WO1986002004A1 - Stabilization of biological substances - Google Patents

Stabilization of biological substances Download PDF

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Publication number
WO1986002004A1
WO1986002004A1 PCT/US1985/001899 US8501899W WO8602004A1 WO 1986002004 A1 WO1986002004 A1 WO 1986002004A1 US 8501899 W US8501899 W US 8501899W WO 8602004 A1 WO8602004 A1 WO 8602004A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
aqueous composition
antigen
preparation
residue
Prior art date
Application number
PCT/US1985/001899
Other languages
French (fr)
Inventor
Jack E. Dickinson (Deceased)
John S. Paxos
Original Assignee
Preco, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Preco, Inc. filed Critical Preco, Inc.
Publication of WO1986002004A1 publication Critical patent/WO1986002004A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5306—Improving reaction conditions, e.g. reduction of non-specific binding, promotion of specific binding
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54393—Improving reaction conditions or stability, e.g. by coating or irradiation of surface, by reduction of non-specific binding, by promotion of specific binding
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
    • G01N33/545—Synthetic resin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses

Definitions

  • the invention pertains to compositions which stabilize the functional activity of antibodies and antigen preparations for long periods of time at normal ambient temperatures.
  • Chemical additives as for example, protective proteins such as bovine serum albumin; saccharides such as dextrin and mannose; and ammonium salt suspensions, have been used previously to stabilize biological sub ⁇ stances.
  • Mechanical processes such as spray drying and freeze drying also have been used.
  • Test surfaces containing dried immunological components are described in, for example, U.S. Patent No. 3,666,421 and U.S. Patent No. 3,770,383. Such systems have been limited to materials of high stability or require storage at reduced temperatures to achieve stability.
  • U.S. Patent No. 4,498,321 describes a fixative and preservative composition for histology, cytology and proteinaceous preparations comprising a mixture of pyrrolide-2-one, a polyol, urea, and a zinc salt of a non-oxidizing organic or inorganic acid.
  • the activity of biological substances is stabilized for long periods of time at normal ambient temperatures, that is, from about 0° to about 40°C.
  • the inven ⁇ tion pertains to an aqueous composition which uses as stabilizing components a water soluble pyrrole and at least one saccharide polyol.
  • the preferred water sol- uble pyrroles are 2-pyrrolidone and pyrrole, especially 2-pyrrolidone.
  • the polyol is a saccharide such as sucrose, glucose, sorbitol, fructose, dextrin, corn syrup, and the like, the selection depending upon the characteristics of the biological substances to be sta ⁇ bilized and the matrix in which the substance appears.
  • the pyrrole and saccharide are mixed in a polar aqueous solvent, preferrably water, to which may be optionally added an alcohol, such as methanol and ethanol.
  • the preferred formulation of the aqueous com ⁇ position of the invention contains a water soluble pyrrole, such as but not limited to, 2-pyrrolidone, in a concentration range of about 0.01% to about 5% by weight, and one or more saccharide polyols in a usual concentration range of about 0.01% to about 10% by weight in a polar aqueous solvent.
  • a water soluble pyrrole such as but not limited to, 2-pyrrolidone
  • the preferred water soluble pyrrole, 2-pyrrolidone is used in a preferred concentration range of 0.1% to 2% by weight.
  • the ratio of saccharide to water soluble pyrrole thus is from about 200:1 to about 02:1.
  • the evaporative residue obtained upon evapora ⁇ tion of this aqueous composition of the water soluble pyrrole and the saccharide, alone or in combination with other compounds, so as to remove unbound water has the ability to stabilize the functional activity of a wide variety of biological substances at normal ambient tem ⁇ peratures.
  • a particularly important application is the stabilizing effect upon protein molecules, including lipoproteins, glycoproteins and polypeptides, most not ⁇ ably normally labile antibodies and antigens utilized in diagnostic compositions. It appears the evaporative residue of the composition exerts its stabilizing effect by protecting the internal hydrogen bonding of the protein structure from disruption.
