DK175832B1 - Ultrasoniske kontrastmidler og fremgangsmåde til fremstilling deraf samt deres anvendelse - Google Patents
Ultrasoniske kontrastmidler og fremgangsmåde til fremstilling deraf samt deres anvendelse Download PDFInfo
- Publication number
- DK175832B1 DK175832B1 DK199001864A DK186490A DK175832B1 DK 175832 B1 DK175832 B1 DK 175832B1 DK 199001864 A DK199001864 A DK 199001864A DK 186490 A DK186490 A DK 186490A DK 175832 B1 DK175832 B1 DK 175832B1
- Authority
- DK
- Denmark
- Prior art keywords
- microparticles
- optionally
- ultrasonic contrast
- synthetic
- preparation
- 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
- A61K49/00—Preparations for testing in vivo
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/228—Host-guest complexes, clathrates, chelates
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nanotechnology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Crystallography & Structural Chemistry (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Molecular Biology (AREA)
- Medical Informatics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Saccharide Compounds (AREA)
- Steroid Compounds (AREA)
Description
DK 175832 B1
Den foreliggende opfindelse angår mikropartikler ifølge krav l's indledning, fremgangsmåder til fremstilling deraf samt deres anvendelse som diagnostika og terapeutika.
5 Det er kendt, at cardiale ekko-kontraster kan opnås ved hjælp af perifer injektion af opløsninger, der indeholder fine gasblærer (J. Roeland, Ultrasound Med. Biol. 8:471-492, 1982). Disse gasblærer opnås i fysiologisk acceptable opløsninger, f.eks. ved hjælp af rystning, anden omrøring eller ved hjælp af carbondioxid. De er imidlertid i henseende til antal og størrelse ikke standardiserede og kan kun reproduceres utilstrækkeligt. End-10 videre er de i reglen ikke stabiliserede, så at deres levetid er ringe. Deres gennemsnitlige diameter ligger for det meste over erythrocytstørrelse, så at ingen lungekapillarpas-sage med efterfølgende kontrastdannelse af organer, såsom venstre hjerte, lever, nyre eller milt, er mulig. Endvidere egner de sig ikke til kvantificeringer, da det af dem frembragte ultralyd-ekko er sammensat af flere processer, der ikke kan adskilles fra 15 hinanden, såsom blæredannelse, sammensmeltning og opløsning. Det er således f.eks.
ikke muligt ved hjælp af disse ultralydkontrastmidler via måling af kontrastforløbet i myocardiet at opnå udsagn med hensyn til transittiderne. Hertil kræves kontrastmidler, hvis spredningslegemer ikke er underkastet nogen egen kinetik.
20 Endvidere findes der ultralydkontrastmidler i form af partikler (Ophir, Gobuty, Mc
Whirt og Maklad, Ultrasonic Backscatter from Contrast-producing Collagen Micro-spheres, Ultrasonic Imaging 2:66-67, 1980). Endvidere anvendes (Ophir, Mc Whirt,
Maklad, Aqueous Solutions as Potential Ultrasonic Contrast Agents, Ultrasonic Imaging 1:265-279, 1979, samt Tyler, Ophir og Maklad, In-vivo Enhancement of Ultraso-25 nic Image Luminance by Aqueous Solutions with High Speed of Sound, Ultrasonic Imaging 3:323-329, 1981) opløsninger med højere massefylde som ultralyd-kontrast-midler. Det er også kendt at anvende emulsioner som ultralydkontrastmidler (Mattrey og Andre, Ultrasonic Enhancement of Myocardial Infarction with Perfluorcarboncom-pounds in Dogs, Am. J. Cardiol. 54:206-210,1984).
30 DK 175832 B1 2
Det har vist sig, at de gasfrie kontrastmidler alt i alt kun har en ringe effektivitet. De gasholdige præparater har ulempen af en kun ringe stabilitet in-vivo. Derudover er størrelsen af gasblæreme for det meste ikke standardiserbar. Tilstrækkelige kontrasteffekter er i al almindelighed ikke mulige i det arterielle karsystem efter perifer venøs injek-5 tion.
