SK279031B6 - Method of pasteurization of blood plasma product and an agent to carry out this method - Google Patents
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Abstract
Description
Spôsob pasterizácie krvného plazmového produktu, zvoleného zo súboru zahŕňajúceho roztok plazmy na terapeutické použitie na kompenzáciu nedostatku krvných zrážacích faktorov V, XI a XIII, totálnu plazmu na terapeutické použitie a supernatant kryoprecipitovanej plazmy, zbavenej kryoproleínov, spočíva v tom, že sa k plazmového produktu pridajú prísady, zahŕňajúce 500 až 800 g sorbitolu, 100 až 1000 j heparínu, 3 až 5 mmol chloridu vápenatého a 1 až 10 g lyzínu, kde všetky množstvá sú vztiahnuté na jeden liter spracovávaného plazmového produktu. Vzniknutá zmes sa pasterizuje a pridané prísady sa odstránia dialýzou. Prostriedok na uskutočnenie tohto spôsobu je tvorený zmesou sorbitolu, heparínu, chloridu vápenatého a lyzínu v pomere 500 až 800 g : 100 až 1000 j : 3 až 5 mmol: : 1 až 10 g. Riešenie umožňuje pasterizáciu veľkých objemov plazmy, až niekoľko stoviek litrov.A method for pasteurizing a blood plasma product selected from the group consisting of a plasma solution for therapeutic use to compensate for the lack of blood clotting factors V, XI and XIII, total plasma for therapeutic use, and cryoprecipitated plasma-free supernatant is added to the plasma product. additives including 500-800 g sorbitol, 100-1000 µl heparin, 3-5 mmol calcium chloride and 1-10 g lysine, all amounts based on one liter of plasma product to be processed. The resulting mixture was pasteurized and the added ingredients were removed by dialysis. The composition for carrying out the process is a mixture of sorbitol, heparin, calcium chloride and lysine in a ratio of 500 to 800 g: 100 to 1000 µ: 3 to 5 mmol: 1 to 10 g. The solution allows pasteurization of large volumes of plasma, up to several hundred liters.
Oblasť technikyTechnical field
Vynález sa týka spôsobu pasterizácie krvného plazmového produktu, zvoleného zo súboru, zahŕňajúceho roztok plazmy na terapeutické použitie na kompenzáciu nedostatku krvných zrážacích faktorov V, XI a XIII, totálnu plazmu na terapeutické použitie a supernatant kryoprecipitovanej plazmy, zbavenej kryoproteínov a prostriedku na vykonávanie tohto spôsobu.The invention relates to a method of pasteurizing a blood plasma product selected from the group consisting of a plasma solution for therapeutic use to compensate for the lack of blood clotting factors V, XI and XIII, total plasma for therapeutic use, and cryoprecipitated plasma supernatant, depleted cryoproteins.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Totálna ľudská plazma, zbavená kryoproteínov, sa stále používa pri substitučnej terapii u vážne popálených osôb a ťažko zranených pacientov a pacientov po veľkých chirurgických zákrokoch, tzn. vo všetkých prípadoch, kedy dochádza k značnému úbytku tekutín.Total human plasma, freed from cryoproteins, is still used in substitution therapy in severely burned and severely injured patients and patients after major surgery, ie. in all cases where there is a significant loss of fluid.
Pri tomto type terapie sa obyčajne používa plazma od individuálnych darcov, zdravých osôb, prešlých predbežnými testami na vylúčenie rizika prenosu vírusových ochorení. Tento postup však neumožňuje vylúčiť všetky riziká kontaminácie vírusmi v prcscrologickom štádiu, najmä rôznymi vírusmi hepatitídy a vírusom AIDS.In this type of therapy, plasma from individual donors, healthy persons, who have undergone preliminary tests to eliminate the risk of transmission of viral diseases, is usually used. However, this procedure does not exclude all risks of viral contamination in the pre-ecological stage, in particular various hepatitis viruses and AIDS virus.
Bolo by preto výhodné nájsť metódu vírusovej inaktivácie, ktorá by neovplyvňovala rôzne biologické funkcie plazmy.It would therefore be advantageous to find a method of viral inactivation that does not affect the various biological functions of plasma.
