IE51827B1 - Quick disintegrating pressed shapes containing pharmaceutical active substances - Google Patents

Quick disintegrating pressed shapes containing pharmaceutical active substances

Info

Publication number
IE51827B1
IE51827B1 IE2643/81A IE264381A IE51827B1 IE 51827 B1 IE51827 B1 IE 51827B1 IE 2643/81 A IE2643/81 A IE 2643/81A IE 264381 A IE264381 A IE 264381A IE 51827 B1 IE51827 B1 IE 51827B1
Authority
IE
Ireland
Prior art keywords
pharmaceutical active
pressed shapes
active substances
containing pharmaceutical
substances according
Prior art date
Application number
IE2643/81A
Other versions
IE812643L (en
Original Assignee
Ciba Geigy Ag
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
Application filed by Ciba Geigy Ag filed Critical Ciba Geigy Ag
Publication of IE812643L publication Critical patent/IE812643L/en
Publication of IE51827B1 publication Critical patent/IE51827B1/en

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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Abstract

Quick-disintegrating pressed shapes e.g. tablets containing pharmaceutical active substances, which shapes consist essentially of a compressed mixture of a) a pharmaceutical active substance in a granular delayed-release form, and b) a disintegrating agent having a high disintegrating capacity as well as good binding properties. The pharmaceutical active substance is coated with a mixture of ethyl cellulose and a polyacrylate to provide the delayed-release form.

