DK175311B1 - Vanduoplöselige polypeptider - Google Patents
Vanduoplöselige polypeptider Download PDFInfo
- Publication number
- DK175311B1 DK175311B1 DK198805189A DK518988A DK175311B1 DK 175311 B1 DK175311 B1 DK 175311B1 DK 198805189 A DK198805189 A DK 198805189A DK 518988 A DK518988 A DK 518988A DK 175311 B1 DK175311 B1 DK 175311B1
- Authority
- DK
- Denmark
- Prior art keywords
- water
- peptide
- composition according
- pharmaceutical composition
- insoluble
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
Description
i DK 175311 B1
Den foreliggende opfindelse angår farmaceutiske præparater indeholdende terapeutisk aktive, men vanduopløselige polypeptider, hvilke præparater giver en kontinuerlig, reguleret og forlænget afgivelse af sådanne peptider, når de anbringes i fysiologiske omgivelser ved hjælp af implantater eller injektioner under huden eller , 5 i muskulaturen på dyr og mennesker.
Den foreliggende opfindelse angår endvidere anvendelse af bionedbrydelige og bio-kompatible polymerer og copolymerer som matrix, i hvilken de vanduopløselige polypeptider er dispergeret, indesluttet eller indkapslet.
10
Behovet for tilvejebringelse af forlænget afgivelse af peptider til parenteral administration har været erkendt i lang tid (jfr. T.M.S. Chang, "Biodegradable Semipermeable Microcapsules containing enzymes, hormones, vaccines and other biolo-gicals" i 3. Bioengineering 1, 25 (1976); R. Langer, "Controlled Release of Macro-15 molecules" i Chemtech, februar 1982, s. 98-105; F.G. Hutchinson og BJ.A. Furr, "Biodegradable carriers for the sustained release of polypeptides" i TIBTECH, april 1987 (bind 5), s. 102-106).
En række sådanne formuleringer, men anvendt på vandopløselige polypeptider, er 20 beskrevet i EP 0052510, ’’Microencapsulation of water soluble polypeptides’’ og i EP 0058481, "Continuous release pharmaceutical compositions".
I kendte præparater med kontinuerlig peptidafgivelse (EP-A2 0211267) anvendes sådanne peptidsalte, som oprindeligt har høj vandopløselighed.
25
Det hidtil ukendte, overraskende og helt uventede træk ved den foreliggende op- ·» findelse ligger i, at terapeutisk nyttige præparater med landvarig og reguleret afgi-t velse med fordel kan fås ved anvendelse af i det væsentlige vanduopløselige pep tider, som har en umåleligt lav opløselighed i vandig opløsning ved stue- eller 30 legemstemperatur, men giver en effektiv og reguleret afgivelse af sådanne peptider, når præparater deraf administreres parenteralt i fysiologiske, i det væsentlige vandige omgivelser.
