IE43449B1 - Process reducing the anticomplementary activity of gamma globulins - Google Patents
Process reducing the anticomplementary activity of gamma globulinsInfo
- Publication number
- IE43449B1 IE43449B1 IE2826/75A IE282675A IE43449B1 IE 43449 B1 IE43449 B1 IE 43449B1 IE 2826/75 A IE2826/75 A IE 2826/75A IE 282675 A IE282675 A IE 282675A IE 43449 B1 IE43449 B1 IE 43449B1
- Authority
- IE
- Ireland
- Prior art keywords
- gamma globulin
- aqueous solution
- gamma
- solution
- hydroxyethyl starch
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
1495159 Gamma globulin PLASMESCO AG 29 Dec 1975 [2 Jan 1975] 53020/75 Heading A5B [Also in Division C3] The compatability of gamma globulin precipitated from blood or blood products is improved by dissolving the precipitated gamma globulin in an aqueous solution containing from 1 to 30% of a hydroxyethyl starch having a molecular weight of 1000 to 900000 and thereafter recovering the gamma globulin from this solution. In an example gamma globulin precipitate is dissolved in a buffered aqueous solution at pH 6.7 in a concentration of about 6%. About 10% of hydroxyethyl starch (M.W. 1000 to 900000) is added to this solution which facilitates separation of existing gamma globulin aggregates and simultaneously protects non-aggregated gamma globulin molecules. After addition of 10% of polyethyleneglycol the mixture is centrifuged. The remaining supernatant phase is mixed with 20% polyethylene glycol at pH 7.2 and centrifuged. The resulting precipitate is taken up in saline solution and is suitable for the therapeutic use.
Description
The present invention relates to a process for reducing the inticomplementary activity and thus of improving the compatibility, ihen injected intravenously, of gamma globulins precipitated from jlood or blood products.
Blood is a liquid which consists of solid and liquid compon:nts. The solid components include the red and white blood ;orpulscles as well as the blood platelets or thrombocytes. The ilasma, i.e. the liquid portion of the blood, contains about 90% >£ water and 10% of dissolved solids. The substances dissolved in ;he plasma include, among other substances, gamma globulin which ,s used for the therapy and prophylaxis of infections. For the solation of gamma globulin, all of the other substances contained n the plasma must be removed as far as possible, in order that as mre as possible a gamma globuline is provided.
For the precipitation and isolation of gamma globulin from lood, there is used particularly a process which is known by the ane COHN-Method. 11 (COHN et al., J. Amer. Chem, Soc., Vol, 68,
Ρ 459... 475, and Vol, 72, pp. 465 ... 474)· This process starts ith a mixture of plasma from various blood samples. Principally, this involves a fractionated precipitation under various conditions, in a first stage, as the first sediment there is initially separated mainly fibrinogen at a temperature of minus 3°C and at a pH of 7-2 with an ethanol addition of 8%. The supernatant liquid is precipitated in a second stage with about 19% of ethanol at a pH of 5·6. The precipitate contains mainly gamma globulin. For the purification of this precipitate (designated as COHN-Fraction ΓΓ-ΙΙ1), this precipitate is re-dissolved and thereafter initially re-precipitated at a pH of 5 and with 8% of ethanol. The remaining supernatant phase is thereafter again precipitated with 25% of ethanol, and at a pH of 7·2. . The resulting precipitate comprises at least 90% of gamma globulin. The precipitate is received by a suitable buffer solution, and after the sterile filtration this precipitate is ready for application to human beings.
Xt has been found that in numerous instances the gamma globulin preparations which have been obtained in the above-indicated, or in another manner, are of anticomplementary activity such that complications result from corporeal reactions in the case of intravenous application.
Accordingly, it has already been attempted to increase or improve the intravenous compatibility of gamma globulins. As examples, the following methods or processes described in the literature may be mentioned:
(1) Treatment with suitable enzymes;
(2) hydrolysis at high hydrogen ion concentration (e.g. at a pH of 4.0);
(3) modification by means of beta-propiolactone.
However, it has been found that these previously proposed processes act to modify the gamma globulin molecules and to alter their chemical structure to such an extent that their activity is educed and their average retention time in the organism is hortened.
