IE50372B1 - Stable solutions of hydrogenated egotalkaloids - Google Patents

Stable solutions of hydrogenated egotalkaloids

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Publication number
IE50372B1
IE50372B1 IE2340/80A IE234080A IE50372B1 IE 50372 B1 IE50372 B1 IE 50372B1 IE 2340/80 A IE2340/80 A IE 2340/80A IE 234080 A IE234080 A IE 234080A IE 50372 B1 IE50372 B1 IE 50372B1
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IE
Ireland
Prior art keywords
composition according
present
compound
formula
component
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Application number
IE2340/80A
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IE802340L (en
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Sandoz Ltd
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Publication date
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Publication of IE802340L publication Critical patent/IE802340L/en
Publication of IE50372B1 publication Critical patent/IE50372B1/en

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C07D519/02—Ergot alkaloids of the cyclic peptide type

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Stable pharmaceutical solns. contain a hydrogenated rye ergot alkaloid (I) or one of its salts, and heparin (II) or one of its salts, together with a stabilising medium (where R is H or 1-4C alkyl; R1 is methyl, ethyl or isopropyl; R2 is isopropyl, sec.-butyl, isobutyl or benzyl; and X is H or OMe). The stabilising medium is a mixt. of water and aliphatic mono- or polyols together with an N-acylated aniline, and urea and/or calcium EDTA salt. Previous combinations of (I) and (II) tend to form an insoluble salt on storage. The new solns. do not suffer from this drawback and can be stored, then given by innection.

