EP0458887A1 - Dispositif de distribution - Google Patents

Dispositif de distribution

Info

Publication number
EP0458887A1
EP0458887A1 EP90903866A EP90903866A EP0458887A1 EP 0458887 A1 EP0458887 A1 EP 0458887A1 EP 90903866 A EP90903866 A EP 90903866A EP 90903866 A EP90903866 A EP 90903866A EP 0458887 A1 EP0458887 A1 EP 0458887A1
Authority
EP
European Patent Office
Prior art keywords
capsule
piece
plug
water
female piece
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.)
Pending
Application number
EP90903866A
Other languages
German (de)
English (en)
Inventor
Marion Eileen Mcneill
Abdul Rashid
Howard Norman Ernest Stevens
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.)
BTG International Ltd
Original Assignee
BTG International Ltd
National Research Development Corp UK
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
Priority claimed from GB898903566A external-priority patent/GB8903566D0/en
Priority claimed from GB898921155A external-priority patent/GB8921155D0/en
Application filed by BTG International Ltd, National Research Development Corp UK filed Critical BTG International Ltd
Publication of EP0458887A1 publication Critical patent/EP0458887A1/fr
Pending legal-status Critical Current

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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • This invention relates to novel devices for the controlled release of an active material especially a pharmaceutically active drug. More particularly this invention relates to devices which are adapted to administer the active material over a relatively short period following a delay after administration - a pulsed release device.
  • this invention provides a controlled release device which comprises a capsule containing active material, said capsule being formed from at least two interpenetrating pieces, the male portion of which is formed from a water swellable material and swells so as to disengage the female piece upon exposure to an aqueous medium.
  • the device comprises a capsule having at least one orifice extending through the wall of the capsule which orifice is closed by a water swellable plug such that upon immersion in an aqueous medium said plug swells and separates from the capsule.
  • the male, piece is of such material and of such dimensions that its swellin-g does result in its ejection from the orifice in the capsule wall that ejection takes place after a reproducible time interval following the exposure of the device to an aqueous medium. Thereafter the contents of the capsule are released into the surrounding medium.
  • the devices are advantageous particularly as oral dosage forms for use in man since they enable the maximum quantity of active material to be incorporated into a capsule of any given size.
  • the male piece may be constructed from any water swellable material which is biologically and medically compatible, non-allergenic, insoluble in and non irritating to body fluids and tissues.
  • the water swellable material is preferably a hydrogel.
  • the choice of the material used to form the water swellable piece in any particular device will vary according to a number of parameters which affect the desired delay following immersion in the aqueous medium before the contents are released.
  • the rate of swelling and the degree of swelling of the material are important parameters 1n determining the delay obtained from a particular device.
  • the material should always be such that when formed into a male piece of appropriate dimensions for use in a particular device it will maintain a substantially water-tight fit between the male and female portions throughout the delay period.
  • the time delay before the plug is ejected from the orifice is inversely proportional to the rate of swelling of the material from which it is constructed.
  • the dimensions of the plug may also be used to vary the delay time.
  • delay is proportional to the length of that part of the male piece which lies within the jaws defining ' the orifice of the female piece, i.e. in the preferred embodiment the length of the plug within the orifice.
  • the position of the plug within the orifice may also be utilised to regulate the delay before the plug is ejected.
  • the outer surface of the plug is recessed so as to lie below the level of the mouth of the orifice the ejection of the plug will be delayed by a time which is a function of the depth of the recess.
  • the devices of this invention comprise a retaining means situated on the interior face of the orifice. The means which may conveniently
  • the delay time after immersion in an aqueous medium until the plug is ejected may be varied by the empirical adjustment of one or more of the above parameters.
  • the delay time may vary over a wide Interval say anything from 0.5 hours to 12 hours according to the application but may extend over much greater intervals e.g. up to 7 or even 14 days or longer 1n applications where such lengthy delays are advantageous.
