NZ200244A - Gallopamil or verapamil as calcium-antagonistic active compounds in sustained release pharmaceutical compositions - Google Patents
Gallopamil or verapamil as calcium-antagonistic active compounds in sustained release pharmaceutical compositionsInfo
- Publication number
- NZ200244A NZ200244A NZ200244A NZ20024482A NZ200244A NZ 200244 A NZ200244 A NZ 200244A NZ 200244 A NZ200244 A NZ 200244A NZ 20024482 A NZ20024482 A NZ 20024482A NZ 200244 A NZ200244 A NZ 200244A
- Authority
- NZ
- New Zealand
- Prior art keywords
- active compound
- verapamil
- calcium
- sustained release
- gallopamil
- 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
- A61K9/20—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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K31/275—Nitriles; Isonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Abstract
1. A pharmaceutical composition which contains a calcium-antagonistic active compound, with or without additional active compounds, is intended for oral administration to produce a sustained action for continuous therapy and contains only the sustaining dose of active compound, bound to pharmaceutical auxiliaries, wherein the calcium-antagonistic active compound is Gallopamil or Verapamil and wherein, at the sustaining dose, the ratio of the constituents with rapid release of active compound to those with sustained release of active compound is from 1 : 0.6 to 1 : 6.
Description
New Zealand Paient Spedficaiion for Paient Number £00244
2 00244
Priority Dats(s): . 7;
Compsste Specification FSied:
Class:
PubHcatson Date: . .£.7. AVH J9.84 .. P.O. Journal No: .
Patents Form No. 5
NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION
"PHARMACEUTICAL COMPOSITION"
WE, BASF Aktiengesellschaft, a German Joint Company organised and existing under the laws of the Federal Republic of Germany, with a registered office at 6700 Ludwigshafen, Federal Republic of Germany, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
2 002 4 4-
_ i^_ o.z. 0050/35072
Pharmaceutical composition The present invention relates to a novel pharmaceutical composition which contains a calcium-antagonistic active compound, with or without additional active compounds .
In therapy by medication, the use of oral pharmaceutical compositions with sustained release of the active constituents is conventionally practiced and is in particular necessary to lengthen the time for which a drug acts, especially in the case of drugs with relatively 10 short biological half-lives. Compositions for oral administration which show sustained release of the active compounds substantially increase patient compliance.-...^ The fact that these pharmaceutical forms have to be taken less frequently than conventional non-sustained release compositions ensures greater therapeutic safety.
Moreover, the use of compositions for oral administration with sustained release of the active compounds often avoids undesirable concentration peaks in the plasma.
Sustained release compositions are required to have an initial phase with rapid active compound release followed by a phase in which the concentration is sustained, so as to lengthen the period for which the plasma concentration is at the therapeutically desired level. The initial phase is absolutely essential in order to reach the '
requisite plasma level very rapidly. This type of sustained-release drug is described as ideal, cf.
Pharmazeutische Technologie (Thieme Verlag, Stuttgart),
200244
_ 2 - O.Z. 0050/35072
1978, page 487. Frequently also, sustained release drugs which do not have an initial dose effect, but only release the sustaining dose, are employed - especially in therapeutic agents for long-term or continuous treatment. The sustaining dose is released uniformly, in a persistant manner.
On repeatedly taking a drug, a steady state is set up between the active compound eliminated from the plasma and the active compound taken up by the plasma,
the steady state depending on the biological half-life.
To reach steady state concentrations of the therapeutically required order, frequent administration is necessary with compounds of short half-lives, and this is undesirable from the point of view of patient compliance .
A similar situation applies to compounds of longer half-life, where a major proportion is metabolized before reaching the body's principal circulatory system (as in the case of the first-pass effect in the intestine and/or the liver). Consequently, sustained release composi tions of compounds exhibiting a pronounced first-pass effect are generally viewed very critically (Der Internist 19 (1978), 333, Pharm. Ind. 40 (1978), 374, especially page 381, left-hand column).