Description

The present invention relates to pharmaceutical compositions in the form of stable solutions and comprising as active ingredients a combination of a) a compound of formula I, wherein R is hydrogen or C^_^alkyl, R^ is methyl, ethyl or isopropyl, R2 is isopropyl, sec.-butyl, isobutyl or benzyl, and X is hydrogen or methoxy, or a pharmaceutically acceptable acid addition salt thereof; and S0372 b) heparin or a pharmaceutically acceptable salt thereof.
Previous attempts to prepare pharmaceutical compositions in solution form comprising mixtures of active ingredients a) and b) as aforesaid (for example of dihydroergotamine and dihydroergovaline or their salts, e.g. the methane sulphonate, Or Of 6-nor-6-isopropyl-9,10-dihydro-21p-methyl-5'a-benzyl-ergopeptine or its salts, e.g. the maleate, and of heparin or its salts, e.g. the sodium salt) have not met with success.
First the individual ingredients are themselves unstable in solution. Secondly when combined in solution, the ingredients a) and b) react to form difficultly soluble salts which precipitate out of the solution.
The obtained solutions accordingly possess very low stability. They cannot be kept in reserve for periods of more than a few hours and are thus of little practical value.
S0372 Various proposals have been made to surmount this problem. Thus it has been suggested to use e.g. the methane sulphonate sait of dihydroergotamine in the form of a solid solution employing polyvinyl-pyrrolidone. Salt formation can be delayed in this manner, but only for a relatively limited period of time. More recently lyophilised preparations have been developed for use in the preparation of injectable solutions.
As an alternative, individually stabilized solu10 tions comprising components a) and b) separately, have been developed. The individually stabilized solutions are then brought into admixture shortly before administration.
Clearly none of these proposals provides a satis15 factory, practical answer to the problem. The development of stabilized solution forms comprising ingredients a) and b) in combination, having a prolonged shelf-life, capable of transport and storage and ready for use as and when required has remained a major objective. in accordance with the present invention it has now surprisingly been found that the above problems may be overcome and clear solutions of components a) and b) in combination obtained, which are stable over prolonged periods of time, e.g. for two years and more, employing a carrier medium comprising c) water; d) a pharmaceutically acceptable monoor poly-alcohol; e) an acetanilide anaesthetic or a pharmaceutically acceptable acid addition salt thereof; and f) urea and/or mono-calcium di-sodium ethylenediaminetetraacetate.
Accordingly the present invention provides, in a first aspect a pharmaceutical composition in stable solu10 tion form comprising as active ingredients a combination of a component a) and a component b) as hereinbefore defined and a carrier medium comprising components c),d),e) and f) as hereinbefore defined.
Preferably the compositions according to the inven15 tion have a pH of from 4 to 6.
Suitable pharmaceutically acceptable acid addition salt forms of the compounds of formula I, include e.g. the methane sulphonates, maleates and tartrates. Suitable pharmaceutically acceptable salts of heparin include e.g. the sodium, potassium and calcium salt.
Preferred ingredients a) are dihydroergotamine or a pharmaceutically acceptable acid addition salts thereof, in particular the methane sulphonate, dihydroergovaline or a pharmaceutically acceptable acid addition salt thereof, 25 in particular the methane sulphonate and 6-nor-6-isopropyl5 S0372 9,10-dihydro-2'p-methyl-51α-benzyl-ergotpeptine and the pharmaceutically acceptable acid addition salts thereof, in particular the maleate. When b) is present in pharmaceutically acceptable salt form this is preferably the sodium salt.
The ingredients a) and b) are preferably present in a ratio of 1 mg compound of formula I: 500 to 70,000 I.U., more preferably 2,000 to 20,000 X.U. heparin.
When ingredient a) and/or b) is present in pharmaceucically acceptable salt form the equivalent amount of salt form giving the stated ratios for the free compound is employed.
Components c) and d) are preferably present in an amount of 45 to 72'% and 28 to 55% respectively based on the total volume of the composition.
Preferred components d) are ethanol, propylene glycol; polyethylene glycol having an average molecular weight of 400, diethylene glycol and glycerol, as well as mixtures thereof. More preferably component d) comprises a mixture of (i) ethanol and (ii) triethylene glycol or of (iii) glycerol and (iv) propylene glycol. In such mixtures (i) and (ii) are preferably present in a ratio of from 1 : 6 to 10, more preferably 1 : 8 parts by weight and (iii) and (iv) are preferably present in a ratio of from 1 : 8 to 12, more preferably 1 : 10 parts by weight.
By the term acetanilide anaesthetic as used In respect of component e) is meant any member of the class of physiologically acceptable acetanilide derivatives having anaesthetic activity; including the various known anaesthetically active 2-amino-N-phenyl-acetanilide derivatives. Preferred acetanilide anaesthetics are 2-(diethylamino) -N-(2,6-dimethyl-phenyl)-acetamide (also known as Lidocaine) , 2-(butylamino)-N-(2-chloro-6-methylphenyl)-acetamide (also known as Hostacain) and 2-(2-di10 ethylaminoacetamido)-m-toluic acid methyl ester (also known as Baycain). Apart from their clearly advantageous anaesthetic properties e.g. when the compositions are administered by injection, it has surprisingly been found that the presence of ingredient e) is essential in con15 tributing to the long-term stability properties of the inventive compositions.