  • the device will be constructed in such a way that the plug is ejected whilst the inner surface thereof remains dry, i.e. before any significant quantity of water enters the capsule.
  • Such devices will be constructed so as to ensure that the plug maintains a water-tight seal within the orifice and that no significant quantity of water permeates through the plug prior to Its ejection.
  • the walls of the female piece of the capsule may ⁇ be formed from any material which is biologically and medically compatible with, non allergenic and insoluble in and non-irritating to body fluids and tissues.
  • the walls may be formed from a biodegradable material provided that the material retains its structural integrity for at least the length of the delay time.
  • the walls of the female piece of the capsule are preferably constructed so as to be impermeable to the passage of water. Where water permeable materials are employed the device should be preferably constructed so as to avoid the permeation of any significant quantity of water Into the interior of the capsule prior to the ejection of the plug from the orifice.
  • the walls of the female piece are preferably constructed from a material which is not water swellable. Where the walls of the capsules are not of uniform construction, that portion of them which define the jaws of the orifice will preferably be constructed from material which is not water swellable. Where any portion of the female piece and in particular that which defines the jaws of the orifice is constructed from a water swellable material, the preferred materials possess a lower rate and a lower degree of swelling than that used to form the male piece.
  • the device will preferably be designed so as to ensure that the joint between the male and female piece remains water-tight.
  • the walls of the capsule will be constructed so as to ensure that they retain their structural integrity at least until the capsule separates into two pieces.
  • the capsule may be formed in any convenient shape, for example spheroidal, ellipsoidal or cylindrical. Capsules which are generally cylindrical are preferred.
  • a preferred form of the device of the present Invention comprises a hollow cylinder open at one or both ends, having a plug of water swellable material In the open end or ends. Such devices may be readily formed, e.g. from an extruded plastic tube cut into lengths and optionally sealed at one end and closed at the open end or ends by the insertion of a plug or plugs.
  • the capsule may be formed by forming a cylinder around a rod; by coating a solution of polymer or organosol onto a former; by compression or injection moulding of a suitable thermoplastic polymer; by powder compression or by direct reaction moulding.
  • the plug may be inserted so that its top is flush with the end face of the tube or may be inserted to a greater depth so that the walls of the cylinder extend beyond the outer surface of the plug.
  • the length of the plug and the depth of its insertion will be predetermined so as to control the delay prior to the ejection of the plug.
  • the plug is conveniently cylindrical in shape and such shapes may be readily cut from a rod of material.
  • the plug may adopt other geometries such as cone sections.
  • the ratio of the length of these cylindrical plugs to their diameter 1s preferably in the range 0.1:1 to 20:1 and more preferably in the range 0.2:1 to 2:1.
  • the cylindrical devices are conveniently of a size wJiich may be swallowed and hence they find use as oral dosage forms for ⁇ jan in particular, but also in animals.
  • the length of the hollow cylinder will be in the range 5 to 100 mm, preferably 10 to 30 mm and the external diameter will be in the range 1 mm to 20 mm.
  • the devices will have external dimensions corresponding to those of known oral dosage forms, e.g. capsules having sizes in the range triple zero to zero and from 1 to 8.
  • the length of the plug will preferably be from 1 to_r5 np.
  • the plug may preferably be recessed to a depth of not more than 5 mm and preferably not more than 2 mm.
  • the devices of this invention may be significantly smaller so as to facilitate the inclusion of a plurality of devices in a single dosage form, e.g. a capsule. This enables different release patterns to be obtained.
  • the contents of the device may take the form of th ⁇ active material as such, e.g. as a particulate solid or may take the form of any other convenient dosage form.
  • the active material may be combined with a conventional exciptent and be Introduced Into the device as a powder or as a fluid solution or suspension (provided that the fluid medium does not Interact significantly with the materials used to form the wall of the capsule) or take the form of compressed tablets of exciptent and carrier. Either a single tablet or a plurality of such tablets may be introduced.
