US3791988A - Diagnostic test for glucose - Google Patents
Diagnostic test for glucose Download PDFInfo
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- US3791988A US3791988A US00237528A US3791988DA US3791988A US 3791988 A US3791988 A US 3791988A US 00237528 A US00237528 A US 00237528A US 3791988D A US3791988D A US 3791988DA US 3791988 A US3791988 A US 3791988A
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- Prior art keywords
- glucose
- chloride
- composition
- tetrazolium
- solution
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- 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 title abstract description 29
- 239000008103 glucose Substances 0.000 title abstract description 29
- 238000002405 diagnostic procedure Methods 0.000 title description 2
- 239000000203 mixture Substances 0.000 abstract description 32
- 108010015776 Glucose oxidase Proteins 0.000 abstract description 7
- 239000004366 Glucose oxidase Substances 0.000 abstract description 7
- 235000019420 glucose oxidase Nutrition 0.000 abstract description 7
- 229940116332 glucose oxidase Drugs 0.000 abstract description 7
- FFISWZPYNKWIRR-UHFFFAOYSA-N 5-oxidophenazin-5-ium Chemical compound C1=CC=C2[N+]([O-])=C(C=CC=C3)C3=NC2=C1 FFISWZPYNKWIRR-UHFFFAOYSA-N 0.000 abstract description 5
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 abstract description 5
- 239000013060 biological fluid Substances 0.000 abstract description 2
- 238000010348 incorporation Methods 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- 239000012530 fluid Substances 0.000 description 13
- SQHWUYVHKRVCMD-UHFFFAOYSA-N 2-n,2-n-dimethyl-10-phenylphenazin-10-ium-2,8-diamine;chloride Chemical class [Cl-].C12=CC(N(C)C)=CC=C2N=C2C=CC(N)=CC2=[N+]1C1=CC=CC=C1 SQHWUYVHKRVCMD-UHFFFAOYSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 125000003831 tetrazolyl group Chemical group 0.000 description 10
- 239000000872 buffer Substances 0.000 description 8
- -1 formazan compound Chemical class 0.000 description 8
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 5
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 5
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 5
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical class C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 4
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 210000001124 body fluid Anatomy 0.000 description 4
- 239000010839 body fluid Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 239000000174 gluconic acid Substances 0.000 description 4
- 235000012208 gluconic acid Nutrition 0.000 description 4
- JORABGDXCIBAFL-UHFFFAOYSA-M iodonitrotetrazolium chloride Chemical compound [Cl-].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C=CC=CC=2)=N1 JORABGDXCIBAFL-UHFFFAOYSA-M 0.000 description 4
- QLAJNZSPVITUCQ-UHFFFAOYSA-N 1,3,2-dioxathietane 2,2-dioxide Chemical compound O=S1(=O)OCO1 QLAJNZSPVITUCQ-UHFFFAOYSA-N 0.000 description 3
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 3
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- GGMPWJFLOZWKBV-UHFFFAOYSA-N [Cl-].CN(C=1C=2C=CC=CC2CC2=C3C(C=CC12)=CC=[NH+]O3)C Chemical compound [Cl-].CN(C=1C=2C=CC=CC2CC2=C3C(C=CC12)=CC=[NH+]O3)C GGMPWJFLOZWKBV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- FSVCQIDHPKZJSO-UHFFFAOYSA-L nitro blue tetrazolium dichloride Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 FSVCQIDHPKZJSO-UHFFFAOYSA-L 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RONADMZTCCPLEF-UHFFFAOYSA-M tetrazolium violet Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C3=CC=CC=C3C=CC=2)=NN1C1=CC=CC=C1 RONADMZTCCPLEF-UHFFFAOYSA-M 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- YTEJSAFVYHDCSN-UHFFFAOYSA-K zinc;benzo[a]phenoxazin-9-ylidene(dimethyl)azanium;trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Zn+2].C1=CC=C2C(N=C3C=CC(C=C3O3)=[N+](C)C)=C3C=CC2=C1 YTEJSAFVYHDCSN-UHFFFAOYSA-K 0.000 description 2
- WYFYSTBFFDOVJW-UHFFFAOYSA-L 2-[4-[4-(3,5-diphenyltetrazol-2-ium-2-yl)phenyl]phenyl]-3,5-diphenyltetrazol-2-ium;dichloride Chemical compound [Cl-].[Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC(=CC=2)C=2C=CC(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=NN1C1=CC=CC=C1 WYFYSTBFFDOVJW-UHFFFAOYSA-L 0.000 description 1
