EP0697890A1 - Comprime a biodisponibilite renforcee contenant comme principe actif de l'acide diphosphonique de dichloromethylene - Google Patents

Comprime a biodisponibilite renforcee contenant comme principe actif de l'acide diphosphonique de dichloromethylene

Info

Publication number
EP0697890A1
EP0697890A1 EP93917636A EP93917636A EP0697890A1 EP 0697890 A1 EP0697890 A1 EP 0697890A1 EP 93917636 A EP93917636 A EP 93917636A EP 93917636 A EP93917636 A EP 93917636A EP 0697890 A1 EP0697890 A1 EP 0697890A1
Authority
EP
European Patent Office
Prior art keywords
tablet
active ingredient
tablets
weight
clodronic acid
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.)
Withdrawn
Application number
EP93917636A
Other languages
German (de)
English (en)
Inventor
Walter Preis
Bernd Müsel
Günter Neugebauer
Rolf-Dieter Gabel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HESTIA PHARMA GmbH
Original Assignee
Roche Diagnostics GmbH
Boehringer Mannheim GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=25927331&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP0697890(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from DE9307393U external-priority patent/DE9307393U1/de
Priority claimed from DE19934322057 external-priority patent/DE4322057A1/de
Application filed by Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Publication of EP0697890A1 publication Critical patent/EP0697890A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to tablets with improved bioavailability of the active substance dichloromethylene diphosphonic acid (clodronic acid) or a physiologically tolerable salt thereof and an addition of microcrystalline cellulose as a pharmaceutical auxiliary, medicament packs containing these tablets, the use of dichloromethylene diphosphonic acid together with microcrystalline cellulose for the production a tablet with improved bioavailability and the process for producing this tablet.
  • dichloromethylene diphosphonic acid also known under the name clodronate
  • clodronate is used in medicaments for the treatment of osteolysis due to bone metastases of solid tumors and for the treatment of hypercalcaemia (cf., for example, DE-18 13 659 ).
  • biphosphonates such as e.g. B. clodronic acid or its physiologically acceptable salts can be used successfully in the treatment of osteoporosis and osteoporosis pain.
  • the treatment requires four capsules a day, in severe cases up to eight capsules a day. This corresponds to a daily dose of 1360 - 2720 mg clodronic acid.
  • EP 0 275 468 describes such formulations with an active ingredient content of 80-95%.
  • the preparation Ostac (R) has a percentage content of the active substance disodium clodronate tetrahydrate of about 500 mg (corresponding to 91%) with a total weight of the capsule filling mass of about 550 mg.
  • the object of the invention was to provide a dosage form with increased bioavailability of the active ingredient clodronic acid to provide, whereby the total daily dose to be administered to the patient can be reduced and thus the number of dosage forms to be taken daily can be reduced or smaller dosage forms, such as tablets, can be used with the same frequency of ingestion.
  • tablets with an addition of microcrystalline cellulose as dosage forms bring about a higher bioavailability of the active ingredient in comparison with the capsules when administered to humans.
  • the tablets according to the invention enable the total daily dose of clodronic acid to be reduced to values of up to 60%. This means that, for example, instead of the usual amount of 1360 mg of clodronic acid, a daily total dose of about 820 mg of clodronic acid has a comparable therapeutic effect.
  • the tablets according to the invention lead to a reduction in the total daily dose to about 800 - 1100 mg.
  • tablets in order to reduce the frequency of ingestion, tablets can be produced that replace the usual intake of four Ostac ( R ) capsules.
  • the excellent bioavailability achieved with the formulation according to the invention makes it possible, depending on the desired daily frequency of ingestion, to vary the active substance content per tablet and thus the tablet size as desired within certain limits.
  • this daily dose can be administered by two, three or four tablets according to the invention with an active ingredient content of 442 mg, 295 mg or 221 mg clodronic acid.
  • the tablet size can thus be adapted to the respective requirements.
