SE445171B - PROCEDURE FOR PREPARING A LIPOSOM SUSPENSION CONTAINING A MEDICINAL PRODUCT - Google Patents
PROCEDURE FOR PREPARING A LIPOSOM SUSPENSION CONTAINING A MEDICINAL PRODUCTInfo
- Publication number
- SE445171B SE445171B SE8000443A SE8000443A SE445171B SE 445171 B SE445171 B SE 445171B SE 8000443 A SE8000443 A SE 8000443A SE 8000443 A SE8000443 A SE 8000443A SE 445171 B SE445171 B SE 445171B
- Authority
- SE
- Sweden
- Prior art keywords
- resins
- liposome suspension
- process according
- groups
- suspension
- Prior art date
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
8000443-5 kolven, som innehåller återstoden som tunt skikt, och det hela underkastas därefter under en tidrymd från 10 sekunder till några timmar för en mekanisk eller ultraljudsskakbehandling. 8000443-5 the flask, which contains the residue as a thin layer, and the whole is then subjected for a period of time from 10 seconds to a few hours for a mechanical or ultrasonic shaking treatment.
Det därvid erhållna dishomogena skiktet, i allmänhet betecknat liposomsuspension, måste renas frân_fysikaliskt icke-bundet läkemedel. 2)' Separation av liposomerna från.fysikaliskt icke-bundet läkemedel: Detta förfarande genomföres vanligen genom eluering på en kromatografisk kolonn under användning av hartser, som uteslutande besitter molekylsiktfunktion, såsom Sepharoseßfl 2B, 4B eller 6B eller liknande.The resulting dishomogenic layer, generally referred to as liposome suspension, must be purified from physically unbound drug. 2) Separation of the liposomes from physically unbound drug: This procedure is usually carried out by elution on a chromatographic column using resins which possess exclusively molecular sieve function, such as Sepharose 2, 2B, 4B or 6B or the like.
Liposomerna utvinnes först under det att det fria läkemedlet hållas kvar av hartset.The liposomes are first recovered while the free drug is retained by the resin.
Därefter följer en ultracentrifugeringsbehandling vid 100 000 g och därefter sker tvättning, alltid genom ultracentrifugering med buffrad lösning. En annan använd metod är dialys.This is followed by an ultracentrifugation treatment at 100,000 g and then washing, always by ultracentrifugation with buffered solution. Another method used is dialysis.
Föreliggande uppfinning avser ett nytt förfarande för rening av det dishomogena, som liposomsuspension kända skiktet såväl med hjälp av flytande som även fasta,syntetiska eller organiska reaktionsbenägna polymerer, som kan användas som jonbytare, exempelvis styren, divinylbensen, akryl- eller metakrylsyra, vilka är kända som jonbytarhartser. a Den exakta mängden av ett eller flera av de ovan anförda hart- serna införes direkt i kolven, vilken innehåller den liposom- suspension som skall renas, varpå den skakas lO - 60 minuter.The present invention relates to a new process for purifying the dishomogeneous layer known as liposome suspension, both by means of liquid and also solid, synthetic or organic reactive polymers, which can be used as ion exchangers, for example styrene, divinylbenzene, acrylic or methacrylic acid, which are known as ion exchange resins. a The exact amount of one or more of the above resins is introduced directly into the flask, which contains the liposome suspension to be purified, after which it is shaken for 10 - 60 minutes.
Efter filtrering genom ett sinterglasfilter, som innehåller jon- bytarhartset med absorberat fysikaliskt icke-bundet läkemedel, erhålles den rena liposomsuspensionen, som kan frystorkas. Detta förfarande för rening av liposomsuspensionen med jonbytarhartser uppvisar den stora fördelen att högkoncentrerade liposomsuspen- sioner (upp till 5 mg/ml Doxorubicin.HCl) kan upprätthållas som icke kunde upprätthållas genom kromatografi på en molekylsikt- kolonn (maximalt 0,3 mg/ml). Den sålunda erhållna liposomsuspen- 8000443-5 sionen är mycket stabil och har icke tendens till sedimentation, såsom är fallet för sådana som erhållits genom ultracentrifuge- ring.After filtration through a sintered glass filter containing the ion-exchange resin with absorbed physically unbound drug, the pure liposome suspension is obtained, which can be lyophilized. This process for purifying the liposome suspension with ion exchange resins has the great advantage that highly concentrated liposome suspensions (up to 5 mg / ml Doxorubicin.HCl) can be maintained which could not be maintained by chromatography on a molecular sieve column (maximum 0.3 mg / ml). . The liposome suspension thus obtained is very stable and does not have a tendency to sedimentation, as is the case for those obtained by ultracentrifugation.