- VCESGVLABVSDRO-UHFFFAOYSA-L 2-[4-[4-[3,5-bis(4-nitrophenyl)tetrazol-2-ium-2-yl]-3-methoxyphenyl]-2-methoxyphenyl]-3,5-bis(4-nitrophenyl)tetrazol-2-ium;dichloride Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC(=CC=2)[N+]([O-])=O)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC(=CC=2)[N+]([O-])=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VCESGVLABVSDRO-UHFFFAOYSA-L 0.000 description 1
- LPXQRXLUHJKZIE-UHFFFAOYSA-N 8-azaguanine Chemical compound NC1=NC(O)=C2NN=NC2=N1 LPXQRXLUHJKZIE-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940093430 polyethylene glycol 1500 Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- MUUHXGOJWVMBDY-UHFFFAOYSA-L tetrazolium blue Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 MUUHXGOJWVMBDY-UHFFFAOYSA-L 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/54—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving glucose or galactose
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/803—Physical recovery methods, e.g. chromatography, grinding
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
- Y10T436/143333—Saccharide [e.g., DNA, etc.]
- Y10T436/144444—Glucose
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
- Emergency Medicine (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
AN IMPROVED DIAGNOSTIC COMPOSITION FOR THE QUANTITATIVE DETERMINATION OF GLUCOSE IN BIOLOGICAL FLUIDS COMPRISING GLUCOSE OXIDASE, A PHENAZIN AND/OR PHENOXAZIN-DERITAVE AND A TETRAZOLIUM SALT AS WELL AS THE INCORPORATION THEREOF UPON A BIBULOUS CARRIER ARE DESCRIBED.
Description
United States Patent 3,791,988 DIAGNOSTIC TEST FOR GLUCOSE Dieter Josef, Pratteln, and Alfred Lampart, Magden,
Switzerland, and Pirmin Schwartz, Weil am Rhine, Germany, assignors to Hoifmann-La Roche Inc., Nutley,
NbDrawing. Filed Mar. 23, 1972, Ser. No. 237,528 Int. Cl. com 33/16 US. 01. 252-408 13 Claims ABSTRACT OF THE DISCLOSURE An improved diagnostic composition for the quantitative determination of glucose in biological fluids comprising glucose oxidase, a phenazin and/or phenoxazin-derivative and a tetrazolium salt as well as the incorporation thereof upon a bibulous carrier are described.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to new and improved diagnostic compositions which are useful in both the qualitative and quantitative determination of glucose in fluids, particularly body fluids such as blood, serum, plasma, urine and the like.
The quantitative determination of glucose in body fluids is of great importance to diabetic individuals who must have frequent checks on the level of glucose in their body fluids as a means of regulating the sugar intake in their diets. The qualitative determination of glucose in body fluids is of importance in routine testing of patients in doctors offices, clinics, institutions, and hospitals as well as in the mass screening of individuals for the presence of the disease.
The ideal diagnostic composition for the detection of glucose in fluids must be simple so as not to require a high degree of technical skill on the part of the technician administering the test, sufliciently rapid to be utilized in large scale qualitative screening determinations and be sensitive and accurate enough to be useful to the clinician. Additionally, such a composition must be sufliciently stable to meet all situations such as prolonged storage and the advance preparation of solutions for large scale screening operations. The present invention pertains to such a composition.
In recent years the methods of determining glucose concentration in fluids have been primarily based on the enzymatic oxidation of glucose with glucose oxidase and oxygen with subsequent detection and measurement of the resulting peroxide or gluconic acid oxidation products by means of a color reaction. Such methods suffer from the disadvantage of having fluctuations in results due to variations in the oxygen content of different samples. Further, with such methods it can never be guaranteed that oxidation process proceeds quantitatively.
