CA1072444A - Method of recovering immunoglobulin - Google Patents
Method of recovering immunoglobulinInfo
- Publication number
- CA1072444A CA1072444A CA275,585A CA275585A CA1072444A CA 1072444 A CA1072444 A CA 1072444A CA 275585 A CA275585 A CA 275585A CA 1072444 A CA1072444 A CA 1072444A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- polyol
- tion
- carbon atoms
- peg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- 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
- C07K16/065—Purification, fragmentation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Abstract
Abstract of Disclosure Immunoglobulins or gammaglobulins are recovered in a pure and anticomplementary condition by fractionated pre-cipitation of blood plasma with a polycondensed di or polyol, such as PEG, in the presence of a mono or poly-alkanoic acid having 4 to 12 carbon atoms, such as caprylic acid.
Description
~7'~
The presen-t inven-tion rela-tes -to a me-thod of recovering immunoglobulin suitable for intravenous adminis-tration~
by frac-tiona-ted precipita-tion of blood plasma, serum or a fraction -thereof wi-th a polycondensed di or polyol.
Immunoglobulins comprising gammaglobulins have therapeutic merit as they are suitable ~or preparing immunizing prepara-tions.
Immunoglobulin is found in blood plasma of animal origin, from which i-t may be recovered by various precipitation and purification processes. Hence, gammaglobulin can bs recovered as concentrated solutions by a method developed by Cohn et al, cf. J. Clin. Invest. Chem. Soc., 68, 479-75 (1946). According to Cohn, it is possible to obtain a frac-tion II being a 16.5% concentrate and which may be injected intramuscularly.
In the said prior-art method there are formed molecule aggregates of gammaglobulin rendering the products unsuitable for intravenous adminis-tration. Hence, Cohn9s method comprises precipitation with alcohol which has a water-expelling effect and may lead to irreversible denaturation, whereby the globulin is rendered anti-complementary. It has been attempted to avoid this by means o~ special separation processes and/or by chemical modification of the gammaglobulin.
Hence~ the prior ar-t teaches an improved ~ractiona-ting pro-~L~7~
cess in which the cJamma~lobulin l~ precipitated fro~ blood plasma by rneans of polyethylene glycol (PEG) as precipitant, cf.
U.S. Patent No. 3,415,80~. Thls eliminates -the undesired denatur-ation, hut the purity of the precipitated product is unsatis-factory.
According to Canadian Patent No. 1,016,069, this pre-cipitation process may be improved by replacing polyethylene glycol b~ a block copolymer of ethylene oxide and polyoxy-propylene polymer of a further specified nature and observing some specific precipitation conditions.
In this manner it is possible to improve the yield by recovery of gammaglobulin. The precipitated products, however, are not always of satisfactory purity with sufficiently low anticomplementary activity.
The present invention is based on the observation that the fractionated precipitation of immunoglobulins, also known as gammaglobulins, by means of polyethylene glycol of other poly~
condensed di or polyol may be rendered appreciably more specific if the precipitation is carried out in the presence of a mono or polyalkanoic acid having from 4 to 12 carbon atoms, whereby i.e.
fibrinogen and lipoproteins are removed.
According to the present invention, there is provided a method of recovering purified immunoglobulin suitable for intravenous administration wherein blood plasma, serum or a fraction thereof is subjected to a fractionated precipi~ation using a combination of polycondensed polyol and a mono or poly alkanoic acid having frorn 4 to 12 carbon atoms as a precipitant.
In the method according to the invention there is ob-tained in a simple manner purified immunoglobulin of a surprisingly high degree of purity coupled with a high yield. The . .
, .
~72~4 yield equals tha-t which it is possible to obtain by the best of the a~oresai~ methods. ~, The claimed method may be used in connection wi-t~ any polycondensed di or polyglycol such as polyethylene glycol of varying molecular weights, e.g. 2000 to 12000, pre~er-ably L~ooo to 6000, or polypropylene glycol. Also copolymers of ethylene oxide with propylene oxide or polyethers are suitable.
Sul-table as mono or polyalkanoic acid is any alkanoic acid having from 4 to 12 carbon atoms. Preferred according to the invention is an alkanoic acid having ~rom 6 to 9 car-bon atoms, pre~erably caprylic acid. Examples of other sui-table alkanoic acids are caproic acid and nonanic acid.