  • the composition can be mixed with rheumatoid antigen which is coated on small latex particles, the evaporative residue of which forms the basis for a diagnostic medical device for the detec- tion of rheumatoid factor associated with rheumatoid arthritis and other similar diseases.
  • RPR antigen absorbed to particles of the water insol ⁇ uble dye toluidene red.
  • the mixture of this antigen and the composition of the invention is stable at ordinary room temperature (from about 2°C to about 35°C) for long periods of time.
  • the mixture of the composition of the invention and the TRUST antigen is dried by evaporation to form a convenient stable dry reagent which, when reconstituted with the test sample, allows the detection of syphilis. A positive is easily visualized with the unaided eye by observing obvious clumping of the red dye particles.
  • Another application is stabilization of anti ⁇ bodies.
  • the stabilization cellular stroma is the stabilization cellular stroma.
  • the composition when mixed with dyed horse erythrocyte stroma, becomes the basis of a diagnostic medical device for the detection of infectious mononucleosis, serum sickness and Forssman antibodies which is stable at room temperature. It is sometimes desirable to add other sub ⁇ stances to the basic aqueous composition. For example, it is often advantageous to add substances which, upon evaporative drying, are capable of forming a protective skin such as polyalkene acrylamides or hydroxymethyl- cellulose.
  • Particularly useful in some applications is the addition to the aqueous composition of sufficient polyvinyl alcohol, or a mixture of polyvinyl alcohol and polyvinyl acetate, to increase the viscosity and elas ⁇ ticity of the final evaporative residue. This not only improves the physical properties but also can be used to control the reaction of the antibody or antigen to improve sensitivity.
  • a buffer mixture into the basic composition to achieve pH stability.
  • surfactants to the basic compound, particularly when the biologically active sub ⁇ stance is colloidal or has been rendered colloidal by absorption on or binding to an insoluble substance such as polystyrene beads.
  • Inorganic salts also may be added.
  • the antigen or antibody and composition of the invention may be dried on an inert, solid, water insol ⁇ uble strip surface, such as glass, plastics, plastic- coated cards and the like.
  • the surface is a plastic such as polystyrene, polyacrylate, polymeth- acrylate or polyvinylchloride.
  • the preferred surface to accept the evaporative residue is a white coextruded polystyrene card containing concave depressions or wells having a diameter at the flat surface of the card of 19 mm. Into such depressions is placed a measured drop of the composition which is then allowed to dry by evapora ⁇ tion.
  • the concave depression becomes a convenient reaction vessel when the evaporative residue is recon ⁇ stituted with a sample, the preferred sample for such testing being blood serum.
  • the above solution is added to a suspension of gamma globulin attached to latex particles in a ratio of from about 1:9 to about 1:3 stabilizer:latex suspension, the preferred ratio being 1:9.
  • the resulting suspen ⁇ sion may be used in the preparation of a diagnostic medical device for the detection of rheumatoid factor.
  • a small volume of the above mixture is placed in the depression or well of a polystyrene card pre ⁇ viously described.
  • the spot is allowed to dry by evaporation at room temperature, as for example, at about 25°C and a relative humidity of about 22%.
  • the evaporation may be unaided or a gentle stream of air may be used.
  • the device When unbound water has been removed, the device is covered with aluminum foil fixed to the poly ⁇ styrene strip.
  • the evaporative residue contains the diagnostic reagent is stable at normal ambient tempera ⁇ tures of from just over the freezing point of water to about 40°C with no loss of biological activity for periods exceeding one year.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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Abstract

The evaporative residue of composition comprising a water soluble pyrrole, and at least one saccharide in a polar aqueous solvent stabilizes the functional activity of biological substances such as normally labile antigens and antibodies at normal ambient temperatures.

