GB2521119A

GB2521119A - Indication device

Info

Publication number: GB2521119A
Application number: GB1319169.7A
Authority: GB
Inventors: James Gordon Campbell
Original assignee: Surescreen Diagnostics Ltd
Current assignee: Surescreen Diagnostics Ltd
Priority date: 2013-10-30
Filing date: 2013-10-30
Publication date: 2015-06-17
Also published as: GB201319169D0

Abstract

An indication device (dip strip) for providing a visual indication of the presence of a substance in a material such as urine, comprises a carrier with an active ingredient which changes colour when brought into contact with the substance, the active ingredient being provided on a first part only of the surface of the carrier, with a part of the surface surrounding the first part being coloured such that a change in colour of the active ingredient due to the presence of the substance provides a visual contrast with the surrounding parts of the surface. The device enables the change in colour due to the presence of the substance to be seen more easily against the carrier background.

Description

Indication Device

Field of the invention

This invention relates to an indication device, and particularly an indication device for providing a visual indication of the presence of a substance in material, and particularly but not exclusively for providing a visual indication of the presence of a substance in human urine.

Background to the invention

Currently most urine screening is done with urine reagent dip strips that use chromographic or colour chemistry to establish the presence or absence of a substance in urine. For example sugar in urine is a good indicator of diabetes and the use of a dip strip that changes colour when sugar is present in the urine has been widely adopted as an early indicator for diabetes. Blood in urine is a good indicator of a urinary infection or kidney problem. The technology exists for colour chemistry to detect a wide range of substances that either indicate ill health or signal a change in body chemistry.

Some dip strips use chemistry that detects the presence of a substance whereas others change colour progressively. That change is a reliable indicator of the actual concentration of that substance in a urine sample. Indeed, this technology is suitable not just for urine samples but other bodily fluids or foodstuffs, fish tank water quality, effluent monitoring and the like.

Hitherto, these dip strips are either read visually, often by holding against a chart such as a colour chart, or their chromographic spectrum is read in a machine. Often, that machine will provide a visual display or a print out of the result that identifies how much of the substance is present. That information is helpful in diagnosis but machines are expensive and not very portable. Machines are not suitable in many remote cases where urine reagent strips are used.

More recently there has been a desire to request patients to carry out this testing themselves. That allows patient care to be taken away from the hospital and into the hands of the individual. This move means that the user has to read the result on these dip strips. That poses problems with interpretation as the visual colour matching requires a certain amount of experience, and experts worry that different lighting conditions, colour blindness, and confusions about what the result means renders the dip strips unsuitable for remote testing by patients in particular. Part of the problem exists because the chromographic chemistry itself is often coloured at the start, and changes in colour can be quite subtle.

Brief descrirtion of various embodiments of the invention According to the present invention there is provided an indication device for providing a visual indication of the presence of a substance in a material, the device including a carrier, an active ingredient on the carrier which changes colour when brought into contact with the substance, the active ingredient being provided on a first part only of the surface of the carrier, with a part of the surface surrounding the first part being coloured such that a change in colour of the active ingredient due to the presence of the substance provides a visual contrast with the surrounding parts of the surface.

In a first configuration the colour of the surrounding part is substantially the same as that of the first part in the absence of the substance, such that when the substance is brought into contact with the first part a colour contrast is provided relative to the surrounding parts.

In a second configuration the colour of the surrounding part is substantially the same as that of the first part with the substance at a particular concentration, such that when the substance at a different concentration is brought into contact with the first part a colour contrast is provided relative to the surrounding part.

In particular when the substance at a higher concentration is brought into contact with the first part a colour contrast is provided relative to the surrounding part.

The first part may be provided in the form of a symbol which will become visible relative to the surrounding part.

In a third configuration the colour of the surrounding part varies thereacross to correspond to different concentrations of the substance, such that when the substance is brought into contact with the first part a colour contrast is provided relative to the surrounding part where differing concentrations of the substance are provided relative to the adjacent surrounding part.

The colour of the surrounding part adjacent the first part may be provided in a particular shape with the colour of the surrounding part varying so as to correspond to increasing concentrations of the substance, such that when the colour of the first part corresponds to the surrounding part adjacent the first part this indicates the concentration of the substance. An indication of concentrations may be marked on the carrier on the surrounding part adjacent the first part. The particular shape may be a line.

The carrier may have a dye of a required colour applied to at least the surrounding part. The dye may be applied to the whole of the carrier.

The dye may be inert, and may be stable at least in the presence of the substance and the material.

The dye may be an azo dye. The dye may include a pre-mordant to fix the dye on the carrier.

A buffer material may be provided on the carrier, which material may include potassium aluminium sulphate solution and/or sodium carbonate solution. A surtactant may be provided on the carrier.

The carrier may be in the form of an absorbent pad.

The active ingredient may be printed on to the carrier, and may be printed using dye transfer or microarray transfer.

The substance may be urobilinogen, and the active ingredient may include 4-Methoxybenzenediazonium.

The substance may be glucose, and the active ingredient may include glucose oxidase, peroxidise, and potassium iodide.

The substance may be bilirubin, and the active ingredient may include sodium nitrite, 2,4-dichlorobenzene diazonium and Sulphosalicylic acid.

The substance may be ketones, and the active ingredient may include sodium nitroprusside.

The substance may be blood, and the active ingredient may include Cumene Hydroperoxide and o-Tolidine.

The substance may be ionic solutes, and the active ingredients may include Bromothymol blue and Poly vinyl ether-ALT-maleic acid anhydrous.

The substance may be a protein, and the active ingredients may include Tetrabromophenol.

The substance may be a nitrite, and the active ingredient may include P-arsanilic acid.

The substance may be Leukocyte, and the active ingredient may include Induced Indole amino acid ester.

Detailed description of various embodiments of the invention Embodiments of the present invention will now be described by way of

example only.

A sheet of cellulose membrane typically 100 microns thick is dyed with a 3% solution of an azo dye of 128C Pantone and fixed with a 1% aluminium chloride mordant into which has been added 0.02% surfactant such as Tween 20. Once dried, this membrane is cut into 5mm wide strips and one strip is stuck along the bottom of one side of a polythene sheet of 200 microns thickness, using double sided adhesive tape. Another sheet of cellulose membrane of the same thickness is dyed with a very pale pink dye colour blended to match a 1% solution of tetrabromophenol. Once dried, this membrane is cut into 5mm wide strips and one strip is stuck on the said polythene sheet just above the first strip, allowing a gap of 2mm between them that is sufficiently wide to prevent transfer of dye from one to the other when they are wetted.

This sheet is then cut into strips typically 5mm wide such that the bottom of each strip has a slightly pink pad and below that on the bottom of the strip is a yellow pad.

In this example the pads are designed to test for protein on the upper strip and glucose on the lower strip. Accordingly a solution of the active ingredients is applied to the surface of each pad but because the solution is essentially the same colour these applications are not obvious when dry. In this example the active ingredients are applied in the form of a cross on the pad in this example using a Biorad Versarray Chipwriter Pro which can apply continuous dots 500 microns in diameter. Alternative methods of application include pad transfer printing or inkjet printing for example.

In this example the active ingredient for the protein pad (the top pad on the strip) is tetrabromophenol dissolved in a solvent with buffering chemicals to maintain base pH in urine that differs in acidity of alkalinity to the test. Such a buffer in our example consists of citric acid. The binding of tetrabromophenol blue to proteins is pH dependent. Albumin binds at a pH between 5 and 7; other proteins bind only at a pH below 5 and with less affinity than albumin; and Bence-Jones protein does not bind at any pH. Since urinary pH is usually between 5 and 6, urine dipstick testing is essentially albumin specific. The lower limit of sensitivity for urine dipstick testing is about 250 mgIL. Once applied to the pad this active ingredient is not obvious on the coloured background of the pad. Preferably the background colour also contains the same buffering chemicals so that even when urine of significantly different pH is applied to the test the buffer in the active ingredient is not overcome by the urine.

In this example the pad that is designed to detect glucose is applied in the same manner. Using a Chipwriter Pro allows chemistry to be applied sequentially such that chemicals which are incompatible in solution may nevertheless be applied is sequence on the pad. The protein pad is impregnated with glucose oxidase, peroxidise, and potassium iodide. In this process glucose oxidase targets specifically the breakdown of glucose catalysed by peroxidise to form reduction of the potassium iodide to release iodine that acts as a coloured indicator.

Likewise similar actions can be used to adapt the test strip to other applications previously described along with others, as indicated below.

In these embodiments the test is used as follows. The urine of a well person contains no protein or glucose. Dipping the strip into this urine causes no change to the active ingredients and so the strip remains unchanged.

The urine of an ill person for example a pregnant woman who is suffering from preeclampsia contains protein or glucose or both. Dipping the strip into this urine causes the active ingredients to undergo their respective chemical reactions, producing a colour change in the form of a cross against the unchanged coloured background when that substance is present. This produces an easy to read indicator of the presence of these substances in the form of an X' against the background. Thus the test provides an easy to read indicator showing medical assistance is needed, without the need to carry out complicated and subjective colour comparisons against colour charts and the like or the necessity to use instruments to read results.

Chemical principles of procedure and active ingredients Urobilinogen: The test is based on the Ehrlich's reaction. The colour changes from light orange-pink to dark pink. This test is made from 4-Methoxybenzenediazonium of an appropriate concentration such as 2.9mg per test.

Glucose: In this test, glucose oxidase catalyzes the oxidation of glucose to form hydrogen peroxide. The hydrogen peroxide thus formed then oxidizes a chromogen on the reaction pad by the action of peroxidase.

Ingredients consist of glucose oxidase 430U, peroxidase 200U, potassium Iodide 12mg.

Bilirubin: This test works by the azo-coupling reaction of bilirubin with a diazonium salt in an acid medium to form an azodye. Colour changes from light tan to beige or light pink.

Ingredients are sodium nitrite 0.733 mg, 2,4-dichlorobenzene diazonium 2.3mg, Sulphosalicylic acid 25mg.

Ketones: This works on the Legal's test using a nitroprusside reaction.

Acetoacetic acid in an alkaline medium reacts with nitroferricanide to produce a colour change from beige to purple. Ingredients include Sodium nitroprusside 23.0mg.

pH: The acid alkali balance test constitutes a double indicator system.

The indicators methyl red and bromothymol blue are used to give distinct colour changes from orange to green to blue. (pH 5.0 to 9.0). Ingredients are Methyl red 0.05mg, Bromothymol blue 0.5mg.

Blood: The test is based on the Pseudo-peroxidase activity of the haem moiety of haemoglobin and myoglobin. The chromogen is oxidized by a hydroperoxide in the presence of haem and changes colour from yellow to blue. Ingredients include Cumene Hydroperoxide 12mg, o-Tolidine 35mg.

Specific Gravity (SG): Ionic solutes present in the urine cause protons to be released from a polyelectrolyte. As the protons are released the pH decreases and produces a colour change of bromothymol blue from blue-green to yellow-green. Ingredients include Bromothymol blue 0.5mg, Poly vinyl ether-ALT-maleic acid anhydrous 140.5mg.

Protein: The protein "error of indicators" works as follows. When pH is held constant by a buffer, indicator dyes release H ions because of the protein present and produces a change in colour from yellow to blue-green.

Ingredients include Tetrabromophenol blue 0.34mg.

Nitrite: The test is based on the diazotization reaction of nitrite with an aromatic amine to produce a diazonium salt. It is followed by an azo-coupling reaction of this diazonium salt with an aromatic compound on the reaction pad. The azo dye produced causes a colour change from white to pink.

Ingredients include P-arsanilic acid 4.5mg.

Leukocyte: This test pad contains an indoxyl ester and diazoniurn salt.

It is followed by an azo-coupling reaction of the aromatic amine formed by leukocytes esterase with a diazonium salt on the reaction pad. The azo dye produced causes a colour change from beige to violet. Ingredients: include Induced Indole amino acid ester 1.3mg.

Passive ingredients Passive ingredients to produce the background colour include azo dyes in combinations to match the colour hues of the active ingredients. In one embodiment, a pre-mordant such as potassium aluminium sulphate is used to prepare the membrane and fix the dye to the membrane such that in urine it does not dissolve and mix with the active ingredient. When control of pH is important for the active ingredient the author has found that a 12% potassium aluminium sulphate solution applied to the membrane followed by a 5% sodium carbonate dip then drying buffers the membrane suitably for active ingredient to be applied and for it to perform successfully. Additionally surfactant such as Tween 20 provides good wetting ability when the membrane is dipped into urine. In one embodiment 0.01% solution has

proven suitable.

It goes without saying that the success of the process depends to a large extent on the compatibility of the colour of the background on the membrane compared to the colour of the active ingredient applied. The blending of dyes to provide the correct background requires that the effect of the mordant is taken into account, and practical considerations require that the membrane is dried and its colour balance measures spectrographically before the active ingredient is mixed and applied. As the concentration of the active ingredient is not critical, some slight variations in shade are possible by adjusting the concentration.

Since a small variation in colour difference between the background dye and the active can be tolerated without confusing the user, small changes in shade of the background can be used to adjust the precise point at which the test becomes positive. During manufacture it has been found useful to prepare a range of shades of the background and the active so that in quality testing of the actual strip, comparisons can be made between the changes observed and the changes expected.

A comparison chart in which the background colours darken in shade slightly from left to right, and at the same time a cross of the active darken in shade from right to left aid manufacture to achieve the right shades of background and active for a particular sensitivity required of the test. Such sensitivity will change from one country to another and from one hospital to another because cut off levels for the common illness markers are not standardised and depend to some extent on the accuracy capability of the institutions and laboratories within that location.

Possible modifications As indicated a wide range of modifications may be made without departing from the scope of the invention, and any of the above features can be combined as particular applications require.

Whilst endeavouring in the foregoing specification to draw attention to those features of the invention believed to be of particular importance it should be understood that the Applicant claims protection in respect of any patentable feature or combination of features hereinbefore referred to and/or shown in the drawings whether or not particular emphasis has been placed thereon.

Claims

CLAIMS1. An indication device for providing a visual indication of the presence of a substance in a material, the device including a carrier, an active ingredient on the carrier which changes colour when brought into contact with the substance, the active ingredient being provided on a first part only of the surface of the carrier, with a part of the surface surrounding the first part being coloured such that a change in colour of the active ingredient due to the presence of the substance provides a visual contrast with the surrounding pads of the surface.
2. A device according to claim 1, in which the colour of the surrounding pad is substantially the same as that of the first part in the absence of the substance, such that when the substance is brought into contact with the first -15 pad a colour contrast is provided relative to the surrounding pads.
3. A device according to claim 1, in which the colour of the surrounding C'sJ pad is substantially the same as that of the first pad with the substance at a particular concentration, such that when the substance at a different concentration is brought into contact with the first part a colour contrast is provided relative to the surrounding pad.
4. A device according to claim 3, in which when the substance at a higher concentration is brought into contact with the first part a colour contrast is provided relative to the surrounding pad.
5. A device according to any of the preceding claims, in which the first pad is provided in the form of a symbol which will become visible relative to the surrounding pad.
6. A device according to claim 1, in which the colour of the surrounding pad varies thereacross to correspond to different concentrations of the substance, such that when the substance is brought into contact with the first part a colour contrast is provided relative to the surrounding part where differing concentrations of the substance are provided relative to the adjacent surrounding part.
7. A device according to claim 6, in which the colour of the surrounding part adjacent the first part is provided in a particular shape with the colour of the surrounding part varying so as to correspond to increasing concentrations of the substance, such that when the colour of the first part corresponds to the surrounding part adjacent the first part this indicates the concentration of the substance.
8. A device according to claim 7, in which the particular shape is a line.

-15
9. A device according to any of claims 6 to 8, in which an indication of C concentrations is marked on the carrier on the surrounding part adjacent the first part. (Si

C'1
10. A device according to any of the preceding claims, in which the carrier has a dye of a required colour applied to at least the surrounding part.
11. A device according to claim 10, in which the dye is applied to the whole of the carrier.
12. A device according to claims 10 or 11, in which the dye is inert.
13. A device according to claim 12, in which the dye is stable at least in the presence of the substance and the material.
14. A device according to any of claims 10 to 13, in which the dye is an azo dye.
15. A device according to any of claims 10 to 14, in which the dye includes a pre-mordant to fix the dye on the carrier.
16. A device according to any of the preceding claims, in which a buffer material is provided on the carrier.
17. A device according to claim 16, in which the buffer material includes potassium aluminium sulphate solution and/or sodium carbonate solution.
18. A device according to any of the preceding claims, in which a surfactant is provided on the carrier.
19. A device according to any of the preceding claims, in which the carrier is in the form of an absorbent pad. *-15
20. A device according to any of the preceding claims, in which the active ingredient is printed on to the carrier. (Si

C'1
21. A device according to claim 20, in which the active ingredient is printed using dye transfer or microarray transfer.
22. A device according to any of the preceding claims, in which the substance is urobilinogen, and the active ingredient includes 4-Methoxybenzenediazonium.
23. A device according to any of claims ito 21, in which the substance is glucose, and the active ingredient includes glucose oxidase, peroxidise, and potassium iodide.
24. A device according to any of claims ito 21, in which the substance is bilirubin, and the active ingredient includes sodium nitrite, 2,4-dichlorobenzene diazoniurn and Sulphosalicylic acid.
25. A device according to any of claims ito 21, in which the substance is ketones, and the active ingredient includes sodium nitroprusside.
26. A device according to any of claims ito 21, in which the substance is blood, and the active ingredient includes Cumene Hydroperoxide and o-To lid in e.
27. A device according to any of claims ito 21, in which the substance is ionic solutes, and the active ingredients include Bromothymol blue and Poly vinyl ether-ALT-maleic acid anhydrous.
28. A device according to any of claims i to 2i in which the substance is a protein, and the active ingredients include Tetrabromophenol. *-15
29. A device according to any of claims I to 21, in which the substance is a nitrite, and the active ingredient includes P-arsanilic acid. (Si

C'1
30. A device according to any of claims ito 21, in which the substance is Leukocyte, and the active ingredient includes Induced Indole amino acid ester.
31. An indication device substantially as hereinbefore described.
32. Any novel subject matter or combination including novel subject matter disclosed herein, whether or not within the scope of or relating to the same invention as any of the preceding claims.