According to the present invention there is provided a process or reducing the anticomplementary activity of gamma globulin recipitated from blood or blood products, wherein the precipitated amma globulin is dissolved in an aqueous solution containing a oncentration of from 1 to 30% of a hydroxyethyl starch having a olecular weight of 1000 to 900,000 and the gamma globulin is ^covered from said solution substantially free of anticomplementary ativity.
With the present process, the structure of the existing gamma Lobulin molecules is altered to minimum degree; and the antijmplementary activity can be greatly reduced as compared with mventional gamma globulin preparations. The retention period in ie organism of the gamma globulin can be Increased, whereby the ’eparation may be more compatible than conventional preparations.
In carrying out the present process, a precipitant is preferably Ided to the solution to precipitate the anti-complementary activity, itch is removed, as by centrifugation. Further precipitant may len be added to precipitate the gamma globulin which is recovered, i by centrifugation, and can then be dissolved in a physiological irmal saline solution. The precipitant is conveniently a polyethylene ycol.
It has been proposed to use polyethylene glycol for the fractnation of blood plasma and the precipitation of purified gamma obuline fractions from considerably diluted aqueous solutions.
has also been proposed preferentially to insolubilize anticomplemtary activity from an aqueous solution of gamma globulin by corporating in said solution from 4.5 to 7g· per 100 ml. of polyhylene glycol of molecular weight of about 6000. However, in ither of these cases is hydroxyethyl starch present.
- 4 43449
Γη the present process, the hydroxyethyi starch appears to facilitate the separation of aggregates present in the gamma globulin and to protect the non-aggregated gamma globulin molecules, so enabling a better separation of the anticomplementary activity to be achieved upon the first addition of precipitant.
Preferably, the aqueous solution in to which the precipitated gamma globulin is introduced is a buffered aqueous solution of hydroxyethyl starch having a pH of from 3.5 to 8.0, preferably from 6.5 to
0.9.
The conccntral. ion of hydroxyethyi starch in the aqueous solution is preferably from S to 10%
Upon dissolving the gamma globulin precipitate in the buffered I1EB solution 10% of polyethylene glycol, as a precipitant, is conveniently added to the mixture. The mixture is made free of unwanted precipitates by centrifugation. In place of the polyethylene glycol, other polymerized polyvalent alcohols may be used as precipitants. The remaining supernatant phase after centrifugation is mixed with 20% of polyethylene glycol at a pH of from 7.0 to 7.2 and then centrifuged anew. Expediently, the thus obtained precipitate is dissolved in a physiological normal saline solution and ad,justed l.o a concentration of about 5% of albumin or protein total content. After the sterile centrifugation, the solution is ready for therapeutic use.
Below, the individual process steps are explained again in an Example.
Separation of the gamma globulin:
The process starts with a collecter plasma which is blended with 8% of ethanol and precipitated at a pH of 7-2 at a temperature of minus 3°C., whereby, Fraction I is separated. The recovered liquid is thereafter mixed with 19% of ethanol at a temperature of minus
- 5 43449
° C and a pH of 5.8, whereby, Fraction IX-XII is separated which consists of gamma globulins. The precipitate is re-dissolved and again precipitated at a pH of 5 with 8% of ethanol. The remaining supernatant phase is then again precipitated with 25% of ethanol at a pH of 7-2. The precipitate obtained in this stage (=Fraction Et) comprises at least 90% of gamma globulin.
Reduction of the anticomplementary activity;
The gamma, globulin precipitate is dissolved in a buffered aqueous solution at a pH of 6.7, in a concentration of about 6%, and the aqueous solution has added thereto about 10% of hydroxyethyl starch (HES), the molecular weight of which is from 1000 to 900,000. The HES renders possible a separation of already existing aggregates and simultaneously protects non-aggregated gamma globulin molecules.
Introduction into a physiological normal saline solution;
After the addition of 10% of polyethylene glycol, the mixture is centrifuged. The remaining supernant phase is mixed with 20% of polyethylene glycol at a pH of 7-2, and centrifuged, The thus obtained precipitate is adjusted to a concentration of 5.2% of albumin in a physiological normal saline solution, and subsequently filtered under sterile conditions. Thereupon, the precipitate is ready for therapeutic use.