Preferably ingredient e) is present in an amount of 1 to 2% by weight based on the total weight of the composition. Ingredient f) is preferably present in an amount of 2 to 5 mg based on an amount of 5,000 I.U. to 2,500 I.U. heparin.
The compositions according to the invention may contain further additives, e.g. stabilizing agents, preserving agents, colouring agents and surfactants, as 378 known in the art. Suitable preserving agents include e.g. chlorocresol or trichloro-tert.-butanol, suitably present in an amount of from 0.2 to 1% based on the total weight of the composition.
The compositions of the invention are suitably put up in unit dosage form, e.g. in the form of ampoules for injection, including e.g. throw-away syringes containing a predetermined amount of the composition. Such unit dosage forms preferably contain 0.5 mg of the compound of formula I and/or 2,500 or 5,000 I.U. heparin per unit dosage.
In addition to the foregoing the present invention also provides a process for the preparation of pharmaceutical compositions in accordance with the invention, which process comprises bringing an active ingredient a) and an active ingredient b) as hereinbefore defined into solution in a carrier medium comprising components c), d), e) and f) as hereinbefore defined.
Preferably the process is carried out step-wise in a procedure comprising 1) preparing a solution of an active ingredient a) in a solvent medium comprising components d) and e); 2) preparing a solution of an active ingredient b) in a solvent medium comprising components c) and f); 3) combining the solutions obtained via steps 1) and 2); and 4) optionally adding additional component c) and/or d).
The process of the invention is preferably carried out with protective gassing, e.g. CO^-gassing, of the solutions. If the pH of the obtained solution is outside the range pH 4 to 6, it is preferably adjusted to within this range e.g. by the addition of an appropriate quantity of a pharmaceutically acceptable acid e.g. an organic acid. When an acid addition salt of a compound of fonnula I is employed as ingredient a), the added acid will preferably correspond to the salt form employed. Thus when ingredient a) is in methane sulphonate salt form, any adjustment of the pH necessary will preferably be effected by addition of methane sulphonic acid.
The obtained composition may be put-up in unit dosage form as hereinbefore described, e.g. by filling into ampoules after filtration, preferably with protective, e.g. CO2, gassing.
The solutions according to the invention may be used for therapeutic treatment or prophylaxis as known in the art; for example as anti-thrombolic agents particularly in the prophylaxis of post-operative thrombosis as described in our Patent Specification No. 44359.
The following examples are illustrative of the present invention: S0372 Example I Preparation of a 5,000 I.U. heparin / 0.5 mg Dihydroergotamine Injectable solution: 1) 18.4 kg of propylene glycol and 1.84 kg of anhydrous 5 glycerol are poured into a 50 litre stirring vessel, and the mixture stirred for 10 minutes with CO2gassing. 0.0286 kg of dihydroergotamine methane sulphonate and 0.426 kg of lidocain hydrochloride are dissolved in the mixture with stirring and CO2~gassing over a period of a further 30 minutes. 2) 18.4 kg of water (suitable for injection) are poured into a 30 litre stirring vessel and stirred for 10 minutes with CO2-gassing. 1.896 kg of heparin sodium salt (= circa 285.7 million I.U.) and 0.114 kg 15 of mono-calcium di-sodium ethylenediaminetetraacetate (commercially available under the name Calcium titriplex (r)) are then dissolved in the water with stirring and C02~gassing over a further 30 minutes. 3) The solution obtained via step 2) above is added with stirring and CC^-gassing to the solution obtained via step 1). The vessel in which solution 2) is obtained is then washed out with 1 kg of water (suitable for injection) and is also added to the step 1) solution.
The combined solutions are stirred for a further 10 minutes with CC^-gassing. The pH of the solution is ca. .7. 4) The solution is made up to a weight of 42.810 ^9 ( = 40 litres) by the addition of water (suitable for injection).
) The obtained solution is pre-filtered using a membranefilter (0.2 pm; Ultipor nm. Pall) and then passed via a sterilized pressure-filtration apparatus having a membrane filter (0.2 μπι: Ultipor nm. Pall) at 1.7 bar with C02 directly into an ampoule-filling machine. The solution is filled in 0 7 ml dosages into 1 ml ampoules under sterile conditions.
Example II Steps 1) - 4) of example I are repeated precisely 15 using the following quantities of ingredients: Step 1) Propylene glycol 15.30 kg Anhydrous glycerol 1.53 kg Dihydroergotamine- methane sulphonate 0.03 kg 20 Lidocain - HOl.HgO 0.32 kg Step 2) Water (for injection) 12.00 kg Heparin-Na salt 0.997 kg (= 150 million I.U.) 25 mono-Calcium di-sodium ethy 1 enedi anti netetraacetate (hexahydrate) 0.12 kg 50378 Step 3) Step 4) (= 30 litres) Step 5) No change The solution is made up to a weight of 32.040 kg by the addition of 30 litres^ of - water (for injection) .
The resultant solution is filled into 1 ml ampoules in 0.5 ml dosages.
Example III i) The method of example I is repeated using an equivalent quantity of a 1 : 10 (parts by weight) mixture of ethanol and triethylene glycol in place of propylene glycol and glycerol in step 1). ii) The method of example I is repeated· using an equivalent quantity of hostacain in place of lidocain in step 2). iii) The method of example I is repeated using an equivalent quantity of Eaycain in place of lidocain in step 2).

