DK151609B - PROCEDURE FOR THE EXTRACTION OF INTRAVENOST COMPATIBLE GAMMAGLOBULIN - Google Patents
PROCEDURE FOR THE EXTRACTION OF INTRAVENOST COMPATIBLE GAMMAGLOBULIN Download PDFInfo
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- DK151609B DK151609B DK047277AA DK47277A DK151609B DK 151609 B DK151609 B DK 151609B DK 047277A A DK047277A A DK 047277AA DK 47277 A DK47277 A DK 47277A DK 151609 B DK151609 B DK 151609B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
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Description
, DK 151609 B, DK 151609 B
Opfindelsen angår en fremgangsmåde til udvinding af intravenøst kompatibelt gammaglobulin fra et udfældet gammaglobulin-råbundfald fra blod, udvundet ved hjælp af kendte metoder, som fx· ved cryoethanol-fraktionering, ved hvilken den antikomplementære gammaglobulin-bestanddel i en vandig opløsning af råbundfaldet bindes til en vandopløselig hydroxyethylstiveIse, HES, og udfældes med polyethylenglycol, hvorefter det indtil da i opløsning forblivende intravenøskompatible gammaglobulin udfældes med en større koncentration af polyethylenglycol som angivet i DE-patentskrift 25.00.076, og kendt fra beskrivelsen til dansk patentansøgning 5843/75 (almindelig tilgængelig 03 JUL 1976).The invention relates to a method for recovering intravenously compatible gamma globulin from a precipitated blood gamma globulin raw material, obtained by known methods, such as by cryoethanol fractionation, in which the anticomplementary gamma globulin component in an aqueous solution of the raw precipitate is bound to a water-soluble hydroxyethyl starch, HES, and precipitated with polyethylene glycol, and then, until then, in solution, intravenous compatible gamma globulin is precipitated with a greater concentration of polyethylene glycol as disclosed in DE patent application 25.00.076, and known from the specification for Danish patent application 5843/75 JUL 1976).
Selv om den anførte fremgangsmåde frembringer et gammaglobulin, som tilfredsstiller alle fordringer i den medicinske praksis, har det dog vist - 2 -However, although the method disclosed generates a gamma globulin which satisfies all requirements of medical practice, it has shown - 2 -
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sig fordelagtigt at forhøje udbyttet og at sikre en bedre reproducerbarhed og en lettelse af fremstillingen*advantageously increase yields and ensure better reproducibility and ease of production *
Denne opgave løses ifølge opfindelsen ved, at der til den vandige, gam-maglobulinholdige opløsning af råbundfaldet yderligere tilsættes en opslem-ning af glimmeragtige lagsilikater i en koncentration på 0,2 - 10 vægt-%, og at man efter forløbet af en tilstrækkelig reaktionstid og tilsætning af po-lyethylenglykolen fjerner den uønskede gammaglobulin-bestanddel sammen med lagsilikaterne.This task is solved according to the invention by further adding to the aqueous, gamma-maglobulin-containing solution of the raw precipitate a slurry of mica-like layer silicates at a concentration of 0.2 - 10% by weight, and after a sufficient reaction time has elapsed. and addition of the polyethylene glycol removes the unwanted gamma globulin component together with the layer silicates.