Also branched alkanoic acids may be used. When using -higher alkanoic acids, such as having from 9 to 12 carbon - atoms~ i-t may be advan-tageous to incorpora-te additionally one or more carboxyl groups with a view to improving water-solubili-ty. The same effect is achieved by using alkanoic acids having substituents containing, for example, one or more hydroxyl groups or amino groups.
The immunoglobulin-containing solution is adva~tageously mixed with from 1 to 8 percent by weight of polyethylene glycol or other polycondensed diol or polyol together with from 0.1 to 5 percent by weight o~ caprylic acid or other alkanoic acid having from L~-to 12 carbon atoms, the precipitation wi-th alkanoic acid according to the ~7;Z~
inven-tion being advan-tageously e~ec-ted a-t a pH of ~rom 3 to 7, preferably from 4.5 to 5.5.
The me-thod according to the invention will now be further illustrated below by means of some examples.
415 ml of human blood plasma containing 10 g of immuno-globulin per liter plasma are adjusted to a pH of 5 0 PEG
3000 is added until a concentration o~ 6 percent, and the solution is left to stand for 45 minutes. The precipitate, being mainly fibrinogen, is separated by centrifuga-tion, and the liquid phase is adjus-ted to a pH of 7Ø After adding additional PEG 3000 to obtain a concentration of 12 percent, the mixture is left to stand for 45 minutes.
The mixture is now centrifugated and the liquid phase containin~ albumin and alpha and beta-globulin is removed.
The precipitate consis-ting of impure immunoglobulin is re-dissolved in an 0.9 percent sodium chloride solution to obtain a protein concentration of about 4 percentO The solution is filtered until clear using a Seitz EK-filter.
The solution formed is admixed with 5 g of caprylic acid and 30 g of PEG 3000 per liter solution, and adjusted to a pH of 4.9. After leaving to stand for 2 hours at 20C
the mixture is centrifugated, and the liquid phase is filtered to obtain a clear solu-tion. This solution is adjusted to pH = 7.0, and PEG 3000 is added until a concentration of 12 percent PEG. This results in pre-cipitation of pure immunoglobulin which is recovered by ~. . . .. ..
~37Z9~
centrifuga-tion and drying. The yield o~ produc-t is 60 percent. The degree of purity as determined by DISC
PAGE (with 5 percen-t polyacrylamide) discloses subs-tan-tial-ly only two bands corresponding to IgG and IgM, respectively. The analysis is per~ormed by applica-tion o~
500 /ug o~ produc-t.
In Grabar and William's immunoelectrophoresis, using rabbi-t antibody against -total human serum protein, there is found substan-tially only three arches, corresponding to IgG, IgM and IgA, respectively.
The purified product may, i~ desired, be conver-ted to an intravenously injectable preparation by dissolution in 0.9 percent sodium chloride solution until a protein concentration o~ about 5 percen-t. The preparation is distinguished by an extremely low anticomplementary activity, for which reason it is particularly suitable ~or intravenous administration.
The procedure according to Example 1 is repeated, except that the human blood plasma is replaced by swine plasma.
The procedure according to Example l is repeated, excep-t that human blood p asma i~ replaced by b ood serum.
.. I
~L~g7~
100 1 of plasma or serum are mixed with 100 1 of 600 g/l PEG 3000 solu-tion. The pH is adjusted to 6.5. The precipi-tate is separa-ted by centrifuga-tion and redissolved in 100 1 of distilled water admixed wi-th 0.015 M of MaCl.
There is added 40 g of PEG 3000 per liter and 5 g o~
caprylic acid per liter~ The pH is adjusted to 5Ø
Standing time 45 minutes. The precipi-ta-te is separated by centrifugation. The cen-trifugate is admixed with additional 40 g of PEG 3000 per liter~ The pH is adjus-ted to 7.5.
The precipitate is separated by centri~ugation and re-dissolved in distilled water with 0.002 M of NaCl. The solution is filtered to clarity (e.g. SEITZ ~ EK-Filter)~
The protein concentra-tion should be 50-100 g/l~ 20 g of DEAE-Sephadex-A25 ~ are added per 100 g o~ protein.
After leaving to s-tand for 60 minutes while s-tirring the DEAE-Sephadex is separated by filtration. The DEAE-Sephadex treatment is repeated. A~ter sterile fil-tra-tion there is obtained an immunoglobulin G preparation ~ree ~rom anticomplementariness and suitable ~or lntravenous administration.
The presen-t inven-tion rela-tes -to a me-thod of recovering immunoglobulin suitable for intravenous adminis-tration~
by frac-tiona-ted precipita-tion of blood plasma, serum or a fraction -thereof wi-th a polycondensed di or polyol.