Det er en hidtil ukendt og overraskende konsekvens af den foreliggende opfindelse, 35 at polypeptider, der normalt er vandopløselige i naturen eller ved syntetisk frem-
I DK 175311 B1 I
I 2 I
I stilling, med fordel kan gøres vanduopløselige ved dannelse af uopløselige additi- I
I onssalte såsom med pamosyre, garvesyre, stearinsyre og andre ikke-toxiske vand- I
I uopløselige syrer, før de mikroindkapsles eller dispergeres i en bionedbrydelig po- I
I lymermatrix. I
I 5 I
I I
I Anvendelse af tungtopløselige eller vanduopløselige derivater er naturligvis vel- I
I kendt, også inden for peptidområdet (jfr. Schally et al., US 4.010.125, spalte 7, „ I
I linje 25), når der er behov for depotdoseringsformer med langsom afgivelse. I
I 10 Nar bionedbrydelige polymerer såsom polymælkesyre, polyglycolsyre, poly- I
I hydroxysmørsyre, polyorthoestere, polyacetaler og lignende anvendes som læge- I
I middeltransportsystemer, har afgivelse af peptiderne på kontinuerlig måde imid- I
I lertid altid krævet en betydelig vandopløselighed. Beskrevne forsøg har vist, at I
I bionedbrydningen af polymerer (såsom fx polylactid og polylactid-co-glycolid) fører I
I 15 til vandoptagelse og dannelse af vandholdige kanaler eller porer, hvorfra peptider I
I lækker ud, fordi de er vandopløselige. I
I Det har nu overraskende vist sig, at peptider kan afgives fra matricer og mikro- I
I kapsler med et særdeles ønskeligt afgivelsesmønster, når deres vandopløselighed I
I 20 formindskes til praktisk talt nul, hvilket er i modstrid med det, der er beskrevet i I
I den kendte teknik. Det har især ifølge opfindelsen vist sig, at afgivelse af visse I
I peptider såsom D-Trp6 LHRH fra polymere matricer er bedre med hensyn til ensar- I
I tethed og varighed, jo mere vanduopløseligt additionssaltet af peptidet er. I
I 25 "Vanduopløselighed" defineres i nærværende sammenhæng som den mængde I
I peptid, der kan måles i opløsning, når saltet dispergeres eller omrøres i 4 timer i I
I destilleret vand ved temperaturer på 40°C eller derunder, idet en sådan mængde - I
I er 25 mg/l eller derunder (0-25 ppm). I
I i
30 Det er meget ønskeligt at administrere biologisk aktive polypeptider kontinuerligt I
og i et længere tidsrum (fra 1 uge til flere måneder). Det er også meget ønskeligt, I
I at afgivelsesmønsteret reguleres, så at man undgår ujævn afgivelse af peptidet i I
I begyndelsen, i midten eller ved afslutningen af den terapeutiske behandlingscyclus. I
I Det har ofte vist sig, at peptider afgives fra bionedbrydelige matricer i etaper I
Ί DK 175311 B1 3 "bursts", også betegnet "burst-effekter"), enten i begyndelsen af cyclen eller ved afslutningen, når polymermatricen er nedbrudt ved hydrolyse.
Et vigtigt træk ved den foreliggende opfindelse er, at afgivelsesmønsteret regule-5 res, og især at den initiale burst-effekt formindskes. Det vanduopløselige peptid afgives i mindre grad end dets vanduopløselige derivater, hvilket således giver en mere langvarig afgivelsestid, og man undgår at overdosere patienten. Ved at omdanne et normalt vandopløseligt peptid til et uopløseligt peptid kan den initiale burst-effekt begrænses (dvs. den mængde peptid, der afgives i løbet af de første 10 24 timer) ifølge opfindelsen til mindre end 30% af den samlede dosis.
Opfindelsen belyses ved nedenstående eksempler.
15 EKSEMPEL 1 50 g af en copolymer af D,L-lactid og glycolid med et 50/50 molforhold mellem D,L-lactid og glycolid og en gennemsnitlig molekylvægt på 50.000 opløses i 950 g methylenchlorid.
20
Opløsningen ledes gennem et milliporefilter for at fjerne eventuelt partikelformigt stof og pyrogener. Til denne opløsning sættes 1 g D-Trp6-LHRH-pamoat, og der dispergeres med en højforskydningsblander.
25 Den resulterende blanding anbringes i en rotationsfordamper, og hovedparten af methylenchloridet fjernes i vakuum. Den resulterende tykke dispersion hældes på en glasplade og spredes med en justerbar skraber, der er indstillet på 0,7 mm.
Efter lufttørring vakuumtørres den resulterende film i 48 timer og ekstruderes der-30 efter gennem en 0,8 mm åbning ved 70°C under tryk. De resulterende stave formales kryogent ved -40°C.
Det resulterende granulære materiale sigtes gennem en 180 pm sigte, og den fraktion, der passerer igennem, opsamles og steriliseres ved udsættelse for gam-35 mastråling på mellem 2,5 og 2,8 Mrad.
