EP0456113A2 - Emballage de verre interne enduite de silicone contenant un produit lyophilisé - Google Patents
Emballage de verre interne enduite de silicone contenant un produit lyophilisé Download PDFInfo
- Publication number
- EP0456113A2 EP0456113A2 EP19910107100 EP91107100A EP0456113A2 EP 0456113 A2 EP0456113 A2 EP 0456113A2 EP 19910107100 EP19910107100 EP 19910107100 EP 91107100 A EP91107100 A EP 91107100A EP 0456113 A2 EP0456113 A2 EP 0456113A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- freeze
- silicone
- product
- dried solid
- glass
- 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
- 239000011521 glass Substances 0.000 title claims abstract description 27
- 229920001296 polysiloxane Polymers 0.000 title claims abstract description 6
- 239000012265 solid product Substances 0.000 title abstract 4
- 238000011065 in-situ storage Methods 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 238000009516 primary packaging Methods 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000012602 primary packaging material Substances 0.000 claims description 3
- 239000004447 silicone coating Substances 0.000 claims 2
- 238000009826 distribution Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract 1
- 238000004108 freeze drying Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 3
- 229960000711 alprostadil Drugs 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000012792 lyophilization process Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000011179 visual inspection Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- -1 polydimethylsiloxane Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229920006268 silicone film Polymers 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 238000005475 siliconizing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
- A61J1/06—Ampoules or carpules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D23/00—Details of bottles or jars not otherwise provided for
- B65D23/02—Linings or internal coatings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]
- Y10T428/131—Glass, ceramic, or sintered, fused, fired, or calcined metal oxide or metal carbide containing [e.g., porcelain, brick, cement, etc.]
- Y10T428/1317—Multilayer [continuous layer]
- Y10T428/1321—Polymer or resin containing [i.e., natural or synthetic]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
- Y10T428/31551—Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]
- Y10T428/31609—Particulate metal or metal compound-containing
- Y10T428/31612—As silicone, silane or siloxane
Definitions
- the invention relates to surface-coated glasses in primary packaging of lyophilisates and their use in the production of lyophilisates.
- Drugs sensitive to moisture that are to be used parenterally by infusion or injection must be stabilized for storage.
- a common method is to dry the drug solution using lyophilization.
- aqueous solutions of the medicinal substances are filled into glass ampoules, vials or vial bottles, frozen and freeze-dried under reduced pressure. Once the drying process has ended, glass ampoules are sealed outside the freeze dryer; vials and sting-cap bottles can be sealed in the freeze dryer with the freeze-dry stoppers already in place.
- composition and concentration of the active ingredient solution containing excipients influence the pharmaceutical quality.
- the temperature and pressure curve as well as the time of freeze drying, the layer thickness of the solution to be freeze-dried, the container geometry with regard to the contact surface with the coolable and heatable shelf, and the moisture in the product closure influence the pharmaceutical quality.
- the reliable exact volume metering of the materials to be dried are just as crucial for production-based production Solution into the container without solution reaching the ampoule neck or the vial rim, as well as avoiding all circumstances which can lead to product residues in the spit or shoulder of the ampoules or between the contact and sealing surface between the vial and stopper.
- the latter contributes decisively to ensuring the removability of the declared dose as well as risks to product stability that occur in the event of product buildup on the sealing surface of the vial rim with the help of ensuring the content homogeneity in the individual ampoules or vials of a batch and the content conformity from batch to batch Avoid plug caused by insufficient sealing.
- the product residues in the neck of ampoules can be seen in the visual inspection of the bulk goods (these are the already closed product containers) and must be sorted out.
- the lack of consistency and shape of the product cake leads to a loss of production or yield in the case of ampoules, which increases the cost of production depending on the raw material and manufacturing costs.
- the product adhesion between the sealing surface of vials with their plugs is not easily recognizable in the visual inspection of the bulk goods; after the protective caps have been applied, it is completely hidden. This leakage leads to the uncontrolled penetration of air humidity into the vials during storage and thus harbors the risk of hydrolytic decomposition of the active substances.
- the object of the present invention is to avoid the disadvantages described above.
- This object has been achieved in that surface-coated glasses are used in the production of lyophilisates and in primary packaging for lyophilisates by means of siliconization.
- siliconized glass surfaces are used under the designation "glass grade II” (Hartke, Mutschler, editor, DAB 9 commentary, volume I, page 353, Scientific publishing company mbH Stuttgart, Govi Verlag GmbH, Frankfurt 1987).
- siliconization is used in injection bottles and ampoules in order to "facilitate the drainage of liquid residues when emptying, which is particularly important in the case of expensive filling goods such as antibiotics" (H.Sucker, P.Fuchs, P.Speiser, ed Pharmaceutical Technology page 762, Georg Thieme Verlag Stuttgart 1978); U.S. P 2,504,482; GB patent 702,292.