Description

The invention relates to quick-disintegrating pressed shapes containing pharmaceutical active substances in a granular delayed-release form.
It is known that pharmaceutical active substances can 5 be mixed together and coated with coating substances retarding the release of the active substances, the mixture then being processed into the form of granules, which can either be administered directly in this form, or be administered after being filled into capsules or lo after further processing into tablet form. Granular delayed-release forms of pharmaceutical active substances known hitherto have various disadvantages . There are difficulties in connection with their production: the mode of production is complicated, or the use of organic solvents is necessary, or the auxiliaries used are not ideal with regard to the effect aimed at, namely, the correctly delayed release of active substances. Problems arise also with respect to the external properties of these granules, fcr example unsatisfactory free flowability or sensitivity to moisture, disadvantages which become unpleasantly evident either with the direct administration, that is to say, with dosing and possibly with the simultaneous taking of food or stimulants, or with the Filling of the capsules. Furthermore, individual doses of above 600 mg packed in capsules are not suitable since the capsules are too large to be swallowed.
The rapidly-disintegrating medicament-pressed shapes according to the invention are characterised in tha't they consist essentially of a compressed mixture of a) a medicament in granulated retard-form comprising granulated or crystalline pharmaceutical active substance which is coated with coating materials consisting essentially of a homogeneous mixture of a water-insoluble but water-dispersible poly (H+meth)acrylic acid - (methyl+ethyl) ester and a waterinscluble but water-dispersible ethyl cellulose in the weight ratio of 2.5 : 1 to 1 tc 5 : 1, but particularly in the ratio of 3 : lj and b) as disintegrating agent, a crosslinked polyvinyl pyrrolidine having a high disintegrating capacity as well as good binding properties.
Pharmaceutical preparations in a granular delayedrelease form are known, particularly as coated granules or in matrix form, that is, for example, also absorbed on ion-exchangers.
The two coating materials used according to the invention are known individually as coating materials. Each applied on its own is not however suitable for the purpose of the present invention. The first-mentioned is very thermoplastic and coated granules produced therewith tend to stick together, and the second-mentioned, when used in customary amounts and in normal processing, gives in the ease of the present mode of application a coating which has an insufficient retarding effect. It was therefore not possible to anticipate that the combination of the coating materials, individually unsuitable for the present purpose, would give an excellent result in every respect.
The pharmaceutical active substance granules produced according to the invention are hence free-flowing, insensitive to moisture and neutral in taste, and they produce the desired delayed release of active substance with great uniformity. A microscopic examination has moreover shown that the individual active-substance granule is very evenly coated, so that it substantially retains its original shape. It is thus possible with a homogeneous starting material to easily obtain a homogeneous end product.
Suitable active substances for the granular delayedrelease form of pharmaceutical active substances according to the invention are in particular granular or crystalline substances. Especially suitable are solid granules or monocrystals within the range of size of 0.3 - 2 mm (diameter), which have a certain mechanical strength, a property which is of special importance when the coated granules are subsequently to be processed into pressed shapes. Preferred pharmaceutical active substances are potassium chloride of size 0.3-1.2, especially 0.5-1.2 mm diameter; pirprofes Of size 0.5-1.2 mm diameter; and diclofenac-sodium of size 0.1-0.3 mm diameter.
Suitable as coating materials are on the one hand in particular polyacrylates of the formula R R l l ··· - CH_ - C - CH- - C - ··· I I C - 0 C « 0 I I OR' OR' R - H, CHg R' » CHg, C2H5 Substances of this type are obtained'by emulsion polymerisation, and they contain the copolymer having a molecular weight of some 100,000 in the form of latex particles with a diameter of around or below 1 zum. A corresponding product which is particularly suitable is sold by RBhm Pharma GmbH, Darmstadt (Fed. Rep. of Germany) under the name of Eudragit (Trade Mark) E30D; this is in the form of an aqueous dispersion, and is an ethyl acrylate/methyl methacrylate 70:30 by weight copolymer having a molecular weight of 800.000.
And on the other hand the coating material used is preferably ethyl cellulose. A particularly suitable product is that sold by FMC Corporation, Philadelphia, (Pennsylvania, USA) under the name of Aquacoat (Trade Mark) ECD-30, this being in the form of a 30% by weight aqueous polymeric dispersion having a low particle size (latex form) and a narrow particle-size distribution.
It is advantageous to mix together with the granules coated according to the invention small amounts, for example 0.5 to 1%, by weight of colloidal silicon dioxide, for example Aerosil (Trade Mark), vAiich is marketed by Degussa, Frankfurt (Fed.
Rep. of Germany). The free flowability cf the granules is improved by this addition. There can naturally be added to the coating-material mixture also other auxiliaries in small amounts, for example dyestuffs or flavouring agents.
The pharmaceutical active-substance granules used according to the invention can be produced in a manner known per se. This applies also in the case of the coated granules. These are produced in the fluidised-bed spraying apparatus known for this purpose, or in coating pans.
The coating-material mixture is fed in as an aqueous dispersion at room temperature, and spraying is best performed with air at a temperature of 25 co 30°C. The individual granules are readily obtained in this manner, that is to say, no undesirable agglomeration of granules occurs .
Surprisingly, che pharmaceutical active-substance granules used according to the invention can readily be pressed together with a disintegrating agent having a high disintegrating capacity and good binding properties, and with the customary auxiliaries otherwise used for forming tablets, within a wide dosage range into moulded shapes, for example tablets or capsule- or rod-shaped compressed products . The formed shapes thus obtained have the property of rapidly disintegrating into separate granules in the stomach of che person being treated and hence becoming well dispersed. A localised overconcencracion of che active substance in the digestive tract is in this way prevented, and a uniform, slowly occurring release of active substance dispersed over a large resorption area is ensured. It has been verified by microscopic examination that the individual granules have scarcely been damaged as a result of compression, so that on release of the active substance from the granules, the active substance is able to bring into effect its original advantageous properties virtually completely. When a formed or moulded shape has to be produced with two or more active substances, the individually dyed pharmaceutical active-substance granules can be prepared separately, a factor which facilitates identification, and which renders che pacient aware of che fact that che preparation being taken contains two or core active substances.
