NO179127B - Method for pasteurizing blood plasma and mixing for its execution - Google Patents
Method for pasteurizing blood plasma and mixing for its execution Download PDFInfo
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- NO179127B NO179127B NO920791A NO920791A NO179127B NO 179127 B NO179127 B NO 179127B NO 920791 A NO920791 A NO 920791A NO 920791 A NO920791 A NO 920791A NO 179127 B NO179127 B NO 179127B
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- plasma
- concentration
- sorbitol
- heparin
- lysine
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- 210000002381 plasma Anatomy 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 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 claims description 15
- 239000000600 sorbitol Substances 0.000 claims description 15
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 12
- 239000004472 Lysine Substances 0.000 claims description 12
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 12
- 229960002897 heparin Drugs 0.000 claims description 12
- 229920000669 heparin Polymers 0.000 claims description 12
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 11
- 239000001110 calcium chloride Substances 0.000 claims description 11
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 11
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 8
- 238000000502 dialysis Methods 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims 1
- 238000009928 pasteurization Methods 0.000 abstract description 10
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- 230000000087 stabilizing effect Effects 0.000 abstract description 3
- 108010091326 Cryoglobulins Proteins 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 10
- 235000011148 calcium chloride Nutrition 0.000 description 7
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 5
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 5
- 239000003114 blood coagulation factor Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- 241000700605 Viruses Species 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 102000004411 Antithrombin III Human genes 0.000 description 2
- 108090000935 Antithrombin III Proteins 0.000 description 2
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- 108010054218 Factor VIII Proteins 0.000 description 2
- 102000001690 Factor VIII Human genes 0.000 description 2
- 108090000113 Plasma Kallikrein Proteins 0.000 description 2
- 229960005348 antithrombin iii Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 229960000301 factor viii Drugs 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- 102100026735 Coagulation factor VIII Human genes 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010014172 Factor V Proteins 0.000 description 1
- 108010074864 Factor XI Proteins 0.000 description 1
- 108010071289 Factor XIII Proteins 0.000 description 1
- 102100037362 Fibronectin Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- DZTHIGRZJZPRDV-LBPRGKRZSA-N N-acetyl-L-tryptophan Chemical compound C1=CC=C2C(C[C@H](NC(=O)C)C(O)=O)=CNC2=C1 DZTHIGRZJZPRDV-LBPRGKRZSA-N 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 102100038124 Plasminogen Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229940019700 blood coagulation factors Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1025—Acyltransferases (2.3)
- C12N9/104—Aminoacyltransferases (2.3.2)
- C12N9/1044—Protein-glutamine gamma-glutamyltransferase (2.3.2.13), i.e. transglutaminase or factor XIII
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/16—Blood plasma; Blood serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0023—Heat
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
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- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21027—Coagulation factor XIa (3.4.21.27)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte for pasteurisering av blodplasma samt en blanding for utførelse av fremgangsmåten. The present invention relates to a method for pasteurizing blood plasma and a mixture for carrying out the method.
Disse og andre trekk ved oppfinnelsen fremgår av patent-kravene. These and other features of the invention appear in the patent claims.
Blandingen ifølge oppfinnelsen gjør det mulig å stabilisere blodplasma under pasteurisering. Plasmaet er særlig egnet i forbindelse med substitusjonsterapier for plasma- og blod-koagulasjons faktor V, XI og XIII. The mixture according to the invention makes it possible to stabilize blood plasma during pasteurisation. The plasma is particularly suitable in connection with substitution therapies for plasma and blood coagulation factors V, XI and XIII.
Total humant plasma eller humant plasma uten kryoproteiner anvendes fremdeles som substitusjonsterapi for personer med alvorlige forbrenninger og individer som er alvorlig skadet eller som har gjennomgått store operasjoner, dvs. i alle de tilfeller hvor pasientene har gjennomgått et betydelig fluid-tap. Total human plasma or human plasma without cryoproteins is still used as replacement therapy for people with severe burns and individuals who are seriously injured or who have undergone major operations, i.e. in all cases where the patients have undergone a significant fluid loss.