The accompanying drawing shows in Figure 1 thereof the structural formula of hydroxyethyl starch (HES), and in Figure 2 thereof immune electrophoresis diaphragms (lEP) of various gamma globulins or of normal sera, respectively, which have been prepared in accordance with the conventional and novel processes.
The upper half of each diagram of Fig. 2 shows the IEP diagram of a normal blood serum, whereas the lower half shows the diagram of
- 6 43440 (a) standard gamma globulin, (b) proteolytically modified gamma globulin, (c) beta-propiolactone-modified gamma globulin.
(d) gamma globulin as prepared in accordance with the present process.
Samples (a) to (c) each represent a commercially available modified preparation. In addition to the gamma globulin line (elongated crescent-shaped line in the right hand portion of the diagram), these samples also show additional albumin or protein components of the human blood. Owing to the chemical modification, the gamma globulin lines of samples (a) and (b) are shown blurred. Sample (c) exhibits a varied position as compared with the gamma globulin line of the control serum.
In contrast, it is clearly evident that sample (d) consists substantially exclusively of pure gamma globulin as the crescentshaped line of the spectrum is distinctly present in the normal serum.
It can be concluded from the diagrams that the gamma globulin obtained by the process has a purity of substantially 100% so as to completely correspond to the gamma globulin of the original blood serum. The latter fact means that the molecules are not modified or chemically varied. These characteristics result in the further advantageous properties of the gamma globulin according to the present process which have also been verified by tests, namely its absolutely positive intravenous compatibility and its greatly reduced anticompLementary activity to intracorporeal antibodies, which properties couid be clearly demonstrated in in-vitro tests.
As another advantage, storage tests have shown a particularly high stability of gamma globulins prepared in the above disclosed .30 manner, using the steps of this invention.
Claims (12)
1. A process for reducing the anticomplementary activity of gamma gloculin precipitated from blood or blood products, wherein the precipitated gamma globulin is dissolved in an aqueous solution containing a concentration of from 1 to 30% of a hydroxyethyl starch having a molecular weight of 1000 to 900,000 and the gamma globulin is recovered from said solution substantially free of anti-complementary activity.
2. A process as claimed in Claim 1, wherein a precipitant is added to the solution to precipitate the anticomplementary activity which is removed.
3. A process as claimed in Claim 2, wherein the anticomplementary activity is removed by centrifugation.
4. A process as claimed in Claim 2 or 3, wherein further precipitant is then added to precipitate the gamma globulin which is recovered and dissolved in a physiological normal saline solution.
5. A process as claimed in Claim 4, wherein the gamma globulin is recovered by centrifugation.
6. A process as claimed in anyone of claims 2 to 5, wherein the precipitant is polyethylene glycol.
7. A process as claimed in any preceding claim, wherein the aqueous solution is a buffer aqueous solution of hydroxyethyl starch having a pH of 3.5 to 8.0.
8. A process as claimed Ln any preceding claim, wherein the aqueous solution is a buffered aqueous solution of hydroxyethyl starch having a pH of 6.5 to 6.9·
9. A process as claimed in any preceding claim, wherein the concentration of hydroxyethyl starch in said aqueous solution is 8 to 10% - 8 43448
10. A process as claimed in any preceding claim, wherein the concentration of gamma globulin in said aqueous solution is 6% and the concentration of hydroxyethyl starch is 10%
11. A process in accordance with Claim 1 for reducing the anti5 complementary activity of gamma globulin precipitated from blood or blood products substantially as hereinbefore described in the foregoing Example.
