US3686395A - Process for preparation of storage stable hepatitis-free serum - Google Patents

Process for preparation of storage stable hepatitis-free serum Download PDF

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US3686395A
US3686395A US3686395DA US3686395A US 3686395 A US3686395 A US 3686395A US 3686395D A US3686395D A US 3686395DA US 3686395 A US3686395 A US 3686395A
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serum
plasma
silicic acid
irradiation
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Wolfgang Stephan
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Biotest AG
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14Blood; Artificial blood
    • A61K35/16Blood plasma; Blood serum
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011Methods 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

Abstract

Preparation of lipoprotein-free, stable and sterile serum by intimately admixing blood serum or plasma with 250 to 500 mg. colloidal silicic acid per gram of total protein and following removal of the silicic acid subjecting the serum or plasma to irradiation with ultraviolet light and sterile filtration. The separated colloidal silicic acid can be treated for elution of the adsorbed lipoproteins, the latter being suitable for use as a biochemical or immunochemical reagent.

Description

United States Patent Stephan [451 Aug. 22, 1972 154] PROCESS FOR PREPARATION OF STORAGE STABLE HEPATITIS-FREE SERUM [72] lnventor: Wolfgang Stephan, Gartenstr. 186,

Neuisenberg, Germany [73 Assignee: Biotest Serum Institut GmbH, Frank- 7 furt Main-Niedeirad, Germany [22] Filed: Oct. 7, 1970 [21] Appl. No.: 78,949

Related US. Application Data [.63] Continuation-in-part of Ser. No. 627,625, April I 3, 1967, abandoned.

[30] Foreign Application Priority Data 3,284,434 11/1966 Sutherland ..260/112 OTHER PUBLICATIONS Journal of the American Medical Association (JAMA), Vol. 138, No. 3,p. 255, 1948. Rose, A Nylon Blood and Plasma Filter," Science, Vol. 98, No. 2534, p. 92, 1943. Nikkila & Oker-Blom, Science, Vol. 116, pp. 685- 86, December 1952.

'Clausen et al., Isolation of Ceruloplasmin," Protides of the Biological Fluids, 9th Colloqu im, pp. 269- 275, I

V. Cohn (ll), Blood Proteins and Their Therapeutic Value, Harvard Medical School, pp. 1- 6, 1945 (Reprint from Science, Vol. 101, pp. 51- 56, 1945).

Primary ExaminerAlbert T. Meyers Assistant Examiner-Doris J. Funderburk Att0rneyBurgess, Dinklage & Sprung ABSTRACT Preparation of lipoprotein-free, stable and sterile serum by intimately admixing blood serum or plasma with 250 to 500 mg. colloidal silicic acid per gram of total protein and following removal of the silicic acid subjecting the serum or plasma to irradiation with u1- traviolet light and sterile filtration. The separated colloidal silicic acid can be treated for elution of the adsorbed lipoproteins, the latter being suitable for use as a biochemical or immunochemical reagent.

8 Claims, N0 Drawings PROCESS FOR-PREPARATION OF STORAGE STABLE HEPATlTlS-FREE SERUM This application is a continuation-in-part of application Ser. No. 627,625 filed Apr. 3, 1967 now abandoned.

This invention relates to lipoprotein-free, stable serum and plasma and more particularly to stable hepatitis-free serum and plasma and to a process for making the same.

It is known that blood plasma and blood serum become cloudy after a certain period of time due to denaturation of the unstable protein components therein, and then can no longer be used for infusion.

it has hitherto not been possible to determine by means of animal experiments or in vitro analysis whether serum'or plasma contains hepatitis virus. The risk of contamination with hepatitis virus is a serious problem and exists especially where relatively large blood banks are in use. .However, it has not been possible to this day to prepare stable hepatitis-free preserved plasma or serum without the use of chemical additives and without denaturation of the serum proteins taking place. v I

lmmunoelectrolytic investigations of serum and plasma which has been stored for l to 2 years has established that the instability is due 'not to the fibrinogen present but particularly to the presence of lipoproteins, in particular alpha -lipoprotein. Adsorption of fibrinogen and other coagulation factors from plasma using bentonite (l.P. Soulier, Extrait de la Revue Francais dEtudes cliniques et biol., 1959, 2, Volume IV, pages 153 to. 156) has already been proposed, as has the adsorption of lipoproteins and lipids from serum by the preparation of coeroloplasmin using silicic acid (J. Clausen, A. Hansen and R. Jensen, Protides of the Biological Fluids, 9th Colloquium, Bruges 1961, Elsevier Amsterdam 1962, page 269). However, nothing is known of the storage stability of the plasma and serum treated in this way.

