DK173552B1 - Use of Prostaglandin E1 Derivatives for the Preparation of Pharmaceutical Preparations for Transcutaneous Administration - Google Patents
Use of Prostaglandin E1 Derivatives for the Preparation of Pharmaceutical Preparations for Transcutaneous Administration Download PDFInfo
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- DK173552B1 DK173552B1 DK198800775A DK77588A DK173552B1 DK 173552 B1 DK173552 B1 DK 173552B1 DK 198800775 A DK198800775 A DK 198800775A DK 77588 A DK77588 A DK 77588A DK 173552 B1 DK173552 B1 DK 173552B1
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Abstract
Description
DK 173552 B1DK 173552 B1
Den foreliggende opfindelse angår anvendelse af prostaglandin-E,-derivater (PGE,-derivater) til fremstilling af farmaceutiske præparater til transkutan indgift.The present invention relates to the use of prostaglandin E, derivatives (PGE, derivatives) for the preparation of pharmaceutical preparations for transcutaneous administration.
DE patentskrift nr. 27 53 986 og det tilsvarende US patentskrift nr. 4.205.178 beskriver 6-keto-prostaglandin-E,-derivater, navnlig 6-keto-PGE,-methylesteren.U.S. Patent No. 27,533,686 and corresponding U.S. Patent No. 4,205,178 disclose 6-keto-prostaglandin-E, derivatives, in particular the 6-keto-PGE, methyl ester.
5 Et antal biologiske og farmakologiske virkninger er beskrevet for disse forbindelser. Forskellige indgiftsveje er angivet for forskellige typer af sygdomme, der skal behandles, f.eks. oral, intravenøs, subkutan, intraarteriel, bukkal, rektal og intravaginal indgift.A number of biological and pharmacological effects are described for these compounds. Different routes of administration are indicated for different types of diseases to be treated, e.g. oral, intravenous, subcutaneous, intra-arterial, buccal, rectal and intravaginal administration.
Fokal administration er beskrevet i forbindelse med hudbeskadigelser og hudsygdomme ved eller i nærheden af stedet for skaden eller sygdommen.Focal administration is described in association with skin damage and skin diseases at or near the site of the injury or disease.
10 6-keto-prostagIandin-Erderivater er også beskrevet i DE patentskrift nr. 28 40 032, hvori der også refereres til forskellige former for farmakologisk aktivitet og administration.10 6-keto-prostaglandin derivatives are also disclosed in DE patent specification 28 40 032, which also refers to various forms of pharmacological activity and administration.
Prostaglandin E, (PGE,) og 6-keto-prostaglandin E, (6-k-PGE,) kan anvendes til behandling af flere sygdomme. Disse sygdomme indbefatter perifere occlusionssygdomme, 15 komplikationer ved ateriosclerose såsom Meniéres sygdom eller akut tab af hørel- se, akut myocardial infarkt, ustabil angina pectoris, akutte iskæmiske slagtilfælde, impotens, bronchial astma, svækket hårvækst og afstødning efter nyretransplantationer; se H. Sin-zinger og W. Rogatti, Prostaglandin E, in atherosclerosis, Springer Verlag, Berlin -Heidelberg - New York, 1986; S. Schrey, PGE,, Therapie der arteriellen Verschluss-20 krankheit, Universitatsdruckerei og Verlag Dr. C. Wolf und Sohn, Miinchen, 1985.Prostaglandin E, (PGE,) and 6-keto-prostaglandin E, (6-k-PGE,) may be used to treat multiple diseases. These diseases include peripheral occlusion diseases, atherosclerosis complications such as Meniere's disease or acute hearing loss, acute myocardial infarction, unstable angina pectoris, acute ischemic stroke, impotence, bronchial asthma, impaired hair growth and rejection; see H. Sinzinger and W. Rogatti, Prostaglandin E, in atherosclerosis, Springer Verlag, Berlin-Heidelberg - New York, 1986; S. Schrey, PGE ,, Therapy of arterial closure-20 disease, Universitatsdruckerei and Verlag Dr. C. Wolf and Son, Miinchen, 1985.