I EP A2 123 235 og 0 122 624 beskrives gasblæreholdige ultralydkontrastmidler, som kan passere lungekapillareme og dermed bevirke den ønskede kontrastvirkning.
10 EP A2 0 224 934 beskriver ultralyd-kontrastmidler i form af gasfyldte gelatine- eller al-bumin-hullegemer. Anvendelsen af legemsfremmede eller legemets egne denaturerede æggehvider er imidlertid uheldig på grund af den dermed forbundne allergene risiko.
Med intet af de hidtil kendte ultralydkontrastmidler lykkes det at vise et organ med til-15 strækkelig signalintensitet ved hjælp af selektiv koncentrering efter intravenøs indgivelse. Kvantificeringer er derfor i øjeblikket ikke mulige.
Opfindelsen tager sigte på at angive ultralyd-kontrastmidler på basis af mikropartikler, der foruden voluminer, der kan bestemmes og reproduceres, har en væsentlig længere 20 levetid end hidtil kendt, har god forligelighed uden allergent potentiale og kan koncentreres intracellulært i RES og dermed også i leveren eller milten.
Ifølge opfindelsen opnås dette ved hjælp af mikropartikler, som består af en syntetisk, bionedbrydelig polymer og en gas og/eller en væske med et kogepunkt under 60°C.
25
Som syntetiske, bionedbrydelige polymerer kan nævnes polyestere af o, β-, γ- eller e-hydroxycarboxylsyrer, polyalkylcyanoacrylater, polyaminosyrer, polyamider, poly-acrylerede saccharider eller polyorthoestere.
30 Særligt egnede har 3 DK 175832 B1 polymælkesyre, poly-€-caprol acton, copolymerer af mælkesyrer og glycolsyre eller e-caprolacton, polyhydroxysmørsyre, polyhydroxyvalerianesyre, copolymerer af hydro* xysmør- og hydroxyvalerianesyre, polymerer af glutaminsyre og/eller lysin, polydioxa-non, polymerer eller copolymerer af aminosyrer og/eller terephthalsyre, phthalsyre eller 5 sebacylsyre, polyacryldextran, polyacrylstivelse, polyacrylamid, polyurethan, polyester, polyacetal, polyaminotriazol eller polyalkylcyanoacrylater vist sig at være.
10 Mikropartikleme indeholder gasser og/eller væsker med et kogepunkt under 60°C i fri eller bundet form. Anvendelsen af en gas-væske-blanding i ultralyd-kontrastmidleme er ligeledes mulig.
Som gasser kan eksempelvis anvendes luft, nitrogen, ædle gasser, hydrogen, carbondi-15 oxid, ammoniak, oxygen, methan, ethan, propan, butan, ethylen eller andre hydrocar-boner eller blandinger deraf.
Som inkluderbare væsker anvendes fortrinsvis 20 1,1-dichlorethylen, 2-methyl-2-buten, isopropylchlorid, 2-methyl-l,3-butadien, 2-bu-tyn, 2-methyl-l-buten, dibromdifluormethan, furan, 3-methyl-l-buten, isopentan, di-ethylether, 3,3-dimethyl-1-butyn, dimethylaminoacetone, propylenoxid, N-ethylme-thylamin, brommethan, N-ethyldimethylamin, methylenchlorid, pentan, cyklopentan, 2,3-pentadien og cyklopenten eller blandinger deraf.
25
Mikropartikleme kan fordelagtigt også indeholde materialer med lave damptryk og/eller lave kogepunkter, især etheriske olier.
Ved tilsætning af osmotisk aktive materialer, eksempelvis kogsalt, galactose, glucose 30 eller fructose, kan den fysiologiske isotoni indstilles.
DK 175832 B1 4
Opfindelsen angår også fremgangsmåder til fremstilling af ultralydkontrastmidler, der består af syntetiske, bionedbrydelige polymerer.