  • the larger tablets are particularly advantageous when there is a fear that the patient will not consistently follow the intake required several times a day and will prefer to take them once or twice a day.
  • the smaller tablets are advantageous in such cases when the patient has difficulty swallowing the larger tablets and thus prefers to take smaller tablets several times a day.
  • the active substance content per tablet is determined in an analogous manner, depending on the desired requirements with regard to the frequency and size of the tablets.
  • a conventional Ostac ( R ) capsule (340 mg clodronic acid) can be replaced by a tablet according to the invention with an active ingredient content of approximately 220 mg.
  • the active ingredient is used in the form of the tetrahydrate of the sodium salt, this means a reduction in the amount of active ingredient in the dosage form from 500 mg to about 325 mg.
  • Two conventional Ostac ( R ) capsules (total dose 680 mg clodronic acid) can be replaced by a tablet according to the invention with an active ingredient content of approximately 440 mg. According to the information under point a), this means a reduction in the amount of active substance from 1000 mg to 650 mg of the tetrahydrate of disodium clodronate, or in relation to the anhydrous form from 800 mg to 520 mg.
  • Three conventional Ostac ( R ) capsules (total dose 1020 mg clodronic acid) can be replaced by a tablet according to the invention with an active ingredient content of approximately 660 mg or by two tablets each with 330 mg.
  • the above calculation of the active substance content of the tablet according to the invention was based on the results from bioequivalence studies in humans, from which it emerged that the intake of a tablet with an active substance content of 520 mg (based on the anhydrous form of sodium clodronate) is bioequivalent for taking two common Ostac ( R ) capsules, each with an active substance content of 400 mg.
  • the measurement of serum Concentration of clodronic acid in the blood of several patients gave largely comparable values over a period of 16 hours.
  • the tablets according to the invention can be used in particular for the treatment of osteoporosis. Since it is often long-term therapy in these cases, the advantageous reduction in the daily dose of clodronic acid and thus the minimization of possible side effects is of particular importance.
  • the tablet according to the invention contains the active substance dichloromethylene diphosphonic acid in an amount of 50-900 mg, preferably 200-700 mg, based on the content of clodronic acid.
  • the physiologically tolerable salts of clodronic acid in particular the alkali salts, preferably the disodium salt, are preferably used, which can be used either as tetrahydrate or in anhydrous form.
  • other physiologically acceptable salts such as. B. the lithium, potassium, ammonium or calcium salt or their hydrates can be used.
  • the percentage content of the active ingredient (based on clodronic acid) is 10-65% by weight, preferably 50-60% by weight, in particular approximately 55% by weight, based on the total weight of the tablet core.
  • the amount of active ingredient is preferably 74-88%, in particular about 80% of the total weight of the tablet.
  • microcrystalline cellulose is 1 to 20% by weight, based on the total weight of the tablet core, in particular 5 to 15% by weight or 8 to 12% by weight.
  • the microcrystalline cellulose content is particularly preferably about 10% by weight.
  • the microcrystalline cellulose is preferably used as Avicel (R) .
  • Avicel R
  • other equivalent ones can also be used Agents such as other modified cellulose derivatives or polyethylene glycol (PEG) 4000-6000 can be used.
  • the tablet also contains one or more pharmaceutically customary auxiliaries or carriers, such as e.g. Fillers, lubricants, disintegrants, binders or mold release agents.
  • auxiliaries or carriers such as e.g. Fillers, lubricants, disintegrants, binders or mold release agents.
  • Starch potato, wheat and corn starch
  • lactose glucose, mannitol, calcium carbonate, calcium phosphate, cellulose, talc or other products known in the art for this purpose are suitable as such.
  • the proportion of pharmaceutical auxiliaries and carriers can vary within wide limits depending on the active ingredient content of the tablet and is in each case 0.1-20% by weight.
  • the proportion of the fillers is about 3-10%, preferably 5-7% by weight, based on the total weight of the tablet.