- Siliconization can also be used on syringes to reduce the friction of the plunger or the stopper (in the case of a two-chamber syringe) with the syringe barrel.
- siliconization serves to reduce glass adsorption; Franz et al. U.S.-P 3,717,498.
- a further embodiment of the invention relates to a method for preventing the product rejection of lyophilisates by placing the product to be lyophilized in glass primary packaging material coated on the inside with a silicone layer and lyophilizing to form a compact product template.
- Baysilon H® is an aqueous emulsion made of polydimethylsiloxane from Bayer AG, Leverkusen, Germany.
- the silicone is dried or stoved in a continuous oven, the throughput time being 40 minutes at a temperature of 300 ° C.
- the siliconized ampoules are subjected to a three-time washing process with bi-distilled water at 50 ° C and a subsequent sterilization phase of 3 minutes at 300 ° C without damaging the silicone film.
- a solution with a composition per ampoule of 20 ⁇ g PGE1 as an approximately 3% inclusion complex of ⁇ -cyclodextrin and 50 mg lactose ⁇ H2O in 400 ⁇ l water was prepared for injections.
- This solution was metered in volume in alternatively 5 ml glass ampoules, glass grade I or 5 ml glass ampoules, glass grade I with additional baked-on siliconization, which had been applied with a commercially available aqueous silicone oil emulsion, as described above.
- the glass ampoules containing PGE 1 solution were then subjected to a standard lyophilization process and the same process, but with variations in freeze-drying time, temperature and drying time.
- the ampoules are finally removed from the chamber and sealed by melting the ampoule ends.
Landscapes
- Health & Medical Sciences (AREA)
- Mechanical Engineering (AREA)
- Hematology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Medicinal Preparation (AREA)
- Laminated Bodies (AREA)
- Containers Having Bodies Formed In One Piece (AREA)
- Packging For Living Organisms, Food Or Medicinal Products That Are Sensitive To Environmental Conditiond (AREA)
- Wrappers (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Glass Compositions (AREA)
- Drying Of Solid Materials (AREA)
- Surface Treatment Of Glass (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19904014665 DE4014665C2 (de) | 1990-05-08 | 1990-05-08 | Oberflächenvergütete Gläser in Primärpackmitteln von Lyophilisaten und deren Verwendung bei der Herstellung von Lyophilisaten |
DE4014665 | 1990-05-08 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0456113A2 true EP0456113A2 (fr) | 1991-11-13 |
EP0456113A3 EP0456113A3 (en) | 1992-11-25 |
EP0456113B1 EP0456113B1 (fr) | 1995-07-19 |
Family
ID=6405912
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19910107100 Revoked EP0456113B1 (fr) | 1990-05-08 | 1991-05-02 | Emballage de verre interne enduite de silicone contenant un produit lyophilisé |
Country Status (8)
Country | Link |
---|---|
US (1) | US5335769A (fr) |
EP (1) | EP0456113B1 (fr) |
JP (1) | JP3293840B2 (fr) |
AT (1) | ATE125223T1 (fr) |
DE (2) | DE4014665C2 (fr) |
DK (1) | DK0456113T3 (fr) |
ES (1) | ES2075909T3 (fr) |
GR (1) | GR3017371T3 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0768905A1 (fr) * | 1994-07-06 | 1997-04-23 | Science Incorporated | Ensemble seringue de melange et d'administration |
US8512691B2 (en) | 1996-12-24 | 2013-08-20 | Biogen Idec Ma Inc. | Stable liquid interferon-beta formulations |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5595687A (en) * | 1992-10-30 | 1997-01-21 | Thomas Jefferson University | Emulsion stability |
DE19535669A1 (de) * | 1995-09-26 | 1997-04-03 | 4P Rube Goettingen Gmbh | Behälter |
WO2003061687A1 (fr) * | 2002-01-18 | 2003-07-31 | Asahi Kasei Pharma Corporation | Preparation a concentration elevee de thrombomoduline soluble |
US8372419B2 (en) * | 2004-03-10 | 2013-02-12 | Scil Technology Gmbh | Coated implants, their manufacturing and use thereof |
US7784638B2 (en) * | 2005-02-03 | 2010-08-31 | Wki Holding Company, Inc. | Glassware with silicone support |
US7575127B2 (en) * | 2005-02-03 | 2009-08-18 | Wki Holding Company, Inc. | Glassware with silicone gripping surfaces |