I DK 175311 B1 I
I 4 I
I EKSEMPEL 2 I
I Der gås frem som beskrevet i eksempel 1, idet D-Trp6-LHRH-pamoat I
I erstattes med D-Trp6-LHRH-stearinsyresalt. I
I 5 I
I EKSEMPEL 3 I
I Der gås frem som beskrevet i eksempel 1 under anvendelse af pamoatet af D-Phe- I
I t-:-\ I
I 10 Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 som det vanduopløselige peptid.
I EKSEMPEL 4 I
I 15 Fremgangsmåden ifølge eksempel 1 anvendes med ét af følgende vanduopløselige I
I pamoater: I
I D-Nal(2)6-LHRH-pamoat, I
I D-Ser(O-tBu)6-des-Gly10-Azgly10-LHRH-pamoat, I
I 20 D-Ser(But)6-LHRH(l-9)-ethylamid'pamoat, I
I D-Leu6-des-Giy10-LHRH-ethylamid-pamoat. I
I EKSEMPEL 5 I
I 25 I
I Der gås frem som beskrevet i eksempel 1-4 med D,L-lactid-co-glycolid-polymerer, I
I hvor molforholdet var 67% D,L-lactid, 33% glycolid, 75% D,L-lactid, 25% glycolid - I
I eller 100% D,L-lactid. I
I
I 30 I
I EKSEMPEL 6 I
I Der gås frem som beskrevet i eksempel 1-5 med de vanduopløselige pamoater, I
I tannater eller stearater af ét eller flere af følgende peptider: oxytocin, vasopressin, I
I 35 ACTH, calcitonin, epidermiral vækstfaktor, prolactin, inhibin, interferon, LHRH, so- I
DK 175311 B1 5 mato-statin, insulin, glucagon, atrium-natriuretisk faktor, endorphin, en renin-inhibitor, GHRH, peptid-T eller syntetiske analoge og modifikationer deraf.
Afgivelsesmønster i dyr (rotter) 5
Et typisk afgivelsesmønster for en implanteret formulering af D-Trp6‘LHRH-pamoat i rotter er følgende: ng/ml radioanalyseret D-Trp6'LHRH i plasma (gennemsnit af 6 rotter): (t0) 0,04, (1 time) 7,74, (6 timer) 0,80, (dag 2) 0,85, (dag 4) 0,77, (dag 7) 0,25, (dag 11) 0,12, (dag 14) 0,11, (dag 18) 0,11, (dag 21) 0,14, (dag 25) 10 0,18.
Ovenstående eksempler er ikke en begrænsning af de beskrevne vanduopløselige peptider eller de anvendte bionedbrydelige polymerer, hvilket er klart for fagfolk.
15 De i EP-A-0 211 267 nævnte peptidsalte blev med hensyn til peptidsaltenes vand-opløselighed sammenlignet i nærværende ansøgning:
Forsøgene blev udført ved 25°C. Som standard blev anvendt en opløsning af 5-6 mg af peptidsaltet i 50 ml vand. 10 mg af det i peptidet uopløselige salt blev fyldt 20 op til 10 ml med destilleret vand og omrørt i én time. Efter stabilisering (15 minutter ved 25°C) blev suspensionen centrifugeret og analyseret.
25 1 35
I DK 175311 B1 I
I I
I De vundne koncentrationer fremgår af nedenstående tabel: I
I Salt Peptid Koncentration I
I 5 i mg/ml I
I Myristat MSH 112 I
I Palmitat MSH 121 I
I Stearat MSH 82 I
I 10 Pamoat D-Leu6-des-Gly10-LHRH-ethylamid-pamoat I
I (jvf. Eksempel IV) I
I j \ I
I Pamoat D-Phe-Cys*Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 I
I (Eksempel III) I
I 15 Pamoat D-Trp6-LHR,H-pamoat 7 I
I (Eksempel I) I
I Pamoat Ac-D-Nal-D-pCI-Phe-D-Trp-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-A-La-NH2 4 I
I Som resultat fik man, at vandopløseligheden af de i EP-A-0 211 267 nævnte pep- S
I 20 tidsalte er betydeligt højere end opløseligheden af de peptidsalte, som er nævnt i I
I nærværende beskrivelse. I
I i
Claims (11)
1. Farmaceutisk præparat med en matrix af en bionedbrydelig polymer og et vand-uopløseligt, i matricen dispergeret peptidsalt, hvor polymeren er valgt fra gruppen bestående af polylactider, polyglycolider, copolymerer af mælke- og glycolsyre og mælkesyre og blandinger deraf, og at peptidsaltet har en opløselighed på ikke over ' 30 25 mg/ml, når den i fire timer dispergeres og udrøres i destilleret vand ved 40°C, og hvor præparatet i vandige, fysiologiske omgivelser frigør peptidet kontinuerligt i et tidsrum på mindst én uge, men ikke mere end 30% af den totale mængde peptid i løbet af de første 24 timer.
