US3814668A - Method and device for the semi-quantitative determination of glucose in aqueous fluids - Google Patents

Method and device for the semi-quantitative determination of glucose in aqueous fluids Download PDF

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US3814668A
US3814668A US86673069A US3814668A US 3814668 A US3814668 A US 3814668A US 86673069 A US86673069 A US 86673069A US 3814668 A US3814668 A US 3814668A
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glucose
test
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device
test device
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W Hendershot
L Johnson
K Blake
B Haden
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Bayer Corp
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    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING 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
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/54Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving glucose or galactose
    • YGENERAL 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
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00Chemistry: molecular biology and microbiology
    • Y10S435/805Test papers

Abstract

Improved method and device for the semi-quantitative determination of glucose in aqueous fluids such as urine comprising glucose oxidase, a water soluble iodide salt, and a substance having peroxidative activity. The composition is incorporated with a carrier member therefor and/or a semi-permeable membrane such as ethylcellulose. A preferable embodiment of the present invention comprises the inclusion of a background coloring material such as brilliant blue FCF in the test composition.

Description

United States Patent METHOD AND DEVICE FOR THE SEMI-QUANTI- TATIVE DETERMINA'IION 0F GLUCOSE IN AQUEOUS FLUIDS Kenneth Allen Blake Billy Ihrperflhden, and William Fred Hendershot, Ellrhart, Ind., and Laveli Rolfson Johnson, Salt Lake City, Utah, sssignors to Miles Laboratories, Inc, Elirhart, Ind.

No Drawing. Filed Oct. 15, 1969, Ser. No. 866,730 Int. Cl. G01n 31/14 US. Cl. 195-103.5 C 16 Claims ABSTRACT OF THE DISCLOSURE Improved method and device for the semi-quantitative determination of glucose in aqueous-fluids such as urine comprisingglucose oxidase, a water soluble iodide salt, and a substance having peroxidative activity. The composition is incorporated with a carrier member therefor and/or a semi-permeable membrane such as ethylcellulose. A preferable embodiment of the present invention comprises the inclusion-of a background coloring material such as brilliant blue FCF in the test composition.

BACKGROUND OF THE PRESENT INVENTION The detection of gucose in urine as well as the determination of its concentration therein is of great importance for diabetic patients who must control theirdiets so as to regulate their sugar intake and who must frequently be guided in this regard bye-regular check on urine glucose. But beyond its usefulness in regular urine testing on known diabetics by both patients and physicians, this glucose indicator may aisobe used eificiently in routine urinalysis in hospitals and physicians" offices, in diabetes detection and screening programs, in the diflerentiation of glucosuria from other meliturias, and the like.

Because early diagnosis and continued controlarevso important in diabetes, a urine-sugar test, to.be of.- the greatest value, must be conveniently rapid, simpleenough for any patient to use with ease, accurate enough to serve the clinician, and sensitive enough to reflect variations in the patients condition. Morever, the test device must be sufliciently quantitative to accurately measure increments of glucose concentration'and th'us diflerentiate various medical conditions.

Procedures forthe detection andestim'ation-of'sugss' in urine are well known in clinical chemistry. One such procedure utilizes Benedict's copper reduction test, an-

other employs a self heating alkaline copper reduction test in table form, still another involvesstestwhichrdepends solely on the actionof enzymes. This latterenzymatie glucose test, comprises the presence of glucose oxidase, s peroxidative material, and achromogen which responds when the test composition is contacted witha body fluid containing glucose. Such indicator materials are generally oxidation-reduction indicators.

The enzymatic glucose test systems described hereinabove, have usually been incorporated with a carrier means therefor. Such carrier means usually comprise bibulous celluolse strips into or unto which the test composition is incorporated. It has been found, however, that such enzymatic glucose test devices are notsutiiciently quantitative, that is, they are not -capable of differentiating 3,814,668 Patented June 4. 1974 p CC small increments of glucose in body fluids such as urine.