Suitable as disintegrating agents having a high disintegrating capacity and good binding properties for che formed shapes obtainable according to the invention are in particular crosslinked polyvinylpolypyrrolidone (PVPP), for exanple Polyplasdone (Trade Mark, XL marketed by the GAF Corporation, New York, N.Y. (USA), or Hollidon (Trade Mark) CL (BASF, Ludwigshafen/Rhein, Fed. Rep. of Germany).
In the case of the auxiliaries otherwise customarily used for tabletting, these are in particular binders, lubricants and antisticking agents.
The usual tablet-compressing machines can be used for producing the formed shapes obtainable according to the invention.
Since the mechanical strength of the formed shapes is surprisingly good, it is possible to produce all the desired customary forms, for example tablets and capsules or rod-shaped moulded products, with or without breaking grooves. These pressed products can be provided if desired with a protective coat of lacquer known for this purpose.
All pharmaceutical active substances which can be used for peroral administration and fcr which a delayed release in the gastro-intestinal tract is desired are essentially suitable, in the form of granules or crystals of an appropriate size, for being processed according to the invention. The present invention is however particularly advantageous with respect to the use of active substances which, when used at a fairly high concentration, can cause local irritation of the mucous lining of the gastrointestinal tract, and which are administered in large single doses. This applied for example in the case of potassium chloride administered in the treatment of hypopotassaemia, or in the case of lithium salts in psychotherapy.
The following Examples further illustrate the present invention.
Example 1 Composition per dose per batch potassium chloride 5 crystals having a particle si2e of 0.5 - 1.2 nm 1000.0 mg 5000.0 g Eudragit E30D solid 180.0 mg 900.0 s Aquacoat ECD solid 55.0 mg 275.0 cr O Aerosil 200 4.0 mg 20.0 s Aerosil 200 6.0 mg 30.0 s Polyplasdone XL 150.0 mg 750.0 g magnesium stearate 5.0 mg 25.0 g 1400.0 mg 7000.0 s Production A) Coated granules 1. starting material: potassium chloride; 2. Eudragic E3OD and Aquacoat ECD are mixed together with slight stirring; 2o 3. 1. sprayed with 2. in a fluidised-bed granulator (fluidised-bed granulator Aeromatik ST 7): - sprayed according to co-current principle, - the mixture of the dispersions is stirred during the spraying operation, - inlet-air temperature 28°C, - throughput about 80 g/minute; 4. drying at 28°C inlet-air temperature (fluidised-bed dryer Aeromatik ST 7) for about 10 minutes; . dry coated granules are mixed with Aerosil 200 for 10 minutes; □. mixture 5. is sieved, sieve size 1.5 - 2.0 mm.
Properties: free-flowing, tasteless, release properties for potassium chloride (Van der Kamp disintegration tester, in water at 37°C): after 1 hour about 24 Z after 2 hours about 45 w te after 4 hours about 81 z after 6 hours about 96 z .
B) Pressed shapes Coated granules, Aerosil 200, Polyplasdone XL and magnesium stearate are mixed together for 15 minutes. The mixture is subsequently compressed, on a commercial tablet-compressing machine, into the form of rodlets (for example Korsch EKO); punch size 20.7 x 8.6 an. Properties: decomposition in water-at 37°C <5 minutes, release properties for potassium chloride (Van der Kamp disintegration tester, in water at 37°C): after 1 hour about 30 Z after 2 hours about 50 Z after 4 hours about 80 Z after 6 hours about 98 ar te Example 2 Composition per dose per batch potassium chloride crystals having a particle size of 0.3 - 0.8 mm 600.0 mg 900.0 8 Eudragit E30D solid 115.0 mg 172.5 g Aquacoat ECD solid 35.0 mg 52.5 8 Aerosil 200 5.0 mg 7.5 g Polyplasdone XL 92.0 mg 138.0 g magnesium stearate 3.0 mg 4.5 g 850.0 mg 1275.0 g Production A) Coated granules: 1. starting material: potassium chloride; 2. Eudragit E30D and Aquacoat ECD 30 are mixed together with slight stirring; 3. 1. sprayed with 2. in a fluidised-bed granulator (fluidised-bed granulator Aeromatik Strea 1): - sprayed according to co-current principle, - the mixture of the dispersions is stirred during the spraying operation, - air-inlet temperature 28’C, - throughput about 8 g/minute; 4. drying at 28°C air-inlet temperature (fluidised-bed dryer Aeromatik ST 7) for about 10 minutes; . dried coated granules are mixed with Aerosil 200 for 1C minutes; 6. mixture 5. is sieved, sieve size 1.5 - 2.0 mm.
Properties : free-flowing, tasteless, release properties for potassium chloride (Van der Kamp disintegration tester, in water at 37°C): after 1 hour about 38 τ after 2 hours about 74 % after 3 hours about 96 X B) Pressed shapes Coated granules, cross-linked polyvinylpolypyrrolidone and magnesium stearate are mixed together for 15 minutes. The mixture is subsequently compressed, on a ccmnercial tablet-compressing machine, into the form of rodlets (for example Korsch EKO); punch size 20.7 x 8.6 mm.
Properties decomposition in water at 37°C 5 minutes, release properties for potassium chloride (Van der Kamp disintegration tester, in water at 37°C): after 1 hour afcer 2 hours after 3 hours about 42 Z about 70 Z about 90 Z Example 3 Composition dose me/batch e pirprofen crystals (0.5 mm) Eudragit E30D (solid) Aquacoat ECD 30 (solid) Aerosil 200 Polyplasdone XL cottonseed oil (hydr.) Production A) Coated granules 1. starting material: pirprofen, 2. Eudragit E30D and Aquacoat with slight stirring; 600.0 mg/g 24.0 mg/g (80 g of dispersion) 6.0 mg/g (20 g of dispersion) .0 mg/g 150.0 mg/g .0 mg/g .
ECD30 are mixed together 3. 1. sprayed with 2. in a fluidised-bed granulator Aeromatik Strea 1: - sprayed according to co-current principle, - dispersion is stirred, - air-inlet temperature 35°C, - throughput about 8 g/minute; 4. drying at 35°C air-inlet temperature (fluidised-bed dryer Strea 1) for about lo minutes; . dry coated granules are mixed with Aerosil 200 for about 10 minutes, 6. mixture 5. sieved through sieve-size 1.5 2.0 mm.
B) Pressed shapes - 5. mixed with Polyplasdone XL and hydrogenated cottonseed oil for 15 minutes in a tumbler mixer, type Turbula (Trade Mark); - homogeneous mixture 6. compressed, on a tablet press EKO, into the form of rod-shaped tablets, 16.4 χ 8.6 mm.
Test data disintegration in water at 370c} into 30 sec. disintegration in gastric juice J particles mln‘