Stabilized plasma protein solutions are generally prepared by fractionation. Adsorption on bentonite and treatment with monochloroacetate are also known (Donald Dawson et al. lSR Volume II, No. 1, January, 1962, 31). However, fractionation yields only plasma protein solutions which contain no therapeutically important fractions. With the other processes, it is not possible to achieve any stability.

It is, therefore, an object of the present invention to protect sera and plasma against deterioration on storage.

it is another object to protect sera and plasma from deterioration caused by lipoproteins present therein.

lt isstill another object to protect sera and plasma from deterioration caused by lipoproteins present therein without the use of chemical additives and without subsequent denaturation of the serum protein.

These and other objects will become apparent in the following description and claims.

In accordance with the present invention, it has now been found that colloidal silicic acid is capable under certain reaction conditions quantitatively to absorb not only alpha alpha and fi-lipoproteins but in addition the fibrinogen present in serum and plasma. When serum and plasma are treated by intimately contacting the same with colloidal silicic acid, protein solutions are obtained which still contain all the therapeutically important constituents and which are substantially stable to storage due to the complete removal of fibrinogen which is unstable in solution as well as the complete removal of the lipoproteins, so that at a constant refrigeration temperature 4 to 6C) storage is possible for up to 2 years without any appearance of cloudiness and without any loss of therapeutic activity.

More specifically, the present invention is directed to a process for the preparation of lipoprotein-free, stable and sterile serum, which is characterized in that blood serum or blood plasma is intimately mixed with 250 to 500 mg. of colloidal silicic acid per gram of total protein and is thereafter purified, following removal of the silicic acid, by a combined treatment with UV irradiation (UV ultraviolet) and sterile filtration.

. Preferably, the sterile filtration is carried out first and UV-irradiation thereafter, although the sequence is not critical. A

The treatment of the plasma and serum according to the invention is preferably carried out at temperatures of up to 50C, in particular-between 20 and 50C. The preferred pH range during the processing lies between 6.5 and 8. The duration of the mixing process depends on the type of apparatus used for mixing.

Mixing times as used in practice consist for example, of l to 8 hours treatment using mixers rotating at a suitable speed.

The UV-irradiation is preferably carried out at an intensity of 1 mW/cm minute.

It has been found that as a result of the treatment according to vthe invention, viruses analogous to the hepatitis virus are largely removed from the plasma or serum. It has already been indicated above thatwith the present state of the art, it is not possible to carry out experiments with the hepatitis virus on the animal. (in vivo) or in vitro. Therefore, it is necessary to rely on tests carried out with analogous viruses, the presence of which can be scientifically proved. The coli-phage has been described by LoGrippo as a particularly suitable analog for the hepatitis virus (lnvestigations of the Use of ,B-Propiolactones in Virus Inactivation; G.A. LoGrippo, Annals of the New York Academy of Science, Volume 83, Article 4, pages 578 to 594, 13th January, 1960). Using test plasma and sera infected with coli-T -phages, it can be demonstrated that with an initial concentration of 10 phages/ml, the treatment according to the invention with silicic acid results in sera or plasma having a maximum concentration of 10 phages/ml. Complete removal of all the phages is achieved if the treatment with colloidal silicic acid is followed by UV-irradiation, preferably in a continuous flow apparatus as for example that marketed by the firm of Dill.

Two processes have hitherto been employed for removing viruses:

1. Pasteurization by heating for 10 hours at 60C.

- This process cannot be applied to serum since nu-' merous serum proteins become denatured under these conditions. 2. Combination of B-propiolactone treatment UV- irradiation (G.A. LoGrippo et al., Fed.

Proceedings, 152518, 1956). This method permits sterilization of sera and plasma under careful con ditins, but the storage stability is not increased thereby.

, By the process according to the invention, in contrast, preserved plasma or serum is obtained which is stable in storage and free from hepatitis virus.

Quantitative removal of viruses may be achieved especially if a filtration step using layer filters of a suitable nature and pore size, and preferably if asbestoscontaining filters impervious to bacteria, are employed in a filtration step carried out between the adsorption operation and UV-irradiation.

Starting from serum or plasma having an average virus concentration of about /cc, this combined adsorption, filtration and UV treatment resulted in phagefree preserved serum as is set out in the following table.

The model viruses used were coli-T-phages.

The adsorbed lipoproteins can be eluted from the silicic acid precipitate'which is obtained by the process of the invention, largely without denaturation, by utilizing concentrated salt solutions in the alkaline pH range. Concentration of the lipoproteins thus recovered can be effected by a preceding elution of other adsorbed proteins by means of salt solutions of low concentratlon.

The lipoprotein solution is suitable for use as a biochemical and immunochemical reagent, in particular for medical diagnosis.

The storage stable lipoprotein-free sera and plasma canbe used as infusion liquids as for any of the other conventional uses for which such materials are conventionally employed.

The exact mechanism of the adsorption phenomenon between the silicic acid and the lipoproteins is not fully understood but it is apparently complex since other adsorbents such as montmorillonite and bentonite, for example, do not produce the same results.

The colloidal silicic acid used in the practice of the invention can be any of those commercially available, especially those sold as Aerosil silica by DEGUSSA of Germany or as Cab-O-Sil by Cabot in the United States. Since the products are ultimately intended for human administration, the only requirement is that the adsorbent not contain any interfering contaminants. Thus, for example, the whole Aerosil silica line is suitable except for those which contain substantial amounts of starch, e. g. Aerosil compositum, or hydrophobic-imparting radicals, e.g. Aerosil R. 972, and their Cab-O- Sil counterparts. Thus the surface area and particle size of the colloidal silicic acid may vary widely embracing, for example, the entire spread of commercial products which have primary particle sizes of about 3 to 50 m,u. and densities ranging from about 2.5 up to as high as 7.8 pounds per cubic foot, achieved by compression. The standard products are known as Aerosil 200 or Cab-O-Sil M-5 which have medium range surface areas of about 200 square meters per gram. Because of their higher surfaces Cab-O-Sil H-S or Aerosil 300, having 300 square meters of surface per gram, are even more effective on a weight basis; the extra high surface products such as Cab-O-Sil EH-S and Aerosil 380 have 380 square meters of surface per gram and are most effective. In the other direction, the surface area could be as low as square meters per gram, e.g Aerosil MOX 80, or even as low as 50 square meters per gram, e.g. Aerosil OX 50, although somewhat larger quantities would be required for a given result. The surfaces are all so large, however, that the indicated range of about 250 to 500 mg. of colloidal silicic acid per gram of total protein covers the practical operations; if materials of lower surface area are used, the upper part of the weight range will be required and/or possibly longer contact times, higher surface area materials performing their role in lesser amounts and/0r shorter times.

For a fuller understanding of the nature and objects of the invention, reference may be had to the following Examples which are given merely as further illustrations of the invention and are not to be construed in a limiting sense.

EXAMPLE 1 A 1 liter flask was filled with 20 g of colloidal silicic acid. (The exact product employed was the silicic acid marketed by the firm DEGUSSA under the Trade Name Aerosil.) Thereafter 200g of glass beads (0.4 cm diameter), were introduced into the flask and it was closed with muslin and sterilized in hot air for 2 hours at l80C. The serum which was to be treated (pH 7.5) was then introduced into the flask under sterile conditions. After the flask had been sealed, it was rotated for 4 hours at a rate of 40 to 50 revolutions per minute overhead. (The adsorption efiect is in the main directly dependent on the speed of rotation.) The contents of the flask were then heated for 4 hours at 45C in a water bath without stirring or shaking, and thereafter centrifuged after cooling for 30 minutes at 5,000 revolutions per minute. The flask contents were then subjected to UV irradiation in a Dill apparatus. The liquid was then filtered off under sterile conditions. After 4 weeks storage at +5C, the liquid if necessary could be filtered off from the slight precipitate which sometimes forms.

The silicic acid precipitate was worked up as follows:

The voluminous precipitate was frozen at 20C, thawed at room temperature, and centrifuged for 15 minutes at 5,000 revolutions per minute. The upper layer, which demonstrated on paper electrophoresis and immunoelectrophoresis substantially the same composition as the main portion of adsorbed serum or plasma, was filtered under sterile conditions after UV irradiation, and thereafter filtered again, if necessary, after 4 weeks storage at 5C.

Sera prepared in this manner were found to be both acutely and chronically toxicologically compatible and entirely free from pyrogens.

