物質が該当する。
適切な作用物質は例えば以下の通りである:
アセブトロール、アセチルシステイン、アセチルサリチル酸、アシクロビア、アルプラゾラム、アルブミン、アルファカルシドール(alfacalcidol)、アラントイン、アロプリノール、アンブロキソール、アミカシン、アミロリド、アミノ酢酸、アミオダロン、アミトリプチリン、アムロジピン(amlodipine)、アモキシシリン、アンピシリン、アスコルビン酸、アスパルテーム、アステミゾール(astemizole)、アテノロール、ベクロメタゾン、ベンゼラジド、水酸化ベンザルコニウム、ベンゾカイン、安息香酸、ベータメタゾン、ベザフィブレート(bezafibrate)、ビオチン、ビペリデン、ビソプロロール(bisoprolo1)、ブロマゼパム、ブロムヘキシン、ブロモクリプチン、ブデソニド(budesonide)、ブフェキサマック、ブフロメジル(buflomedil)、ブスピロン(buspirone)、カフェイン、カンフル、カプトプリル、カルバマゼピン、カルビドーパ、カルボプラチン、セファクロル、セファレキシン、セファドロキシル、セファゾリン、セフィキシム、セフォタキシム、セフタジジム、セフトリアキソン、セフロキシム、アキセチル(axetil)、クロラムフェニコール、クロロヘキシジン、クロルフェニラミン、クロルタリドン、コリン、シクロスポリン、シラスタチン(cilastatin)、シメチジン、シプロフロキサシン(ciprofloxacin)、シサプリド(cisapride)、シスプラチン、クラリトロマイシン、クラブラン酸、クロミプラミン、クロナゼパム、クロニジン、クロトリマゾール、クロザピン、コデイン、コレスチラミン、クロモグリシン酸、シアノコバラミン、シプロテロン、デソゲストレル(desogestrel)、デキサメタゾン、デクスパンテノール、デキストロメトルファン、デキストロプロポキシフェン(dextropropoxiphen)、ジアゼパム、ジクロフェナック、ジゴキシン、ジヒドロコデイン、ジヒドロエルゴタミン、ジルチアゼム、ジフェンヒドラミン、ジピリダモール、ジピロン、ジソピラミド、ドンペリドン、ドーパミン、エナラプリル、エフェドリン、エピネフリン、エルゴカルシフェロール、エルゴタミン、エリトロマイシン、エストラジオール、エチニルエストラジオール、エトポシド(etoposide)、ユーカリ(Eucalyptus globulus)、ファモチジン、フェロジピン(felodipine)、フェノフィブレート(fenofibrate)、フェノテロール、フェンタニル、フラビンモノヌクレオチド、フルコナゾール(fluconazole)、フルナリジン、フルオロウラシル、フルオキセチン(fluoxetine)、フルルビピロフェン、フロセミド、ゲンフィブロジル(gemfibrozil)、ゲンタマイシン、イチョウ(Gingko biloba)、グリベンクラミド、グリピジド(glipizide)、カンゾウ(Glycyrrhiza glabra)、グアイフェネシン、ハロペリドール、ヘパリン、ヒアルロン酸、ヒドロクロロチアジド、ヒドロコドン、ヒドロコルチゾン、ヒドロモルホン、水酸化イプラトロピウム、イブプロフェン、イミペネム(imipenem)、インドメタシン、イオヘキソール(iohexol)、イオパミドール、イソソルビドジニトレート(isosorbide dinitrate)、イソソルビドモノニトレート(isosorbide mononitrate)、イソトレチノイン(isotretinoin)、ケトチフェン、ケトコナゾール(ketoconazole)、ケトプロフェン、ケトロラック(ketorolac)、ラベタロール、ラクツロース、レシチン、レボカルニチン(levocarnitine)、レボドーパ、レボグルタミド(levoglutamide)、レボノルゲストレル(levonorgestrel)、レボチロキシン、リドカイン、リパーゼ、リシノプリル(lisinopril)、ロペラミド、ロラゼパム、ロバスタチン(lovastatin)、メドロキシプロゲステロン、メントール、メトトレキセート、メチルドーパ、メチルプレドニゾロン、メトクロプラミド、メトプロロール、ミコナゾール、ミダゾラム(midazolam)、ミノサイクリン、ミノキシジル、ミソプロストール(misoprostol)、モルヒネ、総合ビタミンおよびおよび無機塩類、ナイスタチン、N−メチルエフェドリン、ナフチドロフリル(naftidrofuryl)、ナプロキセン、ネオマイシン、ニカルジピン、ニセルゴリン(nicergoline)、ニコチンアミド、ニコチン、ニコチン酸、ニフェジピン、ニモジピン、ニトレンジピン、ニザチジン(nizatidine)、ノルエチステロン、ノルフロキサシン、ノルゲストレル、ノルトリプチリン、オフロキサシン、オメプラゾール、オンダンセトロン(ondansetron)、パンクレアチン、パンテノール、パントテン酸、パラセタモール、ペニシリンG、ペニシリンV、フェノバルビタル、ペントキシフィリン、フェニレフリン、フェニルプロパノールアミン、フェニトイン、ピロキシカム、ポリミキシンB、ポビドン−ヨード、プラバスタチン、プラゾシン、プレドニゾロン、プロパフェノン(propafenone)、プロプラノロール、プソイドエフェドリン、ピリドキシン、キニジン、ラミプリル(ramipril)、ラニチジン、レセルピン、レチノール、リボフラビン、リファンピシン、ルトシド、サッカリン、サルブタモール、サルカトニン(salcatonin)、サリチル酸、セレジリン(selegilin)、シンバスタチン(simvastatin)、ソマトロピン、ソタロール、スピロノラクトン、スクラルフェート、スルバクタム、スルファメトキサゾール、スルピリド、タモキシフェン、テガフール、テプレノン、テラゾシン(terazosin)、テルブタリン、テルフェナジン(terfenadine)、テオフィリン、チアミン、チクロピジン、チモロール、トラネキサム酸、トレチノイン、トリアムシノロンアセトニド、トリアムテレン、トリメトプリム、トロキセルチン、ウラシル、バルプロ酸、バンコマイシン、ベラパミル、ビタミンE、葉酸、ジドブジン(zidovudine)。
その他の作用物質はビタミン、例えばビタミンC、β−カロチン、およびその他のカロチノイド、または植物保護剤である。
有利には作用物質はいわゆる「固溶体」の形、つまりマトリックス中に分子分散で、または固体の分散形で存在する。
全製剤中の作用物質成分A)の量は、そのつどの効力および放出速度により広い範囲で変化してもよい。例えば作用物質の含有量は、全製剤に対して0.1〜90重量%、有利には0.5〜60重量%の範囲である。唯一の条件は該製剤が熱可塑的に加工できることである。
ポリマー成分B)として本発明による製剤は、
B1)水溶性熱可塑性ポリマー10〜90重量%、有利には20〜80重量%、
B2)水不溶性低置換ヒドロキシプロピルセルロース10〜90重量%、有利には20〜80重量%
からなる混合物を含有しており、この場合量の表示はB1)およびB2)の総量に対してである。
水溶性ポリマーB1)は以下のものが挙げられる:
−アルキルセルロース、例えばメチルセルロース、
−ヒドロキシアルキルセルロース、例えばヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、およびヒドロキシブチルセルロース、
−ヒドロキシアルキルアルキルセルロース、例えばヒドロキシエチルメチルセルロース、およびヒドロキシプロピルメチルセルロース、
−ポリビニルピロリドン、
−N−ビニルピロリドンおよびビニルアセテートからなる、ビニルアセテート50重量%までのコポリマー、
−カルボキシアルキルセルロース、例えばカルボキシメチルセルロース、
−ポリサッカリド、例えばアルギン酸およびそのアルカリ塩およびアンモニウム塩、
ならびにこれらの水溶性ポリマーの混合物。
成分B1)は全成分の最終混合物中で50〜180℃、有利には60〜150℃で軟化または溶融するべきであるため、該物質は押出可能である。従ってポリマーのガラス転移温度は180℃以下であるべきである。
「水溶性」とは、20℃の水100g中で少なくとも0.5g、有利には少なくとも2gのポリマーが溶解するか、場合によりコロイド状であることを言う。
有利にはポリマー成分B1としてモル置換度3.0〜4.4を有するヒドロキシプロピルセルロースを使用する。
成分B2)は本発明により、モル置換度0.5〜2、有利には1.5〜1.8を有する低置換ヒドロキシプロピルセルロースであり、該セルロースは例えば米国薬局方/NF XVIIおよび日本薬局方JP XIに記載されているような、いわゆる低置換ヒドロキシプロピルセルロース(L−HPC)である。このようなL−HPCは水不溶性であるが、しかし水で膨潤でき、かつ熱可塑的な挙動をしない。
使用する成分B2)の量は前記の範囲内で有利には、いずれの作用物質放出速度を希望するかにより調整する。迅速な放出の場合、少量、例えば5〜30重量%の使用が推奨される。作用物質の放出の抑制を希望する場合はB2)30〜90重量%の使用が推奨される。