Bolo jasne preukázané, že vírus hepatitídy B je kompletne inaktivovaný zahrievaním počas 10 hodín pri 60 °C v prítomnosti 0,5M citrátu sodného (Tábor et al., Thrombosis Res. 22, 1981, 232-238). Táto operácia však vedie k strate biologickej aktivity niektorých proteínov plazmy (Tábor et al. a Barowcliffe et al., Fr. J. Haematology 55, 1983,37-46).It has been clearly shown that hepatitis B virus is completely inactivated by heating for 10 hours at 60 ° C in the presence of 0.5 M sodium citrate (Tábor et al., Thrombosis Res. 22, 1981, 232-238). However, this operation results in a loss of biological activity of some plasma proteins (Tabor et al. And Barowcliffe et al., Fr. J. Haematology 55, 1983, 37-46).
Rôzne proteíny terapeutického významu, získané čistením z krvnej plazmy, bolo možné podrobiť klasickej pasterizácii pri 60 °C počas 10 hodín v prítomnosti rôznych stabilizátorov. Bolo však zistené, že molekuly, ktoré stabilizujú jednu biologickú aktivitu, môžu byť úplne neúčinné proti inej.Various proteins of therapeutic interest, obtained by purification from blood plasma, could be subjected to classical pasteurization at 60 ° C for 10 hours in the presence of various stabilizers. However, it has been found that molecules that stabilize one biological activity may be completely ineffective against another.
Napríklad albumín je možné stabilizovať acetyltryptofánom a kaprylátom (Gellis et al., J. Clin. Invest. 27, 1948, 239-244), ale tieto stabilizátory nemajú žiadny účinok na plazminogén. Trombín môže byť stabilizovaný vysokými koncentráciami glykozidov (Seegers, Asch. Biochem., 3, 1944, 363-367), ktoré však nechránia protrombín. Prídavok aminokyseliny a cukru poskytol dobré výsledky pri faktore VIII a antitrombínu III (patent DE 29 16 711).For example, albumin can be stabilized with acetyltryptophan and caprylate (Gellis et al., J. Clin. Invest. 27, 1948, 239-244), but these stabilizers have no effect on plasminogen. Thrombin can be stabilized by high concentrations of glycosides (Seegers, Asch. Biochem., 3, 1944, 363-367), but which do not protect prothrombin. The addition of amino acid and sugar gave good results for factor VIII and antithrombin III (DE 29 16 711).
Európsky patent 0 035 204 demonštruje stabilizáciu alfa-antitrypsínu, antitrombínu III, prekallikreínu, fibronektínu a faktora VIII v prítomnosti polyolu, ktorého jediným príkladom je sacharóza; ale ukazuje, že za rovnakých podmienok strácajú faktor IX a prekallikrein všetku svoju terapeutickú aktivitu.European Patent 0 035 204 demonstrates the stabilization of alpha-antitrypsin, antithrombin III, precallikrein, fibronectin and factor VIII in the presence of a polyol, the only example of which is sucrose; but shows that under the same conditions, factor IX and precallikrein lose all of their therapeutic activity.
Tieto rôzne experimentálne údaje potvrdzujú všeobecne prijímanú myšlienku, že vírusovú inaktiváciu totálnej plazmy (čerstvej plazmy, zmrazenej čerstvej plazmy alebo supematantu kryoprecipitátu) nie je možné dosiahnuť pasterizáciou.These various experimental data confirm the generally accepted idea that viral inactivation of total plasma (fresh plasma, frozen fresh plasma or cryoprecipitate supernatant) cannot be achieved by pasteurization.
Pretože však trvá lekárska potreba totálnej plazmy, snažil sa prihlasovateľ nájsť zloženie prostriedku, umožňujúceho súčasnú ochranu biologickej aktivity všetkých požadovaných terapeutických faktorov proti denaturácii behom pasterizácie.However, since there is a medical need for total plasma, the Applicant has sought to find a composition which allows simultaneous protection of the biological activity of all desired therapeutic factors against denaturation during pasteurization.
Potom, čo prihlasovateľ zistil, že určitú mieru ochrany pred tepelnou denaturáciou poskytuje sorbitol, ale s vý sledkami, líšiacimi sa od jednej vzorky plazmy k druhej, a s nízkymi výťažkami, rozhodol sa hľadať rôzne prísady, ktorých zmes so sorbitolom by zvýšila jeho stabilizačnú schopnosť.Having found that sorbitol provides some degree of protection against thermal denaturation, but with results varying from one plasma sample to another and with low yields, the Applicant decided to look for various additives whose mixture with sorbitol would enhance its stabilizing ability.