For denne type behandling anvendes generelt plasma fra indivi-duelle donasjoner, fra friske individer som har gjennomgått tester for å utelukke enhver risiko for overføring av virus-sykdommer. Denne prosedyre gjør det imidlertid ikke mulig å unngå risikoen for viruskontaminering i det pre-serologiske trinn, særlig de forskjellige hepatittviruser og AIDS-viruset. For this type of treatment, plasma from individual donations is generally used, from healthy individuals who have undergone tests to rule out any risk of transmission of viral diseases. However, this procedure does not make it possible to avoid the risk of viral contamination in the pre-serological stage, in particular the various hepatitis viruses and the AIDS virus.
Det vil således være fordelaktig å utvikle en metode for virusinaktivering som ikke påvirker plasmaets forskjellige biologiske funksjoner. It would thus be advantageous to develop a method for virus inactivation that does not affect the plasma's various biological functions.
Det er klart vist at hepatitt B-viruset ble fullstendig inak-tivert med oppvarming ved 60°C i ti timer i nærvær av 0,5 M natriumcitrat (Tabor et al. Thrombosis Res. 22, 1981, 233-238). Denne behandling fører imidlertid til et tap av biologisk aktivitet når det gjelder visse plasmaproteiner (Tabor et al. og Barrowcliffe et al. Fr. J. Haemotology 55, 1983, 37 - 46). It has been clearly shown that the hepatitis B virus was completely inactivated by heating at 60°C for ten hours in the presence of 0.5 M sodium citrate (Tabor et al. Thrombosis Res. 22, 1981, 233-238). However, this treatment leads to a loss of biological activity in the case of certain plasma proteins (Tabor et al. and Barrowcliffe et al. Fr. J. Haemotology 55, 1983, 37-46).
Det har vært mulig å underkaste forskjellige proteiner med terapeutisk verdi og som er renset fra blodplasma, for konvensjonell pasteurisering ved 60°C i ti timer i nærvær av forskjellige stabilisatorer. Det skal imidlertid bemerkes at molekyler som stabiliserer en biologisk aktivitet kan være fullstendig uten virkning på andre aktiviteter. It has been possible to subject various proteins of therapeutic value purified from blood plasma to conventional pasteurization at 60°C for ten hours in the presence of various stabilizers. However, it should be noted that molecules that stabilize one biological activity may be completely without effect on other activities.
Albumin kan f.eks. stabiliseres ved hjelp av acetyltryptofan og kaprylat (Gellis et al. J. Clin. Invest. 27, 1948, Albumin can e.g. is stabilized by means of acetyltryptophan and caprylate (Gellis et al. J. Clin. Invest. 27, 1948,
239 - 244) mens disse stabilisatorer ikke har noen virkning på plasminogen. Trombin kan stabiliseres ved hjelp av høye konsentrasjoner av sukkere (Seegers. Arch. Biochem. 3, 1944, 363 - 367), mens disse ikke beskytter protrombin. Tilsetningen av en aminosyre og et sukker har gitt gode resultater med faktor VIII og antitrombin III (se patentskrift DE 29.16.711). 239 - 244) while these stabilizers have no effect on plasminogen. Thrombin can be stabilized by high concentrations of sugars (Seegers. Arch. Biochem. 3, 1944, 363-367), while these do not protect prothrombin. The addition of an amino acid and a sugar has given good results with factor VIII and antithrombin III (see patent document DE 29.16.711).
EPO patentskrift 0 035 2 04 viser stabilisering av oc-anti-trypsin, antitrombin III, prekallikrein, fibronectin og Faktor VIII i nærvær av en polyol, idet det eneste eksempel på den sistnevnte er sukrose. Patentskriftet viser imidlertid at Faktor IX og prekallikrein taper all deres terapeutiske aktivitet under de samme betingelser. EPO patent 0 035 2 04 shows stabilization of oc-anti-trypsin, antithrombin III, prekallikrein, fibronectin and Factor VIII in the presence of a polyol, the only example of the latter being sucrose. However, the patent document shows that Factor IX and prekallikrein lose all their therapeutic activity under the same conditions.
Disse forskjellige elementer i forbindelse med eksperimentelle data bekrefter den generelt aksepterte idé at virusinaktivering av total plasma (friskt plasma, frossent friskt plasma eller kryopresipitert supernatant) ikke kan oppnås ved pasteurisering. These various elements in conjunction with experimental data confirm the generally accepted idea that virus inactivation of total plasma (fresh plasma, frozen fresh plasma or cryoprecipitated supernatant) cannot be achieved by pasteurization.