Substances exhibiting a pronounced first-pass effect include a range of B-receptor blocking agents, eg. propranolol, or of calcium antagonists, eg. verapamil and gallopamil.
U.S. Patent 4,248,858 describes a novel sustained
1
- 3 - O.Z. 0050/35072
release composition of propranolol. In this, 160 mg of propranolol are present in a compressed core, the release of active compound being sustained because the material is embedded in gelling agents and insoluble polymers. The core is separated from an outer coating, which contains a further 20 mg of propranolol, capable of rapid release, by a film which is resistant to gastric juices and which is intended to prevent the active compound in the sustained release core from being released whilst the core is still in the stomach
This composition is only suitable for substances like propranolol which, on first pass through the liver, forms 4-hydroxypropranolol, whose activity is similar to that of propranolol itself (Brit. J. Pharmacy (1971) 43, 222).
The present invention relates to a novel pharmaceutical composition which contains a calcium-antagonistic active compound, with or without additional active compounds, is intended for oral, administration to produce a sustained action for continuous therapy and contains only the sustaining dose of active compound, bound with pharmaceutical auxiliaries, in which composition the calcium-antagonistic active compound is gallopamil or verapamil and wherein, at the sustaining dose, the ratio of the constituents with rapid release of active compound to those with slow release of active compound is from 1 : 0.6 to 1 : 6.
Verapamil (X = H) and gallopamil (X = OCH^) have the formula
o r*. a o A A
fj ,j w (O i jc
O.Z. 0050/35072
" CH_Ov °CH ^ \ cn ch3 ^
ch3o-/^-c-ch2-ch2-ch2-n-ch2-ck2-/ /~och3
/ ?H"CH3 x ch3
In drugs, the compounds are preferably employed as hydrochlorides.
In addition to these compounds, the novel composition may contain further active compounds, such as diuretics, psychopharmaceuticals and hypotensive agents.
These additional active compounds are present in the phase with rapid and/or slow release of active compound, depending on the order of magnitude of the biological half-life of the particular compound.
The ratio of rapidly released verapamil or gallopamil to slowly released active compound in the by weight pharmaceutical is from 1 : 0.6 to 1 : 6\ preferably from by weight
1 : 1 to 1 : 4/, especially from 1 : 1.2 to 1 : 3 by weight.
This ratio ensures, provided the right dosage is given, that substantially constant and therapeutically correct plasma levels result, the active compounds being released during the time of passage through the stomach and small intestine (as a rule from 3 to 5 hours).
The pharmaceuticals can be prepared in a conventional manner. Thus, coated tablets or layer tablets, in whfch a layer or the core consists of granules of the sustained release composition and a further layer or the coating consists of granules which rapidly release the active compound, or sustained release coated pills, in which the sustained release core is coated with a sugar layer which also contains the
0 0 0 0 A A
iO U <J '•1 ^
- 5 - O.Z. 0050/35072
active compound but releases it rapidly, can be prepared by conventional and widely used methods.
Granules which release the active compound rapidly are obtained by granulating the latter with sugar, cellulose,
starch and binders, the most preferable binders being polyvinylpyrrolidones, and adding mold.lubricants and flow regulators, preferably magnesium stearate^to the granules.
The content of active compound in the granules can vary between 20 and 80% but is preferably from 40 to 80% by weight. If these granules are used as the coating material for coated tablets, or are used in two-layer tablets, it is found that the rate of release of active compound is substantially independent of the pressure used when pressing the tablets..
If gelling agents are used, granules with sustained release of active compound can be obtained, which do not dissolve in the digestive tract but form swollen particles from which the active compound slowly diffuses into the digestive juices.