  • a further alternative is .to Introduce the active material in a modified dosage form, e.g. a coated material such as is described in British Patent 2112730. This, enables the release profile of the device to be modified, e.g.
  • the devices of this invention find wide application in medical, including veterinary, contexts and in horticulture and agriculture as well as outside these areas.
  • Specific classes of drug which may be utilised as the active material in a pulsed release device of this invention include hypnotics, sedatives, tranquilisers, anti-pyretics, anti-inflammatory agents, anti-histamines, anti-tussives, anti-convulsants, anti-asthmatics, muscle relaxants, anti-tumour agents, for example those for the treatment of malignant neoplasia, local anaesthetics, anti-Parkinson agents, topical or der atological agents, diuretics-, for example those containing potassium, such as potassium iodide, preparations for the treatment of mental illness, for example preparations containing lithium for use 1n the treatment of manic depression or containing prostaglandins for the treatment of schizophrenia, anti-spasmodlcs, anti-ulcer agents, ⁇ blockers such as atenolol and
  • the controlled release devices of this Invention arg also useful in the treatment of diabetes and pernicious anaemia where, for example, the controlled release of insulin and cobalamln, respectively, may be utilised.
  • the release devices of this invention are suited to treatment, both prophylactic and therapeutic, of tropical diseases; for example malaria, leprosy, schistosomiasis and clonorchiasls.
  • Examples of drugs which can be used as biologically active substance in release devices of this Invention for the treatment of these and other tropical diseases include quinine, sulphonamldes, rifamycin, clofazimine, thiambutasine, chlorphenyl derivatives, chlorguamide, cycloguanil, pyrimethamine, sulphadiazine, trimethoprim, quinoline derivatives such as pamaqulne, chloroquine, pentaqulne, primaquine and a odiqulne, pararosani ine, sulphamethizole, quinacrine, dapsone, sodium sulphoxone, sulphetrone, sodium hydnocarpate and sodium chaulmoograte. Drugs of particular effectiveness are cycloguanil, pyrimethamine and sulphadiaztne.
  • the release devices of this invention are also very well suited to veterinary applications. Examples include preparations of antibiotics for general antibacterial activity and also in the treatment of anaplasmosis in cattle; preparations for provision of a wide spectrum of activity against both ectoparasites, for example termites and endoparasites including anthropods, " ⁇ frrested larvae stages of nematodes, lungworms and general strongyles: these may comprise avermectins; preparations for provision of activity against tremotode, cestode and roundworm infections: these may comprise amoscanate and praziquantel : preparatlon-s for provision of activity against theileria in cattle: these may comprise biologically active naphthoquinones such as enoctone;- preparations for provision of activity against babesiosis in cattle, horses and dogs: these may comprise berenll, amidocarb and dia pron; preparation for provision of activity against liver fluke in sheep and cattle and against Haemonchus species: these
  • the devices of the present invention may also be combined with another dosage form which will combine the release profile of the novel devices with that of the other dosage form.
  • two separate devices according to this Invention may be joined end to end so that the active materials are separated by a wall.
  • two separate female pieces may be closed by a single male piece or plug.
  • two separate cylindrical pieces may be mounted upon opposite ends of a rod of water swellable material. By controlling the depth of penetration of the rod into each cylindrical piece it is possible to achieve either simultaneous or sequential release of the contents of the cylindrical pieces.
  • a device according to this invention may be joined to or combined with another controlled release device (of appropriate dimensions).
  • a further preferred embodiment of this invention comprises devices coated with an enteric coating so as to pass through the stomach and release the active material 1n the Intestine. Such devices can be designed so as to release the active a set period after they pass out of the stomach. They may be designed to release in the colon.
  • suitable enteric coating agents which may be employed include cellulose acetate phthalate, polyvinyl acetate phthalate, pH sensitive polyacrylate and polymethyacrylate derivatives and hydroxypropylmethyl cellulose phthalate.
  • a further preferred embodiment of this invention comprises those devices wherein the plug comprises an active substance which diffuses into an aqueous medium over a period of time.
  • a particularly preferred embodiment are those devices wherein the plug is formed from a hydrogel comprising an active substance e.g.