Ved "glimmeragtige lagsilikater" forstås silikater, hvis sammensætning gengives ved følgende grænseformler: a) MeJr0_n[(Al3+,Cr3+,Fe3+,Fe2+,Mg2+,Zn2+,Ni2+)2i3(OH)2(Si4_xAlxO)10]x" b) MejY0.n[(Al3+,Cr3+,Fe3+,Fe2+,Mg2+,Zn2+,Ni2+,Li+)^3X}+ (0H)2(Si40)10]x“"Mica-like layer silicates" means silicates whose composition is represented by the following boundary formulas: a) MeJr0_n [(Al3 +, Cr3 +, Fe3 +, Fe2 +, Mg2 +, Zn2 +, Ni2 +) 2i3 (OH) 2 (Si4_xAlxO) 10] x "b) MejY0 n [(Al3 +, Cr3 +, Fe3 +, Fe2 +, Mg2 +, Zn2 +, Ni2 +, Li +) ^ 3X} + (OH) 2 (Si40) 10] x
Kationerne Me* kan udskiftes zeolitisk med andre, også organiske kat-ioner* Som kvsldningsvæske Y kan indføres vilkårlige molkyler med undtagelse af trættede carbonhydrider.The cations Me * can be replaced zeolitically with other, including organic cations * As quenching liquid Y, any molecules can be introduced with the exception of fatigued hydrocarbons.
Mængden af kvældningsvæske kan varieres inden for meget vide grænser.The amount of swelling fluid can be varied within very wide limits.
Da også nængden x af de monovalente kationer pr. (Si, Al g-byggeelement, dvs. lagladningen, varierer, fremkommer der en overordentlig stor mangfoldighed.Since also the amount x of the monovalent cations per (Si, Al g building element, i.e., the layer charge, varies, an extremely large diversity appears.
Ifølge opfindelsen anvendes der som lagsilikat fortrinsvis bentonit med hovedkomponenten montmorillonit eller mineralerne batavit eller vermiculit.According to the invention, as layer silicate, bentonite is preferably used with the main component montmorillonite or the minerals batavite or vermiculite.
Den intensive forskning har navnlig beskæftiget sig med Montmorillonit (jvf. Bibliografi i "Organische Derivate der glimmerartigen Schichtsilikate" af Weiss; angewandte Chemie 1963; side 113 ff.). Montmorillonit består af todimensionalt uendelige makro-anioner, som er elektrostatisk forgrenet over de derimellem liggende kationer. Energien til kvældningen, dvs. til forøgelse af lagafstanden under fjernelse af de positive og negative ladninger fra hinanden, leveres af hydratationen eller solvatationen i kationerne og i an-ionlagene. Da solvatationsenergien almindeligvis er væsentlig mindre end hydratationsenergien, kan der kun indlejres molekylarter med høj dielektricitetskonstant eller med evne til dannelse af hydrogenbroer.In particular, intensive research has dealt with Montmorillonite (cf. Bibliography in "Organische Derivate der glimmerartigen Schichtsilikate" by Weiss; angewandte Chemie 1963; page 113 et seq.). Montmorillonite consists of two-dimensional infinite macro-anions which are electrostatically branched over the cations lying therebetween. The energy for the swelling, ie. for increasing the layer spacing while removing the positive and negative charges from each other is provided by the hydration or solvation in the cations and in the anion layers. Since the solvation energy is generally substantially less than the hydration energy, only high dielectric constant molecular species or with the ability to form hydrogen bridges can be embedded.
Også aminosyrer, peptider og proteiner kan indlejres i glimmeragtige lagsilikater. Proteiner udveksles ved lav pH-værdi næsten kvantitativt. Med stigende pH-værdi synker antallet af de kationiske positioner i proteinerne, og udskiftningen bliver ufuldstændig.Also, amino acids, peptides and proteins can be embedded in mica-like layer silicates. Proteins are exchanged at low pH almost quantitatively. With increasing pH, the number of cationic positions in the proteins decreases and replacement becomes incomplete.
- 3 -- 3 -
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Albuminer, globuliner og prolaminer bindes ligeledes. Hed serumglobuli-ner synes reaktionen kun at skride ca. 20 - 30 Å frem fra silikatkrystallernes rand til det indre. Albuminer udbredes mellem silikatlagene. Lagafstanden på 14, 5 - 15,0 Å viser, at der for det udbredte protein kun står en lagtykkelse på maksimalt 5,5 - 6 A til disposition.Albumins, globulins and prolamines are also bound. For serum globules, the reaction seems to proceed only approx. 20 - 30 Å from the edge of the silicate crystals to the interior. Albumins are propagated between the silicate layers. The layer spacing of 14, 5 - 15.0 Å shows that for the propagated protein only a layer thickness of a maximum of 5.5 - 6 A is available.