One attempt to overcome the above described disadvantage is the addition of an endogeneous oxygen donor, e.g., hydrogen peroxide or the like to the oxidation solution, thereby limiting the measurement of glucose to the relatively insensitive gluconic acid determination. The disadvantage of this approach is the comparative insensitivity of the gluconic acid determination.
The method and composition of the present invention aflords a means whereby the enzymatic oxidation may be utilized to quantitatively determine glucose content Without the disadvantages of prior art processes. Additionally, the method of the invention has the advantage over the prior art of being equally accurate under aerobic and anaerobic conditions and by not being hampered by false positive results due to the presence of ascorbic acid.
In the method of the present invention, the phenazinand/or the phenoxazin derivative enters into the enzy- 3,791,988 Patented Feb. 12., 1974 matic oxidation reaction as a hydrogen acceptor. The reduced form of the phenazinand/or the phenoxazin-derivative(phen, thus formed reacts rapidly in a nonenzymatic reaction with the tetrazolium salt to regenerate the original phenazin and/or phenoxazin-derivative (phen and form a formazan compound which is stable and possesses an intense color. The amount of glucose present is then measured by colorimetrically reading the color of the formazan compound. The reaction may be represented as follows:
glucose phen gluconic acid p red phen d tetrazolium phen formazan Phenazin-derivatives which can be present in the agent provided by the present invention include phenazinium salts in particular methoand etho-compounds. Phenazinium methosulfate is particularly preferred as it is commercially available.
Phenoxazin-derivatives include phenoxazinium salts in particular 7-dimethylamino 1,2 benzophenoxazinium chloride (meldola blue) or 7-dimethyl-amino-2'-hydroxy- 1,2-benzophenoxazinium chloride.
The selection of a particular tetrazolium salt is not critical to the present invention. Examples of suitable compounds include thiazolyl blue [2,5-diphenyl-3-(4,5-dimethyl-2-thiazolyl) mono-tetrazolium bromide],
nitrotetrazolium blue chloride [3,3-dianisyl-4,4'-bis[2- (4-nitrophenyl)-5-phenyl]-tetrazolium chloride],
iodonitrotetrazolium chloride [2-(p-iodophenyl)-3-(pnitrophenyl -5-phenyl-tetrazolium chloride] neotetrazolium chloride [2,2,5,S'-tetraphenyl-3-(4,4'-biphenylene) -ditetrazolium chloride] tetranitrotetrazolium blue [2,2,5,5-tetranitrophenyl-3- (3 ,3 -dimethoxy-4,4'-biphenylene -ditetrazolium chloride],
triphenyltetrazolium chloride, tetrazolium violet [2,5-
diphenyl-3-(a-naphthyD-tetrazolium chloride] and tetrazolium blue [3,3'-dianisyl-4,4'-bis-(3,5-diphenyl) tetrazolium chloride].
Preferred among these are thiazolyl blue, nitrotetrazolium blue chloride and iodonitrotetrazolium chloride.
The diagnostic compositions of the present invention can be provided in a solid form,, e.'g., tablets or powder or, preferably, as a solution in a suitable solvent. Such solutions may be utilized per se or impregnated onto a bibulous carrier such as filter paper, cardboard and the like.
Wherein solutions of the diagnostic compositions of the invention are contemplated, aqueous solutions are preferred. It is expedient, however, to add an organic solvent, e.g., a lower alkanol such as ethanol or a solubilizing agent, e.g., polyethylene glycol, polyoxysorbitanic acid ester or the like to hold in solution the water-insoluble formazans which are formed in the determination reaction. A preferred polyethylene glycol is polyethylene glycol 1500 and a preferred polyoxysorbitanic acid ester is that marketed by Atlas Chemical Industries, Inc., Wilmington, Del. under the trademark Tween 81. This substance chemically is polyoxyethylene(5)sorbitan monooleate. In place of a solvent, a suspending agent such as gelatin or an alginate may be utilized to form a suspension of the formazans as they are produced.