Podstata vynálezuSUMMARY OF THE INVENTION
Predmetom vynálezu je spôsob pasterizácie krvného plazmového produktu, zvoleného zo súboru, zahŕňajúceho roztok plazmy na terapeutické použitie na kompenzáciu nedostatku krvných zrážacích faktorov V, XI a XIII, totálnu plazmu na terapeutické použitie a supernatant kryoprecipitovanej plazmy, zbavenej kryoproteínov, ktorého podstata spočíva v tom. že sa k plazmovému produktu pridajú prísady, zahŕňajúce 500 až 800 g sorbitolu, 100 až 1 000 j heparínu, 3 až 5 mmol chloridu vápenatého a 1 až 10 g lyzínu, kde všetky množstvá sú vztiahnuté na jeden liter spracovávaného plazmového produktu, vzniknutá zmes sa pasterizuje a pridané prísady sa odstránia dialýzou.The present invention provides a method of pasteurizing a blood plasma product selected from the group consisting of a plasma solution for therapeutic use to compensate for the lack of blood clotting factors V, XI and XIII, total plasma for therapeutic use, and cryoprecipitated plasma supernatant deprived of cryoproteins. adding to the plasma product additives comprising 500 to 800 g of sorbitol, 100 to 1000 g of heparin, 3 to 5 mmol of calcium chloride and 1 to 10 g of lysine, all amounts being based on one liter of the processed plasma product, pasteurized and the added ingredients removed by dialysis.
Na jeden liter plazmového produktu sa výhodne pridáva 600 mg sorbitolu, 500 j heparínu, 4 mmol chloridu vápenatého a 4 g lyzínu.Preferably, 600 mg of sorbitol, 500 µl heparin, 4 mmol calcium chloride and 4 g lysine are added per liter of plasma product.
Pasterizácia sa obyčajne vykonáva zahrievaním na 60 ± 1 °C počas 10 hodín. Po pasterizácii sa teplota postupne zníži na 20 °C a potom sa plazmový produkt podrobí dialýze. Dialýza sa uskutočňuje pri pH 7 proti roztoku tlmivého roztoku, obsahujúcemu 4 až 10 mM citrátu sodného, 4mM chloridu vápenatého, 0,13 M chloridu sodného a lyzín s koncentráaciou 4 g/liter. Podľa potreby je možné použiť aj dialyzačné tlmivé roztoky odlišného zloženia. Roztok sa potom zahustí na obnovenie fyziologickej dávky plazmových proteínov. Získaný roztok sa podrobí sterilizačnej filtrácii, kondicionuje a zmrazí alebo lyofilizuje.Pasteurization is usually carried out by heating to 60 ± 1 ° C for 10 hours. After pasteurization, the temperature is gradually reduced to 20 ° C and then the plasma product is subjected to dialysis. The dialysis is performed at pH 7 against a buffer solution containing 4 to 10 mM sodium citrate, 4 mM calcium chloride, 0.13 M sodium chloride and lysine at a concentration of 4 g / liter. Dialysis buffers of different compositions may also be used as desired. The solution is then concentrated to restore a physiological dose of plasma proteins. The solution obtained is subjected to sterilization filtration, conditioned and frozen or lyophilized.
Tento postup je veľmi výhodný, pretože môže byť aplikovaný na veľké dávky plazmy, získané z niekoľkých rôznych odberov. Konkrétne pasterizáciou dávok po 100 až 200 1 alebo viacej je možné po urobení príslušných testov zaručiť ich konštantnú kvalitu.This procedure is very advantageous as it can be applied to large doses of plasma obtained from several different donations. In particular, by pasteurizing batches of 100 to 200 L or more, constant quality can be guaranteed after appropriate tests have been performed.
Predmetom vynálezu je ďalej tiež prostriedok na uskutočnenie uvedeného spôsobu, ktorého podstata spočíva v tom, že je tvorený zmesou sorbitolu, heparínu, chloridu vápenatého a lyzínu v pomeru 500 až 800 g : 100 až 1 000 j: : 3 až 5 mmol : 1 až 10 g.The present invention further provides a composition comprising a mixture of sorbitol, heparin, calcium chloride and lysine in a ratio of 500 to 800 g: 100 to 1000 µ: 3 to 5 mmol: 1 to 5 mmol: 10 g.