Samma resultat uppnås om man istället för jonbytarhartser an- vänder polymerer och sampolymerer utan någon specifik kemisk funktion, som vanligtvis, men icke uteslutande, reagerar på grund av Van der Waals-krafter och i allmänhet är kända som adsorberande hartser. Dessa hartser kan tack vare polaritets- skillnaden mellan de hydrofoba substanser, som bildar liposom- höljena, och läkemedlen med mer eller mindre hydrofil karaktär användas vid reningen av liposomsuspensioner.The same result is obtained if, instead of ion exchange resins, polymers and copolymers are used without any specific chemical function, which usually, but not exclusively, react due to Van der Waals forces and are generally known as adsorbent resins. These resins can be used in the purification of liposome suspensions due to the difference in polarity between the hydrophobic substances which form the liposome envelopes and the drugs with a more or less hydrophilic character.
Den kemiska slutstabiliseringen uppnås genom frystorkning av liposomsuspensionen.The final chemical stabilization is achieved by lyophilization of the liposome suspension.
Uppfinningen âskådliggöres närmare medelst följande exempel.The invention is further illustrated by the following examples.
Exempel l.Example 1
I en förtvålningskolv löstes följande andelar av lipider i klo- roform och indunstades i vakuum till torrhet: 1,5 gram äggleci- tin, 0,4 gram kolesterin och 0,2 gram dicetylfosfat. En lösning av doxorubicinhydroklorid (i en koncentration av lO mg/ml) i fosfatbuffert 0,007N, hälldes i kolven och blandningen behand- lades under l minut med ultraljud. Suspensionen fick stå i 30 minuter under kväve vid rumstemperatur. 2 gram av en metylmet- akrylat-divinylbensenpolymer, som tidigare aktiverats i natrium- form, med fria karboxylgrupper och makroretikulär struktur, som tillåter dess användning även i hydrofoba lösningar, som kan er- hållas i handeln under beteckningen IRC-Sóškrån firma Rohm & Haas, tillsattes därefter (mängden hänför sig till torr massa och motsvarar 5 ml svälltharts).In a saponification flask, the following proportions of lipids were dissolved in chloroform and evaporated in vacuo to dryness: 1.5 grams of egg lecithin, 0.4 grams of cholesterol and 0.2 grams of dicetyl phosphate. A solution of doxorubicin hydrochloride (at a concentration of 10 mg / ml) in phosphate buffer 0.007N, poured into the flask and the mixture was sonicated for 1 minute. The suspension was allowed to stand for 30 minutes under nitrogen at room temperature. 2 grams of a methyl methacrylate-divinylbenzene polymer, previously activated in sodium form, with free carboxyl groups and macroreticular structure, which allows its use even in hydrophobic solutions, which can be obtained commercially under the name IRC-Sóškrån company Rohm & Haas , was then added (the amount refers to dry mass and corresponds to 5 ml of swelling resin).
Kolven skakades ungefär 30 minuter och därefter filtrerades suspensionen genom en glasfritta.The flask was shaken for about 30 minutes and then the suspension was filtered through a glass frit.
De på detta sätt erhållna liposomerna med olika storlek av 0,5 - ... .-._______....._.___..-.-_.___ 8000443-5 2/lm och med en halt av omkring 60 procent av utgângsmängden av doxorubicin stabiliserades genom frystorkning.The liposomes thus obtained with different sizes of 0.5 - ....-._______....._.___..-.-_.___ 8000443-5 2 / lm and with a content of about 60 percent of the starting amount of doxorubicin was stabilized by freeze-drying.
Exempel 2.Example 2.
Samma förfaringssätt som i exempel l användes, varvid samma an- delar av lipider och doxorubicin användes. Ultraljudskaktiden uppgick dock upp till 10 minuter för att man skulle erhålla liposomer med en storlek av mindre än l/Mm.The same procedure as in Example 1 was used, using the same proportions of lipids and doxorubicin. However, the ultrasound shaking time was up to 10 minutes to obtain liposomes with a size of less than 1 / mm 2.
