|Publication number||US3630957 A|
|Publication date||Dec 28, 1971|
|Filing date||Nov 15, 1967|
|Priority date||Nov 22, 1966|
|Also published as||DE1598153A1, DE1598153B2, DE1598153C3|
|Publication number||US 3630957 A, US 3630957A, US-A-3630957, US3630957 A, US3630957A|
|Inventors||Hans-Georg Rey, Pieter Rieckmann, Hans Wielinger, Walter Rittersdorf|
|Original Assignee||Boehringer Mannheim Gmbh|
|Export Citation||BiBTeX, EndNote, RefMan|
|Referenced by (127), Classifications (23)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent US. Cl. 252-408 24 Claims ABSTRACT OF THE DISCLOSURE Diagnostic agents for use in the detection of biochemical and chemical components in blood, urine and other biological fluids are disclosed comprising water-resistant films in which a composition forming color in response to said chemical or biological component is uniformly distributed.
The present invention relates to a new and improved diagnostic agent for use in the detection of chemical and biochemical components in biological fluids, and more particularly relates to test strips for use in the detection of chemical and biochemical components of biological fluids, a process of preparing such test strips and methods for using the same.
The detection of chemical and biochemical components in biological fluids is of ever increasing importance in connection with medical diagnosis and treatment. The detection, i.e. analytical procedures, have already been considerably simplified by the provision of test tablets and test papers. Unfortunately the diagnostic agents of this type leave a lot to be desired with regard to their actual use, as well as with regard to their reliability. Furthermore, the large scale production thereof frequently gives rise to dilficulties. This is particularly true as concerns the diagnostic agents provided for use in the determination of chemical and biochemical components in cloudy and strongly colored liquids, such as whole blood.
It has already been proposed to coat conventional test papers with a semi-permeable film and/or membrane or to hydrophobe impregnated and dried papers. However, these test papers can only be produced by multiple impregnations of filter papers which not only results in technical difliculties from the point of view of production, but also increases their cost considerably. Further, as with an increasing number of process steps, the possible number of production errors increases; either the reliability of the resultant test paper is reduced or additional intermediate controls are necessary, which are of course in and of themselves expensive.
In connection with the determination of the hydrogen ion concentration required to be carried out in cloudy, muddy or strongly colored liquids and fluids, it has already been proposed to use cellulose foils containing indicators (c.f. P. Wullf, Kolloid Z., 40, 341/1926). These cellulose foils constitute however highly swellable, hydrophilic and non-water-resistant membranes which, in addition, are diflicult to produce from a technical point of view. Thus, in the production of such pH test foils, the indicator-containing cellulose solutions must be forced through slits into an acid bath and must subsequently be subjected to a further treatment until there are no longer any acid residues in the foil.
It is an object of the invention to provide a new and improved diagnostic agent, i.e., test strip for use in detecting chemical and biochemical components present, for example, in biological fluids such as blood, urine, etc. and other fluids such as milk, etc.
A further object of the invention is to provide a new and improved diagnostic agent for use in detecting chemical and biochemical components present in biological fluids characterized by the extreme case with which they are produced and used, as well as by their reliability, i.e., accuracy and reproducibility of results.
Still another object of this invention is to provide a new and improved diagnostic agent for safely and reliably detecting single or multiple chemical and biochemical components in biological fluids.
These and other objects and advantages will be apparent from a consideration of the following disclosure.
In accordance with the invention, it has now been found that diagnostic agents for the detection of biochemical and chemical components in biological fluids, which are outstandingly useful and reliable and can be prepared in an economically feasible manner, are obtained by introducing the specific reagents and/or indicators necessary for a detection reaction into a solution or dispersion of the film-forming materials, i.e., the materials required for making the water-resistant films. For this purpose, the film-forming mixture is applied either to a non-retaining substrate or to a substrate to which the film adheres firmly, and the coated or layered substrate is then dried. In the first case, the film can subsequently be removed, as for example by stripping, from the substrate, whereas in the second case, the substrate serves as a carrier for the film so that in this instance the film itself may be mechanically less stable and thinner.
Thus, the diagnostic agents according to the present invention for use in the detection of chemical or biochemical components in biological fluids comprises a waterresistant film in which the reagents for the detection reaction are substantially uniformly distributed, the film possibly being supported on a substrate.
