WO2000049948A2

WO2000049948A2 - Urine collector

Info

Publication number: WO2000049948A2
Application number: PCT/GB2000/000587
Authority: WO
Inventors: Clive William Mulholland; David Ian Thurnham; Christine Anne Northrop-Clewes
Original assignee: University Of Ulster
Priority date: 1999-02-22
Filing date: 2000-02-21
Publication date: 2000-08-31
Also published as: AU2679800A; WO2000049948A3

Abstract

The present invention relates to a urine collector patch to collect samples or urine, particularly from patients who are unable to provide free flowing samples. The device may incorporate test reagents such that the test is carried out in situ. The reagents may be separated from the urine to enable timed tests to be performed. The invention also provides a urine based test for lactose as an indicator of impaired gut integrity.

Description

URINE COLLECTOR

The present invention relates to a device for the collection of urine specimens. The device is particularly suitable for use with paediatric patients. More particularly the invention relates to a device for collecting urine samples which is not required to be attached to a patient . The invention also relates to a urine based test for vitamin A deficiency in babies.

Currently collection of urine specimens from patients, and in particular neonatal, infant, and mentally handicapped patients, often involves the use of urine collection bags. To be able to collect a specimen from an infant requires attachment of a bag to the infant. There are a number of problems associated with this approach. Often it is difficult to ensure that the bag remains attached to the infant, frequently resulting in leakage. The adhesive used to attach the collection bag often causes skin irritation, particularly if frequent specimens are required. This can be a significant problem in very premature infants, who have very fragile skin. In older, more active infants it can often be difficult to ensure that the collection bag remains attached to the child.

Absorbant pads such as sanitary towels can be used to collect urine. However, such pads are not designed to collect fluid to be tested. Therefore, there is no simple way for uncontaminated urine to be removed from these for testing and chemicals used in the absorbent material may react with the urine.

Technology has been developed for use in sanitary towels and in nappies whereby a gel is incorporated into a towel to hold fluid. However, again, these gels have been designed to aid comfort for the wearer and it is very difficult to extract urine from these gels.

The present invention aims to provide a device for collecting a urine sample which does not require to be stuck to the patient and which can be used to collect samples from neonates, infants and mentally challenged patients for testing. The invention also aims to provide such a device incorporating a test or tests. The invention also aims to provide a urine based test for vitamin A deficiency wherein the test is based on urine sampling.

An inadequate supply of vitamin A to meet the needs of women and children is a well recognised problem in large areas of the World. Five to ten million children develop severe deficiency of vitamin A (xerophthalmia) a year and of these half a million go blind and probably die. However, the far greater problem is marginal deficiency, which may affect as many as 200 million children in 90 different countries. Marginal vitamin A deficiency increases the susceptibility to infections and children caught in the downward spiral of disease and poor vitamin A status are at far greater risk of dying than those who are not deficient. Vitamin A intervention studies have been shown to reverse this situation particularly in the first two years of life.

The World Health Organisation (WHO) through its Extended Programme of Immunisation (EPI) is planning to include vitamin A supplementation within the immunisation schedule. An appropriate method to measure vitamin A status (i.e. cheap and easy to use) is needed to monitor the effectiveness of the programme.

Current methods for assessing vitamin A status require a blood sample and involve relatively sophisticated techniques such as high performance liquid chromatography (HPLC) or enzyme-linked immuno- stimulation assays (ELISA) . These assays are needed to measure the active forms of vitamin A i.e. plasma retinol or its metabolites (HPLC) or the transport proteins (retinol -binding protein or transthyretin) by ELISA. Some of the techniques are being used in those Third World Countries where there is sufficient expertise but processing the samples, doing the assay and producing results takes time. Furthermore, all these assays need a blood sample and this is not acceptable in some communities.

Vitamin A is necessary for the growth and differentiation of many tissues but particularly the epithelial tissues. The association between vitamin A deficiency and eye disease is well established but there is also evidence that the epithelium of the gut is impaired in marginal deficiency. The present inventors have shown that vitamin A improves recovery of the integrity of epithelial tissues that has been damaged by viruses or other pathogens during infection.