Particularly suitable gelling agents are alginates, eg. sodium alginate, especially those which, as a by weight ^
%1strength aqueous solution, have a viscosity of from
100 to 3,000 cp at 20°C. . If low-viscosity alginates are used, it is advisable to add water-insoluble natural materials, such as celluloses or starches, whilst when high-viscosity alginates are employed,the addition of soluble substances, such as lactose or low molecular weight polyethylene glycols, is useful. Suitable rates of
~*.0Q24
O.Z. 0050/35072
release can also be achieved by employing polyacrylic acid derivatives and polymethacrylic acid derivatives. The pressure employed for tableting can, in the case of the granules with sustained release of the active compound,
also influence the rate of release.
It is also possible to introduce the active compound in the form of sustained release granules or compressed cores conjointly with the free or non-sustained release active compound into one therapeutic unit, for example a hard gelatin capsule.
The invention makes it possible to provide pharmaceuticals which contain verapamil or gallopamil and give a constant and effective level of action over a long period.
The novel sustained release drugs are exceptionally useful as therapeutic agents for prolonged administration a therapeutically active plasma level with relatively little variation being achieved over the entire period of therapy. A drop in the plasma level into the sub therapeutic range will not occur if the drug is taken regularly. Moreover, the novel sustained release form allows the frequency of administration to be reduced to once or twice daily, thereby substantially improving patient compliance. The safety of the drug is also improved.
Finally, the novel composition has the advantage that it can be prepared very simply, by means of conventional processes.
7 (t% ^*7 a a
O.Z. 0050V-350^73^ *T
EXAMPLE 1
A. Preparation of the starting granules a) Granules with rapid release of active compound
.6 kg of verapamil, 4 kg of cellulose powder, 0.6 kg of v-/ Kollidon VA 64 and 4 kg of lactose were very thoroughly mixed and then moistened by adding 6 liters of water, with stirring. The mixture was then mechanic ally stirred vigorously and kneaded to give a crumbly moist mass which was converted to granules by forcing it through a sieve. The granules were dried and then again sieved. 0.7 kg of cellulose powder and 0.1 kg of magnesium stearate were added, giving granules suitable for pressing.
b) Granules with sustained release of active compound
14 kg of verapamil, 25 kg of sodium alginate, 4 kg of® Kollidon 30 (linear polyvinylpyrrolidone, molecular weight 30,000) and 5 kg of cellulose powder were very thoroughly mixed and moistened with 17 kg of water, while stirring. The mixture was then mechanically stirred vigorously and kneaded to give a crumbly moist mass which was converted to granules by forcing it through a sieve. The granules were dried and then again sieved. 1.75 kg of cellulose powder.and 0.25 kg of magnesium stearate were added, giving granules suitable for pressing.
B. Preparation of the finished tablets
Tablets of the following composition were formed on a press for the production of two-layer tablets:
lower layer: 190 mg of granules Aa (100 mg of verapamil)
onn 0 aa
As J o- (J -jt 'x
_ 8 - O.Z. 0050/35072
upper layer: 500 mg of granules Ab (140 mg of verapamil).
To mask the flavor, the tablets obtained were coated with a film-forming lacquer of cellulose derivatives, conventional plasticizers and dyes.