Immunoglobulins comprising gammaglobulins have therapeutic merit as they are suitable ~or preparing immunizing prepara-tions.
Immunoglobulin is found in blood plasma of animal origin, from which i-t may be recovered by various precipitation and purification processes. Hence, gammaglobulin can bs recovered as concentrated solutions by a method developed by Cohn et al, cf. J. Clin. Invest. Chem. Soc., 68, 479-75 (1946). According to Cohn, it is possible to obtain a frac-tion II being a 16.5% concentrate and which may be injected intramuscularly.
In the said prior-art method there are formed molecule aggregates of gammaglobulin rendering the products unsuitable for intravenous adminis-tration. Hence, Cohn9s method comprises precipitation with alcohol which has a water-expelling effect and may lead to irreversible denaturation, whereby the globulin is rendered anti-complementary. It has been attempted to avoid this by means o~ special separation processes and/or by chemical modification of the gammaglobulin.
Hence~ the prior ar-t teaches an improved ~ractiona-ting pro-~L~7~
cess in which the cJamma~lobulin l~ precipitated fro~ blood plasma by rneans of polyethylene glycol (PEG) as precipitant, cf.
U.S. Patent No. 3,415,80~. Thls eliminates -the undesired denatur-ation, hut the purity of the precipitated product is unsatis-factory.
According to Canadian Patent No. 1,016,069, this pre-cipitation process may be improved by replacing polyethylene glycol b~ a block copolymer of ethylene oxide and polyoxy-propylene polymer of a further specified nature and observing some specific precipitation conditions.
In this manner it is possible to improve the yield by recovery of gammaglobulin. The precipitated products, however, are not always of satisfactory purity with sufficiently low anticomplementary activity.
The present invention is based on the observation that the fractionated precipitation of immunoglobulins, also known as gammaglobulins, by means of polyethylene glycol of other poly~
condensed di or polyol may be rendered appreciably more specific if the precipitation is carried out in the presence of a mono or polyalkanoic acid having from 4 to 12 carbon atoms, whereby i.e.
fibrinogen and lipoproteins are removed.
According to the present invention, there is provided a method of recovering purified immunoglobulin suitable for intravenous administration wherein blood plasma, serum or a fraction thereof is subjected to a fractionated precipi~ation using a combination of polycondensed polyol and a mono or poly alkanoic acid having frorn 4 to 12 carbon atoms as a precipitant.
In the method according to the invention there is ob-tained in a simple manner purified immunoglobulin of a surprisingly high degree of purity coupled with a high yield. The . .
, .
~72~4 yield equals tha-t which it is possible to obtain by the best of the a~oresai~ methods. ~, The claimed method may be used in connection wi-t~ any polycondensed di or polyglycol such as polyethylene glycol of varying molecular weights, e.g. 2000 to 12000, pre~er-ably L~ooo to 6000, or polypropylene glycol. Also copolymers of ethylene oxide with propylene oxide or polyethers are suitable.
Sul-table as mono or polyalkanoic acid is any alkanoic acid having from 4 to 12 carbon atoms. Preferred according to the invention is an alkanoic acid having ~rom 6 to 9 car-bon atoms, pre~erably caprylic acid. Examples of other sui-table alkanoic acids are caproic acid and nonanic acid.
Also branched alkanoic acids may be used. When using -higher alkanoic acids, such as having from 9 to 12 carbon - atoms~ i-t may be advan-tageous to incorpora-te additionally one or more carboxyl groups with a view to improving water-solubili-ty. The same effect is achieved by using alkanoic acids having substituents containing, for example, one or more hydroxyl groups or amino groups.
The immunoglobulin-containing solution is adva~tageously mixed with from 1 to 8 percent by weight of polyethylene glycol or other polycondensed diol or polyol together with from 0.1 to 5 percent by weight o~ caprylic acid or other alkanoic acid having from L~-to 12 carbon atoms, the precipitation wi-th alkanoic acid according to the ~7;Z~
inven-tion being advan-tageously e~ec-ted a-t a pH of ~rom 3 to 7, preferably from 4.5 to 5.5.
The me-thod according to the invention will now be further illustrated below by means of some examples.
415 ml of human blood plasma containing 10 g of immuno-globulin per liter plasma are adjusted to a pH of 5 0 PEG
3000 is added until a concentration o~ 6 percent, and the solution is left to stand for 45 minutes. The precipitate, being mainly fibrinogen, is separated by centrifuga-tion, and the liquid phase is adjus-ted to a pH of 7Ø After adding additional PEG 3000 to obtain a concentration of 12 percent, the mixture is left to stand for 45 minutes.