Pomer sorbitol : heparin : chlorid vápenatý : lyzín v tomto prostriedku, je prednostne 600 g : 500 j : 4 mmol : 4 g·The sorbitol: heparin: calcium chloride: lysine ratio of the composition is preferably 600 g: 500 µl: 4 mmol: 4 g ·
Príklad uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
K 2 1 roztopenej plazmy sa pridá heparin (1000 U), lyzín (8 g) a chlorid vápenatý (220 mg). Tieto dva produkty sa pridávajú ako soli v práškovej forme za mierneho miešania plazmy. Potom sa postupne prileje 1 200 g nerozpusteného sorbitolu.To 2 L of the molten plasma was added heparin (1000 U), lysine (8 g) and calcium chloride (220 mg). The two products are added as salts in powder form with gentle mixing of the plasma. 1200 g of undissolved sorbitol are then gradually added.
Pasterizácia sa uskutočňuje v 5 1 nádobe zahrievaním počas 10 hodín pri použití vodného kúpeľa alebo termostaticky kontrolovanej nádrže. Po pasterizácii sa sorbitol a heparín odstránia dialýzou na umelej obličke alebo na ultrafiltračnom zariadení, ako je Pellicon, na kazetách, pri použití citrátového tlmivého roztoku, obsahujúceho lyzín s koncentráciou 4 g/1, 4 mM CaCl2 a 0,13 M NaCl. Po dialýze je možné obnoviť pomer koagulačných faktorov na približne 1 U/ml, zodpovedajúci kvalitnej terapeutickej plazme, zahustením na rovnakom zariadení. Produkt sa dialy2 žuje pri osmolarite 370 mOsmol/1 a pH 7. Potom sa produkt podrobí sterilnej filtrácii, napríklad pri použití filtra Millipack 40 (Millipore) s pórmi 0,22 pm. Produkt sa vkladá do plastových vreciek v prípade mrazenia alebo do fliaš v prípade lyoftlizácie.Pasteurization is carried out in a 5 L vessel by heating for 10 hours using a water bath or thermostatically controlled tank. After pasteurization, sorbitol and heparin are removed by dialysis on an artificial kidney or on an ultrafiltration device such as Pellicon on cassettes using citrate buffer containing 4 g / l lysine, 4 mM CaCl 2 and 0.13 M NaCl. After dialysis, the coagulation factor ratio can be restored to approximately 1 U / ml, corresponding to a quality therapeutic plasma, by concentration on the same device. The product is dialyzed at an osmolarity of 370 mOsmol / l and pH 7. The product is then subjected to sterile filtration, for example using a Millipack 40 filter (Millipore) having a pore size of 0.22 µm. The product is placed in plastic bags in the case of freezing or bottles in the case of freeze-drying.
Stabilizácia plazmy behom pasterizácie prídavkom vápniku, heparínu a lyzínu umožňuje v porovnaní (uvedené ako proti) s kontrolným produktom, obsahujúcim len lyzín a sorbitol, tieto výťažky:The stabilization of plasma during pasteurization by the addition of calcium, heparin and lysine allows the following yields compared to (indicated as opposed) to a control product containing only lysine and sorbitol:
lyzínu v pomere 500 až 800 g : 100 až 1 000 j : 3 až 5 mmol: 1 až 10 g.lysine in a ratio of 500 to 800 g: 100 to 1000 µl: 3 to 5 mmol: 1 to 10 g.
8. Prostriedok podľa nároku 7, vyznačujúci sa t ý m, že pomer sorbitol : heparín : chlorid vápenatý : lyzín robí 600 g : 500 j : 4 mmol: 4 g.A composition according to claim 7, wherein the ratio of sorbitol: heparin: calcium chloride: lysine is 600 g: 500 µm: 4 mmol: 4 g.