As film-forming agents there can be used those materials which are soluble in organic solvents or which can be dispersed in water, such as cellulose ethers, cellulose esters, cellulose acetate phthalate, polyvinyl esters, polyvinyl acetals, polyacrylic esters, polyacrylamide, polyamides and other film-forming, natural or synthetic polymers, as well as mixtures thereof. Ethyl cellulose, acetyl cellulose, polyvinyl acetate, polyvinyl propionate, polyvinyl butyracetal and latex have proved to be especially useful.
As carriers or supports (substrates) for coating with the films, it is preferred to use synthetic resin foils but it is also possible to use, for example, glass, wood, paper, metal foils and other like materials.
In addition to the reagents which are required for the detection reaction, the film-forming compositions can also contain any of the conventional fillers and adjuvants, such as for example chalk, titanium dioxide, silica gel, starch, talc, pearl white, metal soaps, cellulose powder and the like, as well as suitable thickening agents, emulsifiers, dispersion agents, plasticizers and the like. Pigments can also be included in the films and serve to render the same opaque. The resultant films can be applied to a colored carrier material; in this manner, the reagent foils, in contradistinction to completely transparent foils, can be compared directly with color charts without porcelain tiles or the like being necessary.
The addition of small amounts of wetting agents to the film-forming solutions or dispersions has the effect that the resultant solutions or dispersions can be more uniformly coated onto the hydrophobic synthetic resin foils without the other properties of the diagnostic agents according to the present invention being thereby substantially changed.
The composition of the reagents, as required for the detection of the biochemical and chemical components in body fluids, is, in principle, the same as in the case of the previously known diagnostic agents. Thus, for example, the presence of glucose can be detected with the use of a mixture of glucose oxidase, peroxidase, buffer and color-forming agent; for the detection of blood in urine, there can be used a mixture of peroxide and a color-forming agent and urobilinogen can be detected with p-dialkylamino-benzaldehyde and a strong acid. As examples of other typical clinical tests which are of importance in the analysis of blood and other body fluids, there may be mentioned the Griess nitrite test, the detection of uric acid with the help of uricase-peroxidase and a color-forming agent, the detection of galactose, phosphatases, chlorinesterase, urea, etc.
It was certainly not to have been foreseen that the new diagnostic agents according to the present invention could even be used for the intended purpose since it was to have been assumed that the reagents incorporated as herein water-resistant and, in general, hydrophobic films, would either not react at all with the fluid to be investigated, or would not react quickly enough. Typical hydrophilic and non-water-resistant foils, such as those of cellulose or gelatine, swell in water and are able to take up several times their own weight of water. Nevertheless, in the case of cellulose indicator foils, the take-up of water in comparison with the absorbency of paper is already reduced to such an extent that the Wultf indicator foils must-be dipped in the fluid under investigation for at least one minute. In the case of the determination of pH, using therefor cellulose reagent foils, it only depends upon the migration velocity of the mobile and small hydrogen and hydroxyl ions, whereas in the case of the diagnostic agents according to the present invention, the substantially larger and considerably less mobile molecules of the components to be detected in body fluids must pass through the film material in order to reach the reagents.
It is also surprising that such large and sensitive molecules as those of enzymes also retain their reactivity in the solid solutions of the synthetic resin films. In addition, it is extremely surprising that, in spite of the improved protection of the reagents from external influences, enzyme reactions requiring oxygen, as for example the detection of glucose by means of glucose oxidase, peroxidase and a color forming agent, also take place quickly and without trouble in the diagnostic agents according to the present invention.
The advantage of the new diagnostic agents according to the present invention, in comparison with the previously known test papers and indicator foils, lies in particular in their greatly simplified production. In comparison with the cellulose foils, there is the further advantage that precipitation in an acid bath is not necessary, in connection with which sensitive reagents are destroyed or decomposed. From the chemical point of view, test papers and cellulose foils consist of the same material, namely, cellulose. Since the synthetic resin films according to the present invention can be made from the most varied materials, the most compatible and best suited material for each special purpose can be selected.
