WO2005111606A2

WO2005111606A2 - Use of a film having a hydrophilic surface in medical diagnostic strips

Info

Publication number: WO2005111606A2
Application number: PCT/EP2005/051642
Authority: WO
Inventors: Ingo Neubert; Bernd Bunde
Original assignee: Tesa Ag
Priority date: 2004-05-14
Filing date: 2005-04-14
Publication date: 2005-11-24
Also published as: DE102004024432A1; WO2005111606A3

Abstract

The invention relates to the use of a film for medical diagnostic strips by means of which biological liquids are tested. Said film comprises a carrier material the one or two faces of which are hydrophilized by chemical treatment and said treated surface has the following properties: permanent hydrophilic properties; a surface tension of at least 58 mN/m and a contact angle with water smaller 50°.

Description

tesa Aktiengesellschaft Hamburg

description

"Use of a film with a hydrophilic surface in medical diagnostic strips"

The present invention relates to the use of a film with a hydrophilically modified surface for the construction of medical diagnostic strips for biological liquids, also called biosensors.

In modern medical diagnosis, so-called diagnostic test strips or biosensors are used for more and more analytical test strips. These can be used, for example, to determine the content of glucose, cholesterol, proteins, ketones, phenylalanine or enzymes in biological fluids such as blood, saliva and urine.

Diagnostic test strips for determining and checking blood sugar levels in diabetics are most common. Around 175 million people worldwide suffer from type 1 and type 2 diabetes mellitus. The tendency of this disease is increasing. With this incurable disease, many patients check their blood sugar levels up to 5 times a day in order to optimally match the dosage of medication (insulin) and the food intake, because if the blood sugar level is too high, health damage must be expected. Until now, diabetics had to rely on the support of medical personnel to determine blood sugar levels. In order to make the control of the blood sugar level as easy as possible, a test was developed that allows the patient to determine his blood sugar level with little effort, even without relying on medical personnel.

To determine the blood sugar level, the test person must drop a drop of blood onto a diagnostic test strip. The diagnostic test strip is located in a reading or evaluation device. After a reaction or response time, the Display shows the current blood sugar content. Corresponding reading or evaluation devices are described for example in US 5,304,468 A, EP 1 225 448 A1 and WO 03/08091 A1.

One of the first patents in the technical field of test strips appeared in 1964. US Pat. No. 1,073,596 A describes a diagnostic test and the test strips for analyzing biological body fluids specifically for determining blood sugar. The diagnostic test works by determining a color change that is triggered by an enzyme reaction.

The determination of a change in the concentration of a dye (colorimetric method) is still a method used today in the determination of blood sugar by means of diagnostic test strips. The enzyme glucose oxidase / peroxidase reacts with the blood sugar. The resulting hydrogen peroxide then reacts with the indicator, for example O-tolidine, which leads to a color reaction. This color change can be followed by colorimetric methods. The degree of discoloration is directly proportional to the blood sugar concentration. The enzyme is here on a tissue. This method is described for example in EP 0 451 981 A1 and WO 93/03673 A1.

The modern development of the diagnostic test strips aims to shorten the measuring time between the blood application on the test strips and the appearance of the measured value. In addition to the actual reaction time of the enzyme reaction and the subsequent reactions, the measurement time or the time between the application of the blood on the diagnostic measurement strip and the display of the measurement value also depends considerably on how quickly the blood within the diagnostic strip moves from the blood application point to the reaction site, i.e. to the enzyme is transported.

To shorten the measuring time, inter alia, hydrophilically treated nonwovens or fabrics are used as in US Pat. No. 6,555,061 B in order to transport the blood to the measuring area (enzyme) more quickly. The measuring method is identical to that described in EP 0 451 981 A1. Surface-modified tissues with a wicking effect for the biological fluid are described in WO 93/03673 A1, WO 03/067252 A1 and US 2002/0102739 A1. In the last quote, a plasma treatment of the Tissue reached a blood transport of 1.0 mm / s. When using tissues for the transport of the biological test liquid, such as blood, however, a chromatography effect is observed, that is to say the individual components such as cells are separated from the liquid components. The chromatography effect is explicitly used in WO 03/008933 A2 for the separate examination of the blood components.

A further development of the colorimetric measuring method is the electrical determination of the change in the oxidation potential at an electrode covered with the enzyme. This method and a corresponding diagnostic test strip are described in WO 01/67099 A1. The diagnostic strip is built up by printing various functional layers such as electrical conductors, enzyme, and hot melt adhesive onto the base material made of, for example, polyester. A hydrophilic film (not described in more detail) is then laminated on by thermal activation of the adhesive. The hydrophilic film also serves to accelerate the transport of the blood to the measuring cell.

With this construction, no tissue or fleece is necessary for blood transport. The advantage of this structure and the advantage of the new measurement method are that the measurement of the blood sugar content can take place with much less blood volume of about 5 to 10 μl and in a shorter measurement time.