Eftersom liposomerna icke uppvisade någon fullständigt homogen storlek användes ett icke-granulerat harts som även besitter en Ksiktfunktion. lO ml av ett under beteckningenDowex SQ-X4(É%lOO-200 mesh) i handeln förekommåggåyflšššsæaššårgiIägåšštvar aktiverat i natri- umform, tillsattes för detta ändamål. Efter filtrering erhölls en suspension som innehöll liposomer med en storlek av 0,2 - 0,8/Im och uppvisade 75 procent av utgângsdoxorubicinen. Lipo- somerna stabiliserades genom frystorkning.Since the liposomes did not show a completely homogeneous size, a non-granular resin was used which also possesses a Ksight function. 10 ml of a commercially available Dowex SQ-X4 (É% 100-200 mesh) å šššsæaššårgiIägåšštvar activated in sodium form was added for this purpose. After filtration, a suspension was obtained which contained liposomes with a size of 0.2 - 0.8 .mu.m and showed 75 percent of the starting doxorubicin. The liposomes were stabilized by lyophilization.
Exempel 3.Example 3.
En lösning av 5-fluoruracil i en koncentration av 10 mg/ml i fosfatbuffert 0,007N vid pH 8 hälldes i en förtvålningskolv, som innehöll den lipidfas, som framställts såsom beskrevs oven.A solution of 5-fluorouracil at a concentration of 10 mg / ml in phosphate buffer 0.007N at pH 8 was poured into a saponification flask containing the lipid phase prepared as described above.
Suspensionen behandlades på det i exempel l beskrivna sättet, varvid man som filterharts använde 10 ml av det under bet Ck- . ql .lerël qrsnumarsi ningen Amberlite IRA~40 (Cl) på marknaden förekommande/hartset, som i förväg var aktiverat som hydroklorid.The suspension was treated in the manner described in Example 1, using 10 ml of the filter resin Ck- as the filter resin. ql .lerël qrsnumarsi ning Amberlite IRA ~ 40 (Cl) commercially available / the resin, which was previously activated as hydrochloride.
De sålunda erhållna liposomerna stabiliserades genom frystork- ning.The liposomes thus obtained were stabilized by lyophilization.
Exempel 4.Example 4.
Liposomerna av 5-fluoruracil framställdes, såsom ovan beskrevs, med följande andelar av lipider: 1,5 gram ägglecitin, 0,6 gram kolesterin, 0,2 gram stearylamin.The liposomes of 5-fluorouracil were prepared, as described above, with the following proportions of lipids: 1.5 grams of egg lecithin, 0.6 grams of cholesterol, 0.2 grams of stearylamine.
Som reningssystem användes 10 ml av det under beteckningen _. .-.__ ........_.._-_..--__.-__._....- 8000443-5 ,polymera_granglära; Dowex l®(5O - 100 mesh) på marknaden förekommande/hartset, som i förväg aktiverats. De sålunda erhållna liposomerna stabilise- ras genom frystorkning.As a purification system, 10 ml of it was used under the designation _. .-.__ ........_.._-_.. - __.-__._....- 8000443-5, polymera_granglära; Dowex l® (5O - 100 mesh) on the market / resin, which has been activated in advance. The liposomes thus obtained are stabilized by freeze-drying.
Exempel 5.Example 5.
Exempel 2 upprenañes varvid dock Dowexyhartset ersattes med polymeraigranulagë® gram av det adsorberande/hàrtset"XÄD från firmaRohm & Haas och skaktiden förlängdes till 40 minuter.Example 2 is purified, however, replacing the Dowexy resin with polymeraigranulagë® gram of the adsorbent / resin "XÄD" from Rohm & Haas and the shaking time was extended to 40 minutes.
Efter filtrering genom en glasfritta G l erhölls en liposom- suspension med en halt av omkring 50 procent av utgångsmängden av doxorubicin. Liposomerna stabiliserades genom frystorkning.After filtration through a glass frit G 1, a liposome suspension with a content of about 50 percent of the starting amount of doxorubicin was obtained. The liposomes were stabilized by lyophilization.