Da der i den opløste gammaglobulinmaangde befinder sig både ubeskadigede og beskadigede molekyler, må man bestræbe sig for på en eller anden måde at binde de beskadigede molekyler og dermed gøre dem kemisk forskellige fra de fysiologisk fejlfri molekyler. De beskadigede molekyler er i stand til at danne hydrogenbrobindinger* De indlejres og bindes derfor i forøget grad i silikatlagene, medens de ubeskadigede gammaglobulinmolekyler forbliver i opløsningen. De i lagsilikaternes lag bundne gammaglobulinmolekyler lean derfor let fjernes, fx. ved centrifugering.Since in the dissolved gamma globulin quantity both undamaged and damaged molecules are present, efforts must be made to somehow bind the damaged molecules and thus make them chemically different from the physiologically flawed molecules. The damaged molecules are capable of forming hydrogen bridge bonds * They are therefore embedded and bonded to an increased extent in the silicate layers while the undamaged gamma globulin molecules remain in the solution. Therefore, the gamma globulin molecules bound to the layer silicates are readily removed, e.g. by centrifugation.
Den ifølge opfindelsen Ønskede kationbytterevne viser ifølge HOFMANN (Z.Kristallogr. (A) 98 (1937) 31; Chemie 55 (1942)283) også kaolin og dermed beslægtede stoffer, (fx. Halloysit, AI2O3*2Si02*4H20) og visse glimmeragtige mineraler, som er beslægtet med hensyn til gitteropbygningen·The desired cation exchange capacity according to the invention, according to HOFMANN (Z.Cristallogr. (A) 98 (1937) 31; Chemie 55 (1942) 283) also shows kaolin and related substances (e.g. halloysite, AI2O3 * 2SiO2 * 4H20) and certain mica minerals related to the grid structure ·
Hertil hører også vermiculit og det dermed beslægtede batavit (* jernfrit vermiculit). Strukturformlen for batavit fremgår af WEISS og HOFFMANN (Zeitschrift fur Naturforschung, 6b, 405) som følger: i*Mg2,64Al0,33*l ^^1,94^2,99^1,01°^} °'68+ m9o/34 + 2,34H20These include vermiculite and the related batavite (* iron-free vermiculite). The structural formula for batavit is given in WEISS and HOFFMANN (Zeitschrift fur Naturforschung, 6b, 405) as follows: i * Mg2.64Al0.33 * l ^^ 1.94 ^ 2.99 ^ 1.01 ° ^} ° '68 + m9o / 34 + 2.34H2O
Det har vist sig, at dette materiale såvel som Montmorillonit har indrekrystallinsk kvældningsevne og høj kationbytterevne. Undersøgelserne viste, at batavit optager indtil 5 vægtprocent humanalbumin, hvorved æggehvidestofferne blev indlejret mellem silicatlagene. Også vermiculit med den tilnærmede strukturformel {(Mg3,Al2,Fef,FefI)(OH)2[si3i35Al0/65O10]}0'65'+ 0,65M+ udviser de ønskede egenskaber med hensyn til lagdannelsen og kvældningsev-nen. Vermiculit svarer til et trioktaedrisk montmorillonit, men dets krystaller er meget større, og gitteret er mere regelmæssigt udformet.It has been found that this material as well as Montmorillonite have intracrystalline swelling and high cation exchange capacity. The studies showed that batavite absorbs up to 5% by weight of human albumin, thereby embedding the egg whites between the silicate layers. Also vermiculite with the approximate structural formula {(Mg3, Al2, Fef, FefI) (OH) 2 [si3i35Al0 / 65O10]} 0'65 '+ 0.65M + exhibits the desired properties in terms of layer formation and swelling ability. Vermiculite is similar to a trioctahedral montmorillonite, but its crystals are much larger and the lattice is more regularly formed.