DE 102 34 564 A1 describes a biosensor which is composed of a planar sensor or test strip and a compartmentalized reaction and measuring chamber attachment which is produced by embossing a PVC film. The measuring chamber attachment consists of a sample receiving channel, a measuring chamber, a sample stop channel and a sample collecting area. The embossing depth of this compartment is 10 to 300 μm. The sample receiving channel and the measuring chamber are equipped with a hydrophilic fabric or a surfactant coating for the transport of the biological liquid. A very similar electrochemical sensor is described in US 5,759,364 A. The sensor consists of a printed base plate and an embossed cover film made of PET or polycarbonate. The measuring room is coated with a polyurethane ionomer for accelerated liquid transport.

US Pat. No. 5,997,817 A describes an electrochemical biosensor in which the transport of the biological fluid is likewise carried out via a hydrophilic coating is realized. The coating is ARCARE 8586 (not commercially available) from Adhesive Research Inc. The transport of the biological fluid is assessed in a special but not described capillary test.

In most cases, the diagnostic test strips described are produced by a discontinuous sequence of coating and lamination steps. A 300 to 500 μm thick film made of polyvinyl chloride, polyester or polycarbonate with the dimensions of about 400 x 400 mm is used as the base material. For some time now there have also been attempts to produce the diagnostic strips in continuous processes. The coating and laminating steps are usually followed by a series of cutting operations. Due to the small dimensions of the diagnostic strips of approx. 20 mm x 5 mm, the highest precision is required for the coating, laminating and cutting processes. The diagnostic strips are usually cut at very high cycle rates using cutting machines from, for example, Siebler GmbH or Kinematik Inc.

Problems can arise during the cutting process. If unsuitable materials are used which have insufficient adhesion to one another during the lamination process, delamination is repeatedly observed in the cutting process. This insufficient adhesion can be attributed to an unsuitable adhesive, that is to say an adhesive with a very high shear strength, to an unsuitable adhesive base or to an unsuitable coating of the adhesive base. Typical coatings with surface-active substances such as surfactants for the hydrophilic finishing of surfaces often lead to these delamination problems in the cutting process. A relatively good adhesive strength on the various bonding substrates is obtained if commercially available PSA tapes with low or moderate shear strength are used. In this case, however, the cutting tool becomes contaminated with adhesive residues after a short time. After just a few hours, these contaminants are so strong that the knives, drive units and guide rails of the cutting machine have to be completely replaced and cleaned. This creates considerable costs due to maintenance and downtime.

An exemplary structure of a medical diagnostic test strip is shown schematically in FIG. 1. The test strip 1 is composed of several individual layers 2, 3, 4 and 5. On the base material 3 made of 500 μm PET there are several functional layers printed over the entire surface, for example made of conductive materials or enzymes. This functional layer 3 is connected to a film 5 with a hydrophilically modified surface 4 by, for example, a die cut of a double-sided PSA tape 2. The pressure-sensitive adhesive tape 2 itself has two pressure-sensitive adhesive layers, preferably made of a polyacrylate pressure-sensitive adhesive, between which there is a carrier made of PET. The die cut of the pressure-sensitive adhesive tape 2 forms a channel 6, which is necessary for transporting the biological test liquid to be measured, for example blood, to the measuring cell.

The object of the present invention is to provide a web-shaped hydrophilically modified film which is suitable for building up the same in accordance with the requirements for diagnostic test strips and which, in particular, has a rapid transport of the biological fluid to the measuring cell and a very good bond strength to pressure-sensitive adhesive tapes with shear-resistant adhesives low adhesive application guaranteed.

This problem is solved by a film as set out in the main claim. The subclaims relate to advantageous developments of the subject matter of the invention. Furthermore, the invention includes the possibility of using the pressure-sensitive adhesive tape according to the invention in medical diagnostic strips of biological fluids.

Accordingly, the invention relates to the use of a film for medical diagnostic strips, by means of which biological liquids are examined, the surface of which is hydrophilically modified by chemical treatment, that is to say for at least one year.

Thanks to its permanent hydrophilicity, the modified surface of the film ensures a surface tension of at least 58 mN / m and a contact angle with water of less than 50 °, which means that the biological fluid is quickly transported (spread) to the measuring cell. Surface energy or surface tension is understood to mean the interfacial tension of solids and liquids compared to the vapor phase or air.

The surface energy is defined as the force in the surface per unit length and has the dimension mN / m (10T ³ Newton / meter).

The contact angle that a liquid forms on a solid characterizes its wettability by the liquid. The better the wettability of the liquid phase, the smaller the contact angle. Water is usually used as the liquid phase to determine the contact angle.

The characteristic property of the film according to the invention is the great hydrophilicity and the very good bond strength with layers of adhesive, while at the same time being well compatible with the biological enzyme reaction. This combination of these properties enables the object of the invention, the considerable acceleration of the transport of the biological fluid in the diagnostic strip and the reduction of the problems in the cutting process of the diagnostic test strips to be achieved. The very good transport properties (spreading) of liquids are reflected in a high surface tension of at least 58 mN / m and in a contact angle to water of less than 50 °.