The compositions of the present invention are prepared by simply mixing together the phenazin and/or phenoxazin-deriyative, the tetrazolium salt and glucose oxidase. While the relative concentrations of the components is not particularly critical, it is preferred to have from about 0.1 to about 2.5 millimoles of phenazin and/or phenoxazin-derivative and from about 1.0 to about 10.0 millimoles of tetrazolium salt present for each 0.5 to about 5.0 mg. of glucose oxidase present.
It is preferred in the practice of the present invention to have the pH of the fluid to be tested for glucose content at between about pH 4 and 8, preferably between pH 5.5 and pH 7.5 when the diagnostic composition of the invention is admixed therewith. It is therefore preferred to add a suitable buffer to the diagnostic compositions of the invention. Preferred among the buffering agents common to the art is a phosphate buffer system. Wherein the diagnostic compositions of the invention are in the form of a solution, said solution is preferably from about 0.1 to about 0.4 molar with respect to the buffer. Where the compositions of the invention are in a dry form, a suflicient amount of buffer is added so that a solution formed therefrom will have the desired concentration of buffer. Alternately, the buffer may be added as a solution to the solution of diagnostic composition before conducting the diagnostic determination.
The selection of the particular tetrazolium compound in the practice of the present invention may be determined by the type of test to be conducted. For example, a tetrazolium compound producing a formazan which absorbs light in the spectral range sensitive to the eye can be utilized for qualitative or semi-quantitative glucose determinations such as by the use of bibulous strips impregnated with reagent. Where quantitative determinations are to be carried out utilizing a photometer, the selection of a tetrazolium compound should be made so that the light absorbance of the formazan produced therefrom in the reaction is maximal at the wavelength capacity of the particglar apparatus being utilized. The following table illustrates the wavelength absorption maximum of the formazan produced from preferred tetrazolium compounds in accordance with the invention.
TABLE Wavelength of the absorption maximum of the formazan in Color of the form- Tetrezolium component azan Thlazolyl blue 570 nm Violet. Tetranitrotetrazolium blue 530 nm Blue-red. Nltrotetrazolium blue chloride Blue. Iodonitrotetrazolium chloride. Neotetrazolium chlorlde 560 nm Triphenyltetrazolium chloride 588 mu Tetrazolium violet 510 m Tetrazollum blue 570 nm B e.
polyethylene glycol The following examples serve to further illustrate the invention.
EXAMPLE 1 The following solution was prepared for the quantitative determination of glucose:
Concentration/ml.
of solution thereof Amount of solution Component used Buffer-potassium hos hate pH 7.0 Phenazinium met 05 ate Thlnzolyl blue Glucose oxldase 4 EXAMPLE 2 The procedure of Example 1 was repeated utilizing a buffer solution containing in each ml. 1.0 g. of gelatin. As the formazan compound formed in the reaction was held in suspension treatment with ethanol was not necessary. The photometer reading was taken directly after the two minute incubation period.
Example 3 The procedure of Example 2 was repeated replacing the gelatin with an equal amount of polyoxysorbitanic acid ester (Tween 81, Atlas Powder Co.).
Example 4 The following solution was prepared and impregnated on strips of bibulous material, such as filter paper. The paper was soaked in the solution and dried with the exclusion of light. The thus-formed srips were utilized to Example 5 The following solution was prepared for the quantitative determination of glucose.
Component: Amount, ml. Glucose oxidase (20 mg./ml.) 0.05 Meldola blue (2 mg./ml.) 0.05 Iodonitrotetrazolium chloride (2.5 mg./ml.) 0.40 Buffer (0.2 M potassium phosphate pH 7.0 1%
polyethylenglycol 1500) 1.50
To this solution is added 1 ml. of a sample solution.
-The content of glucose is determined by measuring in a photometer the extinction dilference in comparison with a blank test in the wavelength range of about 492 nm.
What is claimed is:
1. A diagnostic composition for the detection of glucose in fluids consisting essentially of glucose oxidase, a tetrazolium salt and a substance selected from the group consisting of a phenazinium salt, a phenoxazinium salt and mixtures thereof and one or more non-reactive adjuvant materials selected from the group consisting of buffers, solubilizing agents and suspending agents.