Furthermore, the materials used according to the present invention can be worked up much more easily with constant quality, are more homogeneous; and consequently are more dependable. Furthermore, We have found that not only the mechanical stability of the foils, but in addition the stability of the reagents is better than in the case of test papers. Even after the reaction has taken place with the body fluid being analyzed, the new test foils according to the present invention are considerably more stable than the previously used test papers so that the results obtained can, if desired, be evaluated at a later time or can even be checked after several days. Thus, for example, diagnostic agents according to the present invention for the detection of glucose in blood or urine, can be enclosed with a patients examination report and can be filed away with the records relating to the findings in the patients file history.
The production of the new diagnostic agents according to the present invention takes place, in the simplest way, by the application of the film-forming solution or dispersion to a suitable substrate, followed by drying. In the case of the continuous application of narrow film strips onto adhering synthetic resin foils, it is, in addition, possible to apply different reagent mixtures side by side onto a foil. After the drying has been completed, the resultant foil is cut at right angles to the direction of application, to thereby provide narrow strips suitable for simultaneously detecting a variety of components, i.e., there are obtained multi-test strips.
In contradistinction to test papers, the reagent concentration of which cannot be varied as desired because of the absorbency and the saturation limit of the paper, the synthetic resin films according to the present invention can be produced having any desired thickness and with any desired reagent concentration. Since the reagents also cannot be leached out or non-uniformly distributed by chromatographic effects, the fluid to be investigated can, if desired, be left to act upon the film for a comparatively long period of time, a stronger color reaction thereby being produced. Therefore, the new diagnostic agents according to the present invention can be used not only for the previously known test reactions but also for those which, because of the known disadvantages of test papers, have hitherto not been capable of being made up into the considerably simpler and easier used form of a test strip.
The following examples are given for the purpose of illustrating the present invention and are not to be construed as a limitation thereof:
EXAMPLE 1 A reagent film for the detection of glucose in, for example, urine or whole blood, was prepared as follows: A mixture having the following composition was first prepared:
Polyvinyl propionate dispersionl00.00 g.
o-Vanillin- (vanilloyl -hydrazone2.50 g.
Glucose oxidase-0.06 g.
Colloidal silicic acid4.00 g.
Phosphte buffer 0.4 M (pH 5.7)70.00 ml.
Sodium alignate solution (2.5% )-35.00 g.
Organic sodium sulfonate (Rapidnetzer BASF)1.6 g. Methanol-40.00 ml.
There was applied a 400a thick layer of the above mixture onto a white polyvinyl chloride foil and the foil then dried with warm air. There was thusly formed a water-insoluble film which provides graduated violet colors on reaction with glucose in, for example, urine or blood. The reaction with glucose in blood can be seen as soon as the blood is wiped or washed olf the foil. The colors produced in the reactions are very easily seen against the background of the white carrier foil.
EXAMPLE 2 For the production of a reagent foil for use in the detection of glucose in, for example, urine or whole blood, there was first prepared a mixture having the following composition:
Ethyl cellulose-35.00 g.
o-Vanillin- (vanilloyl -hydrazonel .7 g.
Glucose oxidase0.04 g.
Colloidal silicic acid-2.00 g.
Phosphate buffer 0.4 M (pH 5.7)-25.00 ml.
Organic sodium sulfonate-(Rapidnetzer BASF)-- Methanol--75.00 ml.
A 500a thick layer of the above mixture was applied onto a white polyvinyl chloride foil and the foil thereafter dried with warm air. There was obtained a water-insoluble film, the properties of which corresponded to those of the film described in Example 1.
EXAMPLE 3 A diagnostic agent for use in the detection of blood in urine was prepared as follows: A mixture having the following composition was prepared:
Strontium peroxide-2.0 g. Tartaric acid-3.75 g.
Calcium acetate7.0 g. Colloidal silicic acid1.5 g. Sodium carbonate2.0 g. Polyvinyl acetate-5.0 g. Anhydrous isopropanol-70.0 ml.
The above mixture was applied onto a polyvinyl chloride foil so as to provide a 500; thick layer and the thusly treated foil is then dried with warm air. There was obtained a water-insoluble film which, upon being immersed into blood-containing urine, provided a more or less strong color, corresponding to the concentration of blood in the urine specimen.