Therefore, a primary obiectof the present invention is to provide an improvedsemi-quantitative glucose test capable of differentiating small increments of glucose in body fluids such as urine. It is another object to provide an improved glucose test device having excellent stability characteristics. it is yet another object of the present invention to provide a dip and read glucose test device having controlled sample retention properties.

SUMMARY .OF THE INVENTION It has now been found that the above and other objects may be achieved by employing a glucose test formulation comprising glucose oxidase, a peroxidative active substance, and a water soluble iodide salt incorporated with a carrier member and/or coated with a semi-permeable membrane such as with ethyl cellulose, thus achieving a controlled pick up and retention of sample liquid when immersed therein. A preferable embodiment of the present invention comprises incorporating a background coloring material such as a blue dye in the test composition so as to achieve an unusually broad color gradient response.

DESCRIPTION OF THE PREFERRED EMBOD] MENTS As noted hereinabove, it has now been found that the superior semi-quantitative glucose test can be achieved by the utilization of a water soluble iodide as a chromogcn in an enzymatic glucose test system. However, the mere utilization of such an iodide is not sufficient to achieve the desired results. it has been foundvthat if a test device comprising simply glucose oxidase, peroxidase, and an iodide salt is immersed into a urine sample containing glucose and immediately withdrawn therefrom, the relention of excess sample liquid onvthe test device prevents the atmospheric oxygen from reaching the test reaction with the result that the reaction is said to cycle. That is, it is believed that when oxygen is excluded from reaching the, test reaction by. a layer of liquid over the device, a portion of the free iodine acts as an oxidizing agent for the reduced glucose oxidase formed in the reaction. Thus, the iodide does not function as efficiently as an indicator material but participates in the glucose oxidase-glucose reaction.

It has now been found that if a means is provided to prevent the retention of excess liquid sample on the test device, the iodide rather than participating in the glucose oxidase-glucose reaction, functions as an indicator material, thus giving excellent semi-quantitative results.

Thus, it has been found that it's semi-permeable membrane is applied to the surface of an enzymatic glucose test device, or an enzymatic test composition incorporated with a semi-permeable membrane or film forming polymericsubstance, the membrane acts as a means for preventing excess liquid from adhering to the test device allowing atmospheric oxygen to reach the test reaction and consequently permitting the iodide to go to free iodine and functioning eflectively as an indicator material.

The iodide salts contemplated for use in the system of the present invention are those which readily ionize in an aqueous media to form the characteristic iodide ion. Exemplary o! the iodide salts which may be used as indicator' materials are potassium iodide, sodium iodide, and ammonium iodide. in addition to the requirement that the salt be ionizable, it should also be noted that the 3 cationic portion of the molecule must not interfere with the enzymatic catalysis of the glucose oxidation. Of the suitable iodide salt, economic considerations and availability suggest that potassium iodide is the preferable salt of the present invention.

The principles underlying the basic reactions of enzyme tests for glucose are well known. Glucose oxidase catalyzes the aerobic oxidation of gucose to produce gluconic acid and hydrogen peroxide. In this reaction hydrogen removed from the glucose combines with atmospheric oxygen to form the hydrogen peroxide. This reaction may be represented by the following schematic equation:

Glucose O; giuconic acid H1O:

in addition to the use of the enzyme glucose oxidase, the system as noted above must include a material having pcroxidative activity. Among the materials having this activity, a preferable compound is horseradish peroxidase or potato peroxidase. However in addition to these naturally occurring peroxidase materials, other organic materials having similar activity may also be utilized. Exemplary of these other materials are normal whole blood, red blood cells alone, lyophilzcd whole blood, urohemin, metalloporphyrins and similar compounds.

in order to produce a test having the desired stability, reactivity and sensitivity, the aforementioned ingredients when contacted with the fluid being tested should be buffered at a hydrogen ion concentration of about from pll 3.4 to 7.2 with a preferable range of about from PH 5.0 to pH 6.0. Of the numerous buffer: which may be utilized to maintain the pH of the ingredients in the dcsircd range, it has been found that a citric acid-sodium citrate buffer achieves the desired results with a minimum of interferences with the enzymatic reactions involved in the test system. Other means may however be used to maintain an isohydric pH condition such as phosphate, tartrate and glutamate buffer systems.