  • Particularly suitable fillers are corn starch, talc and / or lactose.
  • the proportion of talc is preferably approximately 3.5-5%, the proportion of corn starch approximately 2-5%, in particular approximately 2.5% by weight.
  • the tablet can contain common lubricants. As such, preference is given to silicon dioxide, talc and / or stearic acid or their salts, in particular their magnesium or calcium salts.
  • the total content of lubricants is up to 6% by weight based on the total weight of the tablet.
  • One or more lubricants can be used in the same or different amounts.
  • the content is preferably up to 3% by weight, in particular 0.1-2% by weight.
  • Magnesium stearate and / or talc is preferably used in the range of 0.2-2% by weight.
  • the tablet can also be added with tablet disintegrants, which disintegrate the tablet more quickly when it comes into contact with the stomach. effect liquid.
  • tablet disintegrants are, for example, sodium carboxyethyl starch, crosscar ellose, crospovidone and other similar agents, which can be present in amounts of up to 10% by weight, preferably up to 3% by weight, based on the total weight of the tablet.
  • the tablet core which serves as a reference variable for calculating the weight ratios mentioned above, can be provided with a coating.
  • the coating can serve on the one hand to avoid the unpleasant taste of the tablet as such. In this case, flavors are added during the production of the tablet coating.
  • the coating can also delay the release of the active ingredient.
  • substances are used which, in the form of an applied diffusion film, contribute to a delayed release of the active substance.
  • a tablet according to the invention with an active substance content of approximately 420-460 mg of clodronic acid has a bioavailability of the active substance that corresponds to that of two conventional capsules, each with approximately 340 mg of clodronic acid.
  • the total weight of this tablet according to the invention which therefore contains twice the usual dose, is between 750-850 mg, preferably 790-810 mg, when using the tetrahydrate of sodium clodronate.
  • the lower total weight of the active ingredient results in a lower total weight of the tablet.
  • tablets with an active ingredient content of 500-530 mg and a maximum total weight (based on sodium clodronate tetrahydrate) of 870-970, preferably 900-950 mg can be produced according to the recipe according to the invention.
  • tablets according to the invention can be made available with single and double doses, which are smaller and thus can be administered orally better than would be the case according to the formulations known to date.
  • active ingredient content of clodronic acid corresponding to about 500 mg disodium clodronate tetrahydrate or 400 mg anhydrous disodium clodronate
  • only about 220 mg active ingredient are required according to the formulation according to the invention, whereby the total weight of the tablet is generally between 395 - 410 mg.
  • the tablet according to the invention also shows good dissolution behavior.
  • the dissolution rate of the 440 mg dosage according to the invention (determined according to the USP paddle method) is already at least 60% after 15 minutes and at least 75% after 30 minutes.
  • the invention also relates to pharmaceutical packs containing 30-400 tablets according to the invention for administration in a daily dose of one to three, preferably two tablets (active ingredient content 420-460 or 500-530 mg) or four to eight, preferably four, tablets ( Active ingredient content 200 - 270 mg).
  • the invention furthermore relates to the use of the active substance dichloromethylene diphosphonic acid or a physiologically tolerable salt thereof together with microcrystalline cellulose as a pharmaceutical auxiliary for the production of a tablet with improved bioavailability, preferably a tablet of conventional size with twice the effectiveness compared to a conventional capsule.
  • the tablets according to the invention are produced in a customary manner in that the tablet mass is brought into a suitable granular form by granulation (dry, wet or spray granulation) before compression.
  • the desired amount of the active ingredient for the dosage form to be produced is dry-mixed with about 4 to 8% by weight of the fillers and granulated with a conventional binder, for example corn starch, or even only with water.