Claims (29)

1. A pharmaceutical composition in stable solution form comprising as active ingredient a combination of a) a compound of formula I, wherein R is hydrogen or Cj_ 4 alkyl, is methyl, ethyl or isopropyl, R 2 is isopropyl, sec.-butyl, isobutyl or benzyl, and X is hydrogen or methoxy, or a pharmaceutically acceptable acid addition salt thereof; and b) heparin or a pharmaceutically acceptable salt thereof, and a carrier medium comprising c) water; d) a pharmaceutically acceptable mono- or polv-alcohol; 5 e) an acetanilide anaesthetic or a pharmaceutically acceptable acid addition salt thereof; and f) urea and/or mono-calcium di-sodium ethylenediaminetetraacetate.
2. Composition according to Claim 1, having a pH of from 4 to 6. 1
3. Composition according to Claim 1 or 2, wherein the compound of formula I is dihydroergotamine.
4. Composition according to Claim 1 or 2, wherein the compound of formula I is dihydroergovaline.
5. Composition according to Claim 3 or 4, wherein 1 the compound of formula I is in the form of· the methane sulphonate
6. Composition according to Claim 1 or 2 wherein the compound of formula I is 6-nor-6-isopropyl-9,10dihydro-2'p-methyl-5'α-benzyl-ergopeptine. 20
7. Composition according to Claim 6, wherein the compound of formula I is in the form of the maleate.
8. Composition according to any one of Claims 1 to 7 wherein the heparin is in the form of the sodium salt.
9. Composition according to any one of Claims 1 5 to 8 wherein the compound of formula X and heparin are present in a ratio of 1 mg : 500 to 70,000 I.II.
10. Composition according to Claim 9 wherein the ratio is .1 mg : 2,000 to 20,000 1.1).
11. Composition according to any one of Claims 1 10 to 10 wherein component c) is present in an amount of from 45 to 72% based on the total volume of the composition.
12. Composition according to any one of Claims 1 to 11 wherein component d) is present in an amount of from 15 28%to 55% based on the total volume of the composition.
13. Composition according to any one of Claims 1 to 12 wherein component d) is selected from the group consisting of ethanol, propylene glycol, polyethylene glycol of average mol. wt. ca. 400, diethyleneclycol, 20 glycerol and mixtures thereof.
14. Composition according to Claim 13 wherein component d) comprises either (i) ethanol and (ii) triethylene glycol or (iii) glycerol and (iv) propylene glycol. 50378
15. Composition according to Claim 14 wherein (i) and (ii) are present in a ratio of from 1:6 to 10 parts by weight or (iii) and (iv) are present in a ratio of from 1:8 to 12 parts by weight. 5
16. Composition according to Claim 15 wherein (i) and (ii) are present in a ratio of from 1:8 parts by weight or (iii) and (iv) are present in a ratio of from 1:10 parts by weight.
17. Composition according to any one of Claims 10 1 to 16 wherein the acetanilide anaesthetic is selected from the group consisting of Lidocain, Hostacain and Baycain.
18. Composition according to any one of Claims 1 to 17 wherein the acetanilide anaesthetic is present in 15 an amount of from 1 to 2% based on the total weight of the composition. )9.
19.Composition according to any one of Claims 1 to 18 wherein component f) is present in an amount of 2 to 5 mg based on an amount of 5,000 I.U. to 2,500 I.U. heparin. 20
20. Composition according to any one of Claims 1 to 19 wherein component f) is mono-calcium di-sodium ethylenediaminetetraacetate.
21. Composition according to Claim 20 wherein component f) is in the form of the hexahydrate.
22. Composition according to any one of Claims 1 to 19 in unit dosage form. 50373
23. Composition according to any one of Claims 1 to 22 in ampoule form for injection and containing 0.5 mg of compound of formula I and/or 2,500 or 5,000 I.U. heparin. 5
24. Process for the preparation of a pharmaceutical composition according to any one of Claims 1 to 23 which process comprises bringing an active ingredient a) and an active ingredient b) into solution in a carrier medium comprising components c), d), e) and f). 10
25. Process according to Claim 24, which comprises the individual steps of 1) preparing a solution of an active ingredient a) in a solvent medium comprising components d) and e); 2) preparing a solution of an active ingredient b) in a 15 solvent medium comprising components c) and f); 3) combining the solutions obtained via steps 1) and 2) ; and 4) optionally adding additional component c) and/or d).
26. Process according to Claim 24 or 25 conducted 20 with inert gassing during solution.
27. Process according to any one of Claims 24 to 26 wherein the obtained solution is adjusted to pH 4 to 6.
28. Process according to Claim .24, substantially as herein before described with reference to the accompany25 ing examples. 50373
29. a pharmaceutical composition whenever prepared by a process as claimed in any one of Claims . 24 to 28.
IE2340/80A 1979-11-12 1980-11-11 Stable solutions of hydrogenated egotalkaloids IE50372B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19792945636 DE2945636A1 (en) 1979-11-12 1979-11-12 STABLE SOLUTIONS OF HYDRATED ERGOTAL CALOIDS OR YOUR SALTS AND HEPARIN OR ITS SALTS AND METHOD FOR THE PRODUCTION THEREOF

Publications (2)

Publication Number Publication Date
IE802340L IE802340L (en) 1981-05-12
IE50372B1 true IE50372B1 (en) 1986-04-02

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Family Applications (1)

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IE2340/80A IE50372B1 (en) 1979-11-12 1980-11-11 Stable solutions of hydrogenated egotalkaloids