En fordelagtig fremgangsmåde til fremstilling af ultrakontrastmidleme ifølge opfindel-5 sen består i, at en polymer eller en copolymer opløses i et eller flere med vand ubland-bare organiske opløsningsmidler og derpå, eventuelt efter tilsætning af yderligere opløsningsmidler, emulgeres i vand, og at den opnåede emulsion derpå filtreres og eventuelt tørres.
10 En yderligere fremgangsmåde består i, at en polymer eller en copolymer opløses i et eller flere gasblæreholdige opløsningsmidler og derpå, eventuelt efter tilsætning af et yderligere opløsningsmiddel eller en yderligere polymer, udfældes eller emulgeres i vand, og at den opnåede suspension eller emulsion derpå filtreres og eventuelt tørres.
Til oparbejdningen er også frysetørringsmetoden egnet.
15
Med fordel kan de opnåede produkter finformales.
Ved den beskrevne fremgangsmåde anvendes som opløsningsmiddel eksempelvis furan, pentan, acetone, dioxan, ethylacetat, xylen, methylenchlorid, cyklohexan eller he-20 xan eller også opløsningsmiddelblandinger. Emulsionen kan også tilsættes emulgatorer.
i
Ifølge en anden variant af fremstillingsmetoden går man ikke ud fra en polymer, men fra monomerer, hvoraf polymeren dannes. Derved arbejdes således, at en monomer opløses i et eller flere organiske opløsningsmidler og emulgeres i 5-30 dele vand eller 25 0,01-0,1 N saltsyre, eventuelt under tilsætning af emulgatorer eller puffermaterialer, ved en temperatur under det organiske opløsningsmiddels kogepunkt, og denne emulsion tilsættes en 0,2%-20% vandig opløsning af en anden monomer eller eventuelt en opløsning af et materiale, der hæver pH-værdien, samt tørres eventuelt.
30 Ved en anden arbejdsmåde opløses eller dispergeres en monomer i en eller flere gasblæreholdige væsker, eventuelt under tilsætning af emulgatorer eller puffermaterialcr.
5 DK 175832 B1
Til denne opløsning eller dispersion sættes eventuelt en 0,2%-20% opløsning af en anden monomer eller et materiale, der hæver pH-værdien, i opløst form eller i gasform, og der tørres eventuelt.
5 Eksempelvis anvendes som første monomer terephthaloyl- eller sebacoylchlorid eller cyanacrylsyreester, som anden monomer L-lysin, og som organisk opløsningsmiddel anvendes eksempelvis 2-methyl-l,3-butadien, dioxan, methylenchlorid, toluen eller cyclohexan.
10 Ifølge en yderligere fremgangsmåde fremstilles ultralyd-kontrastmidleme ved, at gas-blærer frembringes i en 0,5-10% vandig opløsning eller dispersion af en monomer, der eventuelt indeholder yderligere tilsætninger, såsom emulgatorer (0,01- 5%) eller kva-si-emulgatorer (0,1-5%), og at et tværbindende materiale og/eller en reaktionsstarter derpå tilsættes.
15
De i det foregående beskrevne ultralydkontrastmidler kan anvendes både til diagnostiske og til terapeutiske fremgangsmåder.
Administrationen af midlerne sker eksempelvis ved hjælp af injektioner.
20
Opfindelsen belyses ved hjælp af de følgende eksempler.
Eksempel 1 25 500 mg polylactid opløses i 4 ml furan og 0,6 ml cyklohexan, og denne opløsning emulgeres i 40 ml af en 0,1% opløsning af polyoxyethylenpolyoxypropylen-polymer med molekylvægt 12.000 (Pluronic® F127), hvorved temperaturen holdes under 15°C under emulgeringen. Temperaturen hæves derpå langsomt til fordampning af det organiske opløsningsmiddel. Derpå bliver den blandede suspension frysetørret.