Exempel 6. 1,5 gram sojalecitin, 0,4 gram kolesterin och 0,3 gram dicetyl- fosfat löstes i CH2Cl2 och till denna lösning sattes en lös- ning av aminosidinsulfat.i 0,02M fosfatbuffert vid pH 6,5 i en koncentration av 3 mg/ml.Example 6. 1.5 grams of soy lecithin, 0.4 grams of cholesterol and 0.3 grams of dicetyl phosphate were dissolved in CH 2 Cl 2 and to this solution was added a solution of aminosidine sulfate in 0.02 M phosphate buffer at pH 6.5 in a concentration of 3 mg / ml.
De båda faserna emulgerades och emulsionen skakades varpå kväve vid rumstemperatur genomblåstes tills metylenkloriden fullstän- digt avlägsnats.The two phases were emulsified and the emulsion was shaken and nitrogen was purged at room temperature until the methylene chloride was completely removed.
Suspensionen stabiliserades 4 timmar vid rumstemperatur, varpå i kolven hälldes en andel harts motsvarande 5 gram torrt harts, som i handeln kan erhållas under beteckningen IRC-50 från firma Rohm & Haas.The suspension was stabilized for 4 hours at room temperature, after which a proportion of resin corresponding to 5 grams of dry resin, which can be obtained commercially under the name IRC-50 from Rohm & Haas, was poured into the flask.
Efter l timmes skakning filtrerades liposomsuspensionen genom en glasfritta för avlägsnande av hartset, som håller kvar det fysikaliskt.icke bundna läkemedlet. Liposomsuspensionen stabi- liserades sedan genom frystorkning.After shaking for 1 hour, the liposome suspension was filtered through a glass frit to remove the resin retaining the physically unbound drug. The liposome suspension was then stabilized by lyophilization.
Exempel 7 Med smmna tillvägagångssätt som beskrevs i exempel 6 löstes 2,3 granlecitin från ägg, 0,65 gram kolesterol och 0,15 gram oktadecylamin i 50 ml metylenklorid och lösningen hälldes i 8000443-5 en kolv som innehöll 250 mg m-bensoylhydratropsyra.(generiskt namn ketoprofen) i 150 ml Na, K-buffertfosfat 0,02M vid pH 7,4.Example 7 Using the same procedure described in Example 6, 2.3 granules of egg, 0.65 grams of cholesterol and 0.15 grams of octadecylamine were dissolved in 50 ml of methylene chloride, and the solution was poured into a flask containing 250 mg of m-benzoyl hydratropic acid. (generic name ketoprofen) in 150 ml Na, K buffer phosphate 0.02M at pH 7.4.
Inert gas (kväve) fick strömma in i kolven som hölls under skakning tills fullständigt avlägsnande av det organiska lös- ningsmedlet och resulterande bildning av liposomsuspension täll vilken sattes lO ml anjonbytarharts IRA 400 (klorid) till- verkat av Rohm & Haas. Efter 30 minuters skakning avlägsnades hartset genom filtrering och den renade liposomsuspensionen lyofiliserades.Inert gas (nitrogen) was allowed to flow into the flask which was kept under shaking until complete removal of the organic solvent and resulting formation of liposome suspension to which was added 10 ml of IRA 400 anion exchange resin (chloride) manufactured by Rohm & Haas. After shaking for 30 minutes, the resin was removed by filtration and the purified liposome suspension was lyophilized.