Claims (6)

1. CLAIMS:1. Rapidly-disintegrating medicament-pressed shapes which consist essentially of a compressed mixture of a) a medicament in granular retard-form comprising a granulated or crystalline pharmaceutical active substance which is coated with coating materials, consisting essentially of a homogeneous mixture of a water-insoluble but water-dispersible poly (H+meth)acrylic acid-(methyl + ethyl) ester and a waterinsoluble but water-dispersible ethyl cellulose in the weight ratio of 2.5 : 1 to 5 : 1; and b) as disintegrating agent a crosslinked polyvinyl pyrrolidone having a high disintegrating capacity as well as good binding properties.
2. Pressed shapes containing pharmaceutical active substances according to Claim! , wherein the mixture ratio of the coating materials is 3 : 1.
3. Pressed shapes containing pharmaceutical active substances according to Claim 1, wherein the coatingmaterial mixture additionally contains colloidal silicon dioxide.
4. Pressed shapes containing pharmaceutical afrtive substances according to any of the preceding claims wherein the pharmaceutical active substance is potassium chloride in the range of size of 0.3 - 1.2 nun diameter.
5. 5 · Pressed shapes containing pharmaceutical active substances according to Claim 4, wherein the pharmaceutical active substance is potassium chloride in the range of size of 0.5 - 1.2 mm diameter. C. Pressed shapes containing pharmaceutical active 10 substances according to any of Claims 1 to 3 , wherein the pharmaceutical active substance is pirprofen in the range of size of 0.5 - 1.2 mm diameter. Pressed shapes containing pharmaceutical active substances according to any of Claims 1 to 3 wherein the 15 pharmaceutical active substance is diclofenac-sodium in the range of size of 0.1 - 0.3 mm diameter.
6. 8. Pressed shapes containing pharmaceutical active substances according to Claim 1 substantially as described with reference to any of the Examples.
IE2643/81A 1980-11-12 1981-11-11 Quick disintegrating pressed shapes containing pharmaceutical active substances IE51827B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH839380 1980-11-12

Publications (2)

Publication Number Publication Date
IE812643L IE812643L (en) 1982-05-12
IE51827B1 true IE51827B1 (en) 1987-04-01

Family

ID=4339640

Family Applications (1)

Application Number Title Priority Date Filing Date
IE2643/81A IE51827B1 (en) 1980-11-12 1981-11-11 Quick disintegrating pressed shapes containing pharmaceutical active substances

Country Status (20)

Country Link
EP (1) EP0052076B1 (en)
JP (1) JPS57109715A (en)
AT (1) ATE13486T1 (en)
AU (1) AU552861B2 (en)
CA (1) CA1178202A (en)
CY (1) CY1429A (en)
DE (1) DE3170764D1 (en)
DK (1) DK154537C (en)
ES (1) ES506981A0 (en)
FI (1) FI76254C (en)
GB (1) GB2086725B (en)
GR (1) GR76337B (en)
HK (1) HK53388A (en)
IE (1) IE51827B1 (en)
IL (1) IL64255A0 (en)
MY (1) MY8700132A (en)
NO (1) NO157964C (en)
NZ (1) NZ198937A (en)
PT (1) PT73963B (en)
ZA (1) ZA817795B (en)