Description

-i-
Description
STABILIZATION OF BIOLOGICAL SUBSTANCES
Technical Field
The invention pertains to compositions which stabilize the functional activity of antibodies and antigen preparations for long periods of time at normal ambient temperatures.
Background Art
Chemical additives, as for example, protective proteins such as bovine serum albumin; saccharides such as dextrin and mannose; and ammonium salt suspensions, have been used previously to stabilize biological sub¬ stances. Mechanical processes such as spray drying and freeze drying also have been used. Test surfaces containing dried immunological components are described in, for example, U.S. Patent No. 3,666,421 and U.S. Patent No. 3,770,383. Such systems have been limited to materials of high stability or require storage at reduced temperatures to achieve stability.
U.S. Patent No. 4,498,321 describes a fixative and preservative composition for histology, cytology and proteinaceous preparations comprising a mixture of pyrrolide-2-one, a polyol, urea, and a zinc salt of a non-oxidizing organic or inorganic acid.
Disclosure of Invention
In accordance with the present invention, the activity of biological substances is stabilized for long periods of time at normal ambient temperatures, that is, from about 0° to about 40°C. Specifically, the inven¬ tion pertains to an aqueous composition which uses as stabilizing components a water soluble pyrrole and at least one saccharide polyol. The preferred water sol- uble pyrroles are 2-pyrrolidone and pyrrole, especially 2-pyrrolidone. The polyol is a saccharide such as sucrose, glucose, sorbitol, fructose, dextrin, corn syrup, and the like, the selection depending upon the characteristics of the biological substances to be sta¬ bilized and the matrix in which the substance appears. The pyrrole and saccharide are mixed in a polar aqueous solvent, preferrably water, to which may be optionally added an alcohol, such as methanol and ethanol.
Best Mode For Carrying Out The Invention
The preferred formulation of the aqueous com¬ position of the invention contains a water soluble pyrrole, such as but not limited to, 2-pyrrolidone, in a concentration range of about 0.01% to about 5% by weight, and one or more saccharide polyols in a usual concentration range of about 0.01% to about 10% by weight in a polar aqueous solvent. The preferred water soluble pyrrole, 2-pyrrolidone, is used in a preferred concentration range of 0.1% to 2% by weight. The ratio of saccharide to water soluble pyrrole thus is from about 200:1 to about 02:1.
The evaporative residue obtained upon evapora¬ tion of this aqueous composition of the water soluble pyrrole and the saccharide, alone or in combination with other compounds, so as to remove unbound water has the ability to stabilize the functional activity of a wide variety of biological substances at normal ambient tem¬ peratures. A particularly important application is the stabilizing effect upon protein molecules, including lipoproteins, glycoproteins and polypeptides, most not¬ ably normally labile antibodies and antigens utilized in diagnostic compositions. It appears the evaporative residue of the composition exerts its stabilizing effect by protecting the internal hydrogen bonding of the protein structure from disruption.
One application of this invention is stabili- zation of antigens. For example, the composition can be mixed with rheumatoid antigen which is coated on small latex particles, the evaporative residue of which forms the basis for a diagnostic medical device for the detec- tion of rheumatoid factor associated with rheumatoid arthritis and other similar diseases.
Another specific application is the stabiliza¬ tion of the "toluidene red, unheated serum test" (TRUST antigen) which forms the basis for a diagnostic syphilis test. This antigen consists of rapid plasma reagin
(RPR) antigen absorbed to particles of the water insol¬ uble dye toluidene red. The mixture of this antigen and the composition of the invention is stable at ordinary room temperature (from about 2°C to about 35°C) for long periods of time. The mixture of the composition of the invention and the TRUST antigen is dried by evaporation to form a convenient stable dry reagent which, when reconstituted with the test sample, allows the detection of syphilis. A positive is easily visualized with the unaided eye by observing obvious clumping of the red dye particles.
Another application is stabilization of anti¬ bodies. For example, a mixture of the composition of the invention with anti-human chorionic gonadotropin, the evaporative residue of which forms a room tempera¬ ture stable reagent which can be employed as the basis for a diagnostic medical device for the direct or indirect detection of human pregnancy.
Another application is the stabilization cellular stroma. For example, the composition, when mixed with dyed horse erythrocyte stroma, becomes the basis of a diagnostic medical device for the detection of infectious mononucleosis, serum sickness and Forssman antibodies which is stable at room temperature. It is sometimes desirable to add other sub¬ stances to the basic aqueous composition. For example, it is often advantageous to add substances which, upon evaporative drying, are capable of forming a protective skin such as polyalkene acrylamides or hydroxymethyl- cellulose.
Particularly useful in some applications is the addition to the aqueous composition of sufficient polyvinyl alcohol, or a mixture of polyvinyl alcohol and polyvinyl acetate, to increase the viscosity and elas¬ ticity of the final evaporative residue. This not only improves the physical properties but also can be used to control the reaction of the antibody or antigen to improve sensitivity.
It also may be advantageous in certain appli¬ cations to incorporate a buffer mixture into the basic composition to achieve pH stability. In addition, it is sometimes convenient to add surfactants to the basic compound, particularly when the biologically active sub¬ stance is colloidal or has been rendered colloidal by absorption on or binding to an insoluble substance such as polystyrene beads. Inorganic salts also may be added.
The antigen or antibody and composition of the invention may be dried on an inert, solid, water insol¬ uble strip surface, such as glass, plastics, plastic- coated cards and the like. Preferrably the surface is a plastic such as polystyrene, polyacrylate, polymeth- acrylate or polyvinylchloride. The preferred surface to accept the evaporative residue is a white coextruded polystyrene card containing concave depressions or wells having a diameter at the flat surface of the card of 19 mm. Into such depressions is placed a measured drop of the composition which is then allowed to dry by evapora¬ tion. The concave depression becomes a convenient reaction vessel when the evaporative residue is recon¬ stituted with a sample, the preferred sample for such testing being blood serum.
The following example will serve to further illustrate the nature of the invention but should not be taken as limitation of the scope of this invention, the invention being solely defined by the appended claims.
Example
Ingredient Concentration
Water 50 ml.
Polyvinyl alcohol/Polyvinyl acetate
(Gelvatol 40/10) 4.0 gm.
Heat to dissolve with stirring, cool, and add:
2-Pyrrolidone 1.0 ml. Ethanol 50 ml.
To the above basic formulation is then added with stir¬ ring 50 ml. of food grade corn syrup.
The above solution is added to a suspension of gamma globulin attached to latex particles in a ratio of from about 1:9 to about 1:3 stabilizer:latex suspension, the preferred ratio being 1:9. The resulting suspen¬ sion may be used in the preparation of a diagnostic medical device for the detection of rheumatoid factor. A small volume of the above mixture is placed in the depression or well of a polystyrene card pre¬ viously described. The spot is allowed to dry by evaporation at room temperature, as for example, at about 25°C and a relative humidity of about 22%. The evaporation may be unaided or a gentle stream of air may be used. When unbound water has been removed, the device is covered with aluminum foil fixed to the poly¬ styrene strip. The evaporative residue contains the diagnostic reagent is stable at normal ambient tempera¬ tures of from just over the freezing point of water to about 40°C with no loss of biological activity for periods exceeding one year.