Claims (7)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT19434/79A IT1110989B (en) | 1979-01-19 | 1979-01-19 | PHARMACEUTICAL FORMS CONSTITUTED BY LIPOSOMES AND RELATED PROCEDURES |
Publications (2)
Publication Number | Publication Date |
---|---|
SE8000443L SE8000443L (en) | 1980-07-20 |
SE445171B true SE445171B (en) | 1986-06-09 |
Family
ID=11157905
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SE8000443A SE445171B (en) | 1979-01-19 | 1980-01-18 | PROCEDURE FOR PREPARING A LIPOSOM SUSPENSION CONTAINING A MEDICINAL PRODUCT |
Country Status (21)
Country | Link |
---|---|
JP (1) | JPS55100313A (en) |
AT (1) | AT370623B (en) |
AU (1) | AU536823B2 (en) |
BE (1) | BE881225A (en) |
CA (1) | CA1148470A (en) |
CH (1) | CH648205A5 (en) |
CS (1) | CS227010B2 (en) |
DE (1) | DE3001842A1 (en) |
DK (1) | DK157060C (en) |
FI (1) | FI70672C (en) |
FR (1) | FR2446635B1 (en) |
GB (1) | GB2041871B (en) |
HU (1) | HU184714B (en) |
IE (1) | IE49141B1 (en) |
IL (1) | IL59120A (en) |
IT (1) | IT1110989B (en) |
NL (1) | NL8000139A (en) |
SE (1) | SE445171B (en) |
SU (1) | SU1367839A3 (en) |
YU (1) | YU44003B (en) |
ZA (1) | ZA80269B (en) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU184141B (en) * | 1979-12-27 | 1984-07-30 | Human Oltoanyagtermelo | Adjuvant particles compositions containing said particles and biologically active substances adsorbed thereon and a process for the preparation thereof |
FR2521565B1 (en) * | 1982-02-17 | 1985-07-05 | Dior Sa Parfums Christian | PULVERULENT MIXTURE OF LIPID COMPONENTS AND HYDROPHOBIC CONSTITUENTS, METHOD FOR PREPARING SAME, HYDRATED LIPID LAMELLAR PHASES AND MANUFACTURING METHOD, PHARMACEUTICAL OR COSMETIC COMPOSITIONS COMPRISING HYDRATED LAMID PHASES |
FR2553002B1 (en) * | 1983-10-06 | 1992-03-27 | Centre Nat Rech Scient | IMPROVED PROCESS FOR OBTAINING UNILAMELLAR LIPOSOMES OF HIGH DIAMETERS, THEIR PHARMACOLOGICAL APPLICATION FOR THE ENCAPSULATING OF AN ACTIVE INGREDIENT FOR ITS EXTEMPORANEOUS ADMINISTRATION AND CORRESPONDING DEVICE |
CA1270198C (en) * | 1984-08-08 | 1990-06-12 | Marcel B Bally | Encapsulation of antineoplastic agents in liposomes |
US5736155A (en) * | 1984-08-08 | 1998-04-07 | The Liposome Company, Inc. | Encapsulation of antineoplastic agents in liposomes |
US4755388A (en) * | 1984-11-09 | 1988-07-05 | The Regents Of The University Of California | Liposome-encapsulated 5-fluoropyrimidines and methods for their use |
IL79114A (en) * | 1985-08-07 | 1990-09-17 | Allergan Pharma | Method and composition for making liposomes |
US6406713B1 (en) * | 1987-03-05 | 2002-06-18 | The Liposome Company, Inc. | Methods of preparing low-toxicity drug-lipid complexes |
AU660288B2 (en) * | 1990-07-31 | 1995-06-22 | Transave, Inc. | Accumulation of amino acids and peptides into liposomes |
DE4107152C2 (en) * | 1991-03-06 | 1994-03-24 | Gregor Cevc | Preparations for non-invasive administration of antidiabetics |
DE4107153A1 (en) * | 1991-03-06 | 1992-09-10 | Gregor Cevc | Compsns. for application of active agents |
JPH04127874U (en) * | 1991-05-13 | 1992-11-20 | 株式会社新潟鐵工所 | Pressure noise mitigation device for concrete pump transport pipes |
JPH04134673U (en) * | 1991-06-07 | 1992-12-15 | 株式会社フジタ | Concrete pumping pressure fluctuation prevention device |
WO1994022430A1 (en) * | 1993-04-02 | 1994-10-13 | The Liposome Company, Inc. | Method of producing liposomes |
IT1270678B (en) * | 1994-10-20 | 1997-05-07 | Bayer Ag | KETOPROFEN LIPOSOMES |
DE19639811A1 (en) * | 1996-09-27 | 1998-04-02 | Artur Herzog Dr Mesmer | Use of a liposome solution to enhance the effectiveness and / or decrease the toxicity of drugs |