PGE, anvendes til behandling af kroniske, arterielle occlusionssygdomme i fase ΙΠ og IV. Denne tilstand kræver intraarteriel eller intavenøs infusion, som giver en alvorlig begrænsning for anvendelsen af PGE,, da infusionen ikke blot er en belastning for ^— patienten, men også indebærer en vis risiko for arteriel blødning. Ingen af indgiftsvejene 25 (i.a. og i.v.) er velegnede til kontinuerlig behandling ved ambulatorisk patientbehand ling. Imidlertid vil langvarig indgift være det mest passende for disse sygdomme. Den DK 173552 B1 2 orale indgift af PGE, er altid problematisk, da enten en meget lav biologisk tilgængelighed gør en en sådan indgift uanvendelig eller da de typiske uønskede virkninger (kvalme, opkastning, diarre) umuliggør en sådan indgift på grund af den høje koncentration af lægemidlet i fordøjelseskanalen, når det indgives oralt.PGE, is used to treat chronic arterial occlusion diseases in stages ΙΠ and IV. This condition requires intra-arterial or intravenous infusion, which severely limits the use of PGE, as the infusion is not only a burden on the ^ patient, but also involves some risk of arterial bleeding. None of the routes 25 (i.a. and i.v.) are suitable for continuous treatment in ambulatory patient care. However, long-term administration will be most appropriate for these diseases. The DK 173552 B1 2 oral administration of PGE is always problematic, as either a very low bioavailability renders such an administration unusable or as the typical undesirable effects (nausea, vomiting, diarrhea) render such an administration impossible due to the high concentration of the drug in the digestive tract when administered orally.
5 EP-A-132.027 beskriver fedtemulsioner, der indeholder prostaglandin-E^alky lester, og som udviser en blodtrykssænkende virkning. Specielt nævnes methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl- og tert-butylester.EP-A-132,027 discloses fat emulsions containing prostaglandin E1 alky ester and which exhibit a blood pressure lowering effect. In particular, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl ester are mentioned.
C.A. 72: 70628w beskriver virkningen af PGEj-estere, som bronchodilatorer. Specielt nævnes PGErmethylester.C.A. 72: 70628w describes the effect of PGE₂ esters as bronchodilators. In particular, PGErmethyl ester is mentioned.
10 Det er formålet med den foreliggende opfindelse at anvise PGE,-derivater til anvendelse ved fremstilling af farmaceutiske præparater til transkatan indgift. PGE^derivateme, som blev særligt udviklet som farmakologisk aktive midler til transkutan indgift, absorberes af huden og spaltes derefter ved hjælp af hydrolaser til prostaglandin E, eller 6-keto-PGE, og alkohol. PGE,-derivaterne opfylder således kravene til ideen med et 15 "forstadielægemiddel" og undgår ulemperne ved PGE, og 6- keto-PGElT når disse indgives arterielt, intravenøst eller oralt.It is the object of the present invention to provide PGE, derivatives for use in the preparation of pharmaceutical preparations for transcathal administration. The PGE3 derivatives, which were especially developed as pharmacologically active agents for transcutaneous administration, are absorbed by the skin and then cleaved by hydrolases to prostaglandin E, or 6-keto-PGE, and alcohol. Thus, the PGE 1 derivatives fulfill the requirements of the idea of a "precursor drug" and avoid the disadvantages of PGE and 6- keto-PGE 11 when administered arterially, intravenously or orally.
Den foreliggende opfindelse angår således anvendelse af prostaglandin-E,-derivater med en almene formel IThus, the present invention relates to the use of prostaglandin E, derivatives of general formula I
° COOR° COOR
H0' OHH0 'OH
DK 173552 B1 3 hvor R, er et hydrogenatom (PGE,) eller et carbonyloxygenatom (6-k-PGE,) og R2 er en CMalkyIgruppe til fremstilling af et farmaceutisk præparat til transkutan indgift.Wherein R 1 is a hydrogen atom (PGE 1) or a carbon oxygen atom (6-k-PGE 1) and R 2 is a C 1-4 alkyl group for the preparation of a pharmaceutical preparation for transcutaneous administration.
Fig. 1 viser absorptionshastigheden for PGE, og PGE,-ethylester, som er blevet bestemt som den kumulative urinudskillelse efter transkutan administration.FIG. Figure 1 shows the absorption rate of PGE, and PGE, ethyl ester, which has been determined as the cumulative urinary excretion after transcutaneous administration.