Claims

WHAT IS CLAIMED IS: 1. An aqueous composition which upon admix ture with a normally labile antibody or antigen prepa- ration and removal of unbound water forms an evaporative residue operable to stabilize at room temperatures the functional activity of said antibody or antigen prepara- tion, said aqueous composition comprising as the stabil- izing component of said evaporative residue a mixture which consists essentially of a water soluble pyrrole and a saccharide in which the ratio of saccharide: pyrrole is from about 200:1 to about 0.2:1.
2. An aqueous composition according to claim 1 wherein said composition comprises a quantity of a polyvinyl alcohol sufficient to increase the viscosity and elasticity of said evaporative residue.
3. An aqueous composition according to claim 2 which also comprises the antibody or antigen prepara- tion to be stabilized.
4. An aqueous composition according to claim 3 in which the antibody or antigen preparation is an antigen preparation.
5. An aqueous composition according to claim 4 wherein the antigen preparation is gamma globulin responsive to rheumatoid factor.
6. An aqueous composition according to claim 5 in which the antibody or antigen preparation is an antibody preparation.
7. An aqueous composition according to claim 6 wherein said antibody preparation is infectious mononucleosis antibody.
8. An aqueous composition according to claim 1 wherein said water soluble pyrrole is 2-pyrrolidone.
9. A diagnostic test device comprising a base strip of material having defined thereon at least one reaction well, the surface of said well being non-absorbent to and insoluble in water and carrying therein at least one evaporative residue of an aqueous composition formed by removal of unbound water from said composition, said aqueous composition and said residue formed therefrom comprising a diagnostic preparation containing a normally labile antibody or antigen and as a stabilizing component a mixture which consists essen- tially of a water soluble pyrrole and a saccharide in which the ratio of saccharide:pyrrole is from about 200:1 to about 0.2:1.
10. A device according to claim 9 wherein a plurality of different materials are deposited in dif- ferent areas of each well of said strip, at least one of said materials being one of said evaporative residues.
11. A device according to claim 9 wherein said strip carries a plurality of said wells, each of said wells carrying the evaporative residue of the same or different diagnostic compositions.
12. A device according to claim 9 wherein said residue comprises a quantity of a polyvinyl alcohol sufficient to increase the viscosity and elasticity of said evaporative residue.
13. A device according to claim 12 in which the antibody or antigen preparation is an antigen preparation.
14. A device according to claim 13 wherein the antigen preparation is gamma globulin responsive to rheumatoid factor.
15. A device according to claim 14 in which the antibody or antigen preparation is an antibody preparation.
16. A device according to claim 15 wherein said antibody preparation is infectious mononucleosis antibody.
17. A device according to claim 16 wherein said water soluble pyrrole is 2-pyrrolidone.
18. A device according to claim 9 wherein said base strip is plastic.
19. A device according to claim 18 wherein said plastic is polystyrene, polyacrylate, polymeth- acrylate, polyvinyl chloride or polyethylene.
20. A device according to claim 19 wherein said plastic is polystyrene.
PCT/US1985/001899 1984-10-04 1985-10-02 Stabilization of biological substances WO1986002004A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US65778684A 1984-10-04 1984-10-04
US657,786 1984-10-04

