WO1993000093A1 - Extended-release form of diltiazem - Google Patents
Extended-release form of diltiazem Download PDFInfo
- Publication number
- WO1993000093A1 WO1993000093A1 PCT/CA1992/000290 CA9200290W WO9300093A1 WO 1993000093 A1 WO1993000093 A1 WO 1993000093A1 CA 9200290 W CA9200290 W CA 9200290W WO 9300093 A1 WO9300093 A1 WO 9300093A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diltiazem
- beads
- extended
- ester
- microporous membrane
- Prior art date
Links
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
-
- 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
Definitions
- the present invention relates to an extended 5 release form of Diltiazem, a process for the manufacture • * thereof and pharmaceutical compositions containing the same.
- Diltiazem hydrochloride is used in medicine principally for its calcium channel blocking properties
- Diltiazem must be administered every 6 to 8 hours, as it has a very short half-life in blood of only about 3 to 4 hours.
- the solvent of the polymer solution used to make the membrane is constituted by organic solvents, such as isopropanol, methanol, acetone, and methylene chloride, which are dangerous to use due to their flammability and/or toxicity.
- organic solvents such as isopropanol, methanol, acetone, and methylene chloride, which are dangerous to use due to their flammability and/or toxicity.
- solvents are also environmentally hazardous. Particular care must be taken to avoid any traces of solvent in the final product because these solvents are toxic and are unsuitable in the product which is administered orally.
- an extended-release galenical form of a pharmaceutically acceptable salt of Diltiazem which comprises beads containing the pharmaceutically acceptable salt of Diltiazem as an active ingredient and a wetting agent, said beads being coated with a microporous membrane comprising a water-soluble or water-dispersible polymer or copolymer, and a pharmaceutically acceptable adjuvant.
- an extended-release galenical composition comprises beads comprising: a) an effective amount of said one or more Diltiazem salts as an active ingredient, and b) a wetting agent, wherein said wetting agent comprises a sugar, C 12 -C 20 fatty acid ester of sucrose or xylose, a glyceride of sucrose, a fatty acid ester of polyoxyethylene, an ether of fatty alcohols and polyoxyethylene, an ester of sorbitan, an ester of polyoxyethylene sorbitan, a glyceride-polyglycide, an alcohol-polyglycide ester or lecithins or any combination thereof, wherein said beads are coated with a microporous membrane of an aqueous dispersion of a water-soluble or water-dispersible polymer or copolymer, for example a neutral copolymer of ethyl acrylate and methyl methacrylate, and a pharmaceutical
- a pharmaceutical composition comprising in capsule form an effective amount of one or more pharmaceutically acceptable salts of Diltiazem, and a wetting agent, wherein said wetting agent comprises a sugar, a C 12 -C 20 fatty acid ester of sucrose or xylose, a glyceride of sucrose, a fatty acid ester of polyoxyethylene, an ether of fatty alcohols and polyoxyethylene, an ester of sorbitan, an ester of polyoxyethylene sorbitan, a glyceride-polyglycide, an alcohol-polyglycide ester or lecithins or any combination thereof, wherein said beads are coated with a microporous membrane of an aqueous dispersion of a neutral copolymer of ethyl acrylate and methyl methacrylate, and a pharmaceutically acceptable adjuvant, and one or more other pharmaceutically active ingredients which are pharmaceutically compatible with said one or more Diltiazem
- a method of treating angina pectoris or hypertension or both in a mammal comprises administering to said mammal an effective amount of an extended-release galenical composition of Diltiazem or a pharmaceutically acceptable salt thereof and a wetting agent in the form of beads, wherein the wetting agent comprises a sugar, a C 12 -C 20 fatty acid ester of sucrose or xylose, a glyceride of sucrose, a fatty acid ester of polyoxyethylene, an ether of fatty alcohols and polyoxyethylene, an ester of sorbitan, an ester of polyoxyethylene sorbitan, a glyceride-polyglycide, an alcohol-polyglycide ester or lecithins or any combination thereof, wherein the beads are coated with a microporous membrane of for example an aqueous dispersion of a neutral copolymer of ethyl acrylate and methyl methacrylate
- the extended-release galenical formulation is adapted to release Diltiazem in 900 ml of water when USP xx ⁇ f apparatus no. 2 is used at 100 rpm, at a rate in the order of: between about 5% and about 20% after 2 hours, for example 9% after two hours (in one embodiment with 5% after 1 hour) ; between about 20% and about 50% after four hours, for example 33-34% after four hours; between about 30% and about 70% after six hours, for example 54% after 6 hours; and between about 50% and about 90% after 8 hours, for example, between about 62% and about 82% after 8 hours.