Da der fremdeles er et medisinsk behov for total plasma, har man prøvd å utvikle en blanding som sikrer samtidig beskyt-telse av den biologisk aktivitet for alle de terapeutiske faktorer av interesse mot denaturering under pasteurisering. As there is still a medical need for total plasma, an attempt has been made to develop a mixture which ensures simultaneous protection of the biological activity of all the therapeutic factors of interest against denaturation during pasteurisation.
Idet man har observert at sorbitol ga en viss grad av beskyt-telse mot termisk denaturering, men hvor resultatene varierte fra en plasmaprøve til en annen, og med lave utbytter, har man søkt etter forskjellige tilsetningsmidler som i blanding med sorbitol ville kunne øke dennes stabiliserende evne. As it has been observed that sorbitol gave a certain degree of protection against thermal denaturation, but where the results varied from one plasma sample to another, and with low yields, a search has been made for various additives which, when mixed with sorbitol, could increase its stabilizing ability.
Blandingen i overensstemmelse med den foreliggende oppfinnelse utgjøres av sorbitol, kalsiumklorid, heparin og lysin, idet sorbitolkonsentrasjonen er mellom 500 og 800 g/l, heparinkonsentrasjonen er mellom 100 og 1000 U/l, kalsiumklorid-konsentrasjonen er mellom 3 og 5 mM, og lysinkonsentrasjonen er mellom 1 og 10 g/l. Konsentrasjonene av de forskjellige bestanddeler er den endelige konsentrasjon i plasmaet som skal pasteuriseres. The mixture in accordance with the present invention consists of sorbitol, calcium chloride, heparin and lysine, the sorbitol concentration being between 500 and 800 g/l, the heparin concentration being between 100 and 1000 U/l, the calcium chloride concentration being between 3 and 5 mM, and the lysine concentration is between 1 and 10 g/l. The concentrations of the various components are the final concentration in the plasma to be pasteurized.
Sorbitolkonsentrasjonen er imidlertid foretrukket 600 g/l, heparinkonsentrasjonen er foretrukket 500 U/ml, lysinkonsentrasjonen er foretrukket 4 g/l, og CaCl2 konsentrasjonen er foretrukket 4 mM. However, the sorbitol concentration is preferably 600 g/l, the heparin concentration is preferably 500 U/ml, the lysine concentration is preferably 4 g/l, and the CaCl2 concentration is preferably 4 mM.
Blandingen ifølge oppfinnelsen tilsettes til friskt plasma eller frosset-tint friskt plasma, eller til det kryopresipi-terte proteinfrie plasma før det sistnevnte underkastes pasteurisering med oppvarming ved 60°C ± 1°C i ti timer. The mixture according to the invention is added to fresh plasma or frozen-thawed fresh plasma, or to the cryoprecipitated protein-free plasma before the latter is subjected to pasteurization with heating at 60°C ± 1°C for ten hours.
Etter pasteurisering nedsettes temperaturen kontinuerlig til 20°C og oppløsningen underkastes dialyse for å fjerne sorbitol og heparin. Dialysebufferen har en pH på 7 og inneholder natriumcitrat i en konsentrasjon mellom 4 og 10 mM, 4 mM kalsiumklorid, 0,13 M natriumklorid og lysin i en konsentrasjon på 4 g/l. Dialysebuffere med andre sammensetninger kan også anvendes når det er påkrevd. Oppløsningen konsentreres deretter for å gjenopprette den fysiologiske dose av plasma-proteinene. Den oppnådde oppløsning underkastes sterilfiltrer-ing, den fordeles hvorpå den fryses eller frysetørkes. After pasteurization, the temperature is continuously lowered to 20°C and the solution is subjected to dialysis to remove sorbitol and heparin. The dialysis buffer has a pH of 7 and contains sodium citrate in a concentration between 4 and 10 mM, 4 mM calcium chloride, 0.13 M sodium chloride and lysine in a concentration of 4 g/l. Dialysis buffers with other compositions can also be used when required. The solution is then concentrated to restore the physiological dose of the plasma proteins. The obtained solution is subjected to sterile filtration, it is distributed, after which it is frozen or freeze-dried.