使用するL−HPCの粒径は本発明では重要でない。
本発明による製剤は成分C)として通例の製薬学的補助物質、例えば増量剤、滑剤、離型剤、流動性調整剤、軟化剤、着色剤、および安定剤を約50重量%までの量で含有することができる。上記量および以下に指示する量はそれぞれ製剤の総重量(=100%)に対してである。
増量剤として例えばマグネシウム、アルミニウム、ケイ素、およびチタンの酸化物、ならびにラクトース、マンニット、ソルビット、キシリット、ペンタエリトリット、およびその誘導体が挙げられ、この場合増量剤の量は約0.02〜50、有利には0.2〜20重量%である。
流動性調整剤として例えば長鎖脂肪酸のモノグリセリド、ジグリセリド、およびトリグリセリド、例えばC12、C14、C16およびC18の脂肪酸、ワックス、例えばカルナウバロウ、ならびにレシチンが挙げられ、この場合その量は約0.1〜30、有利には0.1〜5重量%である。
軟化剤として例えば低分子ポリアルキレンオキシド、例えばポリエチレングリコール、ポリプロピレングリコール、およびポリエチレンプロピレングリコールと並んで、多価アルコール、例えばプロピレングリコール、グリセリン、ペンタエリトリット、およびソルビット、ならびにナトリウムジエチルスルホスクシネート、グリセリンのモノアセテート、ジアセテート、およびトリアセテート、およびポリエチレングリコールステアリン酸エステルが挙げられる。この場合軟化剤の量は約0.5〜15、有利には0.5〜5重量%である。
滑剤として例えばアルミニウムまたはカルシウムのステアリン酸塩、ならびにタルク、およびシリコーンが挙げられ、この場合その量は約0.1〜5、有利には0.1〜3重量%である。
安定剤として例えば光安定剤、酸化防止剤、ラジカルスカベンジャー、および微生物による被害に対する安定剤が挙げられ、この場合その量は有利には約0.01〜0.05重量%である。
本発明による製剤を製造するために、作用物質成分を直接ポリマーBとの物理的混合物の形で溶融するか、あるいは既に存在するポリマー溶融物と共に混合することができる。
その他の点では成分A)と溶融物との混合は自体公知の方法で押出機、有利には一軸スクリューまたは二軸スクリュー押出機で、温度範囲50〜200℃で実施する。作用物質を含有するポリマー溶融物の、本発明による製剤への成形は例えば、欧州特許出願公開第240906号明細書に記載の方法による押出物のカレンダリングにより、ならびにドイツ国特許出願公開第3830355号明細書から公知の加工法により回転ナイフで押出物を、表面が凝固している、体積の等しい、しかしまだ変形可能な粒に粉砕し、かつ引き続き通例のタブレット成形機でプレスして錠剤に加工することにより行う。
補助物質を作用物質およびポリマーBからなる溶融物または溶液に混合することも可能である。さらに補助物質を作用物質と一緒にポリマー溶融物に配合することも可能である。さらに補助物質、作用物質、およびポリマーBからなる混合物を直接溶融することもできる。一般に補助物質、作用物質、およびポリマーBからなる物理的混合物を一緒に溶融することは通例である。
本発明による製剤は薬剤として使用し、かつ錠剤、ペレット剤、顆粒またはカプセルの形で使用する。有利には本発明による製剤で作用物質の放出が抑制された薬剤形を製造する。
所望の場合、固体の製薬学的成形体に、外見および/または味の改善(糖衣錠)のために、または付加的に作用物質の放出を抑制する目的で、通例のコーティングを施すこともできる。作用物質の放出が抑制された経口摂取錠剤にとっては、錠剤が胃の中で浮上し、かつこのことによりその場に滞留する時間が長くなるよう、公知の技術により膜で閉鎖した多孔質の成形体に製造する場合には有利であり得る。
本発明により、特に作用物質の放出が抑制された固体薬剤形を製造する際に、容易な方法で本発明による固体の薬剤形の作用物質の放出プロフィールの調整を達成することが可能となる。意外にもこれはL−HPCの粒径および成形の際の方法パラメータと関わりなく達成される。
例1〜3
表に記載の量の作用物質およびポリマーB1)およびB2)を混合し、二軸スクリュー押出機(ZSK 30、ウェルナー&プフライデラー(Werner & Pfleiderer)社)に入れ、5つの温度帯域を介して押出した。それぞれの温度帯域(バッチ1〜5)をそのつど表Iに示す。押出ダイのリップを介して出る溶融物は空冷式の熱間粉砕によりナイフロール造粒機でペレット化した。