2. The composition of claim 1 wherein said buffer is suitable for maintaining the pH of said fluids between pH 4 and 8.
3. The composition of claim 1 wherein said phenazinium salt is selected from the group consisting of phenazinium methoand phenazinium etho-salts.
4. A test indicator for detecting glucose in fluids consisting essentially of a bibulous carrier impregnated with the composition of claim 1.
5. A test indicator for detecting glucose in fluids consisting essentially of a bibulous carrier impregnated with the composition of claim 1 wherein said phenazinium salt is phenazinium methosulfate and said tetrazolium salt is thiazolyl blue.
6. A test indicator for detecting glucose in fluids consisting essentially of a bibulous carrier impregnated with the composition of claim 1 wherein said phenazinium salt is 7-dimethylamino-1,2- benzophenoxazinium chloride and said tetrazolium salt is iodonitrotetrazolium chloride.
7. A diagnostic composition for the detection of glucose in fluids consisting essentially of a solution of the composition of claim 1 in a solvent consisting essentially of water and a lower alkanol.
8. A diagnostic composition for the detection of glucose in fluids consisting essentially of an aqueous solution of the composition of claim 1 wherein said solubilizing agent is selected from the group consisting of polyethylene gly- 001 1500 and po1yoxyethylene(5)sorbitan monooleate.
9. A diagnostic composition for the detection of glucose in fluids consisting essentially of an aqueous solution of the composition of claim 1 wherein said suspending agent is selected from the group consisting of gelatin and an alginate.
10. The composition of claim 2 wherein said phenoxazinium salt is selected from the group consisting of 7-dimethylamino-1,2-benzophenoxazinium chloride and 7- dimethylamino l,Z-benzophenoxazinium chloride.
11. A test indicator for detecting glucose in fluids consisting essentially of a bibulous carrier impregnated with the composition of claim 2.
12. A diagnostic composition in accordance with claim 13. The composition of claim 3 wherein said phenazinium metho-salt is phenazinium methosulfate.
References Cited UNITED STATES PATENTS 3,123,443 3/1964 Smeby 252-408 X 3,233,974 2/1966 Bradley 252-408 X MAYER WEINBLA'IT, Primary Examiner US. Cl. X.R.
23-230 B, 253 TP; 424-7
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23752872A | 1972-03-23 | 1972-03-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3791988A true US3791988A (en) | 1974-02-12 |
Family
ID=22894111
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00237528A Expired - Lifetime US3791988A (en) | 1972-03-23 | 1972-03-23 | Diagnostic test for glucose |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3791988A (en) |
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| US4066408A (en) * | 1974-10-16 | 1978-01-03 | Ab Kabi | Chromogen-reactive-indicator preparations containing a 3,3'-di(carbonyloxy- or sulfonyloxy-group-containing) benzidine derivative chromogen |
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| US4168205A (en) * | 1976-06-09 | 1979-09-18 | Boehringer Mannheim Gmbh | Method for the determination of substrates or enzyme activities |
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| US4330299A (en) * | 1981-03-09 | 1982-05-18 | Evreka, Inc. | Article and method for measuring glucose level in body fluids |
| WO1982002251A1 (en) * | 1980-12-19 | 1982-07-08 | Mining & Mfg Minnesota | Method and article for determining free acid concentration in liquid |
| JPS57137357A (en) * | 1981-01-07 | 1982-08-24 | Rhone Poulenc Ind | Pasty organopolysiloxane composition forming elastomer thermosettingly |
| EP0085263A1 (en) * | 1981-12-23 | 1983-08-10 | John Richard Baker | Method and reagent for determining glucose levels in blood samples |
| US4606351A (en) * | 1979-04-14 | 1986-08-19 | Max Planck Gesellschaft Zur Foerderung Der Wissenschaften | Optical indicator device for the remote measurement of physical changes in a test subject |
| US4654309A (en) * | 1980-12-19 | 1987-03-31 | Minnesota Mining And Manufacturing Co. | Test method and article for estimating the concentration of free acid in liquid |
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