The mixture is now centrifugated and the liquid phase containin~ albumin and alpha and beta-globulin is removed.
The precipitate consis-ting of impure immunoglobulin is re-dissolved in an 0.9 percent sodium chloride solution to obtain a protein concentration of about 4 percentO The solution is filtered until clear using a Seitz EK-filter.
The solution formed is admixed with 5 g of caprylic acid and 30 g of PEG 3000 per liter solution, and adjusted to a pH of 4.9. After leaving to stand for 2 hours at 20C
the mixture is centrifugated, and the liquid phase is filtered to obtain a clear solu-tion. This solution is adjusted to pH = 7.0, and PEG 3000 is added until a concentration of 12 percent PEG. This results in pre-cipitation of pure immunoglobulin which is recovered by ~. . . .. ..
~37Z9~
centrifuga-tion and drying. The yield o~ produc-t is 60 percent. The degree of purity as determined by DISC
PAGE (with 5 percen-t polyacrylamide) discloses subs-tan-tial-ly only two bands corresponding to IgG and IgM, respectively. The analysis is per~ormed by applica-tion o~
500 /ug o~ produc-t.
In Grabar and William's immunoelectrophoresis, using rabbi-t antibody against -total human serum protein, there is found substan-tially only three arches, corresponding to IgG, IgM and IgA, respectively.
The purified product may, i~ desired, be conver-ted to an intravenously injectable preparation by dissolution in 0.9 percent sodium chloride solution until a protein concentration o~ about 5 percen-t. The preparation is distinguished by an extremely low anticomplementary activity, for which reason it is particularly suitable ~or intravenous administration.
The procedure according to Example 1 is repeated, except that the human blood plasma is replaced by swine plasma.
The procedure according to Example l is repeated, excep-t that human blood p asma i~ replaced by b ood serum.
.. I
~L~g7~
100 1 of plasma or serum are mixed with 100 1 of 600 g/l PEG 3000 solu-tion. The pH is adjusted to 6.5. The precipi-tate is separa-ted by centrifuga-tion and redissolved in 100 1 of distilled water admixed wi-th 0.015 M of MaCl.
There is added 40 g of PEG 3000 per liter and 5 g o~
caprylic acid per liter~ The pH is adjusted to 5Ø
Standing time 45 minutes. The precipi-ta-te is separated by centrifugation. The cen-trifugate is admixed with additional 40 g of PEG 3000 per liter~ The pH is adjus-ted to 7.5.
The precipitate is separated by centri~ugation and re-dissolved in distilled water with 0.002 M of NaCl. The solution is filtered to clarity (e.g. SEITZ ~ EK-Filter)~
The protein concentra-tion should be 50-100 g/l~ 20 g of DEAE-Sephadex-A25 ~ are added per 100 g o~ protein.
After leaving to s-tand for 60 minutes while s-tirring the DEAE-Sephadex is separated by filtration. The DEAE-Sephadex treatment is repeated. A~ter sterile fil-tra-tion there is obtained an immunoglobulin G preparation ~ree ~rom anticomplementariness and suitable ~or lntravenous administration.
Claims (6)
1. A method of recovering purified immunoglobulin suitable for intravenous administration wherein blood plasma, serum or a fraction thereof is subjected to a fractionated pre-cipitation using a combination of polycondensed polyol and a mono or polyalkanoic acid having from 4 to 12 carbon atoms as a precipitant.
2. A method according to claim 1, wherein the polyol is a diol.
3. A method according to claim 1, wherein the mono or polyalkanoic acid is an alkanoic acid having from 6 to 9 carbon atoms.