30 Eksempel 2 DK 175832 B1 6 300 mg a-cyanacrylsyrebuty]ester opløses i 1 ml furan, og denne opløsning emulgeres i 10 ml 0,1 N saltsyre, der indeholder 1% polyoxyethylenpolypropylen-polymer med molekylvægt 12.000 (Pluronic® F127), hvorved temperaturen under emulgeringen holdes under 150C. Efter polymerisationens afslutning bliver den dannede suspension 5 frysetørret.
Eksempel 3 200 mg ocyanacrylsyrebutylester opløses i 0,4 ml isopren og emulgeres i 30 ml 0,01 N 10 saltsyre, der indeholder 1% polyoxyethylenpolyoxypropylen-polymer med molekylvægt 8.350 (Pluronic® F68), hvorved temperaturen under emulgeringen holdes under 10°C. Efter polymerisationens afslutning neutraliseres suspensionen med 0,1 N NaOH og isotoniseres med natriumchlorid.
15 Eksempel 4 400 mg α-cyanacrylsyrebutylester opløses i 0,4 ml methylenchlorid og emulgeres i 60 ml 0,01 N saltsyre, der indeholder 1% polyoxyethylenpolyoxypropylen-polymer med molekylvægt 12.000 (Pluronic® F127), hvorved temperaturen under emulgeringen 20 holdes under 10°C. Efter polymerisationens afslutning neutraliseres suspensionen med 0,01 natronlud og isotoniseres med natriumchlorid. ^
Eksempel 5 25 400 mg polycaprolacton opløses i 6 ml furan og 0,3 ml cyclohexan samt emulgeres i 60 ml 1% polyoxyethylenpolyoxypropylenpolymer med molekylvægt 12.000 (Pluronic® F127), hvorved temperaturen holdes under 15°C. Temperaturen bliver derpå langsomt hævet til fordampning af det organiske opløsningsmiddel. Derefter ftysetørres den dannede suspension.
30
Eksempel 6 7 DK 175832 B1 400 mg terephthalsyredichlorid opløses i 2 ml faran og emulgeres i 50 ml 3% natrium-carbonatopløsning, der indeholder 0,l% polyoxyethylenpolyoxypropylen-polymer med molekylvægt 12.000 (Pluronic® F127). Efter tilsætning af 60 mg L-lysin, der er opløst 5 i 5 ml 0,1% Pluronic® F127, bliver mikrokapsleme centrifugeret og vasket flere gange med 0,1 % Pluronic® F127-opløsning. Før brugen isotoniseres suspensionen med natri-umchlorid.
Claims (13)
1. Ultralydkontrastmiddel bestående af mikropartikler, kendetegnet ved, at mikropar-5 tikleme består af syntetiske, bionedbrydelige polymerer samt en gas og/eller en væske med et kogepunkt under 60°C.
2. Ultralydkontrastmiddel ifølge krav 1, kendetegnet ved, at mikropartikleme som syntetiske, bionedbrydelige polyestere indeholder polyestere af a-, β-, y-, eller é-hydro- 10 xycarboxylsyrer, polyalkylcyanoacrylater, polyaminosyrer, polyamider, polyacrylerede saccharider eller polyorthoestere.
3. Ultralydkontrastmiddel ifølge ethvert af kravene 1-2, kendetegnet ved, at mikropartikleme som organiske væsker med et kogepunkt under 60°C indeholder 1,1-dichlor- 15 ethyl en, 2-methyl-2-buten, isopropylchlorid, 2-methyl-l,3-butadien, 2-butyn, 2-me-thyl-1-buten, dibromdifluormethan, furan, 3-methyl-l-buten, isopentan, diethylether, 3,3-dimethyl-l-butyn, dimethylaminoacetone, propylenoxid, N-ethylmethylamin, brommethan, N-ethyldimethylamin, methylenchlorid, pentan, cyklopentan, 2,3-pentadi-en, cyklopenten eller blandinger deraf. 20
4. Ultralydkontrastmiddel ifølge mindst et af kravene 1-2, kendetegnet ved, at mikropartikleme som gasser indeholder luft, ædle gasser, nitrogen, oxygen, carbondioxid, hydrogen, ammoniak, ethylen, methan, ethan, propan eller butan eller blandinger deraf.