Sammenfattende kan således konstateres, at der til renseprocessen kan anvendes sådanne mineraler, som udviser en lagstruktur, der har kationer mellem silicatlagene, og som er tilbøjelige til kvældning. Ifølge de eksperimentale erfaringer bindes ved sådanne mineraler de defekte gammaglobulin- - 4 -In summary, it can thus be found that for the purification process, such minerals can be used which exhibit a layer structure that has cations between the silicate layers and which are prone to swelling. According to the experimental experience, such defective gamma globulin - 4 -
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molekyler - åbenbart på grund af deres stærke kationaktlvering - , medens de ubeskadigede ikke bindes.molecules - evidently due to their strong cation activation - while the undamaged ones do not bind.
I forbindelse med gammaglobuliner er en fremgangsmåde blevet kendt, hvor den proteinfraktion, som skal renses, i en fysiologisk saltopløsning ved en pH-værdi på 6 - 8.5 tilsættes bentonit (OS-patentskrift 34.49.316).In connection with gamma globulins, a method has been known in which the protein fraction to be purified in a physiological saline solution at a pH of 6 - 8.5 is added bentonite (OS patent 34.49.316).
Det har dog vist sig, at der med den kombinerede anvendelse af hydroxyethyl-stivelse og et materiale, som binder protein, kan opnås en særlig stor renhed, dvs. praktisk taget 100%, naturligt gammaglobulin. Dette er muligt ved stort udbytte og let reproducerbare betingelser, hvis fremgangsmåden ifølge opfindelsen anvendes.However, it has been found that with the combined use of hydroxyethyl starch and a material which binds protein, a particularly high purity can be achieved, i.e. practically 100%, natural gamma globulin. This is possible in high yield and easily reproducible conditions if the method of the invention is used.
Opfindelsen er nærmere forklaret i det følgende ved hjælp af nogle eksempler.The invention is further explained in the following by means of some examples.
Eksempel 1« (a) fraskillelse af gammaglobulinet:Example 1 «(a) Separation of the gamma globulin:
Man går ud fra en samlet plasma, til hvilken tilsættes 8% ethanol, og som blev udfældet ved en pH-værdi på 7,2 ved -3*C. Herved udskilles fraktion I. Til den derover stående væske tilsættes derefter ved -5‘C og en pH-værdi på 5,8 19% ethanol. Derved udskilles fraktionen II-III, som består af gammaglobuliner. Bundfaldet opløses atter og udfældes påny ved pH 5 og 8% ethanol. Den forblivende rest fældes påny med 25% ethanol ved pH 7,2. Det herved dannede bundfald (= fraktion 11) består af mindst 90% gammaglobulin.An overall plasma is added to which 8% ethanol is added and precipitated at a pH of 7.2 at -3 ° C. Fraction I. This is then separated into the supernatant liquid at -5 ° C and a pH of 5.8 19% ethanol. This separates fraction II-III, which consists of gamma globulins. The precipitate is dissolved again and precipitated again at pH 5 and 8% ethanol. The residual residue is precipitated again with 25% ethanol at pH 7.2. The resulting precipitate (= fraction 11) consists of at least 90% gamma globulin.