4. A method according to claim 3, wherein the alkanoic acid is caprylic acid.
5. A method according to claim 1, wherein the preci-pitation is effected at a pH of from 3 to 7.
6. A method according to claim 5, wherein the pH is from 4.5 to 5.5.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK162876AA DK139056B (en) | 1976-04-06 | 1976-04-06 | Method for recovering immunoglobulin suitable for intravenous administration. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1072444A true CA1072444A (en) | 1980-02-26 |
Family
ID=8106680
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA275,585A Expired CA1072444A (en) | 1976-04-06 | 1977-04-05 | Method of recovering immunoglobulin |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | USRE31268E (en) |
| JP (1) | JPS52122620A (en) |
| AR (1) | AR211890A1 (en) |
| AU (1) | AU511474B2 (en) |
| BE (1) | BE852995A (en) |
| CA (1) | CA1072444A (en) |
| CH (1) | CH628813A5 (en) |
| DD (1) | DD129451A5 (en) |
| DE (1) | DE2713817A1 (en) |
| DK (1) | DK139056B (en) |
| ES (1) | ES457482A1 (en) |
| FI (1) | FI61191C (en) |
| FR (1) | FR2347379A1 (en) |
| GB (1) | GB1551865A (en) |
| HU (1) | HU175511B (en) |
| IL (1) | IL51782A (en) |
| IT (1) | IT1075148B (en) |
| NL (1) | NL7703572A (en) |
| NO (1) | NO146763C (en) |
| SE (1) | SE7703843L (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5087695A (en) * | 1988-07-29 | 1992-02-11 | Mcy Laboratories Canada, Inc. | Immunoglobulin extraction utilizing properties of colloidal solutions |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5625114A (en) * | 1979-08-07 | 1981-03-10 | Green Cross Corp:The | Preparation of human gamma globulin |
| US4590002A (en) * | 1984-12-10 | 1986-05-20 | Ortho Diagnostic Systems, Inc. | Methods for preparation of highly purified, gamma globulins free of hepatitis-B-virus infectivity |
| FR2578425B1 (en) * | 1985-03-07 | 1988-06-10 | Nal Transfusion Sanguine Centr | IMMUNOGLOBULIN PREPARATIONS HAVING HIGH TITLES OF ANTI-ALLERGENIC BLOCKING ANTIBODIES, THEIR PREPARATION AND THEIR APPLICATIONS FOR THE TREATMENT OF ALLERGIES |
| FR2632308B1 (en) * | 1988-06-07 | 1991-08-16 | Fondation Nale Transfusion San | PROCESS AND PLANT FOR THE CONTINUOUS FRACTIONATION OF ANIMAL OR HUMAN PLANT PROTEINS |
| US5525519A (en) * | 1992-01-07 | 1996-06-11 | Middlesex Sciences, Inc. | Method for isolating biomolecules from a biological sample with linear polymers |
| US5367054A (en) * | 1993-04-12 | 1994-11-22 | Stolle Research & Development Corp. | Large-scale purification of egg immunoglobulin |
| JP2008500972A (en) * | 2004-05-14 | 2008-01-17 | キリンファーマ株式会社 | Immunoglobulin purification method |
| US20060226086A1 (en) * | 2005-04-08 | 2006-10-12 | Robinson Thomas C | Centrifuge for blood processing systems |
| WO2008127305A2 (en) * | 2006-11-01 | 2008-10-23 | Biogen Idec Ma Inc. | Method of isolating biomacromolecules using low ph and divalent cations |
| US20090292109A1 (en) * | 2008-04-16 | 2009-11-26 | Biogen Idec Ma Inc. | Method of Isolating Biomacromolecules Using Polyalkylene Glycol and Transition Metals |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3100737A (en) * | 1958-02-05 | 1963-08-13 | Auerswald Wilhelm | Method of preparing a plasma protein solution free of active hepatitis virus and product produced thereby |
| NL286954A (en) * | 1962-01-03 | |||
| NL6702923A (en) * | 1966-04-06 | 1967-10-09 | ||
| US3916026A (en) * | 1968-09-19 | 1975-10-28 | Biotest Serum Institut Gmbh | Method for the preparation of gamma-globulin suitable for intravenous use |
| US3869436A (en) * | 1971-06-01 | 1975-03-04 | Statens Bakteriologiska Lab | Method for fractionating plasma proteins using peg and ion-exchangers |
| US3770631A (en) * | 1971-06-29 | 1973-11-06 | Baxter Laboratories Inc | Clarification of blood serum and plasma |
| JPS5620287B2 (en) * | 1972-06-19 | 1981-05-13 | ||