12. Gamma globulin treated bythe process claimed in any preceding claim.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2500076A DE2500076C3 (en) | 1975-01-02 | 1975-01-02 | Process for the production of intravenously tolerated gamma globulins |
Publications (2)
Publication Number | Publication Date |
---|---|
IE43449L IE43449L (en) | 1976-07-02 |
IE43449B1 true IE43449B1 (en) | 1981-02-25 |
Family
ID=5935911
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE2826/75A IE43449B1 (en) | 1975-01-02 | 1975-12-30 | Process reducing the anticomplementary activity of gamma globulins |
Country Status (20)
Country | Link |
---|---|
JP (1) | JPS5512001B2 (en) |
AT (1) | AT344883B (en) |
AU (1) | AU505416B2 (en) |
BE (1) | BE837211A (en) |
CA (1) | CA1058075A (en) |
DD (1) | DD121875A5 (en) |
DE (1) | DE2500076C3 (en) |
DK (1) | DK144679C (en) |
EG (1) | EG11987A (en) |
ES (1) | ES443982A1 (en) |
FR (1) | FR2296429A1 (en) |
GB (1) | GB1495159A (en) |
IE (1) | IE43449B1 (en) |
IL (1) | IL48766A (en) |
IN (1) | IN143525B (en) |
NL (1) | NL179824C (en) |
PL (1) | PL99599B1 (en) |
SE (1) | SE437470B (en) |
SU (1) | SU576898A3 (en) |
ZA (1) | ZA758050B (en) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2604759C2 (en) * | 1976-02-07 | 1983-06-01 | SCHURA Blutderivate GmbH & Co KG, 4150 Krefeld | Method of Obtaining IV Compatible Gamma Globulins |
JPS6016406B2 (en) * | 1976-08-06 | 1985-04-25 | マイヤ−、ル−イス、コ−バル | Method for producing intravenously administrable gamma globulin and gamma globulin prepared thereby |
US4124576A (en) * | 1976-12-03 | 1978-11-07 | Coval M L | Method of producing intravenously injectable gamma globulin |
GB1603244A (en) * | 1977-05-20 | 1981-11-18 | Max Planck Gesellschaft | Medicaments for the suppression of pathological processes |
JPS5822085B2 (en) * | 1977-07-19 | 1983-05-06 | 株式会社ミドリ十字 | Intravenous gamma globulin preparations |
AT359641B (en) * | 1978-09-19 | 1980-11-25 | Immuno Ag | METHOD FOR PRODUCING AN INTRAVENOUS ADMINISTRABLE ANTIBODY-CONTAINING IMMUNOGLOBULIN PREPARATE |
EP0019403B1 (en) * | 1979-05-10 | 1985-07-31 | American Hospital Supply Corporation | Hydroxyalkyl-starch drug carrier |
US4396608A (en) * | 1981-08-24 | 1983-08-02 | Cutter Laboratories | Intravenously injectable immune serum globulin |
DE3271181D1 (en) * | 1982-02-08 | 1986-06-19 | Schweiz Serum & Impfinst | Intravenously administrable human immunoglobuline and process for its preparation |
US4482483A (en) * | 1983-04-06 | 1984-11-13 | Armour Pharmceutical Company | Composition of intravenous immune globulin |
SE8302483L (en) * | 1983-05-02 | 1984-11-03 | Pharmacia Ind | PROCEDURE FOR PURIFICATION OF BIOLOGICALLY ACTIVE SUBSTANCES |
US5945098A (en) * | 1990-02-01 | 1999-08-31 | Baxter International Inc. | Stable intravenously-administrable immune globulin preparation |
DE19907257A1 (en) * | 1999-02-21 | 2000-09-14 | Bernd Horst Meier | Means for controlling the diffusion of injection solutions |
DE10040707A1 (en) * | 2000-08-17 | 2002-03-14 | Braun Melsungen Ag | Injectable aqueous medicament, containing colloid, e.g. hydroxyethyl starch, to modulate mobility, diffusion, pharmacokinetic and electrophoretic properties of active agent and improve effectiveness |
DE10303974A1 (en) | 2003-01-31 | 2004-08-05 | Abbott Gmbh & Co. Kg | Amyloid β (1-42) oligomers, process for their preparation and their use |
CN102898519B (en) | 2005-11-30 | 2015-10-28 | Abbvie公司 | Monoclonal antibody of anti-amyloid beta protein and uses thereof |