EXAMPLE 2
Aa) Following the procedure of Example 1 Aa,
granules with rapid release of active compound were prepared by granulating sugars, celluloses or starches with the active compound and a binder. Mold lubricants and" - flow . ■ regulators, preferably magnesium stearate, 0 were then added, giving granules of the following compositions:
• •• • • •
TABLE 1
Substances
Composition in parts per 100
Verapamil 45
Gallopamil - 45
Corn starch 20 20
Cellulose 34.5 34.5 ® Kollidon VA 64
® Kollidon CI -
Magnesium stearate 0.5 0.5
Lactose . -
53
3
3.5 0.5 20
53
3
3.5 0.5 20
53
23.5 3
0.5 20
50
23 6.5
0.5 20
60
21
40
4.5
0.5 0.5 18.5 45
80
.5 4
0.5 10
l to i
00
o o o
-J :)
CD * f\)B
■t*
2 00244
O.Z. 0050/35072
Ab) Using a method similar to Example 1 Ab, granules with sustained release of active compound were prepared with the following compositions:
Substances
Verapamil Sodium alginate ©Kollidon 30 Lactose
Cellulose powder Magnesium stearate Com starch Polyethylene glycol ® Eudragit RL Methylcellulose ©Kollidon 90
• • •• •
TABLE 2
Composition in parts per 100
37.5 37.5 37.5 37.5 33 34 32
58 50 50 50 50 44 48 62
6 7.5 7.5 7.5 7.5 6.5
- 4.2 - 14.2
4.2
1 0.8 0.8 0.8 0.8 0.6 0.8 0.8
4.2
4.2 3.5 12.4
.2
o
ISl o o
VJl O
s, CJ U1 O
r\j
Substances
?10244
o.z. 0050/35072
TABLE 3
Composition in parts per 100
Gallopamil Sodium alginate ©Kollidon 30 Cellulose powder Magnesium stearate Lactose
50 7.5 4.5 0.5 17.5
22.5 44.4
6.6 5.5 0.4
.6
B. Tablets were prepared, by a method similar to that of Example 1 B, from the granules listed in Tables 1 to 3. The amounts of free active compound were from 60 to 150 mg, and the amounts of bound active compound from 80 to 190 mg in the case of verapamil; for gallopamil, the corresponding values were from 30 to 80 and from 40 to 100 mg, respectively.
EXAMPLE 3
Compressed cores containing 140 mg of verapamil were prepared from the granules obtained as described in Example 1 Ab. The compressed cores were then coated in a press coater with a layer of the granules of Example 1 Aa (active compound content 120 mg of verapamil), and were subsequently coated with a film lacquer, by a method similar to Example IB.
EXAMPLE 4
The granules obtained as described in Example 1 Ab were pressed to form compressed cores containing 150 mg of verapamil or 75 mg of gallopamil. The compressed cores were then provided with coatings of the composition
200244
- 13 - o.z. 0050/35072
shown in Table 4, in such a way that the coatings contained 90 mg of verapamil or 45 mg of gallopamil.
TABLE 4
Substances Composition in parts per 100
Verapamil
26.
3
-
69.5
-
.4
45.
7
Gallopamil
-
26.3
-
69.5
-
-
Water
26.
3
26.3
.2
.2
.8
Sugar
26.
4
26.4
-
-
24.6
.
1
Talc
.
.5
17.4
17.4
8.9
12
Methylcellulose
.
.5
-
-
2.2
3
Gum arabic
-
-
3.5
3.5
0.9
1.
2
®Aerosil
-
-
-
-
2.2
3
Polyethylene glycol 400
-
-
4.4
4.4
-
-
However, this process is involved, since the water must be removed. Moreover it is very difficult to achieve good content uniformity in the coating. The best results were obtained with coatings having a low content of active compound. The cores were given a by weight smooth coating with a 70%/strength aqueous sugar solution (from about 20 to 40 g of the solution being required per 10 kg batch of the cores), and a film coating was then applied on top as described above.
In the Examples the registered trademarks stand for the following materials:
©Kollidon V 64: Copolymer of - vinylpyrrolidone and vinyl acetate in the ration of 6 : 4 by weight.
Claims (3)
- r\ 2 44 - 14 - O.Z. 0050/35072 ® Kollidon 30: ©Kollidon 90: Eudragit RL: ®Aerosil: Linear polyvinylpyrrolidone, molecular weight 49,000 Linear polyvinylpyrrolidone, molecular weight 1,100,000 Polyacrylic acid and polymethacrylic acid derivatives Highly disperse silica 20024-1 O.Z. 0050/35072 is WHAT -t/WE CLAIM IS:- We- olQim: 1. A pharmaceutical composition which contains a calcium-antagonistic active compound, with or without additional active compounds, that is intended for oral administration to produce a sustained action for continuous therapy and contains only the sustaining dose of active compound, bound with pharmaceutical auxiliaries, wherein the calcium-antagonistic active compound is gallopamil or verapamil and wherein, at the sustaining dose, the ratio of the constituents with rapid release of active compound to those with sustained release of active compound is from 1 : 0.6 to 1 : 6 by weight.