Fremgangsmåten ifølge oppfinnelsen for pasteurisering av blodplasma er kjennetegnet ved at sorbitol, heparin, kalsiumklorid og lysin tilsettes til plasmaet før oppvarmingstrinnet hvoretter heparin og sorbitol fjernes ved dialyse. The method according to the invention for pasteurizing blood plasma is characterized by the fact that sorbitol, heparin, calcium chloride and lysine are added to the plasma before the heating step, after which heparin and sorbitol are removed by dialysis.
Denne fremgangsmåte er særlig fordelaktig fordi den kan anvendes på store plasmamengder oppnådd fra en rekke forskjellige innsamlinger. Mer spesielt er det ved pasteurisering av båtener på 100 - 200 1 eller mer mulig å garantere at batchene har konsistent kvalitet etter gjennomføring av passende tester. This method is particularly advantageous because it can be applied to large quantities of plasma obtained from a number of different collections. More specifically, when pasteurizing boats of 100 - 200 1 or more, it is possible to guarantee that the batches have consistent quality after carrying out appropriate tests.
Videre kan plasma-batchene som er pasteurisert ved anvendelse av fremgangsmåten i henhold til oppfinnelsen også tjene som substitusjonsprodukter i pasienter med manglende koagulasjonsfaktorer og hvor der ikke finnes rensede konsentrater som Faktor V, Faktor XI eller Faktor XIII. Furthermore, the plasma batches pasteurized using the method according to the invention can also serve as substitution products in patients with missing coagulation factors and where there are no purified concentrates such as Factor V, Factor XI or Factor XIII.
De pasteuriserte plasmaoppløsninger som er oppnådd ved anvendelse av fremgangsmåten ifølge oppfinnelsen er egnet for behandling av mangler med hensyn til koagulasjonsfaktorer V, XI og XIII og for substitusjonsterapier som nødvendiggjør total plasma eller kryopresipitatsupernatant. The pasteurized plasma solutions obtained using the method according to the invention are suitable for the treatment of deficiencies with respect to coagulation factors V, XI and XIII and for substitution therapies requiring total plasma or cryoprecipitate supernatant.
Det etterfølgende eksempel beskriver en utførelsesform av oppfinnelsen. The following example describes an embodiment of the invention.
EKSEMPEL EXAMPLE
Til to liter tinet plasma tilsettes heparin (1000 U) , lysin Heparin (1000 U), lysine is added to two liters of thawed plasma
(8 g) og kalsiumklorid (220 mg). De to sistnevnte produkter tilsettes som salter i pulverform. Plasmaet underkastes forsiktig omrøring. Deretter innhelles gradvis 1200 g uoppløst sorbitol. (8 g) and calcium chloride (220 mg). The two latter products are added as salts in powder form. The plasma is gently stirred. 1200 g of undissolved sorbitol is then gradually poured in.
Pasteurisering gjennomføres i en 5 liters beholder med oppvarming ved 60°C i ti timer ved anvendelse av et vannbad eller i en termostatisk styrt tank. Etter pasteurisering fjernes sorbitol og heparin ved dialyse med en kunstig nyre eller et ultrafiltreringssystem som Pellicon-systemet på kassetter, ved anvendelse av en citratbuffer som inneholder lysin i en konsentrasjon på 4 g/l, 4 mM CaCl2 og 0,13 M NaCl. Dialysen kan etterfølges av konsentrering ved anvendelse av det samme utstyr for å føre mengdeforholdene med hensyn på koagulasjonsfaktorer tilbake til omtrent 1 U/ml som for et terapeutisk plasma av god kvalitet. Produktet dialyseres ved en osmolaritet på 370 mosmol/1 og ved en pH 7. Produktet sterilfiltreres deretter ved anvendelse av f.eks. et Milli-pack-filter 40 (Millipore) med 0,22 \ im porer. Produktet plasseres deretter i plastbeholdere for nedfrysing, eller i flasker for frysetørking. Pasteurization is carried out in a 5 liter container with heating at 60°C for ten hours using a water bath or in a thermostatically controlled tank. After pasteurization, sorbitol and heparin are removed by dialysis with an artificial kidney or an ultrafiltration system such as the Pellicon system on cassettes, using a citrate buffer containing lysine at a concentration of 4 g/l, 4 mM CaCl2 and 0.13 M NaCl. The dialysis can be followed by concentration using the same equipment to bring the ratios of coagulation factors back to about 1 U/ml as for a good quality therapeutic plasma. The product is dialysed at an osmolarity of 370 mosmol/1 and at a pH of 7. The product is then sterile filtered using e.g. a Milli-pack filter 40 (Millipore) with 0.22 µm pores. The product is then placed in plastic containers for freezing, or in bottles for freeze-drying.