Country Status (22)

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EP (1) EP0028813B1 (en)
JP (1) JPS5686116A (en)
AT (1) AT371997B (en)
AU (1) AU535357B2 (en)
BE (1) BE886008A (en)
CA (1) CA1165692A (en)
CH (1) CH650930A5 (en)
CY (1) CY1332A (en)
DE (2) DE2945636A1 (en)
DK (1) DK155144C (en)
FI (1) FI72045C (en)
GB (1) GB2062468B (en)
GR (1) GR72128B (en)
HK (1) HK40386A (en)
HU (1) HU183244B (en)
IE (1) IE50372B1 (en)
IL (1) IL61447A (en)
KE (1) KE3623A (en)
MY (1) MY8500165A (en)
PH (1) PH22800A (en)
PT (1) PT72041B (en)
ZA (1) ZA807005B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3227122A1 (en) * 1982-07-20 1984-01-26 Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim STABLE SOLUTIONS OF MOTHER CORNAL CALOIDS
CH656533A5 (en) * 1982-12-10 1986-07-15 Sandoz Ag THERAPEUTIC PREPARATION CONTAINING HYDRATED ERGOTAL CALOIDS AND LOW MOLECULAR HEPARINE.
DE3432661A1 (en) * 1984-09-05 1986-03-06 Albert Prof. Dr. 6907 Nußloch Landsberger CARCINOM THERAPEUTIC
AT381232B (en) * 1985-05-13 1986-09-10 Kwizda Fa F Johann METHOD FOR PRODUCING STABLE LIQUID SOLUTIONS OF ERGOL DERIVATIVES
PL373033A1 (en) * 2002-06-20 2005-08-08 Novartis Consumer Health S.A. Nasal compositions comprising a mucopolysaccharide and propylene glycol

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2735587A1 (en) * 1977-08-06 1979-02-15 Sandoz Ag STABLE SOLUTIONS AND METHOD FOR THEIR PRODUCTION
DE2625403A1 (en) * 1976-06-05 1977-12-08 Sandoz Ag Antithrombotic association of medicaments - contains heparin and an ergoline-(8)-carboxylic acid peptidic amide esp. dihydroergotamine opt. with polyvinyl pyrrolidone
DE2809618A1 (en) * 1978-03-06 1979-09-20 Sandoz Ag NEW THERAPEUTIC PREPARATION AND METHOD FOR THE PRODUCTION THEREOF
DE2555481C3 (en) * 1975-12-10 1985-10-03 Sandoz-Patent-GmbH, 7850 Lörrach Production of stable drop solutions of hydrogenated ergot alkaloids
DE2945677A1 (en) * 1979-11-12 1981-05-21 Sandoz-Patent-GmbH, 7850 Lörrach Antithrombotic combination of di:hydro:ergotamine cpd. and heparin - administered using a two-chamber system syringe to avoid instability problems on prolonged storage

Also Published As

Publication number Publication date
ZA807005B (en) 1982-06-30
CH650930A5 (en) 1985-08-30
AT371997B (en) 1983-08-25
ATA550480A (en) 1983-01-15
HU183244B (en) 1984-04-28
PT72041A (en) 1980-12-01
DK155144B (en) 1989-02-20
DE2945636A1 (en) 1981-05-21
GB2062468A (en) 1981-05-28
IE802340L (en) 1981-05-12
FI72045B (en) 1986-12-31
IL61447A0 (en) 1980-12-31
GR72128B (en) 1983-09-16
IL61447A (en) 1983-11-30
DK477880A (en) 1981-05-13
JPS5686116A (en) 1981-07-13
PH22800A (en) 1988-12-12
AU535357B2 (en) 1984-03-15
FI803456L (en) 1981-05-13
AU6426580A (en) 1981-05-21
BE886008A (en) 1981-05-04
EP0028813A3 (en) 1982-08-25
CA1165692A (en) 1984-04-17
PT72041B (en) 1982-01-26
GB2062468B (en) 1983-08-24
DE3068719D1 (en) 1984-08-30
JPH021126B2 (en) 1990-01-10
CY1332A (en) 1986-06-27
FI72045C (en) 1987-04-13
MY8500165A (en) 1985-12-31
HK40386A (en) 1986-06-06
KE3623A (en) 1986-05-16
DK155144C (en) 1989-07-03
EP0028813A2 (en) 1981-05-20
EP0028813B1 (en) 1984-07-25

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