Koniec dokumentuEnd of document
FVIIIcFVIIIc
FVcFVC
FVIIc FIXc koagulovateľný fibrinogén FXIII % proti 66 % % proti 35 % % proti 52 % % proti 49 % % proti 57%FVIIc FIXc coagulable fibrinogen FXIII% versus 66% versus 35% versus 52% versus 49% versus 57%
77% proti 71 %77% vs 71%
Pri tejto koncentrácii vápnika neboli zistené známky aktivácie koagulačných faktorov. Pomer hovädzí FVII/ koagulačný FVII je 0,95 proti 1,09 pri kontrolnom produkte. Stabilita, skúšaná sledovaním aktivity FVIII po 24 hodinách uchovávania produktu v kvapalnom stave a pri teplote miestnosti, sa proti kontrolnému produktu nezmenila (získaných 100 % aktivity). To je v súlade s pomerom PKA < 2 % pre pasterizovaný a kontrolný produkt.No signs of activation of coagulation factors were found at this calcium concentration. The bovine FVII / coagulation FVII ratio is 0.95 versus 1.09 for the control product. The stability, tested by monitoring FVIII activity after 24 hours of storage of the product in liquid state and at room temperature, did not change against the control product (100% activity obtained). This is consistent with a PKA ratio of <2% for the pasteurized and control product.
Skúšky na potkanoch intravenóznou injekčnou aplikáciou takto pasterizovanej plazmy ukazujú absenciu hypertenzívneho účinku a neindikujú žiadnu zmenu srdcového rytmu.Tests in rats by intravenous injection of such pasteurized plasma show the absence of hypertensive effect and indicate no change in heart rhythm.
PATENTOVÉ NÁROKYPATENT CLAIMS
1. Spôsob pasterizácie krvného plazmového produktu, zvoleného zo súboru, zahŕňajúceho roztok plazmy na terapeutické použitie na kompenzáciu nedostatku krvných zrážacích faktorov V, XI a XIII, totálnu plazmu na terapeutické použitie a supematant kryoprecipitovanej plazmy, zbavenej kryoproteínov, vyznačujúci sa tým, že sa k plazmovému produktu pridajú prísady, zahŕňajúce 500 až 800 g sorbitolu, 100 až 1 000 j heparínu, 3 až 5 mmol chloridu vápenatého a 1 až 10 g lyzínu, kde všetky množstvá sú vztiahnuté na jeden liter spracovávaného plazmového produktu, vzniknutá zmes sa pasterizuje a pridané prísady sa odstránia dialýzou.A method for pasteurizing a blood plasma product selected from the group consisting of a plasma solution for therapeutic use to compensate for the lack of blood clotting factors V, XI and XIII, total plasma for therapeutic use, and cryoprecipitated plasma supernatant, deprived of cryoproteins, characterized in that Additives including 500-800 g sorbitol, 100-1000 µg heparin, 3-5 mmol calcium chloride and 1-10 g lysine are added to the plasma product, all amounts based on 1 liter of processed plasma product, pasteurized and added. the ingredients are removed by dialysis.
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9008375A FR2664165B1 (en) | 1990-07-03 | 1990-07-03 | COMPOSITION FOR STABILIZING BLOOD PLASMA DURING PASTEURIZATION. |
| PCT/FR1991/000493 WO1992000767A1 (en) | 1990-07-03 | 1991-06-20 | Composition for stabilizing blood plasma during pasteurization |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK279031B6 true SK279031B6 (en) | 1998-05-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK579-92A SK279031B6 (en) | 1990-07-03 | 1991-06-20 | Method of pasteurization of blood plasma product and an agent to carry out this method |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0497929B1 (en) |
| JP (1) | JP3132828B2 (en) |
| AT (1) | ATE135238T1 (en) |
| AU (1) | AU8062991A (en) |
| CA (1) | CA2065284A1 (en) |
| CZ (1) | CZ281431B6 (en) |
| DE (1) | DE69117920T2 (en) |
| DK (1) | DK0497929T3 (en) |
| ES (1) | ES2084821T3 (en) |
| FI (1) | FI96918C (en) |
| FR (1) | FR2664165B1 (en) |
| GR (1) | GR3020048T3 (en) |
| HU (1) | HU208404B (en) |
| LT (1) | LT3419B (en) |
| LV (1) | LV10384B (en) |
| NO (1) | NO179127C (en) |