2. Farmaceutisk præparat ifølge krav 1, r I DK 175311 B1 I I 7 I I kendetegnet ved, at det vanduopløselige peptid er et farmaceutisk accepta- I I belt salt af LHRH eller en syntetisk fremstillet analog deraf. I I 5
3. Farmaceutisk præparat ifølge krav 1 eller 2, I I kendetegnet ved, at det farmaceutisk acceptable salt er valgt fra gruppen I I bestående af pamoater, tannater og stearater. t I
4. Farmaceutisk præparat ifølge krav 1, I I 10 kendetegnet ved, at det vanduopløselige peptid er et farmaceutisk accepta- I I belt salt af oxytocin, vasopressin, ACTH, calcitonin, epidermal vækstfaktor, prolac- I I tin, inhibin, interferon, somatostatin, insulin, glucagon, atrium-natriuretisk faktor, I I endorphin, en renin-inhibitor, væksthormon-afgivelseshormon, peptid-T og synte- I I tiske analoge og modifikationer deraf. I I 15 I
5. Farmaceutisk præparat ifølge et hvilket som helst af kravene 1-3, I I kendetegnet ved, at det vanduopløselige peptid er pamoatet af I Pi I unu 9 L/'ΐψ ^LiirvR. I 20
6. Farmaceutisk præparat ifølge et hvilket som helst af kravene 1-4, I I kendetegnet ved, at det vanduopløselige peptid er pamoatet af D-Phe- I I Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2. I
7. Farmaceutisk præparat ifølge et hvilket som helst af kravene 1-6, I I 25 kendetegnet ved, at det er i form af injicerbare partikler I I med en størrelse i intervallet 1-500 μΓη. I
8. Farmaceutisk præparat ifølge et hvilket som helst af kravene 1-6, I kendetegnet ved, at det er i fast form, er steriliseret ved gammabestråling I I 30 og er egnet til subkutan implantation. I
9. Farmaceutisk præparat ifølge et hvilket som helst af kravene 1-7, I I kendetegnet ved, at det er steriliseret ved gammabestråling og er suspen- I I deret i en farmaceutisk acceptabel bærer, der er egnet til parenteral administrati- I I 35 on. I 8 DK 175311 B1
10. Fremgangsmåde til fremstilling af et præparat ifølge et hvilket som helst af kravene 1-9, kendetegnet ved, at et vanduopløseligt peptidsalt dispergeres i en opløs-5 ning af polylactid, polyglycolid, en copolymer af mælke- og glycolsyre eller en blanding af sådanne polymerer, opløsningsmidlet fjernes ved tørring, og den re-- suiterende blanding formes til faste partikler, der er egnede til parenteral injektion eller subkutan implantation.