(b) formindskelse af den antikomplementære virksomhed:(b) reducing the anti-complementary activity:
Gammaglobulinbundfaldet optages i en bufret, vandig opløsning med en pH-værdi på 7,0 og i en koncentration på ca. 6%, hvorhos der til den vandige opløsning er tilsat ca. 10% HES. Til opløsningen tilsættes endvidere en vandig opslæmning af bentonit SF (hovedkomponenter: montmorillonit; kornstørrelse under 80μ, producent: SERWA Feinbiochemika, Heidelberg). Opløsningen indeholder derefter 2,5 uægt-% bentonit og omrøres godt. Derefter lader man opløsningen stå i 6 timer ved en temperatur på 15*C ±2‘C. Derpå fjernes ben-tonit'en sammen med de uønskede bestanddele ved centrifugering efter tilsætning af 10% polyethylenglycol.The gamma globulin precipitate is taken up in a buffered aqueous solution with a pH of 7.0 and at a concentration of ca. About 6%, to which about aqueous solution is added approx. 10% HES. In addition, an aqueous slurry of bentonite SF is added to the solution (main components: montmorillonite; grain size below 80µ, manufacturer: SERWA Feinbiochemika, Heidelberg). The solution then contains 2.5% by weight of bentonite and is well stirred. The solution is then allowed to stand for 6 hours at a temperature of 15 ° C ± 2 ° C. The ben-tonite is then removed together with the undesirable constituents by centrifugation after addition of 10% polyethylene glycol.
(c) omdannelse til en fysiologisk kogsaltopløsning:(c) conversion to a physiological saline solution:
Det ved centrifugeringen fremkomne filtrat indeholder de ønskede, som opløsning foreliggende gammaglobulinbestanddele. Filtratet bringes med 0,1 NaOH på en pH-værdi af 7,2, og der tilsættes 20 vægt-% polyethylenglycol. Derved udskilles bundfald af rent gammaglobulin. Bundfaldet udvindes vedThe filtrate obtained by centrifugation contains the desired gamma globulin constituents which are in solution. The filtrate is brought with 0.1 NaOH to a pH of 7.2 and 20% by weight polyethylene glycol is added. This precipitates the precipitation of pure gamma globulin. The precipitate is recovered by
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- 5 - centrifugering og bringes i en fysiologisk kogsaltopløsning op på en koncentration på 5,2% æggehvidestof og sterilfiltreres derpå. Derefter er det klar til terapeutisk anvendelse.Centrifugation and brought to a physiological saline solution to a concentration of 5.2% egg white and then sterile filtered. Then it is ready for therapeutic use.
Eksempel 2.Example 2.
Trinnene (a) og (c) er de samme som i eksempel 1. Trin (b) modificeres som følger :Steps (a) and (c) are the same as in Example 1. Step (b) is modified as follows:
Gamma globulinbundfaldet opløses i en bufret, vandig opløsning med en pH-værdi på 7,4 og i en koncentration på ca. 4 vægt-%, hvorhos der til den vandige opløsning er tilsat ca. 8% HES. Til opløsningen tilsættes yderligere en vandig opslæmning af finmalet vermiculit (partikelstørrelse under 80 μ) i en mængde på op til 5 vægt-%. Det hele omrøres kraftigt. Derefter lader man opløsningen stå 8 timer ved en temperatur på 15*C ±2*C. Til opløsningen tilsættes derefter ca. 10 vægt-% polyethylenglycol. Sluttelig fjernes vermicu-lit’en sammen med de uønskede bestanddele ved centrifugering.The gamma globulin precipitate is dissolved in a buffered aqueous solution with a pH of 7.4 and at a concentration of ca. 4% by weight, to which about aqueous solution is added approx. 8% HES. To the solution is added an additional aqueous slurry of finely ground vermiculite (particle size below 80 µ) in an amount of up to 5% by weight. It is all stirred vigorously. The solution is then left to stand for 8 hours at a temperature of 15 ° C ± 2 ° C. To the solution is then added approx. 10% by weight polyethylene glycol. Finally, the vermiculite, along with the undesirable constituents, is removed by centrifugation.
Derefter følger trin (c).Then step (c) follows.