- an extended-release galenical composition comprising beads containing: a) an effective amount of said one or more Diltiazem salts as an active ingredient, and b) a wetting agent, wherein the wetting agent comprises a sugar, a C 12 -C 20 fatty acid ester of sucrose or xylose, a glyceride of sucrose, a fatty acid ester of polyoxyethylene, an ether of fatty alcohols and polyoxyethylene, an ester of sorbitan, an ester of polyoxyethylene sorbitan, a glyceride-polyglycide, alcohol- polyglycide ester or lecithins or any combination thereof, wherein said beads are coated with a microporous membrane of for example an aqueous dispersion of a neutral copolymer of ethyl acrylate and methyl methacrylate, and a pharmaceutically acceptable adjuvant, wherein the membrane is adapted to release D
- Figure 1 illustrates the effect of the present invention in gradually releasing Diltiazem in a relatively uniform manner over a period of about one day after the 8th once daily administration in comparison with the effect of a conventional product after the 8th day of administration twice daily.
- Figure 2 illustrates in the solid curve, the mean plasma levels obtained when the product of the present invention is taken without food.
- the dotted curve represents mean plasma levels obtained when the product is taken with food.
- the present invention relates to novel galenic forms of Diltiazem being characterized by having an extended-release of the active substance. These galenic forms afford excellent bioavailability while avoiding plasmatic concentration peaks, so that it is now possible to maintain diltiazem plasmatic concentration in a desired, effective range while simplifying the administration of the medicine to only once daily.
- the Diltiazem extended-release galenic forms are substantially characterized by the fact that they are constituted by beads containing a pharmaceutically acceptable salt of Diltiazem as an active substance, associated with at least a wetting agent, the beads being covered with a microporous membrane constituted by at least a water-soluble or water-dispersible polymer or copolymer such as a copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, and a pharmacologically acceptable adjuvant.
- any pharmaceutically acceptable salt of Diltiazem may be prepared in extended release form.
- such salts may include the hydrochloride, sulfate or phosphate salts.
- they may also include the acetate, citrate or lactate salts, for example. It is preferred, however, that the hydrochloride salt be used.
- the microporous membrane whereof the Diltiazem-containing microgranules are covered, is constituted by a mixture of a water-soluble and/or water- dispersible copolymer, including at least one adjuvant which may be the active substance.
- a water-soluble and/or water- dispersible copolymer including at least one adjuvant which may be the active substance.
- the Diltiazem extended release galenic forms are substantially characterized by the fact that they are constituted by beads containing a pharmaceutically acceptable salt of Diltiazem as an active substance, associated with at least a wetting agent, the beads being covered with a microporous membrane constituted by at least a water-soluble or water-dispersible polymer or copolymer such as a copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, and a pharmacologically acceptable adjuvant.
- any pharmaceutically acceptable salt of Diltiazem may be prepared in extended release form.
- such salts may include the hydrochloride, sulfate or phosphate salts.
- they may also include the acetate, citrate or lactate salts, for example. It is preferred, however, that the hydrochloride salt be used.
- the microporous membrane whereof the Diltiazem-containing microgranules are covered, is constituted, by a mixture of a water-soluble and/or water- dispersible copolymer, including at least one adjuvant which may be plastifying agents, pigments, fillers, wetting agent lubricants and antifoam agents.
- a water-soluble and/or water- dispersible copolymer including at least one adjuvant which may be plastifying agents, pigments, fillers, wetting agent lubricants and antifoam agents.
- the active substance-containing beads are presented in form of spherules the diameter of which is between about 0.05 mm and 3 mm, preferably between about 0.1 mm and 2 mm.
- wetting agents associated with the Diltiazem or salt thereof in the beads the following compounds may more particularly be exemplified: sugars, for example saccharose, mannitol, sorbitol and lactose; lecithins;
- C 12 to c 2 o fatty acid esters of saccharose commercialized under the name of sucroesters (Gattefosse, France) or under the name of crodesters (Croda, U .K. ) ; xylose esters or xylites; polyoxyethylenic glycerides; esters of fatty acids and polyoxyethylene (Brijs, Renex and Eumulgines, Henkel, RFA) ; sorbitan fatty acid esters (Span, Atlas, U.S.A.); polyglycides-glycerides and polyglycides-alcohols esters (Gelucires, Gattefosse, France) .