  • the granules obtained in this way are then mixed and mixed in a commercial mixing apparatus with 5-15% by weight of microcrystalline cellulose, up to 6% by weight of lubricant and up to 3% by weight of disintegrant. After the mixing process, the granules are tabletted or, if necessary, previously sprayed with an aroma solution and stored for penetration. The finished tablet can also be covered with a film to improve the taste.
  • the feed materials from items 1-3 are granulated.
  • the additives from items 4-6 are then mixed into the granulate.
  • the mass produced in this way is then compressed into tablets on suitable machines.
  • the yield of optically perfect tablets is 177,215 (88.6%).
  • the granules and the tablet mass are produced analogously to example la).
  • the following table shows the composition of the tablet core:
  • the tablets are particularly suitable for the application of 2 tablets per day and thus replace 4 conventional Ostac capsules.
  • the preparation is carried out analogously to Example 1 for a batch size of 200,000 tablets with an active substance content of clodronic acid of 509 mg (corresponding to 600 mg sodium clodronate, anhydrous; or 750 mg sodium clodronate tetrahydrate) per tablet.
  • composition per tablet core The following table shows the composition per tablet core:
  • the tablets are particularly suitable for the application of 2 tablets per day and thus replace 4 conventional Ostac capsules.
  • the preparation is carried out analogously to Example 1 for a batch large of 100,000 tablets with an active ingredient content of clodronic acid of 678 mg (corresponding to 800 mg sodium clodronate, anhydrous; or 1000 mg sodium clodronate tetrahydrate) per tablet.
  • composition per tablet core The following table shows the composition per tablet core:
  • the preparation is carried out analogously to Example 1 for a batch size of 300,000 tablets with an active ingredient content of clodronic acid of 220 mg (corresponding to 260 mg sodium clodronate, anhydrous; or 325 mg sodium clodronate tetrahydrate) per tablet.
  • composition per tablet core The following table shows the composition per tablet core:
  • Tablet weight / mg 396.5 The tablets are particularly suitable for the administration of 4 tablets per day, in severe cases 8 tablets per day. They replace the conventional Ostac (R) capsules, the total weight of which is 550 mg when using sodium chlorodronate tetrahydrate.
  • the preparation is carried out analogously to Example 1 for a batch size of 300,000 tablets with an active ingredient content of clodronic acid of 254 mg (corresponding to 300 mg sodium clodronate, anhydrous; or 375 mg sodium clodronate tetrahydrate) per tablet.
  • the tablets are particularly suitable for the administration of 4 tablets per day, in severe cases 8 tablets per day. They replace the conventional Ostac (R) capsules, the total weight of which is 550 mg when using sodium chlorodronate tetrahydrate.
  • the same patient group received one tablet with an active substance content of 440 mg clodronic acid.
  • the course of the mean serum concentration of clodronic acid is largely identical, ie bioequivalent to the administration of two Ostac (R) capsules.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des comprimés à biodisponibilité renforcée qui contiennent comme principe actif de l'acide diphosphonique de dichlorométhylène ou un de ses sels physiologiquement tolérables, ainsi que de la cellulose microcristalline comme adjuvant pharmaceutique. L'invention concerne par ailleurs des emballages de médicaments renfermant lesdits comprimés, l'utilisation du principe actif acide diphosphonique de dichlorométhylène conjointement avec de la cellulose microcristalline pour préparer un comprimé à biodisponibilité renforcée, ainsi que le procédé de préparation dudit comprimé.
EP93917636A 1993-05-15 1993-07-24 Comprime a biodisponibilite renforcee contenant comme principe actif de l'acide diphosphonique de dichloromethylene Withdrawn EP0697890A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE9307393U 1993-05-15
DE9307393U DE9307393U1 (de) 1993-05-15 1993-05-15 Tablette mit verbesserter Bioverfügbarkeit, enthaltend Dichlormethylendiphosphonsäure als Wirkstoff
DE4322057 1993-07-02
DE19934322057 DE4322057A1 (de) 1993-07-02 1993-07-02 Tablette mit verbesserter Bioverfügbarkeit enthaltend Dichlormethylendiphosphonsäure als Wirkstoff
PCT/EP1993/001967 WO1994026310A1 (fr) 1993-05-15 1993-07-24 Comprime a biodisponibilite renforcee contenant comme principe actif de l'acide diphosphonique de dichloromethylene