- 2. A pharmaceutical composition substantially as specifically described herein in any one of the Examples.
- 3. A process for the preparation of a pharmaceutical composition substantially as specifically described herein in any one of the Examples. BALDWIN, SON & CAREY
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813113901 DE3113901A1 (en) | 1981-04-07 | 1981-04-07 | ACTIVE SUBSTANCE PREPARATION FOR ORAL APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ200244A true NZ200244A (en) | 1984-08-24 |
Family
ID=6129505
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ200244A NZ200244A (en) | 1981-04-07 | 1982-04-06 | Gallopamil or verapamil as calcium-antagonistic active compounds in sustained release pharmaceutical compositions |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0063266B1 (en) |
| JP (1) | JPS57175113A (en) |
| AT (1) | ATE14076T1 (en) |
| AU (1) | AU555093B2 (en) |
| CA (1) | CA1184497A (en) |
| DE (2) | DE3113901A1 (en) |
| DK (1) | DK157482A (en) |
| ES (1) | ES511208A0 (en) |
| FI (1) | FI821253L (en) |
| GR (1) | GR74770B (en) |
| HU (1) | HU186855B (en) |
| IE (1) | IE52985B1 (en) |
| IL (1) | IL65328A (en) |
| NO (1) | NO157204C (en) |
| NZ (1) | NZ200244A (en) |
| PT (1) | PT74705B (en) |
| ZA (1) | ZA822327B (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4461759A (en) * | 1983-01-03 | 1984-07-24 | Verex Laboratories, Inc. | Constant release rate solid oral dosage formulations of veropamil |
| US4863741A (en) * | 1985-03-25 | 1989-09-05 | Abbott Laboratories | Tablet composition for drug combinations |
| US4874614A (en) * | 1985-03-25 | 1989-10-17 | Abbott Laboratories | Pharmaceutical tableting method |
| LU86077A1 (en) * | 1985-09-18 | 1987-04-02 | Pharlyse Sa | NEW GALENIC FORMS OF VERAPAMIL, THEIR MANUFACTURE AND THE MEDICINAL PRODUCTS CONTAINING THESE NEW GALENIC FORMS |
| LU86099A1 (en) * | 1985-09-30 | 1987-04-02 | Pharlyse | EXTENDED RELEASE GALENIC FORMS OF VERAPAMIL, THEIR MANUFACTURE AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| IE58401B1 (en) * | 1986-06-20 | 1993-09-08 | Elan Corp Plc | Controlled absorption pharmaceutical composition |
| US4981871A (en) * | 1987-05-15 | 1991-01-01 | Abelson Mark B | Treatment of ocular hypertension with class I calcium channel blocking agents |
| US4792452A (en) * | 1987-07-28 | 1988-12-20 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
| DE3809764A1 (en) * | 1988-03-23 | 1989-10-05 | Knoll Ag | MIXTURE OF ALGINATES AND POLYACRYLATES AND THEIR USE |
| US5230901A (en) * | 1988-03-23 | 1993-07-27 | Knoll Ag | Sustained release tablet of a mixture of alginates and polyacrylates |
| EP0366868B1 (en) * | 1988-07-13 | 1992-09-30 | Knoll Ag | Substained release pharmaceutical composition containing alginate |
| US5032406A (en) * | 1989-02-21 | 1991-07-16 | Norwich Eaton Pharmaceuticals, Inc. | Dual-action tablet |
| DE3932378A1 (en) * | 1989-09-28 | 1991-04-11 | Knoll Ag | SOLID MEDICAL FORM WITH A HIGH VERAPAMIL CONTENT |
