IE65925B1 - Aqueous pharmaceutical formulations of erythropoietin and the use thereof - Google Patents
Aqueous pharmaceutical formulations of erythropoietin and the use thereofInfo
- Publication number
- IE65925B1 IE65925B1 IE154991A IE154991A IE65925B1 IE 65925 B1 IE65925 B1 IE 65925B1 IE 154991 A IE154991 A IE 154991A IE 154991 A IE154991 A IE 154991A IE 65925 B1 IE65925 B1 IE 65925B1
- Authority
- IE
- Ireland
- Prior art keywords
- erythropoietin
- epo
- physiologically tolerated
- formulation
- aqueous
- Prior art date
Links
- 102000003951 Erythropoietin Human genes 0.000 title claims abstract description 45
- 108090000394 Erythropoietin Proteins 0.000 title claims abstract description 45
- 229940105423 erythropoietin Drugs 0.000 title claims abstract description 45
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 239000000654 additive Substances 0.000 claims abstract description 6
- 229910001508 alkali metal halide Inorganic materials 0.000 claims abstract description 6
- 150000008045 alkali metal halides Chemical class 0.000 claims abstract description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 238000009472 formulation Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 230000000087 stabilizing effect Effects 0.000 claims description 5
- 239000012062 aqueous buffer Substances 0.000 claims description 4
- 239000007853 buffer solution Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 229910000318 alkali metal phosphate Inorganic materials 0.000 claims 2
- 239000013011 aqueous formulation Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 238000007920 subcutaneous administration Methods 0.000 abstract description 6
- 238000007918 intramuscular administration Methods 0.000 abstract description 5
- 239000008363 phosphate buffer Substances 0.000 abstract description 5
- 102000004169 proteins and genes Human genes 0.000 abstract description 5
- 108090000623 proteins and genes Proteins 0.000 abstract description 5
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 abstract description 4
- 101000920686 Homo sapiens Erythropoietin Proteins 0.000 abstract description 4
- 102000044890 human EPO Human genes 0.000 abstract description 4
- 230000003019 stabilising effect Effects 0.000 abstract 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108010002885 Polygeline Proteins 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000001641 gel filtration chromatography Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000012475 sodium chloride buffer Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1816—Erythropoietin [EPO]
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
Abstract
Aqueous pharmaceutical formulations of proteins with erythropoietin action, especially of natural human and recombinant human erythropoietin (EPO), are described. Highly purified EPO without foreign proteins or other conventional stabilisers retains at least about 78 % of its original activity at room temperature for at least 1 year in a physiologically tolerated aqueous phosphate buffer which contains a physiologically tolerated alkali metal halide but no other stabilising additives and has a pH of 6 to 8. The products in this aqueous pharmaceutical formulation are particularly suitable for subcutaneous or intramuscular administration.
Description
BEHRINGWERKE AKTIENGESELLSCHAFT HOE 90/B 021 - Ma 787 Dr. LP/VO Description Aqueous pharmaceutical formulations of erythropoietin and the use thereof The invention relates to aqueous pharmaceutical formula5 tions of purified erythropoietin, in particular of human native and of recombinant human erythropoietin (rh EPO).
The formulations of the invention - without foreign proteins, sugars, amino acids or other customary stabilizers - retain at least about 78% of their original activity for at least one year at a temperature of 4-8’C.
Erythropoietin (EPO) is a glycoprotein with 166 amino acids, 3 glycosylation sites at amino-acid positions 24, 38 and 83 and a molecular weight of about 34,000. EPO can either be isolated from natural sources such as human urine (cf., for example, Miyake et al., J. Biol. Chem., vol. 252 (1977), 5558-5564) or be prepared by genetic engineering processes (cf., for example, EP-A 0,148,605 and 0,267,678). Aqueous solutions of erythropoietin are unstable at temperatures from about 3°C to room tempera20 ture.
Patients with kidney failure are unable to form EPO and thus suffer from anemia. Attempts to compensate for this undersupply of EPO by administering EPO and to reduce the symptoms of anemia have already been successful. Further clinical uses comprise administration of hEPO for iatrogenic anemia after chemotherapy or radiotherapy of malignant diseases.