In addition to the utilization of an iodide salt as a chromogcn in the present test system, it is preferable that a second indicator substance be included in the test composition. in this regard, it has been found that the inclusion of a blue dyestuff in the test formulation results in a gradient response to the presence of various concentrations of glucose which ranges from blue through various shades of green to brown as the concentration of glucose increases. f such blue dyestuffs, it has also been found preferable to utilize a chromogen which goes from blue to colorless when being oxidized by the hydrogen peroxide produced in the test reaction system. in this regard dyestuffs such as indigo-carmlne and brilliant blue FCF are ideally suited as chromogens. Other dyestuff materials which may be utilized in the present invention are aniline blue, cyanol blue, patent blue, xylene blue .V and Comessie brilliant blue.

in addition to the above test composition constituents which actively participate in the test reaction, other adiuvants may be utilized. Such adjuvants include thickening agents which also function as enzyme stabilizers. In this regard it has been found that a preferable test composition includes the utiiiaztion of such materials as polyvinylpyrrolidone, sodium alginate, gelatin, bovine serum a bumin, polyvinyl alcohol and an interpolymer of methyivinylether and maleic anhydride such-as that described in US. Pat. No. 3,453,180 and known commercially as Grantrcz AN. The preparation of a test composition comprising the active ingredients above noted and including Grantrez and PVP had been found to be exceptionally stable. in regard to the use of polyvinylpyrrolidone, it has been found that the use of this material results in the formation of a color complex with the free iodide which results in an improved indicator system. Such use is preferred in the present composition.

As noted hereinabove, when utilizing an iodide salt as an indicator material in an enzymatic glucose test, it has been found necessary to include in such composition a means for retarding or preventing the adherence of excess liquid sample to the test device. In this regard a semipermeable membrane such as ethylcellulose has been found to prevent such a water retention. Other eellulosic compounds and film forming substances which achieve the same effect may also be utilized. Such compounds include the cellulose ethers and esters as well as various other hydrophobic film forming polymeric materials. Ethylceiluiose has been found especially advantageous for use in the present invention.

As far as actual proportions of active ingredients is concerned, it has been found that a reasonably wide range of concentrations may be used. As a general guide, the following ranges of concentrations may be employed. These figures are based on the solution used to incorporate the test system constituents with the carrier member therefor.

Quantity per ml.

mam restaurant-z Glucose oxidase units 16,000-33,000 Peroxidative active substance mg.. 40-60 Iodide salt g.. l-2 Second chromogen (blue dyestuff) mg l-20 Film forming polymer g 3 0.5-1

1 Based on an assay of 8000 Worthington Units (WU)/mcg. Dissolved in an organic colvent such as benzlne.

As noted at the beginning of this disclosure, it is preferable in the present invention to incorporate the test com position on or with a carrier member and to utilize this combination as a dip and read test device. This may be achieved by various methods, which include, impregnating a bibulous material with a solution of the test composition and thereafter drying the impregnated test device, adhesively fixing to the surface of the carrier, a finely divided, dry, intimate mixture of the ingredients, and the like. The preferable mode of preparation is the impregnation of a bibulous carrier with a. solution or solutions of the test composition, followed by drying. When a bibulous carrier is employed, the carrier material may be any of the variety of substances. For example, filter paper, wood strips, synthetic plastic fiberous materials, nonwoven orwoven fabrics and so on may be utilized in this embodiment. The preferable bibulous material is filter paper having a thickness of about 0.01 inch to about 0.02 inch. Once the carrier member has been impregnated with the basic test composition and dried, and semi-permeable membrane may be then applied by utilizing same in an organic solvent and effecting a second dip of the test device in the polymeric film former followed by a second drying. Another mode of preparation of the present test device simply comprises mixing the test composition with a film .forming polymeric substance and attaching such mixture to a carrier or handle means therefor.