作用物質の放出は撹拌翼法(US薬局方、USP XXIによるパドル法(paddle method))で測定した。該インビトロ法は作用物質を含有する成形体(例えば錠剤、ペレット剤など)の溶解速度の測定のために使用される。
このためにpH値6.8のリン酸塩緩衝液900mlをラウリル硫酸ナトリウム0.1重量%と共に円形底を有する1lの容器中で37℃に調温し、かつ粒径1.25〜1.60mmのペレット剤300gを添加した。ペレット剤の作用物質の放出を、パドルの回転数100rpmの際にそれぞれ1、2、3、4、5、6、7および8時間後にUV分光分析により測定した。
このテストの結果を表IIに示す。
Claims (3)
- 固体の製剤において、
A)1種または数種の作用物質、
B)次のものからなる混合物:
B1)少なくとも1種の熱可塑的に加工できる、モル置換度3.0〜4.4を有する水溶性ヒドロキシプロピルセルロース10〜90重量%、
B2)モル置換度1.5〜1.8を有する水不溶性ヒドロキシプロピルセルロース10〜90重量%、および
C)製剤の全量に対して、1種または数種の製剤学的補助物質0〜50重量%、
の複合溶融押出により得られることを特徴とする、固体の製剤。 - 請求項1記載の製剤の製造方法において、作用物質成分A)をポリマー成分B)および場合により補助物質C)と共に溶融物に加工し、該溶融物を押出し、かつさらに成形して加工することを特徴とする、製剤の製造方法。
- 請求項1の製剤からなる固体の薬剤。
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DE19504832A DE19504832A1 (de) | 1995-02-14 | 1995-02-14 | Feste Wirkstoff-Zubereitungen |
DE19504832.6 | 1995-02-14 | ||
PCT/EP1996/000417 WO1996025151A1 (de) | 1995-02-14 | 1996-02-01 | Feste wirkstoff-zubereitungen |
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JPH10513477A JPH10513477A (ja) | 1998-12-22 |
JP4049810B2 true JP4049810B2 (ja) | 2008-02-20 |
Family
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JP52461596A Expired - Fee Related JP4049810B2 (ja) | 1995-02-14 | 1996-02-01 | 固体の作用物質製剤 |
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DE (2) | DE19504832A1 (ja) |
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1995
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1996
- 1996-02-01 CA CA002211033A patent/CA2211033C/en not_active Expired - Lifetime
- 1996-02-01 DK DK96903958T patent/DK0809488T3/da active
- 1996-02-01 HU HU9702424A patent/HUP9702424A3/hu unknown
- 1996-02-01 CN CNB961919280A patent/CN1177584C/zh not_active Expired - Lifetime
- 1996-02-01 SK SK1043-97A patent/SK104397A3/sk unknown
- 1996-02-01 EP EP96903958A patent/EP0809488B1/de not_active Expired - Lifetime
- 1996-02-01 PL PL96321755A patent/PL321755A1/xx unknown
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- 1996-02-01 ES ES96903958T patent/ES2180738T3/es not_active Expired - Lifetime