  • the devices of this Invention can be designed to provide a variety of release profiles. They are characterised in that they release a sharp pulse of active material either as such and/or in a modified dosage form after a predetermined delay. This feature enables devices which provide pulsed or controlled release profiles or a combination of the two to be designed by combining these characteristic features e.g. with a drug loaded plug a sustained release of active may be obtained during the period of the delay.
  • a device may be prepared which combines these profiles or superimposes them to provide novel devices having improved release profiles.
  • the walls of the female portion of the capsule may be formed from a wide variety of materials. They may be of homogenous construction or they may be laminated. Examples of materials suitable for use in the construction of the walls include polyethylene, polypropylene, poly(methylmethacrylate) , potyvinyl chloride, polystyrene, polyurethanes, polytetrafluoroethylene, nylons, polyformaldehydes, polyesters, cellulose acetate and nitrocellulose.
  • a preferred construction utilises an impermeable coating to cover the exterior of a capsule formed from a water soluble material.
  • the coating may conveniently be formed by dipping a capsule in a solution of any of the above-mentioned materials so as to form a layer which is impermeable to water.
  • the capsule may also be spray coated with solutions of the above materials in which use the exterior has an impermeable coating and the interior may be partially coated.
  • a preferred class of capsules are the conventional hard gelatin or starch capsules coated with a solution of polyvinyl chloride or a polyvinyl acetate copolymer or an ethyl cellulose solution (plasticised as necessary),
  • a further preferred class of capsules are those which are coated with a film of a biodegradable polymer such as certain hy roxy butyric acid copolymers.
  • Such devices are advantageous in that they are simple to construct and insofar as their soluble interiors dissolve in the aqueous medium leaving either a thin flexible coating to be eliminated from the body or a coating which can be degraded in the body.
  • the male piece (that is in the preferred embodiment the plug) used in the devices of this invention may be formed from a wide variety of water swellable materials.
  • the suitability of a material for use in a particular device depends upon its degree of swellability, its rate of swelling when immersed 1n an aqueous medium, the permeability of the material and the relationship of these parameters to the dimensions of the device and the delay which is required before the plug is ejected.
  • the suitability of a particular material may most readily be determined by empirical means.
  • hydrophilic materials from which the plugs may be constructed are hydrogels.
  • suitable synthetic hydrogels which may be employed in the devices of this invention include poly ( hydroxyethyl-methacrylate); poly(N-vinyl- pyrolidone), poly(acrylamide); poly(acrylic acid); poly(v1nyl- alcohol) and poly(methacrylic acid).
  • a particularly preferred class of hydrogels are those crosslinked hydrophilic polymers comprising polyethylene oxide residues, preferably those which contain crystalline regions and have a crystalline melting temperature (Tm) of -10°C to +70°C. Chemical cross!inking may be effected in a manner known jae £.
  • hydrophilic polymer comprises functional groups which comprise an active hydrogen atom
  • chemical crosslinking may be effected by means of a di- or poly-isocyanate [such as bis-(4-isocvanatophenyl)methane or bis-(4-isocyanatocvclohexyl methane] or a di- or poly-linear or cyclic olefinically unsaturated ether (such as acrolein tetramer); for example, as disclosed in our UK Patents 2047093, 2047094 and 2108517, from which it will be apparent that where a diisocyanate or di-olef1nically unsaturated ether 1s used a reactant comprising at least three active hydrogen atoms must also be present to ensure chemical crosslinking.
  • Entanglement crosslinking may be utilised, especially where the hydrophilic polymer has a high (for example, R n greater than 100,000) molecular weight, by chemically crosslinking, in Intimate admixture with the hydrophilic polymer, at least: one monomer of functionality greater than two.
  • monomer include di- and poly-olefinically unsaturated hydrocarbons, such as divinyl benzene, and di- and
  • Preferred hydrophilic polymers comprising polyethylene oxide residues have a number average . molecular weight, R n , , of. the polyethylene oxide greater than 1,500, preferably greater than 3,000; for example, from 4,000 to 12,000 or higher.
  • the hydrophilic polymer may be a homopoTymer or a random, alternating or block copolymer, specially a homopolymer or a random or block copolymer of ethylene oxide with, for example, a ho ologue such as propylene oxide or oxetane.