Publications (1)

Publication Number Publication Date
EP0697890A1 true EP0697890A1 (fr) 1996-02-28

Family

ID=25927331

Family Applications (2)

Application Number Title Priority Date Filing Date
EP93111827A Expired - Lifetime EP0625355B2 (fr) 1993-05-15 1993-07-24 Comprimé à biodisponibilité améliorée contenant l'acide dichlorométhylène-diphosphonique en tant qu'ingrédient actif
EP93917636A Withdrawn EP0697890A1 (fr) 1993-05-15 1993-07-24 Comprime a biodisponibilite renforcee contenant comme principe actif de l'acide diphosphonique de dichloromethylene

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP93111827A Expired - Lifetime EP0625355B2 (fr) 1993-05-15 1993-07-24 Comprimé à biodisponibilité améliorée contenant l'acide dichlorométhylène-diphosphonique en tant qu'ingrédient actif

Country Status (25)

Country Link
US (1) US5650168A (fr)
EP (2) EP0625355B2 (fr)
JP (1) JP3699110B2 (fr)
KR (1) KR100263284B1 (fr)
CN (1) CN1041797C (fr)
AT (2) ATE128363T1 (fr)
AU (1) AU687744B2 (fr)
BR (1) BR9307859A (fr)
CA (1) CA2162470C (fr)
CZ (1) CZ287984B6 (fr)
DE (1) DE59300688D1 (fr)
DK (1) DK0625355T5 (fr)
ES (1) ES2065313T5 (fr)
FI (1) FI111519B (fr)
GR (2) GR940300095T1 (fr)
HU (1) HU220872B1 (fr)
IL (1) IL106743A (fr)
NO (1) NO307548B1 (fr)
NZ (1) NZ254765A (fr)
PL (1) PL173026B1 (fr)
RU (1) RU2134103C1 (fr)
SK (1) SK281193B6 (fr)
TW (1) TW350772B (fr)
UA (1) UA39884C2 (fr)
WO (1) WO1994026310A1 (fr)

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US10226428B2 (en) 2003-09-19 2019-03-12 Sun Pharma Advanced Research Company Ltd. Oral drug delivery system
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CN100370972C (zh) * 2006-01-10 2008-02-27 北京申科联华科技有限公司 一种具有益气养阴、活血复脉功效的片剂及制备方法
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Also Published As

Publication number Publication date
PL173026B1 (pl) 1998-01-30
FI945313A0 (fi) 1994-11-11
AT128U1 (de) 1995-03-27
CA2162470C (fr) 1998-06-16
ATE128363T1 (de) 1995-10-15
BR9307859A (pt) 1996-01-09
EP0625355B2 (fr) 2003-06-25
NO944405L (no) 1994-11-24
NZ254765A (en) 1997-02-24
DK0625355T4 (da) 2003-10-06
HUT70214A (en) 1995-09-28
TW350772B (en) 1999-01-21
IL106743A0 (en) 1993-12-08
FI945313A (fi) 1994-12-13
ES2065313T1 (es) 1995-02-16
US5650168A (en) 1997-07-22
AU4702093A (en) 1994-12-12
JPH08509697A (ja) 1996-10-15
NO944405D0 (no) 1994-11-17
KR960702322A (ko) 1996-04-27
PL307133A1 (en) 1995-05-02
WO1994026310A1 (fr) 1994-11-24
ES2065313T5 (es) 2004-01-01
HU220872B1 (en) 2002-06-29
SK281193B6 (sk) 2001-01-18
CZ10095A3 (en) 1995-10-18
HU9403160D0 (en) 1995-02-28
DE59300688D1 (de) 1995-11-02
GR3017547T3 (en) 1995-12-31
NO307548B1 (no) 2000-04-25
SK4895A3 (en) 1997-01-08
UA39884C2 (uk) 2001-07-16
FI111519B (fi) 2003-08-15
CA2162470A1 (fr) 1994-11-24
KR100263284B1 (ko) 2000-08-01
ES2065313T3 (es) 1995-12-01
GR940300095T1 (en) 1995-01-31
DK0625355T3 (da) 1995-12-27
JP3699110B2 (ja) 2005-09-28
CN1095267A (zh) 1994-11-23
AU687744B2 (en) 1998-03-05
RU2134103C1 (ru) 1999-08-10
EP0625355B1 (fr) 1995-09-27
DK0625355T5 (da) 2003-12-01
CZ287984B6 (cs) 2001-03-14
EP0625355A1 (fr) 1994-11-23
CN1041797C (zh) 1999-01-27
IL106743A (en) 1999-11-30

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