5 Specifikke eksempler på alkylgrupper er grupperne methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl og tertiær butyl.Specific examples of alkyl groups are the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertiary butyl groups.
På grund af fragmenternes ugiftighed er den foretrukne gruppe R2 en ethylgruppe.Due to the non-toxicity of the fragments, the preferred group R2 is an ethyl group.
Fremstillingen af forbindelserne med den almene formel I gennemføres i overensstemmelse med i sig selv kendte metoder over forestring af PGE, og 6-k-PGE,. F.eks. frem-10 stilles methylesteren og ethylesteren ved at omsætte udgangsforbindelsen med henholdsvis diazomethan eller diazoethan; se også Ch. J. Sih et al., J. Am. Chem. Soc., bind 97 (1975), side 857 til 865.The preparation of the compounds of general formula I is carried out in accordance with per se known methods of esterification of PGE, and 6-k-PGE. Eg. the methyl ester and the ethyl ester are prepared by reacting the starting compound with diazomethane or diazoethane, respectively; see also Ch. J. Sih et al., J. Am. Chem. Soc., Vol. 97 (1975), pages 857 to 865.
Forbindelserne med den almene formel I kan anvendes til at behandle kredsløbsinsufficiens f.eks. i hjernen, hjertet og i ekstremiteterne, til at inhibere blodpladeaggregation 15 (trombocytaggregation), impotens og til at behandle allergiske reaktioner, såsom bronchial astma, afstødning efter transplantationer og svækket hårvækst. Typiske eksempler på mangler i den cerebrale blodtilførsel er forbigående cerebral iskæmi, akut tab af hørelse, svimmelhed fremkaldt af kredsløbsinsufficiens og iskæmiske slagtilfælde. Typiske eksempler på mangler ved den myocardiale blodtilførsel er angina pectoris og 20 myocardial infarkt. Typiske eksempler på mangler i blodtilførslen til esktremiteteme er perifere arterille kredsløbsinsufficienser ved ateriosclerose og Raynauds sygdom og Reaynauds syndrom.The compounds of general formula I can be used to treat circuit failure, e.g. in the brain, heart, and extremities, to inhibit platelet aggregation (platelet aggregation), impotence, and to treat allergic reactions such as bronchial asthma, post-transplant rejection, and impaired hair growth. Typical examples of deficiencies in cerebral blood supply are transient cerebral ischemia, acute hearing loss, dizziness caused by circulatory insufficiency and ischemic stroke. Typical examples of deficiencies in myocardial blood supply are angina pectoris and 20 myocardial infarction. Typical examples of deficiencies in the blood supply to the ectrochemicals are peripheral arterial circulatory insufficiency in atherosclerosis and Raynaud's disease and Reaynaud's syndrome.
Forbindelserne med den almene formel I kan også anvendes til at behandle gastrointesti-nale ulcerationer og ulcerationer i huden. Typiske eksempler på gastrointestinale ulcera- DK 173552 B1 4 tioner er ulcus ventriculi, duodenale ulcerationer og ulcerativ colitis (Crohn's sygdom).The compounds of general formula I can also be used to treat gastrointestinal ulcerations and skin ulcerations. Typical examples of gastrointestinal ulcers are ulcer ventriculus, duodenal ulcer and ulcerative colitis (Crohn's disease).
Et typisk eksempel på hudulceration er ulcus cruris. Forbindelserne med den almene formel I har en cellebeskyttende virkning. Cellerne udviser forøget resistens mod skadelige stimuleringer.A typical example of skin ulceration is ulcer cruris. The compounds of general formula I have a cell protective effect. The cells exhibit increased resistance to harmful stimuli.
5 Forbindelserne med den almene formel I kan yderligere anvendes til behandling af hæmatomer, navnlig overfladehæmatomer.The compounds of general formula I can be further used to treat hematomas, especially surface hematomas.