- the beads may contain excipients or carriers, such as:
- Microcrystalline celluloses such as Avicel products (FMC, U.S.A. ) ; methylcelluloses, carboxymethylcelluloses, hydroxyethylcelluloses (Natrosol, Hercules, U.S.A.), hydroxypropyl celluloses (Klucels, Hercules, U.S.A.); and starches.
- water-soluble and/or dispersible film- forming polymers or copolymers constituting the microporous membrane may be mentioned particularly polyacrylates and polymethacrylates of the Eudragit type, such as Eudragit E30D, L30D, RS - 30 D of Rohm Pharm (RFA), ethylcelluloses, such as Ethocels of DOW, U.S.A. and such as AquaCoat of FMC, U.S.A., Hydroxypropyl cellulose and hydroxypropyl- methylcellulose and their derivations.
- Eudragit type such as Eudragit E30D, L30D, RS - 30 D of Rohm Pharm (RFA)
- ethylcelluloses such as Ethocels of DOW, U.S.A. and such as AquaCoat of FMC, U.S.A., Hydroxypropyl cellulose and hydroxypropyl- methylcellulose and their derivations.
- polymers or copolymers may be associated into the microporous membrane with at least one adjuvant as exemplified by the following: plastifying agents, such as triacetin, dibutylphthalate, dibutylsebacate, citric acid esters, polyethyleneglycols, polypropyleneglycols and polyvinylpyrrolidone; pigments, such as iron oxides and titanium oxide; fillers, such as lactose and sucrose; wetting agents, such as surfactive agents of the
- Span and Tween types namely partial esters of fatty acids (lauric, palmitic, stearic and oleic acids) and anhydrides of hexitols derived from sorbitol possibly containing polyoxyethylenic chains, preferably surfactive agents of the Tween type, namely Tween 80, as well as polyethyleneglycols; lubricants, such as magnesium stearate and talc; antifoaming agents, such as silicone oil.
- partial esters of fatty acids lauric, palmitic, stearic and oleic acids
- anhydrides of hexitols derived from sorbitol possibly containing polyoxyethylenic chains preferably surfactive agents of the Tween type, namely Tween 80, as well as polyethyleneglycols
- lubricants such as magnesium stearate and talc
- antifoaming agents such as silicone oil.
- the microporous membrane contains, preferably, talc and/or magnesium stearate as a lubricant, polyvinylpyrrolidone as a plastifying agent, titanium dioxide as a pigment, Tween 80 as an emulsifier, and silicone oil as an antifoaming agent.
- the thickness of the microporous membrane is expressed by the percentage of the coating applied to the uncoated beads.
- the weight of the microporous membranes may be 2 to 35%, preferably, 5 to 22%, of the weight of said microgranules.
- These beads may contain the Diltiazem salt in an amount of 20 to 95% by weight, preferably 30 to 85% by weight.
- the microporous membrane may contain 5 to 95% and, preferably, 30 to 90% of polymers, polymer mixture or copolymers.
- the invention relates also to a medicine containing Diltiazem or salt thereof for extended release, the medicine being constituted by beads containing the Diltiazem or salt, such as the hydrochloride, and at least a wetting agent, coated with at least one polymer-based microporous membrane, the coated beads being contained in capsules, little bags or dosage dispensers.
- the medicine being constituted by beads containing the Diltiazem or salt, such as the hydrochloride, and at least a wetting agent, coated with at least one polymer-based microporous membrane, the coated beads being contained in capsules, little bags or dosage dispensers.
- the present invention relates also to a process for obtaining novel forms of a Diltiazem or salt thereof having extended-release in the gastro-intestinal tractus, said process entailing preparing beads and coating the same with a single microporous membrane.
- the beads of the Diltiazem or salt thereof may be prepared using a conventional technique.
- a first technique consists in mixing the Diltiazem or salt thereof with the wetting agent(s) in a melted or finely divided form, or in solution, in the presence of a solvent, such as water, so as to obtain an extrudable paste or plastic mass. Said paste is thereafter extruded in an extruder and then rendered spherical.
- extruder types are usable, for example the extruder for ALEXANDER WERK (RFA) or the apparatus called X-truder of FUJI-PAUDAL (Japan) .