- 1996-02-01 KR KR1019970705588A patent/KR19980702193A/ko not_active Application Discontinuation
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- 1996-02-01 BR BR9606957A patent/BR9606957A/pt not_active Application Discontinuation
- 1996-02-01 AT AT96903958T patent/ATE220541T1/de active
- 1996-02-01 US US08/875,514 patent/US5939099A/en not_active Expired - Lifetime
- 1996-02-01 DE DE59609451T patent/DE59609451D1/de not_active Expired - Lifetime
- 1996-02-01 JP JP52461596A patent/JP4049810B2/ja not_active Expired - Fee Related
- 1996-02-01 AU AU47860/96A patent/AU4786096A/en not_active Abandoned
- 1996-02-01 WO PCT/EP1996/000417 patent/WO1996025151A1/de active IP Right Grant
- 1996-02-12 IL IL11711296A patent/IL117112A0/xx unknown
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1997
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BR9606957A (pt) | 1997-10-28 |
HUP9702424A2 (hu) | 1998-06-29 |
ES2180738T3 (es) | 2003-02-16 |
FI973320A0 (fi) | 1997-08-13 |
TR199700786T1 (xx) | 1998-02-21 |
CN1174503A (zh) | 1998-02-25 |
DK0809488T3 (da) | 2002-09-02 |
SK104397A3 (en) | 1998-04-08 |
CZ239497A3 (cs) | 1998-01-14 |
ATE220541T1 (de) | 2002-08-15 |
EP0809488B1 (de) | 2002-07-17 |
PL321755A1 (en) | 1997-12-22 |
EP0809488A1 (de) | 1997-12-03 |
DE19504832A1 (de) | 1996-08-22 |
IL117112A0 (en) | 1996-06-18 |
HUP9702424A3 (en) | 2001-03-28 |
KR19980702193A (ko) | 1998-07-15 |
BG101781A (en) | 1998-03-31 |
NO973730L (no) | 1997-08-13 |
JPH10513477A (ja) | 1998-12-22 |
DE59609451D1 (de) | 2002-08-22 |
AU4786096A (en) | 1996-09-04 |
FI973320A (fi) | 1997-10-13 |
CN1177584C (zh) | 2004-12-01 |
NO973730D0 (no) | 1997-08-13 |
ZA961137B (en) | 1997-09-16 |
US5939099A (en) | 1999-08-17 |
PT809488E (pt) | 2002-11-29 |
CA2211033C (en) | 2005-04-26 |
CA2211033A1 (en) | 1996-08-22 |
WO1996025151A1 (de) | 1996-08-22 |
NZ302243A (en) | 1999-01-28 |
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