US7943189B2 (en) | 2007-10-26 | 2011-05-17 | Lee Ferrell | Food preservation packaging system |
USD620817S1 (en) | 2009-03-21 | 2010-08-03 | Wki Holding Company, Inc. | Measuring container |
EP2861526A4 (fr) * | 2012-06-18 | 2015-12-16 | Innova Dynamics Inc | Réduction d'agglomération dans une suspension de nanofils stockée dans un conteneur |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2504482A (en) * | 1949-06-17 | 1950-04-18 | Premo Pharmaceutical Lab Inc | Drain-clear container for aqueous-vehicle liquid pharmaceutical preparations |
JPS5497617A (en) * | 1978-01-18 | 1979-08-01 | Takeda Chemical Industries Ltd | Surface treatment of glass formed body |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB702292A (en) * | 1950-09-13 | 1954-01-13 | Pfizer & Co C | Improvements in or relating to liquid containers |
DE1621011A1 (de) * | 1967-04-13 | 1971-04-29 | Telefunken Patent | Verfahren zum Oberflaechenvergueten von Bauteilen |
US3654926A (en) * | 1969-11-17 | 1972-04-11 | Parke Davis & Co | Mixing vial |
GB1488006A (en) * | 1974-02-13 | 1977-10-05 | Ono Pharmaceutical Co | Prostaglandin analogues |
US3954787A (en) * | 1974-06-18 | 1976-05-04 | Pfizer Inc. | Stabilized E-series prostaglandins |
US3952004A (en) * | 1974-06-18 | 1976-04-20 | Pfizer Inc. | Stabilized E-series prostaglandins |
US4289648A (en) * | 1979-03-20 | 1981-09-15 | Ortho Diagnostics, Inc. | Blood gas controls composition, method and apparatus |
US4254456A (en) * | 1980-02-27 | 1981-03-03 | General Electric Company | Luminaire for assembly line |
DE3707213A1 (de) * | 1987-03-06 | 1988-09-15 | Behringwerke Ag | Verfahren zur herstellung von faktor viii:c-mangelplasma und ein so erhaltenes mangelplasma |
-
1990
- 1990-05-08 DE DE19904014665 patent/DE4014665C2/de not_active Expired - Lifetime
-
1991
- 1991-05-01 JP JP9993391A patent/JP3293840B2/ja not_active Expired - Fee Related
- 1991-05-02 AT AT91107100T patent/ATE125223T1/de not_active IP Right Cessation
- 1991-05-02 DE DE59106007T patent/DE59106007D1/de not_active Revoked
- 1991-05-02 EP EP19910107100 patent/EP0456113B1/fr not_active Revoked
- 1991-05-02 ES ES91107100T patent/ES2075909T3/es not_active Expired - Lifetime
- 1991-05-02 DK DK91107100T patent/DK0456113T3/da active
-
1992
- 1992-11-05 US US07/972,076 patent/US5335769A/en not_active Expired - Lifetime
-
1995
- 1995-09-13 GR GR950402488T patent/GR3017371T3/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2504482A (en) * | 1949-06-17 | 1950-04-18 | Premo Pharmaceutical Lab Inc | Drain-clear container for aqueous-vehicle liquid pharmaceutical preparations |
JPS5497617A (en) * | 1978-01-18 | 1979-08-01 | Takeda Chemical Industries Ltd | Surface treatment of glass formed body |
Non-Patent Citations (1)
Title |
---|
WORLD PATENTS INDEX Week 7937, Derwent Publications Ltd., London, GB; AN 79-66884B & JP-A-54 097 617 (TAKEDA CHEMICAL IND KK) 1. August 1979 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0768905A1 (fr) * | 1994-07-06 | 1997-04-23 | Science Incorporated | Ensemble seringue de melange et d'administration |
EP0768905A4 (fr) * | 1994-07-06 | 1998-03-18 | Science Inc | Ensemble seringue de melange et d'administration |
US8512691B2 (en) | 1996-12-24 | 2013-08-20 | Biogen Idec Ma Inc. | Stable liquid interferon-beta formulations |
US8512692B2 (en) | 1996-12-24 | 2013-08-20 | Biogen Idec Ma Inc. | Methods of treating multiple sclerosis with stable liquid interferon-beta formulations |
US8932574B2 (en) | 1996-12-24 | 2015-01-13 | Biogen Idec Ma Inc. | Stable liquid interferon beta formulations |
US9522174B2 (en) | 1996-12-24 | 2016-12-20 | Biogen Ma Inc. | Stable liquid interferon beta formulations |
Also Published As
Publication number | Publication date |
---|---|
GR3017371T3 (en) | 1995-12-31 |
DE4014665C2 (de) | 1994-06-01 |
US5335769A (en) | 1994-08-09 |
DE59106007D1 (de) | 1995-08-24 |
DE4014665A1 (de) | 1991-11-14 |
EP0456113A3 (en) | 1992-11-25 |
JP3293840B2 (ja) | 2002-06-17 |
ATE125223T1 (de) | 1995-08-15 |
ES2075909T3 (es) | 1995-10-16 |
DK0456113T3 (da) | 1995-12-11 |
JPH05261138A (ja) | 1993-10-12 |
EP0456113B1 (fr) | 1995-07-19 |
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