The mode of use of the test device of the present invention will now be described. In conducting the test for glucose, thedevice is immersed into the fluid being tested which usually is a urine sample and immediately withdrawn. This is done since the pH of the moistened device must usually be dominated by the buffer in the test composition. If the test device were allowed to remain in the fluid for any length of time, there would be a danger that the test composition ingredients would be leached from the carrier into the fluid. However such leaching effect is substantially retarded by the utilization of the semi-permeable membrane described hereinabove. The color developed due to the presence of gulcose in the test liquid is then read by visual comparison with a previously prepared color chart. Various instrumental metrods may also be employed to determine the quality of the color developed,

thus increasing the accuracy of the test by removin the subjective determination of color by the human eye. However as also noted hereinabove, the excellent gradient color response due to the novel inclusion of two chromogcnic substances into the present test composition substantially alleviates such subjective human error.

The actual compounding of the test composition of the present invention will be illustrated by the following example which is included for illustrative purposes only and is not to be construed as placing any limitation upon the inventive concept as disclosed herein.

EXAMPLE The following components were mixed, stepwise for the preparation of 100 ml. of mix.

Component: Quantity (1) Potassium iodide g 1.0 (2) Brilliant blue FCF (FD and C blue No.

l) mg 10.4 (3) Distilled water ml 53 (4) Citric acid, anhydrous g 0.595 (5) Sodium eitrate-2H,O g 5.23 (6) Gantrez. AN 139 (l0% aqueous solution) ml. (7) Polyvinylpyrrolidone (l0% aqueous solution) ml- 5 (8) Peroxidase mg 1 50 (9) Glucose oxidase ml-- 3 33 ZtOOO Worthington untta/ntcg.

' i000 units/ml.

Whatman 3 MM paper was impregnated with the above solution, allowed to drain and dried in a tunnel dryer set at 85 C. for 7 minutes. After removal from the drying tunnel, the impregnated paper was dipped into a solution of 0.85 grams of ethyl cellulose in 100 ml. of benzene. After removal from this second impregnating solultOl'i the paper was again dried, cut into small squares a proximately 5 mm. by 5 mm. and attached to and end of a strip of fluid impervious plastic film 5 mm. wide and approximately 6 cm. long.

The above prepared test devices were contacted with various urines containing increments of glucose of from O to 2% by weight. The results were as follows:

Glucose concentration Color developed As can be noted from the above results, excellent glucose quantitation was achieved employing a formulation prepared according to the teachings of the present invention. A commercial product utilizing ortho-tolidine as an indicator material rather than an iodide salt, was somewhat capable of quantitating the above noted glucose concentration up to but not more than 0.50 gram percent glucose.

what is claimed is:

i. in a test device for the semi-quantitative determination of glucose in urine comprising a bibulous, fibrous carrier member incorporating, in combination, glucose oxidase, a substance having peroxidative activity, and a water soluble iodide salt, the improvement which comprises a hydrophobic coating encompassing the fibers of the bibulous carrier member, said hydrophobic coating being the dry residue deposited through the saturation of the bibulous carrier member with an organic solvent \(iittliOfl of from 0.5 to L0 grams per I00 ml. of a lilm forming material selected from the group con- 6 sisting of hydrophobic cellulose ethers and esters.

2. A test device as in claim 1 wherein the test device additionally includes the presence of a blue dyestufi.

3. A test device as in claim 2 wherein the said dyestufi is selected from the group consisting of brilliant blue FCF, indigo carmine, aniline blue, patent blue, xylene blue V and Comassie blue.