Ved beregninger og målinger på immun-elektrophoresediagrammer kan konstateres, at udbyttet af rent gammaglobulin forøges, når fremgangsmåden ifølge opfindelsen anvendes. Det udvundne gammaglobulin er ikke modificeret eller kemisk ændret. Det er absolut intravenøskompatibelt og har praktisk taget ingen antikomplementære egenskaber. Derudover udviser det en høj stabilitet, således som det kunne påvises ved lagringsforsøg.In calculations and measurements on immuno-electrophoresis charts, it is found that the yield of pure gamma globulin is increased when the method of the invention is used. The recovered gamma globulin is not modified or chemically altered. It is absolutely intravenous compatible and has virtually no anti-complementary properties. In addition, it exhibits high stability, as demonstrated by storage experiments.
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2604759A DE2604759C2 (en) | 1976-02-07 | 1976-02-07 | Method of Obtaining IV Compatible Gamma Globulins |
| DE2604759 | 1976-02-07 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK47277A DK47277A (en) | 1977-08-07 |
| DK151609B true DK151609B (en) | 1987-12-21 |
| DK151609C DK151609C (en) | 1988-06-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK047277A DK151609C (en) | 1976-02-07 | 1977-02-04 | PROCEDURE FOR THE EXTRACTION OF INTRAVENOST COMPATIBLE GAMMAGLOBULIN |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS52117414A (en) |
| AT (1) | AT351672B (en) |
| AU (1) | AU508852B2 (en) |
| BE (1) | BE851151R (en) |
| CA (1) | CA1087524A (en) |
| CH (1) | CH629669A5 (en) |
| DD (1) | DD132758A6 (en) |
| DE (1) | DE2604759C2 (en) |
| DK (1) | DK151609C (en) |
| ES (1) | ES455708A2 (en) |
| FI (1) | FI62624C (en) |
| FR (1) | FR2340738A2 (en) |
| GB (1) | GB1577031A (en) |
| HU (1) | HU177708B (en) |
| IE (1) | IE44591B1 (en) |
| IN (1) | IN144987B (en) |
| MX (1) | MX5356E (en) |
| NL (1) | NL7700975A (en) |
| PL (1) | PL104234B3 (en) |
| SE (1) | SE442707B (en) |
| YU (1) | YU30577A (en) |
| ZA (1) | ZA77684B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2837168A1 (en) * | 1978-08-25 | 1980-03-06 | Blutspendedienst Dt Rote Kreuz | METHOD FOR PRODUCING AN IMMUNAL GLOBULIN SOLUTION SUITABLE FOR INTRAVENOUS APPLICATION |
| JPS60222773A (en) * | 1984-04-19 | 1985-11-07 | Sekisui Chem Co Ltd | Manufacture of latex reagent |
| EP0168506B2 (en) * | 1984-07-07 | 1998-01-07 | Armour Pharma GmbH | Process for preparing gamma globulin suitable for intravenous administration |
| DE3440444A1 (en) * | 1984-11-06 | 1986-05-07 | Dechema Deutsche Gesellschaft für chemisches Apparatewesen e.V., 6000 Frankfurt | METHOD FOR THE PRODUCTION OF COARSE GRAINED LAYERED SILICATES AND THE USE THEREOF AS ADSORBENTS FOR PROTEINS |
| UA64742C2 (en) * | 1997-12-24 | 2004-03-15 | Альфа Терапевтик Корпорейшн | Process for producing intravenously-administrable gamma globulin solution and product manufactured by this process |
| EP3118210B1 (en) | 2014-03-11 | 2019-11-13 | Green Cross Holdings Corporation | Method for purifying immunoglobulin |
| EP3118209B1 (en) | 2014-03-11 | 2020-02-19 | Green Cross Holdings Corporation | Method for purifying immunoglobulin |