The integrity of the gut is closely linked to the - growth and health of the young infants. A test which measures the permeability of two non-metabolised sugars through the gut wall, is used to measure gut integrity. Analysis of data collected in The Gambia, showed that gut integrity in infants was at its best in those months of the year when vitamin A intake was at its highest. In 1997 the inventors carried out studies in Indian infants which showed that gut integrity improved in direct response to vitamin A supplementation.

Associated with the impairment in gut integrity is an alteration in the morphology of the gut. The normal surface of the gut is highly convoluted and the surface is covered with finger-like projections known as villi . These villi become flattened in association with impaired gut integrity. The 'flattening' may occur as a result of a loss of the equilibrium between cell production in the epithelial layer and the 'sloughing off of old cells from the tips of the villi.

The epithelial cells of the gut mature as they move up the sides of the villi. Thus there are different enzyme activities associated with different portions of the villus structure. Lactase is the enzyme necessary for the digestion of lactose. Lactase is found in those cells near the tip of the villi and the lactase enzyme activity appears to fall as flattening of the gut occurs and there is a loss of gut integrity.

According to a first aspect of the present invention there is provided a urine sampling patch comprising an absorbent material to collect urine, a membrane which covers the top surface of the absorbent material which allows the urine to pass through to the absorbent material, and a waterproof backing which covers the bottom surface of the absorbent material .

Preferably the patch has a degree of flexibility to allow for shaping in a support. Typically the support will comprise a nappy or pants.

Preferably an adhesive strip on the back of the patch enables it to be stuck to the support.

Preferably the absorbent material is inert. The absorbent material should preferably not react chemically with urine and should be typically between 3-20mm, more preferably 5-10mm thick. Preferably the covering membrane allows urine to pass through to the absorbent material beneath and prevents urine being kept on the skin.

Different shapes of patches may be available for male and female infants to allow for variable positioning in a support. Also, different sizes of patches may be preferred for use with neonates, toddlers and older patients.

The absorbent material is as absorbent as possible and as thin as possible to improve flexibility of the patch.

The patch may further comprise an aperture in the membrane of the top surface or in the waterproof backing that can be opened, for example by peeling back a strip, to allow urine to be extracted for analysis by traditional means, or to enable a 'normal' dipstick to be inserted into the patch.

Alternatively the patch can be squeezed or rolled up to extract urine from the patch. A lemon squeezer type gadget may be used.

The invention may further comprise or be attachable to a connector or nipple to allow urine to be squeezed directly into a sample tube which maybe plain, or contain a fixed quantity of preservative to stabilise the urine specimen. An option is to incorporate reagent test areas for specific analytes into the patch along with a suitable reading frame .

The reagent areas may be physically separated from urine until after the patch is removed from the nappy. This could be achieved, for example, by enclosing the test area in a 'bubble' using a similar material and approach to 'bubblewrap' packaging.

Preferably the reactions in the test area are initiated by gently squeezing the bubble until it bursts, thus allowing the reagent area to come into contact with urine in the patch.

This embodiment is useful if it is important to know the timing of the test.

It is preferred that the covering membrane only allows urine to pass one way into the patch. For example, the material on each side of the membrane could be of differing sizes. This would create a diffusion concentration gradient that would 'draw' the urine into the patch. The membrane also be preferably transparent or contain a transparent window to allow reading of any reagent test areas that may be incorporated into the patch.

A variety of sizes and shapes of the patch are envisaged. A variety of materials may be used as waterproof backing. Suitable materials include thin plastic film, woven and nonwoven materials, polymeric films or composite materials. These and other materials may be coated to provide a waterproof finish. Suitably the material may be waterproof but breathable to allow vapour to escape .

A variety of different absorbent materials can be employed to collect urine.

Suitable absorbent materials are capable of absorbing any retaining liquid and may comprise or be based on any of the following materials - absorbent sponges, tissue, wood pulp, cellulose or any other known absorbent material or combination of materials.

Different covering membranes may be used to allow one way passage of urine.

Suitable membrane materials may be chosen from the group comprising plastic films, woven or nonwoven fibres, polyester or polypropylene fibres of any suitable combination of natural and/or synthetic fibres which allow passage of fluid or which are made porous or have apertures to allow passage of fluid.

A variety of mechanisms to employ collected urine from the patch for testing may be used.