- RFA ALEXANDER WERK
- X-truder of FUJI-PAUDAL Japan
- an apparatus called "spheronizer” CALEVA Great-Britain
- MARUMERIZER FUJIU-PAUDAL Japan
- Another conventional technique for obtaining beads consists in spraying and/or dusting cores obtained through agglomeration of the Diltiazem or salt thereof, such as the chlorohydrate, contingently mixed to at least a wetting agent, with a dispersion or solution of at least one wetting agent, for example in a known pilling turbine or in a granulating apparatus, such as the CF granulator system of FREUND INDUSTRIAL CO. (Japan), or in a known planetary granulator such as the collette (Belgium) type.
- the obtained beads are dried by any means, for example in an oven or by means of a gas in a fluidized bed.
- said beads are calibrated to the necessary diameter by passage through appropriate screens.
- a pasty or plastic mixture appropriate to be granulated by means of any one of the above described techniques, may contain the following weight proportions of the Diltiazem or salt thereof, wetting agents and carriers or excipients:
- Said microporous membrane may be applied onto said beads by pulverizing an aqueous solution or dispersion of at least one of the above-named polymers and at least one of the above-mentioned adjuvants onto said beads .
- This pulverization may be carried out by spray-gunning or by pulverizing the above-named dispersion into a turbine or fluidized bed .
- the present extended release form composition of Diltiazem salt is administered orally .
- the dosage amount is subject to the response of the individual patient ; however, in general, from about 120 mg to about 480 mg per day of Diltiazem salt is administered per day per patient in total .
- the extended re lease f orm composition of the present invention may include other pharmaceutically active ingredients than the Diltiazem salt , provided that the other active ingredient is not pharmaceutically incompatible with the Diltiazem salt .
- ⁇ -adrenoceptor blocking agents or diuretics may be used in the present compositions .
- drugs such as Propranolol , Atenolol, Labetalol, Prindolol or
- Sotalol may be used, for example .
- diuretic agents drugs such as
- Chlorothiazide may be used, for example .
- additional associated drugs may be present in extended-release form also, if desired; however, they need not be .
- said microporous membrane may be obtained, starting from an aqueous dispersion which contains by weight :
- silicone oil 0 .01 to 2% silicone oil (antifoaming agent) ; 0.05 to 5% polysorbate 80 (wetting agent) 10 to 70% water (carrier)
- Example 1 beads manufacture
- Microcrystalline cellulose (Avicel pH 101) 140 g
- the obtained plastic mass is extruded through a cylinder with 1 mm diameter holes
- the ingredients are introduced in a planetary mixer and dry mixed for approximately 15 minutes . Thereafter, 100 ml water USP is added and the mixing is pursued for 10 minutes more until a plastic mass is obtained. This mass is then extruded through a Fuji Paudal extruder equipped with a 1 mm screen so as to obtain "spaghetties". A spheronizer type caleva is used so as to transform the extruded product into beads. After drying for 12 hours on trays in an oven at 60°C, the beads are sieved so as to eliminate the ones with a size larger than 1.4 mm and with a size smaller that 0.7 mm.
- the amount of beads obtained with size comprised between 0.7 mm and 1.4 mm was 639.1 g (yield 91.3%).
- Example 1 Beads prepared in Example 1 were coated in a STREA-1 (Aeromatic) fluidized bed using the "Top spraying" technique. 440 g of coating suspension of the following composition was applied on 500 g of beads. Thereafter, the coated beads were dried at 50°C during 16 hours. Coating suspension composition:
- Titanium dioxide 5.0 g
- the 900 ml dissolution medium consisted of a phosphate butter of 5.8 pH and a revolution speed of 100 rpm.
- the beads as in Example 2, were coated using a fluidized bed coater equipped with "wurster" system. 8 kg of uncoated beads were introduced in an Aeromatic Aerocoater and 2.77 kg of the following coating suspension was applied at a rate of 30 - 35 g per minute. Thereafter, the coated beads were dried for 15 hours at 45°C.
- Example 4 Pharmacokinetical results The new galenic form of Example 4 was the object of a pharmacokinetical study in comparison with a form in accordance to the prior art as described in U.S. Patent 4,721,619 (Cardizen SR ® ) . Therefore, 6 healthy subjects received successively in a random order 300 mg of each of the 2 products.
- the product of Example 4 was administered at a dose of 300 mg once daily, while the product on the market was administered twice daily at a dose of 150 mg (300 mg daily total dose) for 7 days. On each of the eight days, 11 samples of blood were withdrawn when the product of Example 4 was administered and 15 blood samples were withdrawn after the Cardizen SR ® administration.