CN1278738A (en) | 1997-11-10 | 2001-01-03 | 久光制药株式会社 | Release-sustaining agent for drugs and sustained-release pharmaceutical composition containing same |
JP4283355B2 (en) * | 1997-11-10 | 2009-06-24 | 久光製薬株式会社 | Pharmaceutical sustained-release agent and sustained-release pharmaceutical composition containing the same |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2249552A1 (en) * | 1971-10-12 | 1973-05-30 | Inchema S A | PROCESS FOR THE INCAPSULATION OF IN PARTICULAR WATER-SOLUBLE COMPOUNDS |
JPS5126213A (en) * | 1974-08-21 | 1976-03-04 | Tanabe Seiyaku Co | JOHOSEIBIRYUSHISEIZAINO SEIHO |
US4131815A (en) * | 1977-02-23 | 1978-12-26 | Oceanography International Corporation | Solid piezoelectric sand detection probes |
GB1575343A (en) * | 1977-05-10 | 1980-09-17 | Ici Ltd | Method for preparing liposome compositions containing biologically active compounds |
AU528260B2 (en) * | 1977-09-30 | 1983-04-21 | Farmitalia Carlo Erba S.P.A. | Liposomic suspension |
-
1979
- 1979-01-19 IT IT19434/79A patent/IT1110989B/en active
-
1980
- 1980-01-09 NL NL8000139A patent/NL8000139A/en not_active Application Discontinuation
- 1980-01-14 JP JP219280A patent/JPS55100313A/en active Granted
- 1980-01-14 AU AU54581/80A patent/AU536823B2/en not_active Ceased
- 1980-01-14 YU YU81/80A patent/YU44003B/en unknown
- 1980-01-14 IL IL59120A patent/IL59120A/en unknown
- 1980-01-15 FR FR808000801A patent/FR2446635B1/en not_active Expired
- 1980-01-15 CS CS80309A patent/CS227010B2/en unknown
- 1980-01-15 AT AT0019380A patent/AT370623B/en not_active IP Right Cessation
- 1980-01-15 CA CA000343663A patent/CA1148470A/en not_active Expired
- 1980-01-16 IE IE91/80A patent/IE49141B1/en unknown
- 1980-01-16 ZA ZA00800269A patent/ZA80269B/en unknown
- 1980-01-17 SU SU802869298A patent/SU1367839A3/en active
- 1980-01-17 CH CH370/80A patent/CH648205A5/en not_active IP Right Cessation
- 1980-01-17 HU HU8097A patent/HU184714B/en not_active IP Right Cessation
- 1980-01-17 GB GB8001545A patent/GB2041871B/en not_active Expired
- 1980-01-17 FI FI800151A patent/FI70672C/en not_active IP Right Cessation
- 1980-01-18 DE DE19803001842 patent/DE3001842A1/en active Granted
- 1980-01-18 SE SE8000443A patent/SE445171B/en not_active IP Right Cessation
- 1980-01-18 BE BE0/199021A patent/BE881225A/en not_active IP Right Cessation
- 1980-01-18 DK DK022380A patent/DK157060C/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
CH648205A5 (en) | 1985-03-15 |
HU184714B (en) | 1984-10-29 |
AU5458180A (en) | 1980-07-24 |
YU44003B (en) | 1990-02-28 |
FR2446635A1 (en) | 1980-08-14 |
SU1367839A3 (en) | 1988-01-15 |
ATA19380A (en) | 1982-09-15 |
IE49141B1 (en) | 1985-08-07 |
FI70672C (en) | 1986-10-06 |
NL8000139A (en) | 1980-07-22 |
DK157060C (en) | 1990-04-09 |
GB2041871A (en) | 1980-09-17 |
AU536823B2 (en) | 1984-05-24 |
IE800091L (en) | 1980-07-19 |
ZA80269B (en) | 1981-06-24 |
SE8000443L (en) | 1980-07-20 |
GB2041871B (en) | 1983-04-13 |
DE3001842C2 (en) | 1990-04-26 |
FI70672B (en) | 1986-06-26 |
IT1110989B (en) | 1986-01-13 |
DK157060B (en) | 1989-11-06 |
IL59120A (en) | 1984-05-31 |
DE3001842A1 (en) | 1980-07-31 |
JPS55100313A (en) | 1980-07-31 |
YU8180A (en) | 1983-12-31 |
IT7919434A0 (en) | 1979-01-19 |
FR2446635B1 (en) | 1989-03-10 |
BE881225A (en) | 1980-07-18 |
DK22380A (en) | 1980-07-20 |
CA1148470A (en) | 1983-06-21 |
CS227010B2 (en) | 1984-04-16 |
IL59120A0 (en) | 1980-05-30 |
JPH0133446B2 (en) | 1989-07-13 |
AT370623B (en) | 1983-04-25 |
FI800151A (en) | 1980-07-20 |
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