It may be suitable to alter the make up of reagent test areas to end point reactions to provide a stable coloured product. By doing this the test areas do not need to be separated from the urine. Reactions can take place in the patch as soon as urine has been voided and comes into contact with the reaction areas.

In one preferred embodiment the patch comprises a strip test such as BM-Test^® strips for urinalysis. These strips can be closed from the urine until required by having a closure strip enclose the test and protect the chemistries by keeping it separate from the urine. The strips may be opened by having strings attached which can extend from the patch and which can be pulled away or pealed back to remove the closure strip.

This embodiment is particularly useful for timed tests.

An alternative embodiment comprises a reactant held in a bubble in the patch. The bubble can be physically burst to allow the reactant to come into contact with the urine. This embodiment is also useful for tests which are timed.

The present invention may be used for routine diagnostic and monitoring purposes (e.g. pH, glucose, blood, protein, specific gravity) in neonatal and paediatric units.

It can also be used in primary care settings.

Screening tests for drugs of abuse may be incorporated in the patch. Screening tests for urinary tract infections and meningitis may be incorporated in the patch.

In primary care screening a patch testing for urinary bilirubin could be used for screening for biliary atresia.

According to a second aspect of the present invention there is provided a test for vitamin A deficiency, the test comprising means for detecting lactose in urine.

It is proposed to measure the excretion of lactose in the urine of infants. This is an abnormal situation which occurs as a consequence of impaired gut integrity. Lactose (also known as milk sugar) is the main carbohydrate in milk-based infant foods and lactose is the main source of carbohydrate for infants. The present inventors have found that the presence of lactose in the urine of infants is an indicator of poor vitamin A status.

Lactose is a disaccharide made up from two simple sugars, glucose and galactose. Glucose has 'reducing properties' and can be measured in urine by tests which have already been established to measure glucose in the urine of diabetic patients. Lactose also has reducing properties and it may also be possible to use the same dipsticks to measure the presence of lactose in urine.

In one embodiment the invention provides a dipstick for measuring or detecting the presence of lactose in solution. Preferably the dipstick detects the presence of lactose in urine .

The invention also provides the use of a dipstick for the detection of glucose for the detection of lactose in order to assess vitamin A deficiency in infants.

In an alternative embodiment the invention provides a strip which changes colour in the presence of lactose.

Preferably the strip is presented in a patch as described in the first aspect of the invention which can be incorporated into a disposable diaper.

The invention also provides an absorbent strip incorporatable in a patch for the detection of a substance in urine.

The presence of an absorbent strip in a patch in a diaper could be used to test for one or more of a variety of substances. This has the advantage of not requiring samples of urine to be taken as this is difficult with infants. Also, such strips could be routinely incorporated in patches in diapers to alert a mother or carer to the possibility of infection or unusual metabolism.

In one embodiment a diagnostic patch is incorporated within a nappy. Alternatively a "stick-on" patch can be applied to nappies. The diagnostic patches could be used for a number of possible conditions: In new-boms the strip could be used routinely to test for blood, protein and sugar.

Older babies could be screened for blood, protein sugar or ketones using the "stick-on diagnostic strip".

In jaundiced babies the strip will screen for biliary atresia by measuring urobilinogen/ bilirubin.

In pre-term sick babies urinary sodium/potassium might be monitored.

Urinary tract infections in infancy are often under-diagnosed and so a diagnostic strip in the nappy to measure nitrite and the enzyme, leucocyte esterase could be a useful screening tool.

It might be possible to develop a diagnostic strip to distinguish between bacterial and viral antigens. The chemistry for this would need to be developed.

The diagnostic nappy could also be used to identify babies with Coeliac disease or cow's milk protein intolerance.

The nappy may be used as a diagnostic tool for the detection of lactose in vitamin A deficient infants. The chemistry already exists to detect all the above chemicals in urine, but the tests would need modification to allow their use in the nappy diagnostic method.

A diagnostic nappy as a screening method would be useful in the hospital situation, including premature baby units, but also some might be available over the counter to allow a "worried mother" to screen their babies before visiting their GP.

The present invention will now be discussed with reference to the following examples.

In the figures:

Figure 1 diagrammatically illustrates a patch according to the invention.

Figure 2 illustrates a patch incorporating a strip test.