Fremstillingen af farmaceutiske præparater gennemføres i overensstemmelse med konventionelle metoder. Til fremstilling af farmaceutiske præparater, der skal indgives transkutant, kan forbindelserne med den almene formel I blandes med en bærer i form 10 af en gel, salve eller en flydende bærer enten med eller uden forskellige opløsningsmidler og stabilisatorer. De anvendte emballager er sprøjtepræparatemballager, rør, glas, ampuller og individuelle doser. Når præparatet først er påført til huden enten med eller uden et yderligere tillukkende forbinding absorberes det aktive middel.The preparation of pharmaceutical compositions is carried out according to conventional methods. For the preparation of pharmaceutical compositions to be administered transcutaneously, the compounds of general formula I may be mixed with a carrier in the form of a gel, ointment or liquid carrier either with or without various solvents and stabilizers. The packages used are syringe preparation packages, tubes, glasses, ampoules and individual doses. Once applied to the skin either with or without a further sealing compound, the active agent is absorbed.
Forbindelserne med den almene formel I kan også anbringes enten med eller uden 15 stabilisatorer og opløsningsmidler på et plaster og kan derpå påføres som sådan.The compounds of general formula I can also be applied either with or without 15 stabilizers and solvents to a patch and can then be applied as such.
Omdannelsen af ethylesteren til PGEi i det menneskelige legeme er blevet demonstreret på følgende måde: en isotopmærket PGErethylester påførtes på den ovenfor beskrevne måde. De isotopmærkede urinære metaboliter blev fraskilt ved hjælp af HPLC og sammenlignet med retentionstiden for hovedmetalboliten af PGEj 20 (7a-hydroxy-5,ll-diketotetranorprosta-l,20-dionsyre). Det viste sig, at efter indgift af PGEj-ethylesteren var hovedmetaboliten identisk med hovedmetaboliten efter indgift af PGE,. Dette beviser, at PGErethylester er et forstadielægemiddel og PGEi.The conversion of the ethyl ester to PGE 1 in the human body has been demonstrated as follows: an isotope labeled PGE ethyl ester was applied in the manner described above. The isotope-labeled urinary metabolites were separated by HPLC and compared with the retention time of the main metal bolite of PGE 2 It was found that after administration of the PGE 2 ethyl ester, the main metabolite was identical to the main metabolite after PGE administration. This proves that PGE ethyl ester is a precursor drug and PGE 1.
De efterfølgende eksempler illustrerer opfindelsen.The following examples illustrate the invention.
Eksempel 1 5 DK 173552 B1Example 1 5 DK 173552 B1
Fremstilling af prostaelandin-Eyethvlester.Preparation of Prostelandin-Eyethyl Ester.
Overskud af diazoethan i diethylether (17 mg/ml; 0,3 mmol) sættes til 500 /xg PGE, (1,31 μπιοί) i 500 μ\ ethanol under omrøring og afkøling. Reaktionsblandingen udtages 5 fra køleren og omrøres, indtil den når stuetemperatur. Omrøringen fortsættes derefter i yderligere 30 minutter. Overskuddet af diazoethan og ethanolen fjernes ved stuetemperatur ved hjælp af en strøm af nitrogen. Produktet renses ved højtryksvæskekromatografi (RP 18).Excess diazoethane in diethyl ether (17 mg / ml; 0.3 mmol) is added to 500 µg PGE, (1.31 μπιοί) in 500 μg ethanol with stirring and cooling. The reaction mixture is taken out of the cooler and stirred until it reaches room temperature. Stirring is then continued for another 30 minutes. The excess diazoethane and ethanol are removed at room temperature by a stream of nitrogen. The product is purified by high-pressure liquid chromatography (RP 18).
På samme måde og med et overskud af diazoethan omsættes 500 /xg 6-keto-PGE, i 500 10 μΐ ethanol og bearbejdes i diethylether. Esteren renses ved højtryksvæskekromatografi (RP 18).Similarly, with an excess of diazoethane, 500 µg of 6-keto-PGE, in 500 10 µl of ethanol, is reacted and processed into diethyl ether. The ester is purified by high-pressure liquid chromatography (RP 18).
Eksempel 2 250 μξ prostaglandin-E,-ethylester sammen med en isotopmærket PGE^ethylester i 250 μ\ ethanol oparbejdedes til 2 g i en gelbærer med den nedenfor viste sammensætning.Example 2 250 µl of prostaglandin E, ethyl ester together with an isotope labeled PGE 2 ethyl ester in 250 µl of ethanol were worked up to 2 g in a gel carrier of the composition shown below.
15 Gelen påførtes på overarmen og blev indgnedet i 1 minut. Påføringsområdet dækkedes med en plastfolie.The gel was applied to the upper arm and rubbed for 1 minute. The application area was covered with a plastic wrap.
En uge senere blev 250 μ$ prostaglandin-E, sammen med isotopmærket PGE, i 250 μΐ ethanol blandet med 2 g af en gelbærer af den nedenfor viste sammensætning. Også denne gel blev påført på overarmen og indgnedet i l minut.One week later, 250 μ $ prostaglandin-E, together with the isotope-labeled PGE, in 250 μΐ ethanol was mixed with 2 g of a gel carrier of the composition shown below. This gel was also applied to the upper arm and rubbed for 1 minute.
20 Måling af den absorberede mængde gennemførtes ved at bestemme de isotopmærkede prostaglandinmetaboliter i urinen. Til dette blev den samlede urin opsamlet i portioner \ fra begyndelsen af påføringen og derefter. 4 timer efter påføringen blev plastfilmenMeasurement of the absorbed amount was performed by determining the isotope-labeled prostaglandin metabolites in the urine. For this, the total urine was collected in portions \ from the beginning of application and thereafter. 4 hours after application, the plastic film
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873704825 DE3704825A1 (en) | 1987-02-16 | 1987-02-16 | PROSTAGLANDIN E1 DERIVATIVES AS PHARMACEUTICAL ACTIVE SUBSTANCES AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, IN PARTICULAR FOR TRANSCUTANEAL USE |
| DE3704825 | 1987-02-16 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK77588D0 DK77588D0 (en) | 1988-02-15 |
| DK77588A DK77588A (en) | 1988-08-17 |
| DK173552B1 true DK173552B1 (en) | 2001-02-26 |
Family
ID=6321070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK198800775A DK173552B1 (en) | 1987-02-16 | 1988-02-15 | Use of Prostaglandin E1 Derivatives for the Preparation of Pharmaceutical Preparations for Transcutaneous Administration |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0292643B1 (en) |
| JP (1) | JPS63246331A (en) |
| AT (1) | ATE80616T1 (en) |
| AU (2) | AU623336B2 (en) |
| CA (1) | CA1327359C (en) |
| DE (2) | DE3704825A1 (en) |
| DK (1) | DK173552B1 (en) |
| ES (1) | ES2043696T3 (en) |
| GR (1) | GR3005743T3 (en) |
| HU (1) | HU199687B (en) |
| ZA (1) | ZA881053B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2939569A (en) * | 1957-10-16 | 1960-06-07 | Gay W Roach | Cotton weighing machine |
| US5530027A (en) * | 1993-02-03 | 1996-06-25 | Teijin Limited | External skin treatment agent composition containing prostacyclins as active ingredient |
| US5656663A (en) * | 1993-02-03 | 1997-08-12 | Teijin Limited | External skin treatment agent composition containing isocarbacyclins as active ingredient |
| US6007836A (en) * | 1993-05-28 | 1999-12-28 | Vericade, Inc. | Transdermal vasodilator |
| FR2812191B1 (en) * | 2000-07-28 | 2003-10-17 | Oreal | USE OF PROSTAGLANDIN E2 RECEPTOR AGONISTS (EP-3) TO ATTENUATE, DECREASE OR STOP HAIR AND HAIR GROWTH IN COSMETIC PREPARATIONS |
| FR2812193B1 (en) * | 2000-07-28 | 2003-10-24 | Oreal | USE OF AN ANTAGONIST OF PROSTAGLANDIN EP-2 AND / OR EP-4 RECEPTORS TO ATTENUATE, DECREASE OR STOP HAIR AND HAIR GROWTH IN COSMETIC PREPARATIONS |
| FR2812192B1 (en) * | 2000-07-28 | 2003-01-31 | Oreal | USE OF PROSTAGLANDIN EP-3 RECEPTOR ANTAGONISTS AS A COSMETIC AGENT FOR MITIGATING, REDUCING OR STOPPING HAIR AND HAIR LOSS |
| FR2812190B1 (en) * | 2000-07-28 | 2003-01-31 | Oreal | USE OF NON-PROSTANOIC AGONISTS OF EP-2 AND / OR EP-4 PROSTAGLANDIN RECEPTORS AS A COSMETIC AGENT FOR MITIGATING, DECREASING OR STOPPING HAIR AND HAIR LOSS |
| JP2006522136A (en) | 2003-04-02 | 2006-09-28 | ネックスメド ホールディングス インコーポレイテッド | Prostaglandin composition and its use for the treatment of vasospasm |
| IT1402047B1 (en) * | 2010-10-19 | 2013-08-28 | Cross Pharma Sa | USE OF MEXIPROSTIL IN THE TREATMENT OF INTESTINAL INFLAMMATORY DISEASES |
| CA2838109C (en) | 2011-04-07 | 2020-06-09 | Nexmed Holdings, Inc. | Topical semisolid prostaglandin e1 composition for treating raynaud's disease |
| US8865685B2 (en) * | 2011-06-30 | 2014-10-21 | Johnson & Johnson Vision Care, Inc. | Esters for treatment of ocular inflammatory conditions |
| ITRM20120036A1 (en) * | 2012-02-02 | 2013-08-03 | Robert Davis Steigerwalt Jr | TRANSDERMAL APPLICATION OF PROSTAGLANDINE E1 FOR THE TREATMENT OF OCULAR ISCHEMIA. |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3735005A (en) * | 1970-08-19 | 1973-05-22 | Alza Corp | Method for preparing a viable platelet concentrate |
| AU511711B2 (en) * | 1976-12-30 | 1980-09-04 | Upjohn Company, The | 6-Oxo and 5, 6-Dihalo prostaglandin analogues |
| US4205178A (en) * | 1976-12-30 | 1980-05-27 | The Upjohn Company | 6-Keto prostaglandin E-type compounds |
| JPS6022710B2 (en) * | 1977-09-16 | 1985-06-03 | 小野薬品工業株式会社 | Prostaglandin-like compounds |
| JPS59216820A (en) * | 1983-05-20 | 1984-12-06 | Taisho Pharmaceut Co Ltd | Fat emulsion of prostaglandin |
| US4707495A (en) * | 1985-10-28 | 1987-11-17 | Ortho Pharmaceutical | Peptic ulcer treatment method |
-
1987
- 1987-02-16 DE DE19873704825 patent/DE3704825A1/en not_active Withdrawn
-
1988
- 1988-02-15 JP JP63032571A patent/JPS63246331A/en active Pending
- 1988-02-15 DE DE88102189T patent/DE3874610D1/de not_active Expired - Lifetime
- 1988-02-15 ES ES88102189T patent/ES2043696T3/en not_active Expired - Lifetime
- 1988-02-15 EP EP88102189A patent/EP0292643B1/en not_active Expired - Lifetime
- 1988-02-15 DK DK198800775A patent/DK173552B1/en not_active IP Right Cessation
- 1988-02-15 AT AT88102189T patent/ATE80616T1/en not_active IP Right Cessation
- 1988-02-16 AU AU11766/88A patent/AU623336B2/en not_active Ceased
- 1988-02-16 ZA ZA881053A patent/ZA881053B/en unknown
- 1988-02-16 CA CA000559004A patent/CA1327359C/en not_active Expired - Fee Related
- 1988-02-16 HU HU88742A patent/HU199687B/en not_active IP Right Cessation
-
1992
- 1992-04-24 AU AU15184/92A patent/AU649130B2/en not_active Ceased
- 1992-09-17 GR GR920402069T patent/GR3005743T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU1518492A (en) | 1992-06-25 |
| AU649130B2 (en) | 1994-05-12 |
| HU199687B (en) | 1990-03-28 |
| ES2043696T3 (en) | 1994-01-01 |
| ZA881053B (en) | 1988-08-12 |
| GR3005743T3 (en) | 1993-06-07 |
| JPS63246331A (en) | 1988-10-13 |
| DK77588A (en) | 1988-08-17 |
| AU623336B2 (en) | 1992-05-14 |
| EP0292643A1 (en) | 1988-11-30 |
| HUT46224A (en) | 1988-10-28 |
| DE3704825A1 (en) | 1988-08-25 |
| EP0292643B1 (en) | 1992-09-16 |
| DK77588D0 (en) | 1988-02-15 |
| DE3874610D1 (en) | 1992-10-22 |
| AU1176688A (en) | 1988-08-18 |
| ATE80616T1 (en) | 1992-10-15 |
| CA1327359C (en) | 1994-03-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |
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