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Publication number Priority date Publication date Assignee Title
DE3314003A1 (en) * 1983-04-18 1984-10-18 Boehringer Ingelheim KG, 6507 Ingelheim DIVISIBLE TABLET WITH DELAYED ACTIVE SUBSTANCE RELEASE AND METHOD FOR THE PRODUCTION THEREOF
CH658188A5 (en) * 1984-03-23 1986-10-31 Ciba Geigy Ag STORAGE STABLE QUICK DISASSEMBLING PHARMACEUTICAL PRESSELS.
JPS6144811A (en) * 1984-08-10 1986-03-04 Ss Pharmaceut Co Ltd Sustained release diclofenac sodium pharmaceutical
ES8801121A1 (en) * 1985-02-19 1988-01-01 Key Pharma Controlled release potassium chloride.
JPS61210025A (en) * 1985-03-14 1986-09-18 Teisan Seiyaku Kk Stabilized antibioitc complex granule preparation
WO1987001936A1 (en) * 1985-09-25 1987-04-09 Gerhard Gergely Desintegration tablet and process for its manufacture
KR880701098A (en) * 1986-04-01 1988-07-25 로버어트 에이 아미테이지 Methylprednisolone / sodium carboxymethyl starch tablet composition
GB8628359D0 (en) * 1986-11-27 1986-12-31 Zyma Sa Galenical formulation
GB8702411D0 (en) * 1987-02-03 1987-03-11 Zyma Sa Swellable pellets
GB8707416D0 (en) * 1987-03-27 1987-04-29 Wellcome Found Pharmaceutical formulations
GB8707421D0 (en) * 1987-03-27 1987-04-29 Wellcome Found Pharmaceutical formulations
GB8724763D0 (en) * 1987-10-22 1987-11-25 Aps Research Ltd Sustained-release formulations
CH675537A5 (en) * 1988-03-25 1990-10-15 Ciba Geigy Ag
JPH0273011A (en) * 1988-07-28 1990-03-13 Warner Lambert Co Aqueous polymer dispersion of cellulose and acrylic polymer for preparing drug administration form
JP2514078B2 (en) * 1988-08-22 1996-07-10 エスエス製薬株式会社 Compressed formulation
SK282072B6 (en) * 1991-01-30 2001-10-08 The Wellcome Foundation Limited Water-dispersible tablet containing lamotrigine and its preparation method
US5629016A (en) * 1991-01-30 1997-05-13 Glaxo Wellcome Inc. Water-dispersible tablets
US5698226A (en) * 1993-07-13 1997-12-16 Glaxo Wellcome Inc. Water-dispersible tablets
US6245351B1 (en) 1996-03-07 2001-06-12 Takeda Chemical Industries, Ltd. Controlled-release composition
FR2766089B1 (en) * 1997-07-21 2000-06-02 Prographarm Lab IMPROVED MULTIPARTICULAR TABLET WITH RAPID DELIVERY
KR20080083071A (en) 2003-08-08 2008-09-12 아지노모토 가부시키가이샤 Pharmaceutical preparation containing nateglinide
JP5122380B2 (en) * 2008-06-16 2013-01-16 エーザイ・アール・アンド・ディー・マネジメント株式会社 Quick-disintegrating tablet with controlled drug release and process for producing the same
EP2253306A1 (en) * 2009-05-18 2010-11-24 Royal College of Surgeons in Ireland Orodispersible dosage forms containing solid drug dispersions

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DE2336218C3 (en) * 1973-07-17 1985-11-14 Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz Oral dosage form
US4143129A (en) * 1975-10-11 1979-03-06 Lilly Industries Limited Cephalexin tablets
GB1560475A (en) * 1975-10-11 1980-02-06 Lilly Industries Ltd Pharmaceutical formulation
US4140756A (en) * 1976-06-10 1979-02-20 Mead Johnson & Company Film-coated matrix core tablet

Also Published As

Publication number Publication date
PT73963B (en) 1983-11-23
ATE13486T1 (en) 1985-06-15
NZ198937A (en) 1985-04-30
FI813532L (en) 1982-05-13
NO157964C (en) 1988-06-29
IL64255A0 (en) 1982-02-28
EP0052076A1 (en) 1982-05-19
AU7738281A (en) 1982-05-20
HK53388A (en) 1988-07-22
GB2086725A (en) 1982-05-19
DK499181A (en) 1982-05-13
DK154537B (en) 1988-11-28
FI76254B (en) 1988-06-30
NO157964B (en) 1988-03-14
AU552861B2 (en) 1986-06-26
GB2086725B (en) 1985-08-21
DK154537C (en) 1989-04-17
CA1178202A (en) 1984-11-20
FI76254C (en) 1988-10-10
CY1429A (en) 1988-09-02
PT73963A (en) 1981-12-01
JPH0228564B2 (en) 1990-06-25
MY8700132A (en) 1987-12-31
ES8303090A1 (en) 1983-02-01
DE3170764D1 (en) 1985-07-04
GR76337B (en) 1984-08-04
ZA817795B (en) 1982-10-27
NO813826L (en) 1982-05-13
ES506981A0 (en) 1983-02-01
EP0052076B1 (en) 1985-05-29
JPS57109715A (en) 1982-07-08
IE812643L (en) 1982-05-12

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