4. A test device as in claim 1 wherein the test device further includes a buffer for maintaining the system in a pH range of from about pH 3.4 to pH 7.2.

5. A test device as in claim 1 wherein the film forming material is ethyl cellulose.

6. A test device as in claim 1 where the water soluble iodide salt is selected from the group consisting of potassium iodide, sodium iodide and ammonium iodide.

7. A test device as in claim 6 wherein the iodide salt is potassium iodide.

8. A test device as in claim 1 wherein the material having peroxidative activity is peroxidase.

9. A test device for the semi-quantitative detection of glucose in urine comprising a bibulous, fibrous paper carrier impregnated with the dry residue of an aqueous solution having the following proportions of ingredients per ml. of solution:

Glucose oxidase units 16000-33000 Peroxidative active substance mg 40-60 Water soluble iodide salt g l-Z and thereafter coated with the dry residue of a saturating solution of about from 0.5 to 1.0 grams of ethyl cellulose per 100 ml. of benzene.

10. A test device as in claim 9 wherein the solution additionally contains 1 to 20 mg. of a blue dycstufi.

11. A test device as in claim 10 wherein the blue dyestuff is brilliant blue FCF.

12. A test device as in claim 1 wherein the carrier member is bibulous paper.

13. A process for the semi-quantitative determination of glucose in urine comprising contacting the urine with a test device consisting essentially of a bibulous, fibrous carrier member incorporating the dry residue of a solution of glucose oxidase, a substance having peroxidative activity, and a water soluble iodide salt, the fibers of said carrier member being encompassed by a hydrophobic coating, said hydrophobic coating being the dry residue deposited through the saturation of the bibulous carrier with an organic solvent solution of from 0.5 to l.() grams per I00 ml. of a film forming material selected from the group consisting of hydrophobic cellulose ethers and esters. immediately removing the test device from contact with said urine and within about one minute comparing the color developed hereon with a previously prepared standard color fit e 14. A process as in claim 13 wherein the residue additionally contains a blue dyestulf.

15. A process as in claim 13 wherein the water soluble iodide salt is selected from the group consisting of potassium iodide, sodium iodide and ammonium iodide.

10. In a process for the preparation of a test device for the semi-quantitative determination of glucose in urine comprising the preparation of a solution of glucose oxidane, a substance having peroxidative activity, and a water soluble iodide salt, incorporating said solution with a bibulous, fibrous carrier member therefor, drying said solution and carrier member, the improvement which comprises thereafter saturating said carrier member with an' 'o'rgaiiie solvenisolu'fion of from 0.5 (5 T0 grams per l00 ml. of a film-forming material selected from the group consisting of hydro phobic cellulose ethers and esters resulting in the deposition of a dry. hydrophobic residue coating {11C carrier memb r.

References Cited UNITED STATES PATENTS Adams et a1. 195-103.!) C X Fonner 195103.5 C Scott l95l03.5 C Kcston 23-253 T? Rey cl a1 195-1035 C Harvill ct al. 195-1035 R 8 OTHER REFERENCES Wilson et 111., "Comprehensive Anal. Chem.," Vol. 1c (1962), p. 362.

Welcher, "Organic Analytical Reagents," Vol. IV a (1948),p.505.