EXAMPLE 2 1 liter of human serum and 20g of colloidal silicic acid sterilized using hot air were thoroughly stirred at pH 7.5 (physiological pH) for 4 hours at 45C, and after cooling, centrifuged for 30 minutes at 5,000 revolutions per minute and irradiated with UV light. Thereafter the contents were filtered under sterile conditions. After 4 weeks of storage at 5C, any precipitate which had formed was filtered off.

EXAMPLE 3 1 liter of human ACD plasma was adjusted to a 5.5 percent protein content, and at a pH of 6.5 thoroughly stirred for 4 hours at 45C with 30g of colloidal silicic acid which had been sterilized with hot air. The stirred mixture was then centrifuged, irradiated with UV light and filtered under sterile conditions. After 4 weeks of storage at 5C, the liquid was filtered to remove any precipitate which had formed.

EXAMPLE 4 EXAMPLE 5 A 1 liter flask was filled with 20g of colloidal silicic acid, preferably the silicic acid product sold by the firm DEGUSSA under the Trade Name Aerosil was used. 200g of glass beads having a diameter of 0.4 cm were introduced and the flask closed with muslin and sterilized with hot air for 2 hours at 180C. The serum to be treated (having a pH of 7.5) was introduced into the flask under sterile conditions. After the flask had been sealed, it was rotated for 4 hours at 40 to 50 revolutions per minute overhead. The adsorption as previously noted directly depends on the speed of rotation used. The contents of the flask were then heated for 4 hours at 45C in a water bath without stirring or shaking, and after cooling they were centrifuged for 30 minutes at 5,000 revolutions per minute following filtration using filter layers of suitable nature and pore size, the filtrate was irradiated with UV light using therefor a DILL apparatus. After 4 weeks of storage at +5C, the precipitate, if any had formed, was filtered off.

The silicic acid precipitate remaining was worked up as follows: The voluminous precipitate was frozen at 20C, thawed at room temperature, and centrifuged for minutes at 5,000 revolutions per minute. The upper layer, which was analyzed by paper electrophoresis and immunoelectrophoresis had substantially the same composition as the main portion of adsorbed serum of plasma, was filtered, prior to UV irradiation, using therefor suitable filter layers and preferably asbestoscontaining filters which are impervious to bacteria.

Sera prepared in this manner were both acutely and chronically toxicologically compatible and free from pyrogens.

EXAMPLE 6 1 liter of human serum was thoroughly stirred at pH 7.5 (physiological pH) in admixture with g of hot-air sterilized colloidal silicic acid for 4 hours at 45C. After cooling, the contents were centrifuged for minutes at 5,000 revolutions per minute and were then filtered through asbestoscontaining filters constructed so they were impervious to bacteria. The filtrate was then irradiated with UV light. After 4 weeks of storage at 5C, the precipitate, if any had formed, was filtered off.

The product thereby obtained had the same desirable properties as the product described in Example 5.

EXAMPLE 7 1 liter of human ACD plasma was adjusted so as to have a 5 .5 percent protein content, and at a pH of 6.5 thoroughly stirred for 4 hours at 45C together with 30g of colloidal silicic acid which had been sterilized by hot air. The plasma-silicic acid batch was then centrifuged, filtered through asbestos-containing filters impervious to bacteria, and irradiated with UV light. After 4 hours of storage at 5C, the precipitate, if any had formed, was filtered off.

The serum obtained was both acutely and chronically toxicologically compatible and entirely free from pyrogen.

EXAMPLE 8 1 liter of human ACD plasma was adjusted to a content of 5.5 percent protein, and at a pH of 6.5 thoroughly mixed with colloidal silicic acid, the mixing being carried out for 4 hours at room temperature and then heated for 4 hours at 45C. After cooling, the mix= ture was centrifuged for 30 minutes at 5,000 revolutions per minute, and then filtered through filter layers of a suitable nature and pore size and preferably asbestos-containing filters impervious to bacteria, and irradiated with UV light. After 4 hours of storage at 5C, any precipitate which had formed was filtered off.

EXAMPLE 9 The precipitate which was obtained in the treatment of sera and plasma with colloidal silicic acid was worked up as follows:

1 kg of the silicic acid precipitate was washed free of protein by repeated stirring with 0.9% NaCl solution at pH 7.0, and then stirred three separate times, each time with 2 liters of 10% NaCl solution at pH 9.0, the pH being kept constant by the addition of NaOH.

The top liquids were discarded, and the lipoproteins eluted as follows from the precipitate obtained by centrifugation.