11. Fremgangsmåde til fremstilling af et præparat ifølge et hvilket som helst af kravene 1-9, kendetegnet ved, at et vanduopløseligt peptidsalt dispergeres i en opløsning af polylactid, polyglycolid, en copolymer af mælke- og glycolsyre eller en blanding af sådanne polymerer, der tilsættes et coacervationsmiddel, og de resul-15 terende mikrokapsler hældes i en farmaceutisk acceptabel, hærdende væske, hvorefter mikrokapslerne opsamles fra denne suspension. * i _ ____ _____ -
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8722134A GB2209937B (en) | 1987-09-21 | 1987-09-21 | Water insoluble polypeptides |
GB8722134 | 1987-09-21 |
Publications (3)
Publication Number | Publication Date |
---|---|
DK518988D0 DK518988D0 (da) | 1988-09-16 |
DK518988A DK518988A (da) | 1989-03-22 |
DK175311B1 true DK175311B1 (da) | 2004-08-16 |
Family
ID=10624108
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK198805189A DK175311B1 (da) | 1987-09-21 | 1988-09-16 | Vanduoplöselige polypeptider |
Country Status (23)
Country | Link |
---|---|
US (2) | US5192741A (da) |
JP (1) | JPH0713023B2 (da) |
AT (1) | AT397035B (da) |
AU (1) | AU611944B2 (da) |
BE (1) | BE1001685A5 (da) |
CA (1) | CA1326438C (da) |
CH (1) | CH675968A5 (da) |
DE (2) | DE122004000023I2 (da) |
DK (1) | DK175311B1 (da) |
ES (1) | ES2009346A6 (da) |
FI (1) | FI96919C (da) |
FR (1) | FR2620621B1 (da) |
GB (1) | GB2209937B (da) |
GR (1) | GR1002244B (da) |
IE (1) | IE60608B1 (da) |
IL (1) | IL87790A (da) |
IT (1) | IT1225148B (da) |
LU (1) | LU87340A1 (da) |
NL (1) | NL193818C (da) |
NO (2) | NO178604C (da) |
PT (1) | PT88557B (da) |
SE (1) | SE503406C2 (da) |
ZA (1) | ZA886827B (da) |
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DE4223169C1 (de) * | 1992-07-10 | 1993-11-25 | Ferring Arzneimittel Gmbh | Verfahren zur Mikroverkapselung wasserlöslicher Wirkstoffe |
FR2693905B1 (fr) * | 1992-07-27 | 1994-09-02 | Rhone Merieux | Procédé de préparation de microsphères pour la libération prolongée de l'hormone LHRH et ses analogues, microsphères et formulations obtenues. |
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JOP20200068A1 (ar) | 2017-09-26 | 2020-04-27 | Nanomi B V | طريقة لتحضير جسيمات دقيقة بواسطة تقنية مستحلب مزدوج |
CN110123658B (zh) * | 2019-05-22 | 2022-07-15 | 上海璞萃生物科技有限公司 | 一种具有自组装聚集体结构的超分子多肽及其制备方法 |
IT202000017191A1 (it) | 2020-07-15 | 2022-01-15 | Xbrane Biopharma Ab | Procedimento senza acqua per preparare una composizione farmaceutica per un rilascio più prolungato e controllato di triptorelina o di un suo sale |
CN116803378B (zh) * | 2023-08-24 | 2023-11-17 | 北京福元医药股份有限公司 | 一种格列齐特缓释片剂及其制备方法 |
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PH19942A (en) * | 1980-11-18 | 1986-08-14 | Sintex Inc | Microencapsulation of water soluble polypeptides |
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ATE37983T1 (de) * | 1982-04-22 | 1988-11-15 | Ici Plc | Mittel mit verzoegerter freigabe. |
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CH660488A5 (en) * | 1982-12-17 | 1987-04-30 | Sandoz Ag | (Co)oligomeric hydroxycarboxylic acid derivatives, the preparation thereof, and the use thereof in pharmaceutical compositions |
CH661206A5 (fr) * | 1983-09-23 | 1987-07-15 | Debiopharm Sa | Procede pour la preparation d'un medicament destine au traitement de maladies hormonodependantes. |
JPS60100516A (ja) * | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | 徐放型マイクロカプセルの製造法 |