A single dose of EPO amounts to only a few microgrammes. Because of the short half-life after l.v. administration, physiological plasma levels can best be achieved by subcutaneous injection.
The pharmaceutical formulations of erythropoietin hitherto proposed or available contain added detergents and/or proteins, sugars or polyalcohols, which are intended, on the one hand, to stabilize EPO and, on the other hand, to prevent adsorption of EPO onto the inner wall of the storage container (i.e. the ampoule) (EP-B-0,178,576; EP-A-0,178,665; G. Krystal et al.. Blood vol. 67 (1986), 1, 71 - 79). Subcutaneous or i.m. administration of EPO stabilized in this way results in local inflammation with the formation of granulomas. Highly pure EPO prepared by known processes (EP-A-0,236,059; DS-A 4,667,159; PCT/US 86/01342 (= WO 86/07594)) lost more than 25% of Its activity within one week on storage at 24°C. EP-B-0,178,576 also discloses a solution of human erythropoietin, which has been reductively methylated with 14C-formaldehyde, in PBS; cf. Experiment 1 and 2.
The object on which the invention is based is to provide aqueous pharmaceutical formulations of purified erythropoietin which are free of the customary stabilizing additives and nevertheless have adequate stability at temperatures from about 3"C to room temperature and are suitable in particular for subcutaneous or intramuscular administration.
It has been found, surprisingly, that purified erythropoietin (about 99% pure), especially purified native or recombinant human erythropoietin, is stable for a lengthy period at temperatures from 4 to 8 *C in a physiologically tolerated aqueous phosphate buffer of pH 6 to 8 which contains a physiologically tolerated alkali metal halide, but otherwise no stabilizing additives, in sealed test tubes or glass ampoules.
Hence the invention relates to aqueous pharmaceutical formulations of purified erythropoietin in a physiologically tolerated aqueous phosphate buffer of pH 6 to 8 which contains a physiologically tolerated alkali metal halide, but otherwise no stabilizing additives. A buffer composed of 50 mM sodium phosphate, 100 mM NaCl, pH 7.8, is particularly preferred. The concentration of erythropoietin in the aqueous buffer solution is 50 - 1000 μ$ per ml of buffer solution.
Examples of physiologically tolerated aqueous phosphate buffers are sodium phosphate buffer and potassium phosphate buffer, preferably sodium phosphate buffer. Examples of physiologically tolerated alkali metal halides are sodium chloride and potassium chloride, preferably sodium chloride. A preferred phosphate buffer is a buffer containing 50 mM sodium phosphate, 100 mM NaCl, pH 7.8. This buffer is also called PBS for brevity. The aqueous solutions of erythropoietin in PBS are very well suited for subcutaneous or intramuscular administration.
The invention additionally relates to the use of the aqueous pharmaceutical formulations for preparing injection products for subcutaneous or intramuscular administration. Subcutaneous administration is particularly preferred because, by contrast with the known formulations stabilized with proteins, it causes no irritation or inflammatory pain. This has emerged from clinical trials.
The examples illustrate the invention.
Example 1 Purification of rh EPO The purification of rh EPO started from serum-containing or serum-free medium which was conditioned by rh EPOproducing animal cells by the process described in EP-A 0,267,678, page 6, line 45, to page 9, line 5. The process comprises (1) clarification, concentration and dialysis of the culture medium. - 4 (2) ion exchange chromatography, (3) preparative reverse phase HPLC and (4) gel filtration chromatography.
For the gel filtration chromatography, the column was 5 equilibrated with PBS, i.e. 50 mM sodium phosphate buffer, 100 mM NaCl, pH 7.8. With this buffer solution, rh EPO was eluted in a single symmetrical peak (measurement of the eluate at 280 nm). The resulting rh EPO was at least 99% pure according to SDS-PAGE. (5) Dilution The combined rh EPO fractions from the gel filtration step (4) contained 0.1 - 0.8 mg of EPO per ml and were dispensed in single doses of 100 pg/ml using the sodium phosphate/sodium chloride buffer (PBS) pH 7.8.