The recoveredprecipitate was suspended in 1 liter of H 0, and 450g of solid NaCl were then added thereto. The mixture was then stirred for 1 hour at pH 9.0, the pH being kept constant by the addition of NaOH. After centrifuging, the top layer was dialyzed for 24 hours against 20 liters of 0.7% NaCl solution at 5C, followed by dialysis against 1 liter of 10 percent polyvinyl pyrrolidone K 90. It was thereby concentrated to about 2 percent protein.

The solution was then filtered under sterile conditions, the filter comprising multiple layers of filter material of pore sizes smaller than the solids to be removed.

ln'the foregoing examples the colloidal silicic acid was the standard Aerosil material, i.e. that identified either as Aerosil or Aerosil 200 and having 200 square meters of surface per gram and a primary particle size of about 16 mp. For comparative purposes, a set of side-by-side runs were made with the same silicic acid as well as with others, as follows:

7. EXAMPLE Human serum was stirred for 2 hours at 45C. with 2 grams per 100 of serum of each of the indicated Aerosil adsorbents under the conditions of Example 6 except for omission of the ultraviolet irradiation. For each sample the quantity of lipoprotein absorbed was determined and the following results were obtained:

Adsorbent In an identical run using montmorillonite, obtained from Carl Roth OHG, Karlsruhe, Germany, of undefined particle size and surface area and of 80 percent I purity, less than 5 percent of the lipoproteins were adsorbed.

EXAMPLE 1 1 and examples are set forth by way of illustration and not limitation and that various modifications and changes may be made without departing from the spirit and scope of the present invention.

What is claimed is:

l. A process for the preparation of lipoprotein-free, stable and sterile serum or plasma, which comprises intimately admixing, at temperatures of up to about 50C, a blood member selected from the group consisting of serum and plasma with 250 to 500 mg of colloidal silicic acid per gram of total protein, whereinthe colloidal silicic acid has a primary particle size of about 3 to 50 m, a bulk density of about 2.5 to 7.8 pounds per cubic foot and 'a surface area of about 50 to 380 square meters per gram, and thereafter separating the silicic acid having the adsorbed lipoproteins from the blood member thereon.

2. A process according to claim 1, including the further steps of subjecting the blood member so obtained to UV-irradiation and sterile filtration.

3. A process according to claim 2, wherein said sterile filtration is carried out as a first treatment step, and the UV-irradiation as a subsequent treatment step.

4. A process according to claim 3, wherein prior to said sterile filtration, the silicic acid is separated by filtration, thereafter the serum or plasma so obtained is subjected to sterile filtration and UV-irradiation.

5. A process according to claim 4 wherein temperat 20 d5 C 1 d. wigs 't ii ess a ordihg t o l i i x wherein a pH range of 6.5 to 8 is employed.

7. A process according to claim 2, wherein said UV- irradiation is carried out at an intensity of l mW/cm minute.

8. A process according to claim 1, wherein said mixing is carried out for from 1 to 8 hours.

Claims (7)