  • the hydrophilic polymer for example, polyethylene oxide
  • polyethylene oxide may also be foamed in a manner known ⁇ £r ⁇ e_.
  • the polyethylene oxide may be chemically crosslInked by means of a di- or poly-isocyanate in the presence of water; the polyethylene oxide may also be foamed by the direct injection of a pneumatogen, such as a fluorocarbon; for example, fluorotrichloromethane (e.g. "ARCTON” e ⁇ ICI Ltd: “ARCT0N” is a registered Trademark.
  • the walls of the capsule may also be formed from such hydrogels. However, they will preferably not be constructed from the identical hydrogel as may be employed in the construction of the plug. They will preferably have a lower rate of swelling than that of the plug as this assists in maintaining a water-tight seal.
  • the hydrogels are permeable to water and in this embodiment the devices may be constructed so as " to permit
  • Example 1 * ._ the ejection of the plug.
  • the invention is illustrated by the following examples.
  • Example 1
  • a series of devices were prepared comprising a cylindrical capsule wherein the open end is closed by a plug.
  • the interior of capsule was charged with 9.6 mg of salbutamol sulphate.
  • the capsule was closed with a plug of appropriate diameter and formed from a hydrogel produced by the batch polymerisation of 2.8 parts of Desmodur W [a proprietary -(4-1socyanato cyclohexyDmethane] with 1.2 parts of hexane triol and 1 part of a polyethylene glycol having Mn 8000 using ferric chloride as a catalyst.
  • the release profile of each device was tested in water at 3.7°C using a U.S. Pharmacopoeia dissolution bath. The quantity of drug released was monitored by u.v. spectroscopy. The time at which drug was released was noted.
  • composition of the devices is summarised in the following table:
  • a series of hydrogel cylinders were prepared by batch polymerising 5.5 parts of Desmodur W with 3 parts of hexane triol and 1 part of a polyethylene glycol having Mn 3830 using ferric chloride as the catalyst. The polymerisation was carried out in a suitable mould into which a former was inserted so as to form the hollow cylinders.
  • hydrogel rods were prepared by batch polymerising 2.8 part of Desmodur W, 1.2 parts of hexane triol and 1 pa t of : a polyethylene glycol having Mn 8000 using ferric chloride as the catalyst. •
  • each rod was cut in appropriate lengths to form plugs which were inserted Into an appropriately sized cylinder to form a device according to this invention.
  • Each cylinder contained a quantity of salbutamol sulphate.
  • the release profile of each device was tested in water at 37 ⁇ C using a U.S. Pharmacopoeia dissolution bath. The time at which the drug was released was noted.
  • Two hydrogel rods of the same diameter were produce by polymerising (a) 1 part of polyethylene glycol (Mn 4000), 3 part of hexane triol and 5.5 parts of Desmodur W and (b) 1 part of polyethylene glycol (Mn 4000), 2 parts hexane triol and 4 parts Desmodur W.
  • the rods (a) and (b) exhibited different rates of swelling when immersed in water, (a) being low swelling and (b) moderately swelling. Sections of these rods were used as plugs in two identical capsules formed from a rigid thermoplastic which contained lOmg of sulbutamol sulphate. The release profile of each device was measured using the technique described in the previous example.
  • Example 1 A series of capsules were made from hollow cylinders of various materials closed at one end and plugged with a hydrogel cylinder having the same composition as that employed in Example 1. The devices were charged with salbutamol sulphate and their release profile measured using the identical procedure to that of Example 1. The results were as follows: No. of Devices 6 1 4
  • Example 4 Two series of cylindrical devices were prepared. All of these devices used LDPE capsule identical t ⁇ that utilised in Example 4 except that the capsule length was 18mm. The first series of three devices utilised a plug having a length of 5mm and the second series of three devices a plug of length 7mm. All the plugs were formed from a hydrogel having an identical composition to that utilised in Example 1. The release profiles of the six devices was determined in the manner report ⁇ fl in Example 1.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Formation And Processing Of Food Products (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Encapsulation Of And Coatings For Semiconductor Or Solid State Devices (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Eye Examination Apparatus (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Measuring Pulse, Heart Rate, Blood Pressure Or Blood Flow (AREA)
  • Molding Of Porous Articles (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Massaging Devices (AREA)
  • Surgical Instruments (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Materials For Medical Uses (AREA)