Example 2 Stability testing The stability of the PBS solution of rh EPO obtained as in Example 1 was tested after storage of the single doses in sterile glass tubes, comparing with various stabili20 zers. The activity of rh EPO was measured by the incorporation of 3T into mouse spleen cells treated with phenylhydrazine in a conventional manner. The data shown in the Table which follows are related to the initial activity of the employed rh EPO = 100%. - 5 (a) Storage at 4 - 8"C Stabilizer Amount of stabilizer % activity (wt./wt. relative to after 12 EPO) based on 100 pg months 5 EPO/ml PBS PBS alone - 78.5 PBS + sorbitol 5000 51 PBS + glycerol 6150 0 10 PBS + Haemaccel* 100 68 (b) Storage at 37°C (accelerated test) Stabilizer Amount of stabilizer % Activity after months 1 2 3 6 15 PBS alone - 86.3 39 11.2 9.9 PBS + sorbitol 5000 33.5 10. 7 5.1 0 PBS + Haemaccel* 100 42 14. 8 6.0 5.1 Note: Haemaccel* is a degraded gelatin The surprisingly . better stabilization of rh EPO in PBS 20 (pH 7.8) without further addition of a stabilizer is evident from the Tables. - 6 HOE 90/B 021
Claims (6)
1. Patent claims: 1. An aqueous pharmaceutical formulation of purified erythropoietin in a physiologically tolerated aqueous buffer solution of pH 6 to 8 which contains a physiologically tolerated alkali metal phosphate * and alkali metal halide, but otherwise no stabilizing additives.
2. A formulation as claimed In claim 1, wherein the aqueous buffer solution is composed of 50 mM sodium phosphate, 100 mM NaCl, pH 7.8.
3. A formulation as claimed in claim 1 or 2, wherein the erythropoietin is human native or recombinant erythropoietin.
4. A formulation as claimed in any of claims 1 to 3, wherein the concentration of erythropoietin is 50 - 1000 μς per ml of buffer solution.
5. The use of an aqueous formulation of purified erythropoietin as claimed in any of claims 1 to 4 for preparing injection products.
6. A process for preparing a stable pharmaceutical formulation of erythropoietin as claimed in claim 1, which comprises dissolving erythropoietin with a purity of £ 99% in a physiologically tolerated aqueous buffer solution of pH 6 to 8, said buffer solution containing a physiologically tolerated alkali metal phosphate and alkali metal halide, but otherwise no stabilizing additives. s: I 8. A formulation as claimed in claim 1, substantially as hereinbefore described and exemplified. A process as claimed in claim 6, substantially as hereinbefore described and exemplified. A stable pharmaceutical formulation of erythropoietin as claimed in claim 1, whenever prepared by a process claimed in claim 6 or 8. /5
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4014654A DE4014654A1 (en) | 1990-05-08 | 1990-05-08 | GALENIC AQUEOUS FORMULATIONS OF ERYTHROPOIETIN AND THEIR USE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE911549A1 IE911549A1 (en) | 1991-11-20 |
| IE65925B1 true IE65925B1 (en) | 1995-11-29 |
Family
ID=6405907
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE154991A IE65925B1 (en) | 1990-05-08 | 1991-05-07 | Aqueous pharmaceutical formulations of erythropoietin and the use thereof |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0456153B1 (en) |
| JP (1) | JP2922331B2 (en) |
| KR (1) | KR100203546B1 (en) |
| AT (1) | ATE120646T1 (en) |
| AU (1) | AU652361B2 (en) |