| KR101657690B1 (en) | 2015-06-05 | 2016-09-19 | 주식회사 녹십자홀딩스 | Methods for Preparing Hepatitis B immune globulin derived from plasma |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK144679B (en) * | 1975-01-02 | 1982-05-10 | Armour Pharma | PROCEDURE FOR THE EXTRACTION OF INTRAVENOUS COMPATIBLE GAMMA LOBULINES |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3449316A (en) * | 1967-03-03 | 1969-06-10 | American Cyanamid Co | Process for the purification of gamma globulin employing bentonite |
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1976
- 1976-02-07 DE DE2604759A patent/DE2604759C2/en not_active Expired
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1977
- 1977-01-28 FI FI770290A patent/FI62624C/en not_active IP Right Cessation
- 1977-01-28 IE IE186/77A patent/IE44591B1/en unknown
- 1977-01-31 NL NL7700975A patent/NL7700975A/en not_active Application Discontinuation
- 1977-01-31 SE SE7700960A patent/SE442707B/en not_active IP Right Cessation
- 1977-02-03 AU AU21902/77A patent/AU508852B2/en not_active Expired
- 1977-02-04 DK DK047277A patent/DK151609C/en not_active IP Right Cessation
- 1977-02-04 BE BE6045865A patent/BE851151R/en not_active IP Right Cessation
- 1977-02-04 DD DD7700197241A patent/DD132758A6/en unknown
- 1977-02-04 FR FR7703139A patent/FR2340738A2/en active Granted
- 1977-02-04 HU HU77PA1277A patent/HU177708B/en unknown
- 1977-02-04 PL PL1977195821A patent/PL104234B3/en unknown
- 1977-02-04 YU YU00305/77A patent/YU30577A/en unknown
- 1977-02-04 MX MX775414U patent/MX5356E/en unknown
- 1977-02-04 AT AT74177A patent/AT351672B/en not_active IP Right Cessation
- 1977-02-05 IN IN168/CAL/77A patent/IN144987B/en unknown
- 1977-02-07 GB GB5017/77A patent/GB1577031A/en not_active Expired
- 1977-02-07 ZA ZA770684A patent/ZA77684B/en unknown
- 1977-02-07 ES ES455708A patent/ES455708A2/en not_active Expired
- 1977-02-07 JP JP1172177A patent/JPS52117414A/en active Granted
- 1977-02-07 CA CA271,204A patent/CA1087524A/en not_active Expired
- 1977-02-07 CH CH146277A patent/CH629669A5/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK144679B (en) * | 1975-01-02 | 1982-05-10 | Armour Pharma | PROCEDURE FOR THE EXTRACTION OF INTRAVENOUS COMPATIBLE GAMMA LOBULINES |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2604759A1 (en) | 1977-09-29 |
| MX5356E (en) | 1983-06-29 |
| DK151609C (en) | 1988-06-20 |
| DE2604759C2 (en) | 1983-06-01 |
| FR2340738A2 (en) | 1977-09-09 |
| ZA77684B (en) | 1977-12-28 |
| FI62624B (en) | 1982-10-29 |
| SE442707B (en) | 1986-01-27 |
| ES455708A2 (en) | 1978-01-16 |
| SE7700960L (en) | 1977-08-08 |
| AU508852B2 (en) | 1980-04-03 |
| HU177708B (en) | 1981-12-28 |
| DD132758A6 (en) | 1978-11-01 |
| FI62624C (en) | 1983-02-10 |
| DK47277A (en) | 1977-08-07 |
| IN144987B (en) | 1978-08-05 |
| AT351672B (en) | 1979-08-10 |
| FR2340738B2 (en) | 1981-07-31 |
| AU2190277A (en) | 1978-08-10 |
| JPS52117414A (en) | 1977-10-01 |
| CA1087524A (en) | 1980-10-14 |
| FI770290A (en) | 1977-08-08 |
| IE44591L (en) | 1977-08-07 |
| PL104234B3 (en) | 1979-08-31 |
| JPS6231695B2 (en) | 1987-07-09 |
| YU30577A (en) | 1984-04-30 |
| IE44591B1 (en) | 1982-01-27 |
| ATA74177A (en) | 1979-01-15 |
| GB1577031A (en) | 1980-10-15 |
| BE851151R (en) | 1977-08-04 |
| CH629669A5 (en) | 1982-05-14 |
| NL7700975A (en) | 1977-08-09 |
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