Abstract

Nouveaux dispositifs de libération régulée de matières actives, notamment de produits pharmaceutiques, composés d'au moins deux parties s'interpénétrant. La partie mâle gonfle au contact de l'eau pour dégager la partie femelle. La partie femelle est de préférence faite d'une matière thermoplastique, par exemple LDPE, ou d'une matière soluble telle que la gélatine rendue imperméable par un revêtement extérieur en matière hydrophobe tel que le PVC. Les dispositifs trouvent une application particulière en tant que formes de dosage utilisées chez l'homme.
EP90903866A 1989-02-16 1990-02-15 Dispositif de distribution Pending EP0458887A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB898903566A GB8903566D0 (en) 1989-02-16 1989-02-16 Drug dispensing device
GB8903566 1989-02-16
GB898921155A GB8921155D0 (en) 1989-09-19 1989-09-19 Drug dispensing device
GB8921155 1989-09-19

Publications (1)

Publication Number Publication Date
EP0458887A1 true EP0458887A1 (fr) 1991-12-04

Family

ID=26294964

Family Applications (2)

Application Number Title Priority Date Filing Date
EP90301617A Expired - Lifetime EP0384646B1 (fr) 1989-02-16 1990-02-15 Dispositif de délivrance d'un principe actif
EP90903866A Pending EP0458887A1 (fr) 1989-02-16 1990-02-15 Dispositif de distribution

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP90301617A Expired - Lifetime EP0384646B1 (fr) 1989-02-16 1990-02-15 Dispositif de délivrance d'un principe actif

Country Status (18)

Country Link
EP (2) EP0384646B1 (fr)
JP (1) JPH0818971B2 (fr)
KR (1) KR0141473B1 (fr)
AT (1) ATE90202T1 (fr)
AU (1) AU629915B2 (fr)
CA (1) CA2047738C (fr)
DE (1) DE69001831T2 (fr)
DK (1) DK0384646T3 (fr)
ES (1) ES2043270T3 (fr)
FI (1) FI913880A0 (fr)
GB (1) GB2230442B (fr)
HU (1) HU207940B (fr)
IE (1) IE64761B1 (fr)
NO (1) NO303618B1 (fr)
NZ (1) NZ232561A (fr)
PT (1) PT93170B (fr)
RU (1) RU2104084C1 (fr)
WO (1) WO1990009168A1 (fr)

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JPH0818971B2 (ja) 1996-02-28
NZ232561A (en) 1992-02-25
AU629915B2 (en) 1992-10-15
KR0141473B1 (en) 1998-06-01
NO913081D0 (no) 1991-08-08
GB9003503D0 (en) 1990-04-11
FI913880A0 (fi) 1991-08-16
GB2230442B (en) 1992-11-25
GB2230442A (en) 1990-10-24
DK0384646T3 (da) 1993-07-12
HUT58509A (en) 1992-03-30
KR920700617A (ko) 1992-08-10
IE900556L (en) 1990-08-16
DE69001831T2 (de) 1993-09-16
NO913081L (no) 1991-08-08
ES2043270T3 (es) 1993-12-16
AU5163290A (en) 1990-09-05
RU2104084C1 (ru) 1998-02-10
EP0384646A1 (fr) 1990-08-29
CA2047738C (fr) 2000-02-15
WO1990009168A1 (fr) 1990-08-23
ATE90202T1 (de) 1993-06-15
PT93170A (pt) 1990-08-31
HU902238D0 (en) 1991-11-28
HU207940B (en) 1993-07-28
EP0384646B1 (fr) 1993-06-09
IE64761B1 (en) 1995-09-06
DE69001831D1 (de) 1993-07-15
NO303618B1 (no) 1998-08-10
PT93170B (pt) 1996-12-31
CA2047738A1 (fr) 1990-08-17
JPH04505004A (ja) 1992-09-03

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