| PL (1) | PL166579B1 (en) |
| PT (1) | PT98190B (en) |
| RU (1) | RU2045902C1 (en) |
| SK (1) | SK279031B6 (en) |
| WO (1) | WO1992000767A1 (en) |
| ZA (1) | ZA914848B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2687317B1 (en) | 1992-02-13 | 1995-06-23 | Aetsrn | COMPOSITION FOR STABILIZING BLOOD PLASMA DURING PASTEURIZATION AND PASTEURIZED PLASMATIC SOLUTION FOR THERAPEUTIC USE. |
| DE4240103A1 (en) * | 1992-05-26 | 1993-12-02 | Behringwerke Ag | Process for inactivating viruses in protein preparations |
| DE19508192A1 (en) * | 1995-03-09 | 1996-09-12 | Behringwerke Ag | Stable transglutaminase preparations and process for their preparation |
| US20060019234A1 (en) * | 2004-07-22 | 2006-01-26 | Shanbrom Technologies, Llc | Modern blood banking employing improved cell preservation composition |
| WO2017155678A1 (en) * | 2016-03-10 | 2017-09-14 | Kindheart, Inc | Fake blood for use in simulated surgical procedures |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2916711A1 (en) | 1979-04-25 | 1980-11-06 | Behringwerke Ag | Blood coagulation factors and process for their manufacture |
| DE3176491D1 (en) | 1980-03-05 | 1987-11-26 | Miles Lab | Pasteurized therapeutically active protein compositions |
| DE3045153A1 (en) * | 1980-11-29 | 1982-07-08 | Behringwerke Ag, 3550 Marburg | METHOD FOR THE PRODUCTION OF BLOOD COagulation FACTORS AND THE PREPARATION OF FACTORS IX AND X THEREFORE PRODUCED |
| DE3336631A1 (en) * | 1983-10-08 | 1985-04-18 | Behringwerke Ag, 3550 Marburg | METHOD FOR THE PASTEURIZATION OF PLASMA OR CONCENTRATES OF THE BLOOD COAGINING FACTORS II, VII, IX AND X |
| US4543210A (en) * | 1984-10-04 | 1985-09-24 | Miles Laboratories, Inc. | Process for producing a high purity antihemophilic factor concentrate |
| DK18288D0 (en) * | 1988-01-15 | 1988-01-15 | Nordisk Gentofte | PROCEDURE FOR PASTEURIZATION OF Aqueous SOLUTIONS OF FACTOR VIII |
-
1990
- 1990-07-03 FR FR9008375A patent/FR2664165B1/en not_active Expired - Lifetime
-
1991
- 1991-06-20 SK SK579-92A patent/SK279031B6/en not_active IP Right Cessation
- 1991-06-20 CA CA002065284A patent/CA2065284A1/en not_active Abandoned
- 1991-06-20 AT AT91912152T patent/ATE135238T1/en not_active IP Right Cessation
- 1991-06-20 DE DE69117920T patent/DE69117920T2/en not_active Expired - Lifetime
- 1991-06-20 ES ES91912152T patent/ES2084821T3/en not_active Expired - Lifetime
- 1991-06-20 DK DK91912152.5T patent/DK0497929T3/en active
- 1991-06-20 AU AU80629/91A patent/AU8062991A/en not_active Abandoned
- 1991-06-20 PL PL91294037A patent/PL166579B1/en unknown
- 1991-06-20 EP EP91912152A patent/EP0497929B1/en not_active Expired - Lifetime
- 1991-06-20 WO PCT/FR1991/000493 patent/WO1992000767A1/en active IP Right Grant
- 1991-06-20 JP JP03511111A patent/JP3132828B2/en not_active Expired - Lifetime
- 1991-06-20 RU SU915011827A patent/RU2045902C1/en active
- 1991-06-20 HU HU92701A patent/HU208404B/en unknown
- 1991-06-24 ZA ZA914848A patent/ZA914848B/en unknown
- 1991-07-02 PT PT98190A patent/PT98190B/en not_active IP Right Cessation
-
1992
- 1992-02-27 CZ CS92579A patent/CZ281431B6/en not_active IP Right Cessation
- 1992-02-28 NO NO920791A patent/NO179127C/en not_active IP Right Cessation
- 1992-03-02 FI FI920934A patent/FI96918C/en not_active IP Right Cessation
- 1992-12-24 LV LVP-92-497A patent/LV10384B/en unknown
- 1992-12-29 LT LTIP264A patent/LT3419B/en not_active IP Right Cessation
-
1996
- 1996-05-27 GR GR960401411T patent/GR3020048T3/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PC4A | Assignment and transfer of rights |
Owner name: ETABLISSEMENT FRANCAIS DU SANG, LA PLAINE SAIN, FR Free format text: FORMER OWNER: CENTRE REGIONAL DE TRANSFUSION SANGUINE DE LILLE, LILLE, FR Effective date: 20100412 |
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| MK4A | Patent expired |
Expiry date: 20110620 |