In Figure 1 the patch comprises an upper membrane (1) , an absorbent core (2) and a waterproof backing (3) . An adhesive strip (4) enables the patch to be attached to a support.

In Figure 2 a test strip (5) including reagent areas (6) is incorporated in a patch. The reagent areas can be kept covered until the patch is removed for testing. Pulling on the strings (7) peals back the upper closure strip (8) of the test and allows the reaction areas to react with the urine.

EXAMPLE 1

Vitamin A Intervention Study

Measurement of lactose in the urine of Irish (healthy) and Indian (Vitamin A deficient) infants. The results of the experiment are shown below.

Sample Mean urinary mol lactose/ lactose μmol/g mmol creatinine

Irish infants 286 ± 220 0.2 (Control)

Indian infants 600 ± 236 0.6 (Sample)

Measurements may be influenced by other solutions being tested in study. However there is still clear difference in metabolism of lactose when infants are Vitamin A deficient.

The Indian infants were treated with small amounts of vitamin A (16,000 IU) on a weekly basis over eight weeks. The treatment was not accompanied by any change in lactose excretion over this period, although the measure of gut integrity showed that improvement was taking place. EXAMPLE 2

The following results show the concentration of lactose in the urine of infants of England, Gambia and Pakistan.

Sample Mean urinary Standard Sample lactose μmol/1 Deviation Size

English infants 264 312 18 (0-12 o)

Gambia 0-15 mo average 6 mo

Month 1 1543 2441 110

Month 2 1790 1995 71

Month 3 1570 790 90

Month 4 1832 2120 67

Month 5 1929 2033 78

Pakistan 0-15 mo average 8 mo

Month 1 897 1658 44

Month 2 768 770 42

The English controls are similar to the Irish controls in Example 1. The Pakistani samples have results slightly higher than the Indian ones but the Gambian samples are three times higher than the Indian ones. The results show a trend between Vitamin A deficiency and lactose in urine in infants. A lactose dip stick test would provide a simple test of Vitamin A deficiency.

Claims

1. A urine sampling patch comprising an absorbent material to collect urine, a membrane which covers the upper surface of the absorbent material which enables urine to pass into the absorbent matter and a waterproof backing which covers the bottom surface of the absorbent material .

2. A patch as claimed in claim 1 further comprising adhesive means to secure the patch to a support during sampling.

3. A patch as claimed in claim 1 or claim 2 wherein the absorbent material is inert.

4. A patch as claimed in any of the preceding claims wherein the absorbent materials is between 5-10mm thick.

5. A patch as claimed in any of the preceding claims wherein the membrane only allows urine to pass one way into the absorbent material by creating a diffusion gradient to draw urine into the patch.

6. A patch as claimed in any preceding claim further comprising an openable aperture in the membrane or in the waterproof backing to allow extraction of urine or to allow a dipstick to be inserted.

7. A patch as claimed in any of the preceding claims further comprising a connector or nipple to allow urine to be squeezed into a sample tube.

8. A patch as claimed in any of the claims 1 to 6 further comprising means to enable the patch to be connected to a connector or nipple .

9. A patch as claimed in any of the preceding claims further comprising at least one reagent test.

10. A patch as claimed in claim 9 wherein the reagent is enclosed in a bubble within the patch and wherein the bubble must be burst to enable the reagent to react with the urine.

11. A patch as claimed in claim 9 or 10 wherein the patch further comprises a transparent window or an openable aperture to allow reading of the reagent test areas.

12. A patch as claimed in any of the claims 9 to 11 further comprising a reading frame for use in interpreting the search results.

13. A patch as claimed in any of the preceding claims wherein the patch further comprises an enclosed strip and means to open the strip test.

14. A patch as claimed in claim 14 wherein the means to open the strip test comprises at least one extension attached to at least one end of the strip test which extends or is extendable from the patch.

15. Use of a patch as claimed in any of the preceding claims for diagnostic and/or monitoring purposes.

16. A test for impaired gut integrity comprising a urine based test to detect the presence of lactose in urine .

17. Use of a patch as claimed in any of claims 1 to 14 to detect the presence of lactose in urine.

18. A screening test for Vitamin A deficiency comprising a test as claimed in claim 16.