PL2289909T3 (en) | 2005-11-30 | 2015-04-30 | Abbvie Inc | Screening method, process for purifying of non-diffusible a-beta oligomers, selective antibodies against said non-diffusible a-beta oligomers and a process for manufacturing of said antibodies |
US8455626B2 (en) | 2006-11-30 | 2013-06-04 | Abbott Laboratories | Aβ conformer selective anti-aβ globulomer monoclonal antibodies |
US20100311767A1 (en) | 2007-02-27 | 2010-12-09 | Abbott Gmbh & Co. Kg | Method for the treatment of amyloidoses |
EP2558494B1 (en) | 2010-04-15 | 2018-05-23 | AbbVie Inc. | Amyloid-beta binding proteins |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE348942B (en) * | 1970-06-02 | 1972-09-18 | Statens Bakteriologiska Labor | |
DE2234069A1 (en) * | 1971-07-16 | 1973-02-08 | South African Inventions | METHOD OF MANUFACTURING A PURIFIED GAMMA GLOBULIN |
ZA738779B (en) * | 1972-11-27 | 1974-10-30 | Baxter Laboratories Inc | Production of gamma globulin |
JPS49101516A (en) * | 1973-01-13 | 1974-09-25 |
-
1975
- 1975-01-02 DE DE2500076A patent/DE2500076C3/en not_active Expired
- 1975-12-16 NL NLAANVRAGE7514627,A patent/NL179824C/en not_active IP Right Cessation
- 1975-12-18 SE SE7514388A patent/SE437470B/en not_active IP Right Cessation
- 1975-12-22 DK DK584375A patent/DK144679C/en active
- 1975-12-23 AT AT981675A patent/AT344883B/en active
- 1975-12-26 FR FR7539814A patent/FR2296429A1/en active Granted
- 1975-12-27 JP JP15974275A patent/JPS5512001B2/en not_active Expired
- 1975-12-29 GB GB53020/75A patent/GB1495159A/en not_active Expired
- 1975-12-29 DD DD190614A patent/DD121875A5/xx unknown
- 1975-12-30 ZA ZA00758050A patent/ZA758050B/en unknown
- 1975-12-30 EG EG775/75A patent/EG11987A/en active
- 1975-12-30 ES ES443982A patent/ES443982A1/en not_active Expired
- 1975-12-30 IN IN2413/CAL/75A patent/IN143525B/en unknown
- 1975-12-30 IE IE2826/75A patent/IE43449B1/en unknown
- 1975-12-30 BE BE6045314A patent/BE837211A/en not_active IP Right Cessation
- 1975-12-30 IL IL48766A patent/IL48766A/en unknown
- 1975-12-30 CA CA242,734A patent/CA1058075A/en not_active Expired
- 1975-12-30 AU AU87921/75A patent/AU505416B2/en not_active Expired
- 1975-12-31 SU SU7502306354A patent/SU576898A3/en active
-
1976
- 1976-01-01 PL PL1976186289A patent/PL99599B1/en unknown
Also Published As
Publication number | Publication date |
---|---|
NL179824B (en) | 1986-06-16 |
IE43449L (en) | 1976-07-02 |
DK584375A (en) | 1976-07-03 |
DE2500076C3 (en) | 1982-11-18 |
NL179824C (en) | 1986-11-17 |
ATA981675A (en) | 1977-12-15 |
IL48766A (en) | 1979-11-30 |
IL48766A0 (en) | 1976-02-29 |
IN143525B (en) | 1977-12-17 |
CA1058075A (en) | 1979-07-10 |
JPS5512001B2 (en) | 1980-03-29 |
JPS5191321A (en) | 1976-08-10 |
AT344883B (en) | 1978-08-10 |
NL7514627A (en) | 1976-07-06 |
FR2296429A1 (en) | 1976-07-30 |
EG11987A (en) | 1981-12-31 |
AU505416B2 (en) | 1979-11-22 |
SU576898A3 (en) | 1977-10-15 |
DK144679B (en) | 1982-05-10 |
PL99599B1 (en) | 1978-07-31 |
ES443982A1 (en) | 1977-07-16 |
BE837211A (en) | 1976-06-30 |
DE2500076B2 (en) | 1979-02-22 |
GB1495159A (en) | 1977-12-14 |
DE2500076A1 (en) | 1976-07-08 |
FR2296429B1 (en) | 1978-12-01 |
SE437470B (en) | 1985-03-04 |
DK144679C (en) | 1982-10-11 |
DD121875A5 (en) | 1976-09-05 |
AU8792175A (en) | 1977-07-14 |
SE7514388L (en) | 1976-07-05 |
ZA758050B (en) | 1976-12-29 |
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