U.S. C1. X.R. 195-99; 23-253 T1

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US3814668A US3814668A (en) 1969-10-15 1969-10-15 Method and device for the semi-quantitative determination of glucose in aqueous fluids
CA 94236 CA926282A (en) 1969-10-15 1970-09-28 Method and device for the semi-quantitative determination of glucose in aqueous fluids
ES384417A ES384417A1 (en) 1969-10-15 1970-10-10 A test device and method for the semiquantitative deter- mination glucose in aqueous fluids.
GB4866970A GB1320957A (en) 1969-10-15 1970-10-13 Test device for the determination of glucose in aqueous fluids
NL7014994A NL7014994A (en) 1969-10-15 1970-10-13
BE757507A BE757507A (en) 1969-10-15 1970-10-14 Method and element IMPROVED semi-quantitative determination of glucose in aqueous fluids
DE19702050481 DE2050481B2 (en) 1969-10-15 1970-10-14 Diagnostiziermittel semi-quantitative determination of glucose in urine
JP8974470A JPS5039558B1 (en) 1969-10-15 1970-10-14
DK521970A DK139795C (en) 1969-10-15 1970-10-14
FR7037103A FR2065939A5 (en) 1969-10-15 1970-10-14

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USRE28575E (en) * 1971-03-01 1975-10-21 Indicator for detecting hydrogen peroxide and peroxidative compounds containing alpha naphthoflavone
US3920580A (en) * 1973-07-12 1975-11-18 Miles Lab Liquid control solution
US3964871A (en) * 1974-12-18 1976-06-22 Becton, Dickinson And Company Method and device for detecting glucose
US3971702A (en) * 1974-01-09 1976-07-27 Shionogi & Co., Ltd. Diagnostic composition for saccharide determination
US4042329A (en) * 1974-12-18 1977-08-16 Becton, Dickinson And Company Method and device for detecting cholesterol
US4059407A (en) * 1976-04-14 1977-11-22 Becton, Dickinson And Company Disposable chemical indicators
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
US4160008A (en) * 1978-01-26 1979-07-03 Miles Laboratories, Inc. Multilayered test device for determining the presence of a liquid sample component, and method of use
EP0036543A1 (en) * 1980-03-20 1981-09-30 Miles Laboratories, Inc. Improved method and device for the semiquantitative determination of glucose in aqueous fluids and method of preparing the device
US4340669A (en) * 1981-02-12 1982-07-20 Miles Laboratories, Inc. System for the determination of glucose in fluids
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USRE28575E (en) * 1971-03-01 1975-10-21 Indicator for detecting hydrogen peroxide and peroxidative compounds containing alpha naphthoflavone
US3920580A (en) * 1973-07-12 1975-11-18 Miles Lab Liquid control solution
US3971702A (en) * 1974-01-09 1976-07-27 Shionogi & Co., Ltd. Diagnostic composition for saccharide determination
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
US3964871A (en) * 1974-12-18 1976-06-22 Becton, Dickinson And Company Method and device for detecting glucose
US4042329A (en) * 1974-12-18 1977-08-16 Becton, Dickinson And Company Method and device for detecting cholesterol
US4059407A (en) * 1976-04-14 1977-11-22 Becton, Dickinson And Company Disposable chemical indicators
US4160008A (en) * 1978-01-26 1979-07-03 Miles Laboratories, Inc. Multilayered test device for determining the presence of a liquid sample component, and method of use
US4981805A (en) * 1980-01-18 1991-01-01 Fuji Photo Film Co., Ltd. Method of using chemical analysis slide
US5192693A (en) * 1980-01-18 1993-03-09 Fuji Photo Film Co., Ltd. Method of using chemical analysis slide
US4303753A (en) * 1980-03-20 1981-12-01 Miles Laboratories, Inc. Method and device for the semiquantitative determination of glucose in aqueous fluids
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GB1320957A (en) 1973-06-20 application
CA926282A1 (en) grant
DK139795B (en) 1979-04-17 grant
FR2065939A5 (en) 1971-08-06 application
JPS5039558B1 (en) 1975-12-17 grant
ES384417A1 (en) 1973-09-16 application
BE757507A (en) 1971-03-16 grant
DE2050481A1 (en) 1971-04-29 application
DK139795C (en) 1979-10-15 grant
NL7014994A (en) 1971-04-19 application
DE2050481B2 (en) 1976-12-23 application
CA926282A (en) 1973-05-15 grant

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