Plasmastabilisering gjør det således mulig å oppnå følgende utbytter, i forhold til (som indikert i det etterfølgende med "versus") et kontrollprodukt som inneholder kun lysin og sorbitol: Plasma stabilization thus makes it possible to obtain the following yields, in relation to (as indicated in the following by "versus") a control product containing only lysine and sorbitol:
Det er ikke observert noen tegn på aktivering av koagula-sjonsfaktorene i nærvær av den ovennevnte kalsiummengde. For-holdet mellom bovin FVII/koagulant FVII er således 0,95 mot 1,09 for kontrollproduktet. Stabiliteten som er testet ved å måle aktiviteten av FVIII etter at produktet var oppbevart i 24 timer i en flytende tilstand og ved omgivelsestemperatur, påvirkes ikke uheldig ved sammenligning ved kontrollprøven (gjenvinning av 100 % aktivitet). Dette er i overensstemmelse med en PKA på < 2 % for de pasteuriserte produkter og kontrollproduktene. No signs of activation of the coagulation factors in the presence of the above-mentioned amount of calcium have been observed. The ratio between bovine FVII/coagulant FVII is thus 0.95 against 1.09 for the control product. The stability tested by measuring the activity of FVIII after the product had been stored for 24 hours in a liquid state and at ambient temperature is not adversely affected by comparison with the control sample (recovery of 100% activity). This is in accordance with a PKA of < 2% for the pasteurized products and the control products.
I tillegg indikerte forsøk på rotter gjennom intravenøs injeksjon av det således pasteuriserte plasmaet fravær av en hypertensiv virkning og ga ingen forandring i hjerterytme. In addition, tests on rats through intravenous injection of the thus pasteurized plasma indicated the absence of a hypertensive effect and produced no change in heart rhythm.
Claims (4)
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 (4)
| Publication Number | Publication Date |
|---|---|
| NO920791L NO920791L (en) | 1992-02-28 |
| NO920791D0 NO920791D0 (en) | 1992-02-28 |
| NO179127B true NO179127B (en) | 1996-05-06 |
| NO179127C NO179127C (en) | 1996-08-14 |
Family
ID=9398269
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO920791A NO179127C (en) | 1990-07-03 | 1992-02-28 | Method for pasteurizing blood plasma and mixing for its execution |
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 |
| US11682319B2 (en) | 2016-03-10 | 2023-06-20 | Intuitive Surgical Operations, 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 |
| EP0035204B2 (en) | 1980-03-05 | 1991-05-22 | Miles Inc. | 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 AT AT91912152T patent/ATE135238T1/en not_active IP Right Cessation
- 1991-06-20 AU AU80629/91A patent/AU8062991A/en not_active Abandoned
- 1991-06-20 PL PL91294037A patent/PL166579B1/en unknown
- 1991-06-20 DE DE69117920T patent/DE69117920T2/en not_active Expired - Lifetime
- 1991-06-20 RU SU915011827A patent/RU2045902C1/en active
- 1991-06-20 HU HU92701A patent/HU208404B/en unknown
- 1991-06-20 SK SK579-92A patent/SK279031B6/en not_active IP Right Cessation
- 1991-06-20 ES ES91912152T patent/ES2084821T3/en not_active Expired - Lifetime
- 1991-06-20 EP EP91912152A patent/EP0497929B1/en not_active Expired - Lifetime
- 1991-06-20 CA CA002065284A patent/CA2065284A1/en not_active Abandoned
- 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 DK DK91912152.5T patent/DK0497929T3/en active
- 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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