US4547370A (en) * | 1983-11-29 | 1985-10-15 | The Salk Institute For Biological Studies | GnRH Antagonists |
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US4632979A (en) * | 1984-06-18 | 1986-12-30 | Tulane Educational Fund | Therapeutic LHRH analogs |
GB8416234D0 (en) * | 1984-06-26 | 1984-08-01 | Ici Plc | Biodegradable amphipathic copolymers |
US4647653A (en) * | 1984-08-23 | 1987-03-03 | Tulane Educational Fund | Therapeutic peptides |
ZA855567B (en) * | 1984-08-31 | 1986-03-26 | Salk Inst For Biological Studi | Insulin-selective somatostatin analogs |
CH660302A5 (fr) * | 1984-10-17 | 1987-04-15 | Debiopharm Sa | Procede de micro-encapsulation en phase heterogene de substances medicamenteuses hydrosolubles. |
JPS61172813A (ja) * | 1985-01-28 | 1986-08-04 | Japan Atom Energy Res Inst | ポリ乳酸を担体とする徐放性複合体の製造方法 |
EP0190833B1 (en) * | 1985-02-07 | 1991-03-27 | Takeda Chemical Industries, Ltd. | Method for producing microcapsule |
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IL79134A (en) * | 1985-07-29 | 1991-06-10 | American Cyanamid Co | Continuous release peptide implants for parenteral administration |
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DE3734223A1 (de) * | 1987-10-09 | 1989-04-20 | Boehringer Ingelheim Kg | Implantierbares, biologisch abbaubares wirkstofffreigabesystem |
CA2012901A1 (en) * | 1989-04-05 | 1990-10-05 | Quirico Branca | Amino acid derivatives |
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1987
- 1987-09-21 GB GB8722134A patent/GB2209937B/en not_active Expired - Lifetime
-
1988
- 1988-07-04 DE DE122004000023C patent/DE122004000023I2/de active Active
- 1988-07-04 DE DE3822459A patent/DE3822459C2/de not_active Expired - Lifetime
- 1988-09-08 IE IE272788A patent/IE60608B1/en not_active IP Right Cessation
- 1988-09-12 AT AT0223488A patent/AT397035B/de not_active IP Right Cessation
- 1988-09-13 ZA ZA886827A patent/ZA886827B/xx unknown
- 1988-09-13 CA CA000577205A patent/CA1326438C/en not_active Expired - Lifetime
- 1988-09-14 FR FR8811991A patent/FR2620621B1/fr not_active Expired - Lifetime
- 1988-09-16 GR GR880100619A patent/GR1002244B/el not_active IP Right Cessation
- 1988-09-16 DK DK198805189A patent/DK175311B1/da active Protection Beyond IP Right Term
- 1988-09-16 AU AU22326/88A patent/AU611944B2/en not_active Expired
- 1988-09-16 ES ES8802838A patent/ES2009346A6/es not_active Expired
- 1988-09-19 FI FI884297A patent/FI96919C/fi not_active IP Right Cessation
- 1988-09-19 NO NO884154A patent/NO178604C/no not_active IP Right Cessation
- 1988-09-19 IL IL87790A patent/IL87790A/xx active Protection Beyond IP Right Term
- 1988-09-20 PT PT88557A patent/PT88557B/pt not_active IP Right Cessation
- 1988-09-20 CH CH3494/88A patent/CH675968A5/fr not_active IP Right Cessation
- 1988-09-20 SE SE8803321A patent/SE503406C2/sv not_active IP Right Cessation
- 1988-09-20 NL NL8802323A patent/NL193818C/nl not_active IP Right Cessation
- 1988-09-20 BE BE8801079A patent/BE1001685A5/fr not_active IP Right Cessation
- 1988-09-20 US US07/247,060 patent/US5192741A/en not_active Expired - Lifetime
- 1988-09-20 IT IT8805213A patent/IT1225148B/it active
- 1988-09-21 LU LU87340A patent/LU87340A1/fr unknown
- 1988-09-21 JP JP63238626A patent/JPH0713023B2/ja not_active Expired - Lifetime
-
1994
- 1994-02-10 US US08/196,872 patent/US5776885A/en not_active Expired - Lifetime
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2005
- 2005-05-03 NO NO20050012C patent/NO2005012I2/no unknown
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