| US3880989A (en) * | 1973-01-30 | 1975-04-29 | Baxter Laboratories Inc | Production of antisera comprising fractionating plasma or serum with an ethylene oxide-polyoxypropylene block copolymer |
| US3808189A (en) * | 1973-03-15 | 1974-04-30 | American Cyanamid Co | Isolation of gamma globulin preparations enriched in iga and igm using polyethylene glycol |
| JPS5417002B2 (en) * | 1974-02-18 | 1979-06-27 | ||
| CA1064396A (en) * | 1975-02-18 | 1979-10-16 | Myer L. Coval | Fractional precipitation of gamma globulin with polyethylene glycol |
| DE2527064C3 (en) * | 1975-06-18 | 1979-11-15 | Biotest-Serum-Institut Gmbh, 6000 Frankfurt | Process for the production of an intravenous native human immunoglobulin preparation with a natural half-life and unchanged antibody activity compared to the starting material |
| US4021540A (en) * | 1975-07-28 | 1977-05-03 | Ortho Diagnostics Inc. | Preparation of a hepatitis B immune globulin and use thereof as a prophylactic material |
| FR2322611A2 (en) * | 1975-09-06 | 1977-04-01 | Biotest Serum Institut Gmbh | GAMMA-GLOBULIN PREPARATION PROCESS |
| US4075193A (en) * | 1976-11-26 | 1978-02-21 | Parke, Davis & Company | Process for producing intravenous immune globulin |
| US4124576A (en) * | 1976-12-03 | 1978-11-07 | Coval M L | Method of producing intravenously injectable gamma globulin |
-
1976
- 1976-04-06 DK DK162876AA patent/DK139056B/en not_active IP Right Cessation
-
1977
- 1977-03-29 DE DE19772713817 patent/DE2713817A1/en not_active Withdrawn
- 1977-03-29 BE BE176213A patent/BE852995A/en not_active IP Right Cessation
- 1977-03-30 IL IL51782A patent/IL51782A/en unknown
- 1977-03-31 GB GB13575/77A patent/GB1551865A/en not_active Expired
- 1977-03-31 IT IT21982/77A patent/IT1075148B/en active
- 1977-03-31 AR AR267073A patent/AR211890A1/en active
- 1977-04-01 NL NL7703572A patent/NL7703572A/en not_active Application Discontinuation
- 1977-04-01 SE SE7703843A patent/SE7703843L/en not_active Application Discontinuation
- 1977-04-01 HU HU77NO212A patent/HU175511B/en unknown
- 1977-04-02 ES ES457482A patent/ES457482A1/en not_active Expired
- 1977-04-04 AU AU23910/77A patent/AU511474B2/en not_active Expired
- 1977-04-04 DD DD7700198240A patent/DD129451A5/en unknown
- 1977-04-05 CH CH428777A patent/CH628813A5/en not_active IP Right Cessation
- 1977-04-05 FR FR7710326A patent/FR2347379A1/en active Granted
- 1977-04-05 CA CA275,585A patent/CA1072444A/en not_active Expired
- 1977-04-05 NO NO771225A patent/NO146763C/en unknown
- 1977-04-05 FI FI771071A patent/FI61191C/en not_active IP Right Cessation
- 1977-04-06 JP JP3858877A patent/JPS52122620A/en active Pending
-
1981
- 1981-08-13 US US06/292,386 patent/USRE31268E/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5087695A (en) * | 1988-07-29 | 1992-02-11 | Mcy Laboratories Canada, Inc. | Immunoglobulin extraction utilizing properties of colloidal solutions |
Also Published As
| Publication number | Publication date |
|---|---|
| ES457482A1 (en) | 1978-03-16 |
| DK139056C (en) | 1979-05-21 |
| AR211890A1 (en) | 1978-03-31 |
| FI61191C (en) | 1982-06-10 |
| IL51782A0 (en) | 1977-05-31 |
| USRE31268E (en) | 1983-06-07 |
| FI771071A (en) | 1977-10-07 |
| SE7703843L (en) | 1977-10-07 |
| JPS52122620A (en) | 1977-10-15 |
| NL7703572A (en) | 1977-10-10 |
| IL51782A (en) | 1980-12-31 |
| DE2713817A1 (en) | 1977-10-27 |
| BE852995A (en) | 1977-07-18 |
| FR2347379A1 (en) | 1977-11-04 |
| AU2391077A (en) | 1978-10-12 |
| FI61191B (en) | 1982-02-26 |
| GB1551865A (en) | 1979-09-05 |
| NO146763B (en) | 1982-08-30 |
| NO146763C (en) | 1982-12-08 |
| DK139056B (en) | 1978-12-11 |
| CH628813A5 (en) | 1982-03-31 |
| NO771225L (en) | 1977-10-07 |
| IT1075148B (en) | 1985-04-22 |
| FR2347379B1 (en) | 1981-11-20 |
| DD129451A5 (en) | 1978-01-18 |
| HU175511B (en) | 1980-08-28 |
| DK162876A (en) | 1977-10-07 |
| AU511474B2 (en) | 1980-08-21 |
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