| IT1264696B1 (en) * | 1993-07-09 | 1996-10-04 | Applied Pharma Res | PHARMACEUTICAL FORMS INTENDED FOR ORAL ADMINISTRATION ABLE TO RELEASE ACTIVE SUBSTANCES AT A CONTROLLED AND DIFFERENTIATED SPEED |
| US5695781A (en) * | 1995-03-01 | 1997-12-09 | Hallmark Pharmaceuticals, Inc. | Sustained release formulation containing three different types of polymers |
| US6083532A (en) | 1995-03-01 | 2000-07-04 | Duramed Pharmaceuticals, Inc. | Sustained release formulation containing three different types of polymers and tablet formed therefrom |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1154810B (en) * | 1961-04-01 | 1963-09-26 | Knoll Ag | Process for the preparation of basic substituted phenylacetonitriles |
| DE1467781A1 (en) * | 1963-07-15 | 1968-12-05 | Boehringer Sohn Ingelheim | Process for the production of coated tablets with extended release of active ingredients |
-
1981
- 1981-04-07 DE DE19813113901 patent/DE3113901A1/en not_active Withdrawn
-
1982
- 1982-02-22 GR GR67376A patent/GR74770B/el unknown
- 1982-03-23 IL IL65328A patent/IL65328A/en unknown
- 1982-03-23 CA CA000399116A patent/CA1184497A/en not_active Expired
- 1982-03-31 EP EP82102695A patent/EP0063266B1/en not_active Expired
- 1982-03-31 AT AT82102695T patent/ATE14076T1/en active
- 1982-03-31 NO NO821084A patent/NO157204C/en unknown
- 1982-03-31 DE DE8282102695T patent/DE3264519D1/en not_active Expired
- 1982-04-01 JP JP57052378A patent/JPS57175113A/en active Pending
- 1982-04-05 PT PT74705A patent/PT74705B/en unknown
- 1982-04-05 ZA ZA822327A patent/ZA822327B/en unknown
- 1982-04-06 AU AU82384/82A patent/AU555093B2/en not_active Ceased
- 1982-04-06 NZ NZ200244A patent/NZ200244A/en unknown
- 1982-04-06 DK DK157482A patent/DK157482A/en not_active Application Discontinuation
- 1982-04-06 HU HU821058A patent/HU186855B/en not_active IP Right Cessation
- 1982-04-06 ES ES511208A patent/ES511208A0/en active Granted
- 1982-04-06 IE IE812/82A patent/IE52985B1/en unknown
- 1982-04-07 FI FI821253A patent/FI821253L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO157204B (en) | 1987-11-02 |
| CA1184497A (en) | 1985-03-26 |
| PT74705A (en) | 1982-05-01 |
| DK157482A (en) | 1982-10-08 |
| HU186855B (en) | 1985-10-28 |
| EP0063266A2 (en) | 1982-10-27 |
| IE820812L (en) | 1982-10-07 |
| PT74705B (en) | 1983-11-14 |
| GR74770B (en) | 1984-07-12 |
| ES8307496A1 (en) | 1983-08-16 |
| ES511208A0 (en) | 1983-08-16 |
| DE3264519D1 (en) | 1985-08-08 |
| JPS57175113A (en) | 1982-10-28 |
| DE3113901A1 (en) | 1982-10-28 |
| ATE14076T1 (en) | 1985-07-15 |
| IE52985B1 (en) | 1988-04-27 |
| AU8238482A (en) | 1982-10-14 |
| AU555093B2 (en) | 1986-09-11 |
| NO821084L (en) | 1982-10-08 |
| EP0063266A3 (en) | 1983-05-04 |
| IL65328A0 (en) | 1982-05-31 |
| IL65328A (en) | 1985-06-30 |
| EP0063266B1 (en) | 1985-07-03 |
| NO157204C (en) | 1988-02-10 |
| ZA822327B (en) | 1983-03-30 |
| FI821253A0 (en) | 1982-04-07 |
| FI821253L (en) | 1982-10-08 |
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