| CA (1) | CA2041989C (en) |
| DE (2) | DE4014654A1 (en) |
| DK (1) | DK0456153T3 (en) |
| ES (1) | ES2073063T3 (en) |
| IE (1) | IE65925B1 (en) |
| NO (1) | NO301805B1 (en) |
| PT (1) | PT97584B (en) |
| ZA (1) | ZA913435B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9917606A (en) * | 1998-11-06 | 2002-12-31 | Bio Sidus S A | Procedure for the purification of recombinant human erythropoietin from cell culture supernatants and recombinant human erythropoietin obtained with such procedure |
| WO2001087329A1 (en) | 2000-05-15 | 2001-11-22 | F. Hoffmann-La Roche Ag | Liquid pharmaceutical composition containing an erythropoietin derivate |
| DE10234192B4 (en) | 2002-07-26 | 2009-11-26 | Epoplus Gmbh Co.Kg | Use of erythropoietin |
| EP1537876A1 (en) | 2003-12-01 | 2005-06-08 | BioGeneriX AG | Erythropoietin solution formulation |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57149228A (en) * | 1981-03-11 | 1982-09-14 | Ajinomoto Co Inc | Novel erythropoietin and its preparation |
| JPH0686480B2 (en) * | 1983-02-21 | 1994-11-02 | 雪印乳業株式会社 | Monoclonal antibody for erythropoietin production |
| JPS6191131A (en) * | 1984-10-09 | 1986-05-09 | Chugai Pharmaceut Co Ltd | Method and composition for preventing adsorption of pharmaceutical |
| JPS6197229A (en) * | 1984-10-18 | 1986-05-15 | Chugai Pharmaceut Co Ltd | Stable erythropoietin preparation |
| DE3729863A1 (en) * | 1987-09-05 | 1989-03-16 | Boehringer Mannheim Gmbh | STABILIZED ERYTHROPOIETIN LYOPHILISATES |
-
1990
- 1990-05-08 DE DE4014654A patent/DE4014654A1/en not_active Withdrawn
-
1991
- 1991-04-29 AU AU76183/91A patent/AU652361B2/en not_active Expired
- 1991-05-06 DE DE59105075T patent/DE59105075D1/en not_active Expired - Lifetime
- 1991-05-06 KR KR1019910007286A patent/KR100203546B1/en not_active IP Right Cessation
- 1991-05-06 AT AT91107308T patent/ATE120646T1/en not_active IP Right Cessation
- 1991-05-06 ES ES91107308T patent/ES2073063T3/en not_active Expired - Lifetime
- 1991-05-06 EP EP91107308A patent/EP0456153B1/en not_active Expired - Lifetime
- 1991-05-06 DK DK91107308.8T patent/DK0456153T3/en active
- 1991-05-07 ZA ZA913435A patent/ZA913435B/en unknown
- 1991-05-07 PT PT97584A patent/PT97584B/en not_active IP Right Cessation
- 1991-05-07 CA CA002041989A patent/CA2041989C/en not_active Expired - Lifetime
- 1991-05-07 IE IE154991A patent/IE65925B1/en not_active IP Right Cessation
- 1991-05-07 NO NO911788A patent/NO301805B1/en not_active IP Right Cessation
- 1991-05-08 JP JP3131953A patent/JP2922331B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE4014654A1 (en) | 1991-11-14 |
| DE59105075D1 (en) | 1995-05-11 |
| KR100203546B1 (en) | 1999-06-15 |
| ES2073063T3 (en) | 1995-08-01 |
| AU7618391A (en) | 1991-11-14 |
| PT97584B (en) | 1998-08-31 |
| ZA913435B (en) | 1992-02-26 |
| CA2041989A1 (en) | 1991-11-09 |
| EP0456153B1 (en) | 1995-04-05 |
| KR910019636A (en) | 1991-12-19 |
| IE911549A1 (en) | 1991-11-20 |
| JPH04225923A (en) | 1992-08-14 |
| NO911788L (en) | 1991-11-11 |
| CA2041989C (en) | 2001-07-31 |
| PT97584A (en) | 1992-01-31 |
| DK0456153T3 (en) | 1995-08-07 |
| NO301805B1 (en) | 1997-12-15 |
| ATE120646T1 (en) | 1995-04-15 |
| AU652361B2 (en) | 1994-08-25 |
| NO911788D0 (en) | 1991-05-07 |
| JP2922331B2 (en) | 1999-07-19 |
| EP0456153A1 (en) | 1991-11-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |