EP0437435A1 - Synthetic matrices and derived assay calibrators - Google Patents
Synthetic matrices and derived assay calibratorsInfo
- Publication number
- EP0437435A1 EP0437435A1 EP89906249A EP89906249A EP0437435A1 EP 0437435 A1 EP0437435 A1 EP 0437435A1 EP 89906249 A EP89906249 A EP 89906249A EP 89906249 A EP89906249 A EP 89906249A EP 0437435 A1 EP0437435 A1 EP 0437435A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- matrix
- acid
- buffer
- calibrators
- polyvinylpyrrolidone
- 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.)
- Withdrawn
Links
- 238000003556 assay Methods 0.000 title claims description 16
- 239000011159 matrix material Substances 0.000 claims abstract description 43
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 25
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 25
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 25
- 239000000872 buffer Substances 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 235000002639 sodium chloride Nutrition 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- -1 alkali metal salt Chemical class 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical group OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims description 8
- 229940089468 hydroxyethylpiperazine ethane sulfonic acid Drugs 0.000 claims description 8
- 239000003755 preservative agent Substances 0.000 claims description 8
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 7
- 229930182566 Gentamicin Natural products 0.000 claims description 7
- 229960002518 gentamicin Drugs 0.000 claims description 7
- 230000002335 preservative effect Effects 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 claims description 4
- NUFBIAUZAMHTSP-UHFFFAOYSA-N 3-(n-morpholino)-2-hydroxypropanesulfonic acid Chemical compound OS(=O)(=O)CC(O)CN1CCOCC1 NUFBIAUZAMHTSP-UHFFFAOYSA-N 0.000 claims description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 4
- 229940033663 thimerosal Drugs 0.000 claims description 4
- 229940044120 2-n-octyl-4-isothiazolin-3-one Drugs 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- OSDLLIBGSJNGJE-UHFFFAOYSA-N 4-chloro-3,5-dimethylphenol Chemical compound CC1=CC(O)=CC(C)=C1Cl OSDLLIBGSJNGJE-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- ACGUYXCXAPNIKK-UHFFFAOYSA-N hexachlorophene Chemical compound OC1=C(Cl)C=C(Cl)C(Cl)=C1CC1=C(O)C(Cl)=CC(Cl)=C1Cl ACGUYXCXAPNIKK-UHFFFAOYSA-N 0.000 claims description 2
- 229960004068 hexachlorophene Drugs 0.000 claims description 2
- 239000001048 orange dye Substances 0.000 claims description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 2
- 239000001044 red dye Substances 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 229960003885 sodium benzoate Drugs 0.000 claims description 2
- 239000001043 yellow dye Substances 0.000 claims description 2
- AVGVFDSUDIUXEU-UHFFFAOYSA-N 2-octyl-1,2-thiazolidin-3-one Chemical compound CCCCCCCCN1SCCC1=O AVGVFDSUDIUXEU-UHFFFAOYSA-N 0.000 claims 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- MDNWOSOZYLHTCG-UHFFFAOYSA-N Dichlorophen Chemical compound OC1=CC=C(Cl)C=C1CC1=CC(Cl)=CC=C1O MDNWOSOZYLHTCG-UHFFFAOYSA-N 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 229960004365 benzoic acid Drugs 0.000 claims 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims 1
- 239000004327 boric acid Substances 0.000 claims 1
- 229960003887 dichlorophen Drugs 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- AJDUTMFFZHIJEM-UHFFFAOYSA-N n-(9,10-dioxoanthracen-1-yl)-4-[4-[[4-[4-[(9,10-dioxoanthracen-1-yl)carbamoyl]phenyl]phenyl]diazenyl]phenyl]benzamide Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2NC(=O)C(C=C1)=CC=C1C(C=C1)=CC=C1N=NC(C=C1)=CC=C1C(C=C1)=CC=C1C(=O)NC1=CC=CC2=C1C(=O)C1=CC=CC=C1C2=O AJDUTMFFZHIJEM-UHFFFAOYSA-N 0.000 claims 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 239000001103 potassium chloride Substances 0.000 claims 1
- 235000011164 potassium chloride Nutrition 0.000 claims 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical group C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 claims 1
- 238000003018 immunoassay Methods 0.000 abstract description 15
- 238000004458 analytical method Methods 0.000 abstract description 9
- 239000012491 analyte Substances 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000001105 regulatory effect Effects 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 29
- 102000004169 proteins and genes Human genes 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 210000002966 serum Anatomy 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 8
- 229960002695 phenobarbital Drugs 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 210000002700 urine Anatomy 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- JPMIIZHYYWMHDT-UHFFFAOYSA-N octhilinone Chemical compound CCCCCCCCN1SC=CC1=O JPMIIZHYYWMHDT-UHFFFAOYSA-N 0.000 description 5
- 239000013643 reference control Substances 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 3
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- 230000009286 beneficial effect Effects 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
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- 238000001727 in vivo Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical class OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
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- 238000012216 screening Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- UJMBCXLDXJUMFB-GLCFPVLVSA-K tartrazine Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-GLCFPVLVSA-K 0.000 description 2
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
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- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- 239000006173 Good's buffer Substances 0.000 description 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
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- 241000212342 Sium Species 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
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- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
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- CEQFOVLGLXCDCX-WUKNDPDISA-N methyl red Chemical compound C1=CC(N(C)C)=CC=C1\N=N\C1=CC=CC=C1C(O)=O CEQFOVLGLXCDCX-WUKNDPDISA-N 0.000 description 1
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Classifications
-
- 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
- G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2496/00—Reference solutions for assays of biological material
- G01N2496/25—Reference solutions for assays of biological material containing added polymers to stabilise biological material against degradation or maintain viscosity or density, e.g. gelatin, polyacrylamides or polyvinyl alcohol
- G01N2496/35—Polyvinylpyrrolidone, e.g. PVP
Definitions
- the present invention relates to protein-free polyvinylpyrrolidone based formulations for use as matrices in the preparation of calibrators or standards for immunoassays or clinical chemistry procedures.
- Human or mammalian blood products such as human serum or plasma
- two to eight calibrators containing specific levels of analyte are used in an immunoassay for the purpose of con ⁇ structing a dose-response curve (standard curve) by means of which the signal responses of reference controls and unknown specimens can be calculated in terms of concentration or mass units of a given analyte.
- Similar reference controls or calibrators are also utilized for verifying assay performance in other clinical chemistry procedures.
- the ideal calibratory solution or matrix would be one which is compositionally fully defined and would exactly match the composition of the unknown specimen except for the unknown analyte concentration. These conditions are rarely attainable in practice due to the wide compositional variability of normal and abnormal physiological blood or urine specimens.
- the next best calibratory solution would be a matrix that approximately matches the typical specimen composition, such as homologous human serum-based calibrators made from pooled analyte-free human serum for use in the assay of human serum specimens.
- typical specimen composition such as homologous human serum-based calibrators made from pooled analyte-free human serum for use in the assay of human serum specimens.
- some techniques utilized for removal of endogenous analytes frequently induce major alterations in the lipid and/or protein composi ⁇ tions and thereby aggravate the mismatch between the specimen and the calibrator.
- Affinity chro atography selectively removes the analyts without significant alteration of the matrix.
- it is a costly procedure and is generally used only for removal of endogenous analytes present in extremely low concentrations.
- calibrator matrices containing heterologous animal sera or human or bovine albumin fractions in appropriate buffer for ⁇ mulations
- Such protein-based matrices encompass virtually all calibrator formulations that are currently used in commer ⁇ cial immunoassay kits for the analysis of human and animal blood or urine specimens.
- Other shortcomings of protein-based calibrators are enumerated as follows:
- Mast (U.S. Pat. No. 3,920,580) prepared controls con ⁇ taining synthetic polymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, dextran and the like for use in the enzymatic analysis of glucose in blood or serum by means of dry reagent strips.
- U.S. Pat. No. 4,506,018 pro ⁇ posed blood diluents containing ethoxylated polypropylene con ⁇ densates.
- U.S. Pat. No. 3,876,375 utilized alkylene polyols in biological compositions intended as reference controls in diagnostic analyses. Hydroxyethyl starch was proposed as a plasma substitute in U.S. Pat. No.
- polyvinylpyrrolidone has been used extensively in-vivo as a plasma extender since the 1940's (Polyvinylpyrrolidone, chap. 21. L. Blecher, et al., from Handbook of ater-Soluble Gums and Resins, R.L.Davidson, McGraw-Hill, 1980) . There is no know prior art on the use of polyvinylpyrrolidone in liquid protein-free calibrators or standards for use in immunoassays or clinical chemistry protocols.
- an object of this invention to pro ⁇ vide optimal calibrator matrices suitable for incorporating known quantities of diverse analytes, singly or in combina ⁇ tion, that are commonly quantified in clinical and immunoassay laboratories.
- Another object of this invention is to provide compositionally defined synthetic formulations that are com ⁇ parable to serum or plasma in terms of their physical or immunological characteristics as well as in their responses under assay conditions.
- a further object of this invention is to provide calibrator solutions that are stable at room temperatures or refrigerator temperatures for an extended period of time.
- the present invention provides a protein-free liquid matrix useful for preparing control standards and calibrators for assays which comprises water, a buffer and between about 0.1% and 10% by weight polyvinylpyrrolidone.
- the invention also concerns a control solution or calibrator for use in immunoassay and chemical analysis which comprises the matrix of the present invention and an analyte and the use of this control solution or calibrator in immunoassays or chemical analysis of unknown biologically active, naturally occurring materials.
- FIGURE 1 illustrates the results obtained with three synthetic serum formulations of this invention compared to an albumin-based matrix in an enzyme immunoassay (EIA) for T3 (triiodothyronine) .
- EIA enzyme immunoassay
- FIGURE 2 depicts a comparison of a synthetic and an albumin-based matrix in a phenobarbital enzyme immunoassay.
- the present invention provides a protein-free liquid matrix useful for preparing control standards and calibrators for assays which comprises water, a buffer and between about 0.1 and 10% by weight polyvinylpyrrolidone.
- calibrator solutions for analyzing diverse analytes may be formed by adding polyvinylpyrrolidone to certain buffered solutions containing one or more analytes at known levels.
- polyvinylpyrrolidone in such solu ⁇ tions to form protein-free calibrators, results are obtained in diverse assays that are identical or comparable to the results observed when calibrator solutions are based on human or animal matrices.
- polyvinylpyrrolidone improves calibratory solutions in the formulations of this invention
- polyvinylpyrrolidone exerts this beneficial effect by virtue of its similarity to proteins in terms of physicochemical parameters, such as its polyamide structure, molecular weight, viscosity and osmotic pressure.
- Polyvinylpyrrolidone like albumin and prealbumins, also reversibly binds certain lipophilic and hydrophilic molecules and thereby can act anal ⁇ ogous to these proteins as carrier or storage agent prior to or during assay incubations.
- this binding capability is believed to be a critical factor in the rates of antigen-antibody interactions that occur during incubation in the calibrator solutions as well as in the specimen solution. In immunological reactions, these rates must either be matched or controlled to reach a common end point or plateaus at the conclusion of the incubation period in order to obtain valid assay results. In enzymatic chemistry procedures, an analyte- polyvinylpyrrolodine complex, for example, with cholesterol, could modulate the enzyme kinetics.
- polyvinylpyrrolidone in the calibrator solutions of this invention permits optimization of their compositional and/or their physicochemical parameters (such as osmolality and pH) so as to achieve optimal matching of the calibrator-response curves with the specimen-response curves when the incubations were done at temperatures ranging from 0° to about 60° C, preferably from 2 ' to about 45" C.
- the calibrator solution includes, in addition to one or more analytes, between 0.1 and 10% polyvinylpyrrolidone, preferably between 0.1 and 5%.
- the polyvinylpyrrolidone included in the calibrators is of a high molecular weight of about 10,000 to about 80,000 daltons, preferably about 40,000 daltons, and preferably also of a pharmaceutical grade.
- a pretreatment with a suitable reducing agent such as hydrogen gas with noble metal catalysts, sodium borohydride, potassium borohydride or the like, in order to reduce reactive func ⁇ tional groups, such as peroxides, hydroperoxides, epoxides, aldehydes and ketones, or residual polymerization catalysts which, may have a deleterious effect on the functionality or stability of the analyte in the calibrator solution.
- Preferred buffers include phosphates, borates, tris (hydroxymethyl) aminomethane (TRIS) , Good's buffers, such as N,N-bis-(2-h ⁇ droxymethyl)-glycine, salts of acetic or phthalic acid, or like buffers.
- these buffers also permit modulation of calibrator response by means of appropriate pH changes within the claimed pH range.
- the most preferred buffers are hydroxyethylpiperazineethanesulfonic acid (HEPES) , mor- pholinopropanesulfonic acid (MOPS) or MOPSO.
- the calibrator solution includes in the calibrator solution common salts, such as alkali metal salts of the halogens, a phosphate or a sulfate.
- Preferred salts include sodium chloride, potas ⁇ sium chloride, potassium phophate and the like. It is believed that these salts further permit modulation of the osmotic pressure of the calibrator solutions so that they more closely emulate serum or urine matrix effects. Satisfactory calibrator solutions are obtainable with between about 0 to 3% salt, preferable between about 0.1 to 2.0% salt, and osmolality between about 100 and 800 os/Kg.
- a preservative so as to avoid microbial growth therein.
- Such preservatives may be selected from the numerous materials which are known to have this prop ⁇ erty and, furthermore, do not interfere in the assay.
- Repre ⁇ sentative compositions for this function include sodium azide, thimerosal, Cialit-tm, octhilinone or 2-octyl-4-isothiazolin-3- one (sold under the commercial tradename Kathon-tm by Rohm & Haas) , sodium benzoate, hexachlorophene, sorbic acid, quaternary ammonium compounds, p-chloro-m-xylenol and gentamicin.
- the preservative may be included in an amount corresponding to acceptable levels for each preservative, such as between about 0.001 to 1.0%.
- adjuvants may be added to the calibrator solution to obtain a particular color or physical appearance such as red, orange or yellow dyes, to mimic the color of serum or urine.
- calibrators prepared from the synthetic matrices of this invention using, for example, digoxin, T4, gentamicin, TSH, cholesterol also performed satisfactorily.
- these calibrators in the analysis of diverse chemical or biochemical entities comprising normal and abnormal metabolities, elec ⁇ trolytes, vitamins, steroids, therapeutic drugs, drugs of abuse, peptides, polypeptides, polypeptide hormones, proteins, glycoproteins, enzyme polynucleotides, polysaccharides , indus ⁇ trial toxicants and the like by means of appropriate immunoas ⁇ says or clinical chemistry procedure.
- the invention also concerns a control solution or calibrator for use in immunoassay and chemical analysis which comprises the above described matrix and an analyte and meth ⁇ ods of using the control solution or calibrator in immunoas ⁇ says or chemical analysis on unknown biologically active, naturally occurring materials.
- T3 calibrators were formulated by adding appropriate amounts of an accurately prepared T 3 stock solu ⁇ tion to provide T 3 does levels of 0, 0.5, 2.0 and 4.0 ng/mL to:
- T 3 calibrators were compared in a typical T 3 enzyme immunoassay (EIA) format. The results are tabulated in TABLE I and the standard curves are shown in FIG ⁇ URE l. TABLE 1
- phenobarbital calibrators were prepared by spik ⁇ ing with appropriate amounts of a phenobarbital stock solution to provide phenobarbital dose levels of 0, 5, 25 and 50 ug/roL in:
- Example 3a proved useful as a synthetic urine substitute.
- a stock solution of water-soluble cholesterol (polyoxyethylene cholesterol sebacate, Sigma, Cat. No. #C ⁇ 1145) was preparede and appropriate aliquots were spike into the matrix of Example 4a. to provide total cholesterol levels of 185 and 245mg/dL. These calibrators proved useful in com ⁇ dismissal cholesterol assays.
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Abstract
La présente invention concerne une matrice liquide sans protéine utile pour la préparation de standards et de calibreurs de commande pour des analyses, la matrice comprenant de l'eau, un tampon et entre 0,1 et 10 % environ en poids de polyvinylpyrrolidone. L'invention concerne également un calibreur ou solution de régulation utilisé dans une immunoanalyse ou dans une analyse chimique et qui consiste en la matrice de la présente invention et un analyte, ainsi que l'utilisation de cette solution ou calibreur de régulation dans des immunoanalyses ou des analyses chimiques de substances d'origine naturelle biologiquemnt actives et inconnues.The present invention relates to a protein-free liquid matrix useful for the preparation of control standards and calibrators for analyzes, the matrix comprising water, a buffer and between approximately 0.1 and 10% by weight of polyvinylpyrrolidone. The invention also relates to a regulatory calibrator or solution used in an immunoassay or a chemical analysis which consists of the matrix of the present invention and an analyte, as well as the use of this regulatory solution or calibrator in immunoassays or chemical analyzes of biologically active and unknown substances of natural origin.
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US19440188A | 1988-05-16 | 1988-05-16 | |
US194401 | 1988-05-16 |
Publications (2)
Publication Number | Publication Date |
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EP0437435A1 true EP0437435A1 (en) | 1991-07-24 |
EP0437435A4 EP0437435A4 (en) | 1991-08-14 |
Family
ID=22717464
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP19890906249 Withdrawn EP0437435A4 (en) | 1988-05-16 | 1989-05-16 | Synthetic matrices and derived assay calibrators |
Country Status (4)
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EP (1) | EP0437435A4 (en) |
JP (1) | JPH03505482A (en) |
AU (1) | AU3693489A (en) |
WO (1) | WO1989011654A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4104302C2 (en) * | 1991-02-13 | 1998-10-22 | Fresenius Ag | Process for checking and calibrating measured value displays of an analyzer for physiological liquids |
DE4202923A1 (en) * | 1992-02-01 | 1993-08-05 | Behringwerke Ag | METHOD FOR DETERMINING ANTIGENS OR ANTIBODIES IN THE PRESENCE OF AN IMMUNE COMPLEX |
DE19653082A1 (en) * | 1995-12-21 | 1997-06-26 | Bionostics Inc | Liquid control solutions for blood analysis |
US5723284A (en) * | 1996-04-01 | 1998-03-03 | Bayer Corporation | Control solution and method for testing the performance of an electrochemical device for determining the concentration of an analyte in blood |
US7531362B2 (en) * | 2001-06-07 | 2009-05-12 | Medmira Inc. | Rapid diagnostic assay |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2262804A1 (en) * | 1974-03-01 | 1975-09-26 | Biotrol Sa Lab | Solns. for comparison with blood serum - contain polyvinylpyrrolidone to give similar viscosity |
DE2942657A1 (en) * | 1979-10-22 | 1981-04-30 | Basf Ag, 6700 Ludwigshafen | METHOD FOR PRODUCING POLYVINYLPYRROLIDONE, WHOSE AQUEOUS SOLUTION HAS A HIGH VISCOSITY, THROUGH HEAT TREATMENT OF AQUEOUS SOLUTIONS OF COMMON POLYVINYLPYRROLIDONE |
WO1987006343A1 (en) * | 1986-04-09 | 1987-10-22 | Bionostics, Inc. | Multiple control standard for blood analysis |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK151919C (en) * | 1979-06-28 | 1988-08-15 | Radiometer As | PROCEDURE, REFERENCE LIQUID, AND REFERENCE LIQUID SYSTEM FOR SIMILAR CALIBRATION AND / OR QUALITY CONTROL OF CALCIUM SENSITIVE ELECTRODE AND PH ELECTRODE |
US4458021A (en) * | 1982-05-03 | 1984-07-03 | American Hospital Supply Corporation | Blood gas control |
-
1989
- 1989-05-16 WO PCT/US1989/002108 patent/WO1989011654A1/en not_active Application Discontinuation
- 1989-05-16 AU AU36934/89A patent/AU3693489A/en not_active Abandoned
- 1989-05-16 JP JP50604389A patent/JPH03505482A/en active Pending
- 1989-05-16 EP EP19890906249 patent/EP0437435A4/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2262804A1 (en) * | 1974-03-01 | 1975-09-26 | Biotrol Sa Lab | Solns. for comparison with blood serum - contain polyvinylpyrrolidone to give similar viscosity |
DE2942657A1 (en) * | 1979-10-22 | 1981-04-30 | Basf Ag, 6700 Ludwigshafen | METHOD FOR PRODUCING POLYVINYLPYRROLIDONE, WHOSE AQUEOUS SOLUTION HAS A HIGH VISCOSITY, THROUGH HEAT TREATMENT OF AQUEOUS SOLUTIONS OF COMMON POLYVINYLPYRROLIDONE |
WO1987006343A1 (en) * | 1986-04-09 | 1987-10-22 | Bionostics, Inc. | Multiple control standard for blood analysis |
Non-Patent Citations (1)
Title |
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See also references of WO8911654A1 * |
Also Published As
Publication number | Publication date |
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EP0437435A4 (en) | 1991-08-14 |
AU3693489A (en) | 1989-12-12 |
WO1989011654A1 (en) | 1989-11-30 |
JPH03505482A (en) | 1991-11-28 |
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