5. Ultralydkontrastmiddel ifølge mindst et af kravene 1-4, kendetegnet ved, at den fy siologiske isotoni er indstillet ved tilsætning af osmotisk aktive materialer, især kogsalt, mannitol, galactose, glucose og fructose.
6. Fremgangsmåde til fremstilling af ultralydkontrastmidler med mikropartikler af syn-30 tetiske, bionedbrydelige polymerer ifølge ethvert af kravene 1 eller 2-4, kendetegnet ved, at en polymer eller copolymer opløses i et eller flere med vand ublandbare organi- DK 175832 B1 ske opløsningsmidler og derpå, eventuelt efter tilsætning af et yderligere opløsningsmiddel, emulgeres i vand, og den opnåede emulsion derpå filtreres og eventuelt tørres.
7. Fremgangsmåde til fremstilling af ultralydkontrastmidler med mikropartikler af syn-5 tetiske, bionedbrydelige polymerer ifølge ethvert af kravene 1-4, kendetegnet ved, at en polymer eller copolymer opløses i et eller flere opløsningsmidler indeholdende gasblærer og derpå, eventuelt efter tilsætning af et yderligere opløsningsmiddel eller en yderligere polymer, udfældes eller emulgeres i vand, og den opnåede suspension eller emulsion derpå filtreres og eventuelt tørres. 10 S. Fremgangsmåde ifølge krav 6 eller 7, kendetegnet ved, at der som opløsningsmiddel anvendes furan, pentan, acetone, dioxan, ethylacetat, p-xylen, methylenchlorid, cyclohexan eller n-hexan eller en deraf bestående opløsningsmiddelblanding.
9. Fremgangsmåde ifølge krav 6 eller 7, kendetegnet ved, at emulsionen tilsættes en emulgator.
10. Fremgangsmåde til fremstilling af ultralydkontrastmidler med mikropartikler af syntetiske, bionedbrydelige polymerer ifølge ethvert af kravene 1 og/eller 2-4, kende- 20 tegnet ved, at en monomer opløses i et eller flere organiske opløsningsmidler og emulgeres i 5-30 dele vand eller 0,01-0,1 N saltsyre, eventuelt under tilsætning af emulgatorer eller puffermaterialer, ved en temperatur under det organiske opløsningsmiddels kogepunkt, og at denne emulsion tilsættes en 0,2%-20% vandig opløsning af en anden monomer eller eventuelt en opløsning af et materiale, der hæver pH-værdien, og even-25 tuelt tørres.
11. Fremgangsmåde til fremstilling af ultralydkontrastmidler med mikropartikler af syntetiske, bionedbrydelige polymerer ifølge ethvert af kravene 1 og/eller 2-4, kendetegnet ved, at en monomer opløses eller dispergeres i en eller flere gasblæreholdige 30 væsker, eventuelt under tilsætning af emulgatorer og/eller puffermaterialer, og denne opløsning eller dispersion eventuelt tilsættes en 0,2%-20% opløsning af en anden mo- DK 175832 B1 norner eller et materiale i opløst form eller gasform, der hæver pH-værdien, samt eventuelt tørres.
12. Fremgangsmåde ifølge krav 10 eller 11, kendetegnet ved, at der som første mo-5 norner anvendes terephthalyol- eller sebacoylchlorid eller cyanacrylsyreester, som anden monomer anvendes L-lysin og som organisk opløsningsmiddel anvendes 2-me-thyl-l,3-butadien, methylenchlorid, toluen, dioxan eller cyclohexan.