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Publication Number Publication Date
WO1986002004A1 true WO1986002004A1 (en) 1986-04-10

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988002861A1 (en) * 1986-10-13 1988-04-21 Anawa Laboratorien Ag Process for manufacturing a receptor preparation for a radio-receptor assay and kit-oriented radio-receptor assay in accordance with the process
WO1995000174A1 (en) * 1993-06-25 1995-01-05 Public Health Laboratory Service Board Storage of antibodies
EP1288663A1 (en) * 2000-11-20 2003-03-05 Matsushita Electric Industrial Co., Ltd. Extrasomatic diagnostics

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU609524A1 (en) * 1976-12-20 1978-06-05 Центральный Ордена Ленина И Ордена Трудового Красного Знамени Научно-Исследовательский Институт Гематолигии И Переливания Крови Solution for freezing bone marrow
US4162242A (en) * 1977-03-28 1979-07-24 Chevron Research Company Polyol stabilization additive for polypyrrolidone
US4493821A (en) * 1982-02-04 1985-01-15 Harrison James S Preservative and fixative preparations for biological systems

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU609524A1 (en) * 1976-12-20 1978-06-05 Центральный Ордена Ленина И Ордена Трудового Красного Знамени Научно-Исследовательский Институт Гематолигии И Переливания Крови Solution for freezing bone marrow
US4162242A (en) * 1977-03-28 1979-07-24 Chevron Research Company Polyol stabilization additive for polypyrrolidone
US4493821A (en) * 1982-02-04 1985-01-15 Harrison James S Preservative and fixative preparations for biological systems

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACT, Vol. 67, issued 1967, "Stable Aqueous Suspensions of Coenzyme Q" Abstract No. 25402d *
CHEMICAL ABSTRACT, Vol. 74, issued 1971, KALUGINA et al, "Effect of Solutions of some Synthetic Polymers on the Formed Elements of Preserved Blood", Abstract No. 29987r *
CHEMICAL ABSTRACT, Vol. 79, issued 1973, GOEDICKE, "Stabilization of Aqueous Pepsin Solutions" Abstract No. 139647r *
CHEMICAL ABSTRACT, Vol. 99 issued 1983, "Preparation of Stable Immobilized Solid-Phase Reagents" Abstract No. 154814z *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988002861A1 (en) * 1986-10-13 1988-04-21 Anawa Laboratorien Ag Process for manufacturing a receptor preparation for a radio-receptor assay and kit-oriented radio-receptor assay in accordance with the process
US4992366A (en) * 1986-10-13 1991-02-12 Anawa Laboratorien Ag Process for producing a receptor preparation for a radioreceptor assay and kit-correct radioreceptor assay according to the process
WO1995000174A1 (en) * 1993-06-25 1995-01-05 Public Health Laboratory Service Board Storage of antibodies
EP1288663A1 (en) * 2000-11-20 2003-03-05 Matsushita Electric Industrial Co., Ltd. Extrasomatic diagnostics
EP1288663A4 (en) * 2000-11-20 2007-11-21 Matsushita Electric Ind Co Ltd Extrasomatic diagnostics

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