- Fig. 1 shows that the Diltiazem plasma levels obtained after a once daily administration of one of the products of the present invention are comparable to the ones obtained after a twice daily administration of the product of the previous art.
- the bioavailability expressed by the areas under the curve of the 2 products is equivalent (no statistical detectable difference) .
- the maximal concentration and the fluctuations obtained after a once daily administration of the product of the present invention is lower than the one obtained with Cardizen SR after a twice daily administration.
- Example 4 The product of Example 4 was given to 24 healthy volunteers and the bioavailability was measured after a single oral dose of 300 mg given with and without food.
- Example 4 The product of Example 4 given with food is bioequivalent to the administration without food to within less than 20%, regarding the area under the curve, mean residence time and maximum concentration. The larger interval obtained for K a was due to the higher variability of this parameter, the difference between the treatment means remaining small (6.%) .
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69229949T DE69229949T2 (en) | 1991-06-26 | 1992-06-25 | MEDICINAL PRODUCTS CONTAINING DILTIAZEM WITH DELAYED DELIVERY OF ACTIVE SUBSTANCES |
EP92914768A EP0591424B1 (en) | 1991-06-26 | 1992-06-25 | Extended-release form of diltiazem |
DK92914768T DK0591424T3 (en) | 1991-06-26 | 1992-06-25 | Diltiazem-containing extended-release drug |
CA002111085A CA2111085C (en) | 1991-06-26 | 1992-06-25 | Extended-release form of diltiazem |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US721,396 | 1991-06-26 | ||
US07/721,396 US5288505A (en) | 1991-06-26 | 1991-06-26 | Extended release form of diltiazem |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993000093A1 true WO1993000093A1 (en) | 1993-01-07 |
Family
ID=24897820
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CA1992/000290 WO1993000093A1 (en) | 1991-06-26 | 1992-06-25 | Extended-release form of diltiazem |
Country Status (8)
Country | Link |
---|---|
US (2) | US5288505A (en) |
EP (1) | EP0591424B1 (en) |
AT (1) | ATE184196T1 (en) |
AU (1) | AU2243092A (en) |
CA (1) | CA2111085C (en) |
DE (1) | DE69229949T2 (en) |
DK (1) | DK0591424T3 (en) |
WO (1) | WO1993000093A1 (en) |
Cited By (8)
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WO1994023700A1 (en) * | 1993-04-22 | 1994-10-27 | Rijksuniversiteit Gent Laboratorium Voor Farmaceutische Technologie | High release solid preparation, preparation and use thereof |
AT403988B (en) * | 1994-05-18 | 1998-07-27 | Lannacher Heilmittel | SOLID ORAL RETARDED PREPARATION |
WO2000071095A2 (en) * | 1999-05-19 | 2000-11-30 | Cenes Drug Delivery Limited | Release of poorly soluble agents |
DE19928312A1 (en) * | 1999-06-16 | 2000-12-21 | Schering Ag | Drug preparation with delayed drug delivery |
US6214385B1 (en) | 1995-01-05 | 2001-04-10 | Grant W. Heinicke | Controlled absorption diltiazem pharmaceutical formulation |
WO2001041744A1 (en) * | 1999-12-10 | 2001-06-14 | Biovail Laboratories Incorporated | Chronotherapeutic diltiazem formulations and the administration thereof |
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US7108866B1 (en) * | 1999-12-10 | 2006-09-19 | Biovall Laboratories International Srl | Chronotherapeutic diltiazem formulations and the administration thereof |
WO2001064829A1 (en) * | 2000-03-01 | 2001-09-07 | The Procter & Gamble Company | Solid bodies |
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EP2556826A1 (en) | 2011-08-08 | 2013-02-13 | Valpharma S.p.A. | Modified-release multiparticulate formulation of diltiazem HCL |
Also Published As
Publication number | Publication date |
---|---|
DK0591424T3 (en) | 1999-12-20 |
ATE184196T1 (en) | 1999-09-15 |
EP0591424A1 (en) | 1994-04-13 |
EP0591424B1 (en) | 1999-09-08 |
CA2111085A1 (en) | 1993-01-07 |
AU2243092A (en) | 1993-01-25 |
US5529791A (en) | 1996-06-25 |
DE69229949T2 (en) | 2000-03-09 |
US5288505A (en) | 1994-02-22 |
CA2111085C (en) | 1999-04-27 |
DE69229949D1 (en) | 1999-10-14 |
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