13. Fremgangsmåde til fremstilling af ultralydkontrastmidler med mikropartikler af 10 syntetiske, bionedbrydelige polymerer ifølge ethvert af kravene 1 og/eller 2-4, kendetegnet ved, at gasblærer frembringes i en 0,5-10% vandig opløsning af en monomer, der eventuelt indeholder tilsætninger, såsom emulgatorer (0,01-5%) eller kvasi-emulga-torer (0,1-5%), og at der derpå tilsættes et tværbindende materiale og/eller en reaktionsstarter. 15
14. Anvendelse af mikropartikler ifølge ethvert af kravene 1-5, indeholdende en gas el- j ler en organisk væske og syntetiske bionedbrydelige polymerer til fremstilling af et præparat til ultralyddiagnostik eller -terapi. j 20
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DE3803972 | 1988-02-05 | ||
DE3803971A DE3803971C2 (de) | 1988-02-05 | 1988-02-05 | Ultraschallkontrastmittel |
DE3803971 | 1988-02-05 | ||
DE3803972A DE3803972A1 (de) | 1988-02-05 | 1988-02-05 | Ultraschallkontrastmittel |
PCT/DE1989/000069 WO1989006978A1 (en) | 1988-02-05 | 1989-02-01 | Ultrasonic contrast agents, process for producing them and their use as diagnostic and therapeutic agents |
DE8900069 | 1989-02-01 |
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DK186490D0 DK186490D0 (da) | 1990-08-03 |
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DK199001864A DK175832B1 (da) | 1988-02-05 | 1990-08-03 | Ultrasoniske kontrastmidler og fremgangsmåde til fremstilling deraf samt deres anvendelse |
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EP (3) | EP0586875A1 (da) |
JP (2) | JP2907911B2 (da) |
KR (1) | KR0133132B1 (da) |
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AT (1) | ATE109663T1 (da) |
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CA (1) | CA1336164C (da) |
DE (1) | DE58908194D1 (da) |
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- 1989-02-01 EP EP93112378A patent/EP0586875A1/de not_active Withdrawn
- 1989-02-01 ES ES89901933T patent/ES2068917T3/es not_active Expired - Lifetime
- 1989-02-01 WO PCT/DE1989/000069 patent/WO1989006978A1/de not_active Application Discontinuation
- 1989-02-01 KR KR1019890701826A patent/KR0133132B1/ko not_active IP Right Cessation
- 1989-02-01 EP EP89730021A patent/EP0327490A1/de active Pending
- 1989-02-01 IE IE34389A patent/IE66912B1/en not_active IP Right Cessation
- 1989-02-01 DE DE58908194T patent/DE58908194D1/de not_active Revoked
- 1989-02-01 JP JP1501696A patent/JP2907911B2/ja not_active Expired - Lifetime
- 1989-02-01 EP EP89901933A patent/EP0398935B1/de not_active Revoked
- 1989-02-01 HU HU055/89A patent/HU221485B/hu not_active IP Right Cessation
- 1989-02-03 PT PT89635A patent/PT89635B/pt not_active IP Right Cessation
- 1989-02-03 IE IE940809A patent/IE940809L/xx unknown
- 1989-02-03 IL IL89175A patent/IL89175A/xx not_active IP Right Cessation
- 1989-02-03 CA CA000590059A patent/CA1336164C/en not_active Expired - Fee Related
- 1989-02-04 MY MYPI89000146A patent/MY105856A/en unknown
- 1989-02-04 CN CN89100726A patent/CN1033840C/zh not_active Expired - Fee Related
- 1989-02-07 NZ NZ227869A patent/NZ227869A/xx unknown
-
1990
- 1990-06-11 US US07/536,373 patent/US6264959B1/en not_active Expired - Fee Related
- 1990-08-03 FI FI903865A patent/FI99086C/fi not_active IP Right Cessation
- 1990-08-03 DK DK199001864A patent/DK175832B1/da not_active IP Right Cessation
- 1990-08-06 NO NO903443A patent/NO301260B1/no not_active IP Right Cessation
-
1995
- 1995-06-07 US US08/474,468 patent/US6177062B1/en not_active Expired - Lifetime
- 1995-06-07 US US08/477,642 patent/US6071496A/en not_active Expired - Fee Related
- 1995-11-24 JP JP7306254A patent/JP3027326B2/ja not_active Expired - Lifetime
-
1997
- 1997-02-17 NO NO970732A patent/NO304412B1/no not_active IP Right Cessation
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