EXAMPLE 4 In order to provide reagent films for use in the detection of urobilinogen in urine, there was first prepared a mixture having the following composition:
Orthophosphoric acid (85%)20.0 g.
Polyvinyl acetal-20.0 g.
Organic sodium sulfonate (Rapidnetzer BASF)0.5 g. Methanol-100.0 ml.
The mixture was then applied to a polyvinyl chloride foil so as to produce a 300,11. thick layer and the layered foil was then dried with warm air. There was obtained a water-insoluble film which, on being moistened with urobilinogen-containing urine, evidenced a more or less dark red color, depending upon the urobilinogen con centration.
EXAMPLE 5 Reagent films for use in the detection of nitrite in urine were produced, using a mixture having the following composition:
Sulfanilamide2.5 g. Trichloroacetic acid3.0 g. Polyvinyl butyracetal-20.0 g. Methanol100.0 ml.
The above mixture was applied onto a polyvinyl chloride foil to provide a 400 thick layer, and the resultant foil was then dried with warm air. There was obtained a water-insoluble film which, when moistened with nitritecontaining urine, evidenced a more or less dark red color which was directly dependent upon the nitrite content.
EXAMPLE 6 For the production of a regagent film for use in the detection of glucose in, for example, urine or whole blood, there was first prepared a mixture having the following composition:
Polyvinyl propionate dispersion-45.0 g.
Phosphate bufier 0.4 M (pH 5 .5 )45 .0 ml.
Sodium alginate0.5 g.
Organic sodium sulfonate (Rapidnetzer BASF)0.6 g. 3-amino-19-ethyl-carbazole-0.03 g.
Glucose oxidase-0.04 g.
The mixture was then applied to a white polyvinyl chloride foil so as to provide a 300 thick layer of the mixture, and the thusly layered foil dried with warm air. There was obtained a water-insoluble film which on reaction with glucose, for example, in blood in a concentration within the range of 50-250 mg. percent evidenced a strong color.
When a drop of blood was placed on the test strip and then again removed after about one minute, depending upon the glucose concentration, the strip evidenced an orange to blue-green color.
EXAMPLE 7 90 g. of an aqueous dispersion of polyvinyl propionate (Propiofan), 1.3 g. of the sodium salt of a polymannuronic acid (Algipon), 70 ml. of a 0.5 M citrate or phosphate buffer having a pH value of 5.5, 2 g. of organic sodium sulfonate (Texapon P), 320 mg. glucose oxidase, 300 mg. peroxidase and 300 mg. 1-methoxy-4-hydroxynaphthalene in 20 ml. methanol were stirred together to form a homogeneous mixture. This mixture was then applied onto a foil to provide a layer thereof having a thickness of 300 2 and the layered foil dried. A drop of blood or serum placed upon a film produced in this manner, which was then removed after about one minute resulted in that the film assumed a blue color, the strength of the color depending upon the concentration of the glucose in the blood sample. Propiofan, Algipon, and Texapon P are trademarks of BASF, Henkel and Dehydag respectively.
EXAMPLE 8 g. of polyvinyl propionate dispersion (Propiofan), 35 g. of a 1.85% solution of polymannuronic acid (Algipon) in 0.5 M phosphate buffer having a pH value of 5.5, 1 g. of organic sodium sulfonate (Texapon), 0.075 g. peroxidase, 0.15 g. glucose oxidase, 0.045 g. 3-amino-9-ethyl-carbazole and 0.25 g. o-tolidine dissolved in 6 ml. methanol, were stirred to form a homogeneous slurry. 0.50 ml. of a 0.5% methanolic solution of Sico-Fettblau 50401 N (Siegle & Co., Stuttgart- Feuerbach) were then added thereto. The mixture so prepared was applied to a synthetic resin foil at a layer thickness of 300a and the layered foil then dried. When there were applied to the thusly produced foils samples of urine having various glucose concentrations and following a short reaction time, the urine wiped off, then in the case of a glucose concentration of mg. percent the film was colored bright pink; at a concentration of 250 mg. percent it was colored dark orange-pink; at a concentration of 500 mg. percent it was colored green, and at a concentration of 1000 mg. percent it was colored dark green. It is thus apparent that a clearly gradulated color change occurred which was directly correlated to the concentration of glucose.
EXAMPLE 9 For the production of a reagent film for use in the detection of urea there was first prepared a mixture having the following composition:
Polyisobutylene dispersion (Oppanol B,
BASF) 22.50 Sodium alginate solution (1.85%) in 0.15 M phosphate bulfer (pH 6.8) 19.50 Urease 0.25 Brilliant Yellow (E. Merck) 0.02 Organic sodium sulfonate (Texapon P) 0.50
wiped off after 45 seconds. There were obtained, depending upon the urea concentration, colors ranging from yellow-orange to orange to red-orange.
1. A diagnostic agent for use in the detection of chemical and bio-chemical components in biological fluids comprising a homogeneous water-resistant film formed from a mixture of an aqueous dispersion of a natural or synthetic organic polymer and a color forming reagent capable of producing color in response to the presence of a chemical or bio-chemical component in a biological fluid, in which said color forming reagent is uniformly dispersed throughout the film.
2. A diagnostic agent according to claim 1 including a carrier support for said film.
3. A diagnostic agent according to claim 2 wherein said film is removably attached to said carrier support.
4. A diagnostic agent according to claim 2 wherein said film is firmly attached to said carrier support to form an integral structure therewith.
5. A diagnostic agent according to claim 2 wherein said carrier support is a member selected from the group consisting of glass, paper, asbestos, wood, metal and synthetic resins inert to the biological fluid.
6. A diagnostic agent according to claim 1 wherein said water-resistant film is prepared on a basis of at least one polymer selected from the group consisting of polyvinyl esters, polyvinyl acetals, polyacrylic esters, polyacrylamides and polyamides.
7. A diagnostic agent according to claim 1 wherein said water-resistant film is prepared on a basis of at least one member selected from the group consisting of cellulose ethers and cellulose esters.
8. A diagnostic agent according to claim 7 wherein said water-resistant film is based at least partly on ethyl cellulose or acetyl cellulose.
9. A diagnostic agent according to claim 6 wherein the said member is polyvinyl acetate, polyvinyl propionate or polyvinyl butyracetal.
10. A diagnostic agent according to claim 1 wherein said water-resistant film additionally contains at least one member selected from the group consisting of fillers thickening agents, emulsifiers, dispersion agents and plasticizers.
11. A diagnostic agent according to claim 1 wherein said water-resistant film additionally contains a pigment for rendering the same opaque.
12.. A diagnostic agent according to claim 11 wherein said water-resistant film is applied onto a colored carrier support.
13. A diagnostic agent according to claim 1 wherein said water-resistant film comprises Polyvinyl propionate dispersion100.00 g. o-Vanillin-(vanilloyl)-hydrazone2.50 g. Glucose oxidase0.06 g.
Colloidal silicic acid-4.00 g.
Phosphate buffer 0.4 M (pH 5.7)70.00 ml. Sodium alginate solution (2.5% )35.00 g. Organic sodium sulfonate-1.6 g. Methanol-40.00 ml.
in dried form.
14. A diagnostic agent according to claim 1 wherein said water-resistant film comprises Ethyl cellulose-35.00 g. o-Vanillin-(vanilloyl) -hydrazone1.7 g. Glucose oxidase0.04 g.
Colloidal silicic acid-2.00 g.
Phosphate buffer 0.4 M (pH 5.7)25.00 ml. Organic sodium sulfonate-LOO g. Methanol75.00 ml.
in dried form.
15. A diagnostic agent according to claim 1 wherein said water-resistant film comprises o-Tolidine-0.25 g.
Strontium peroxide2.0 g. Tartaric acid3.75 g.
Calcium acetate--7.0 g. Colloidal silicic acid-1.5 g. Sodium carbonate-2.0 g. Polyvinyl acetate5.0 g. Anhydrous isopropanol--70.0 ml.
in dried form.
16. A diagnostic agent according to claim 1 wherein said water-resistant film comprises p-Dimethylamino-benzaldehyde-l .0 g. Orthophosphoric acid )20.0 g. Polyvinyl acetal20.0 g.
Organic sodium sulfonate0.5 g. Methanol100.0 ml.
in dried form.
17. A diagnostic agent according to claim 1 wherein said water-resistant film comprises a-Naphthylamine1.0 g. Sulfanilamide-2.5 g. Trichloroacetic acid3.0 g. Polyvinyl butyracetal20.0 g. Methanol-100.0 ml.
in dried form.
18. A diagnostic agent according to claim 1 wherein said water-resistant film comprises Polyvinyl propionate dispersion45 .0 g. Phosphate buffer 0.4 M (pH 5.5)45.0 ml. Sodium alginate0.5 g.
Organic sodium sulfonate0.6 g. 3-amino-9-ethyl-carbazole0.03 g. o-Tolidine-0.2 g.
Glucose oxidase0.04 g.
in dried form.
19. A diagnostic agent according to claim 1 wherein said water-resistant film comprises g. of an aqueous dispersion of polyvinyl propionate, 1.3 g. of the sodium salt of a polymannuronic acid, 70 ml. of a 0.5 M citrate or phosphate buffer having a pH value of 5.5, 2 g. of organic sodium sulfonate, 320 mg. glucose oxidase, 300 mg. peroxidase and 300 mg. 1-methoxy-4-hydroxy-naphthalene in 20 ml. methanol, in dried form.
20. A diagnostic agent according to claim 1 wherein said water-resistant film comprises 45 g. of a polyvinyl propionate dispersion, 35 g. of a 1.85% solution of polymannuronic acid in 0.5 M phosphate buffer having a pH value of 5.5, 1 g. of organic sodium sulfonate, 0.075 g. peroxidase, 0.15 g. glucose oxidase, 0.045 g. 3-amino-9- ethyl-carbazole and 0.25 g. o-tolidine dissolved in 6 ml. methanol, in dried form.
21. A diagnostic agent according to claim 1 wherein said water-resistant film comprises Polyisobutylene dispersion 22.50 Sodium alginate solution (1.85%) in 0.15 M
phosphate buffer (pH 6.8) 19.50
Yellow indicator dye 0.02
Organic sodium sulfonate 0.50
in dried form 22. Method of detecting a chemical or biochemical component in a biological fluid, which comprises contacting a diagnostic agent according to claim 1 with said fluid and comparing the color of said diagnostic agent with a standard.
23. A diagnostic agent according to claim 1 wherein the film is based at least in part on latex.
24. A diagnostic agent for use in the detection of chemical and bio-chemical components in biological fluids comprising a homogeneous water-resistant film formed from a mixture of an aqueous dispersion of a natural or synthetic organic polymer selected from the group consistiing of cellulose ethers, cellulose esters cellulose acetate phthalate, polyvinyl esters, polyvinyl acetals, polyacrylic esters, polyacrylamide and polyamides, and a color forming reagent capable of producing color in response to the presence of a chemical or bio-chemical component in a biological fluid, in which the color forming reagent is uniformly dispersed throughout the film.
References Cited UNITED STATES PATENTS JOHN T. GOOLKASIAN, Primary Examiner M. E. MCCAMISH, Assistant Examiner US. Cl. X.R.
UNITED SIA'I'I'JS I'A'I'IL'II'I' ur'r'lus s I CERTIFICATE Oh CORRECTION Patent No. 3,630,957 Dated December 28. 1971 Hans-Georg Rey, Pieter Rieckmann, Hans Wielinger and Walter Rittersdorf Inventor(s) It is eertified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
C01. 5, line 71 "19" should be -9-- Col. 5 line 72 Delete "o-To1idi.he-O.2 g." and insert O-Tolidine-O.2g. "line 74, "O-To1idine-0.2g.",
should read Peroxidase-0.02g.
Signed and sealed this L .th day of July 1972.
'( SEAL) Attest:
ROBERT GOTTSCHALKe EDWARD M.FLETCHER, JR. Attestlng Officer Commissioner of .Patents
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|U.S. Classification||436/66, 436/169, 435/14, 436/97, 436/95, 436/110, 435/805, 435/28, 436/108, 422/510|
|International Classification||C12Q1/28, C12Q1/00, C12Q1/54, G01N33/52|
|Cooperative Classification||C12Q1/54, G01N33/521, C12Q1/00, C12Q1/28, Y10S435/805|
|European Classification||C12Q1/54, G01N33/52B, C12Q1/00, C12Q1/28|