  1. 2. A process according to claim 1, including the further steps of subjecting the blood member so obtained to UV-irradiation and sterile filtration.
  2. 3. A process according to claim 2, wherein said sterile filtration is carried out as a first treatment step, and the UV-irradiation as a subsequent treatment step.
  3. 4. A process according to claim 3, wherein prior to said sterile filtration, the silicic acid is separated by filtration, thereafter the serum or plasma so obtained is subjected to sterile filtration and UV-irradiation.
  4. 5. A process according to claim 4 wherein temperatures between 20* and 50*C are employed.
  5. 6. A process according to claim 1 wherein a pH range of 6.5 to 8 is employed.
  6. 7. A process according to claim 2, wherein said UV-irradiation is carried out at an intensity of 1 mW/cm2 minute.
  7. 8. A process according to claim 1, wherein said mixing is carried out for from 1 to 8 hours.
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US3822095A (en) * 1972-08-14 1974-07-02 Block Engineering System for differentiating particles
US3972858A (en) * 1973-12-22 1976-08-03 Behringwerke Aktiengesellschaft Process for the preparation of choleragen
US4136094A (en) * 1977-08-31 1979-01-23 The Regents Of The University Of Minnesota Preparation of intravenous human and animal gamma globulins and isolation of albumin
JPS5446813A (en) * 1977-09-22 1979-04-13 Nippon Sekijiyuujishiya Separation of plasmaprotein
US4164495A (en) * 1976-04-06 1979-08-14 Nordisk Insulinlaboratorium Method of recovering immunoglobulin using a polyol and an alkanoic acid
US4228154A (en) * 1979-02-26 1980-10-14 Armour Pharmaceutical Company Purification of plasma albumin by ion exchange chromatography
US4251510A (en) * 1979-08-15 1981-02-17 Cutter Laboratories, Inc. Intravenously injectable solution of plasma protein fraction free from bradykinin, kininogen and prekallikrein activators and processes for its production
WO1982002900A1 (en) * 1981-02-27 1982-09-02 Inc Amf Tissue culture medium
US4378346A (en) * 1979-08-15 1983-03-29 Tankersley Donald L Intravenously injectable solution of plasma protein fraction free from bradykinin, kininogen and prekallikrein activators and processes for its production
USRE31268E (en) * 1976-04-06 1983-06-07 Nordisk Insulinlaboratorium Method of recovering immunoglobulin using a polyol and an alkanoic acid
WO1984000569A1 (en) * 1982-07-23 1984-02-16 Amf Inc Fibrous media containing millimicron sized particulates
WO1984002916A1 (en) * 1983-01-26 1984-08-02 Amf Inc Tissue culture medium
US4480029A (en) * 1981-04-27 1984-10-30 Baxter Travenol Laboratories, Inc. Biological indicators and their use
EP0124363A2 (en) * 1983-05-02 1984-11-07 Diamond Scientific Co. Photochemical decontamination treatment of whole blood or blood components
US4503039A (en) * 1982-12-21 1985-03-05 Biotest-Serum-Institut Gmbh Coagulant plasma-protein solution
US4511473A (en) * 1982-02-09 1985-04-16 Amf Incorporated Fibrous media containing millimicron-sized particulates
EP0139975A1 (en) * 1983-08-26 1985-05-08 BEHRINGWERKE Aktiengesellschaft Method for the pasteurization of human plasma
US4533634A (en) * 1983-01-26 1985-08-06 Amf Inc. Tissue culture medium
US4639513A (en) * 1984-02-02 1987-01-27 Cuno Inc. Intravenously injectable immunoglobulin G (IGG) and method for producing same
US4764369A (en) * 1983-07-14 1988-08-16 New York Blood Center Inc. Undenatured virus-free biologically active protein derivatives
US4820805A (en) * 1983-07-14 1989-04-11 New York Blood Center, Inc. Undenatured virus-free trialkyl phosphate treated biologically active protein derivatives
US5418130A (en) * 1990-04-16 1995-05-23 Cryopharm Corporation Method of inactivation of viral and bacterial blood contaminants
WO1996009371A1 (en) * 1994-09-21 1996-03-28 Stichting Scheikundig Onderzoek In Nederland Protein mixture prepared from serum for use as component in media for in vitro culture of animal cells
US6187572B1 (en) 1990-04-16 2001-02-13 Baxter International Inc. Method of inactivation of viral and bacterial blood contaminants
US20060110399A1 (en) * 2004-11-18 2006-05-25 Van Holten Robert W Optimal placement of a robust solvent/detergent process post viral ultrafiltration of an immune gamma globulin

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DE2837168A1 (en) * 1978-08-25 1980-03-06 Blutspendedienst Dt Rote Kreuz A method for producing a for intravenous use suitable immunoglobulin solution

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3822095A (en) * 1972-08-14 1974-07-02 Block Engineering System for differentiating particles
US3972858A (en) * 1973-12-22 1976-08-03 Behringwerke Aktiengesellschaft Process for the preparation of choleragen
USRE31268E (en) * 1976-04-06 1983-06-07 Nordisk Insulinlaboratorium Method of recovering immunoglobulin using a polyol and an alkanoic acid
US4164495A (en) * 1976-04-06 1979-08-14 Nordisk Insulinlaboratorium Method of recovering immunoglobulin using a polyol and an alkanoic acid
US4136094A (en) * 1977-08-31 1979-01-23 The Regents Of The University Of Minnesota Preparation of intravenous human and animal gamma globulins and isolation of albumin
JPS6241210B2 (en) * 1977-09-22 1987-09-02 Toyo Sooda Kogyo Kk
JPS5446813A (en) * 1977-09-22 1979-04-13 Nippon Sekijiyuujishiya Separation of plasmaprotein
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FR7395M (en) 1969-11-03 grant
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NL6702923A (en) 1967-10-09 application

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