Furthermore, transport speeds of blood, in particular of at least 1.0 mm / s, preferably at least 1.5 mm / s and particularly preferably of at least 2.0 mm / s, are observed in the capillary test.

The standard methods for surface treatments are corona and flame treatment, i.e. physical treatments. However, these treatments are not stable over time. The surface energy, which is significantly increased by the surface treatment, is reduced to the original value after only a few days.

The surface properties according to the invention are achieved by chemical treatments such as etching the surface with a strong acid. to Surface etching of technical foils, for example, uses oxidizing acids such as chromosulfuric acid or potassium permanganate in combination with sulfuric acid. In the art, polyester films (PET) are usually hydrolyzed on the surface by chemical treatment with, for example, trichloroacetic acid or potassium hydroxide. Further information on the surface treatment of foils can be found in "Polymer Surface" by F. Garbassi et al, John Wiley Verlag 1998 (ISBN 0471971006).

A surface treatment with trichloroacetic acid is carried out, for example, by the company Coveme Spa or Polyfibra Spa. In order to achieve a very high hydrophilicity of the surface, the parameters during the etching with trichloroacetic acid are chosen so that the acid is used in a very concentrated manner, so that the acid acts on the film surface for a relatively long time, i.e. the web speed is slow in the continuous process is (30 to 50 m / min) and that the drying temperature of the film web is only slightly above 100 ° C. During the etching process of the PET film, the ester functionalities are hydrolyzed on the surface. This creates polar hydroxy, carboxy and carboxylate functionalities on the surface. In addition, the crystallinity in the area near the surface is disturbed. This also results in a significant roughening and thus enlargement of the surface.

An increase in the polarity and the roughness of the surface of the film according to the invention is increased in a further advantageous development by the addition of silicon oxide particles in the etching process. The silicon oxide particles are firmly integrated into the film surface. The etching process of foil surfaces has been known for a long time. This surface modification is used to increase the bond strength between the film surface to pressure sensitive adhesives and laminating adhesives. The property of the very good bond strength to pressure-sensitive adhesives is used in the film according to the invention in order to reduce the problems in the cutting processes of the diagnostic test strips. The effect is noticeable by a considerable reduction in the adhesive residue in the cutting process. A delamination of the layers is not observed when using the film according to the invention, since the bond strength of the adhesive to the film according to the invention is always greater than the bond strength to the backing material of the adhesive tape.

A surface-etched film has not previously been used to build up diagnostic measuring strips. The very good transport properties are surprising for the expert (Spread) of the film for biological liquids as well as the excellent biocompatibility with the enzyme detection reactions.

The base materials for the film according to the invention are the carrier materials known and customary to the person skilled in the art, such as films made of polyester, polyethylene, polypropylene, stretched polypropylene, polyvinyl chloride, particularly preferably films made of polyethylene terephthalate (PET). It is also possible to use laminates or coextrudates. This list is not to be understood as conclusive, but further embodiments are included within the scope of the invention.

For processing and use in the diagnostic test strip, it can be advantageous if die cuts with a die form suitable for the application are produced from the film according to the invention.

The thickness of the film according to the invention is preferably 50 to 150 μm.

The hydrophilically modified surface of the film is preferably biocompatible, that is to say that the usual detection reactions with enzymes are not adversely affected or impaired.

Test Methods

surface tension

The surface tension is determined according to DIN 53364 using test inks from Ahlbrand Systems GmbH. Contact Angle Measurement

The contact angle of water on a test object is measured in accordance with DIN EN 828 using a G2 system from Krüss GmbH. Capillary

The transport speed of biological liquids is measured in a capillary test. For this purpose, the hydrophilized film to be tested is laminated on an uncoated and untreated surface of a 350 μm thick PET film using a double-sided adhesive tape with a thickness of 80 μm (tesa® 4980), so that a capillary is formed. For this purpose, two strips of the adhesive tape are laminated in parallel on the base film, so that a channel with an exact width of 1.5 mm is formed between these two strips. This channel is then covered with the hydrophilized film, so that the surface to be tested forms a wall of the channel. The channel or the capillary has the dimensions: height 80 μm, width 1.5 mm and length 5 cm. The capillary is now held 1 mm deep in animal blood. The time required for the liquid front to travel 4 cm is stopped. The speed of the blood front is given in mm / s as the result of the capillary test.

bond strength

To measure the bond strength between the surface-modified film, the adhesive tape tesa® 4883, a double-sided adhesive tape, which is coated with 9 g / m ^{2 of} a very shear-resistant pure acrylic pressure sensitive adhesive, is used. The adhesive tape is laminated onto the modified surface using a 2 kg roll by rolling it four times. Then the force is immediately measured, which is necessary to loosen the bond between the modified film and the adhesive. To do this, it is pulled apart at right angles in a tensile testing machine.

The invention will be explained in more detail below with the aid of several examples, without wishing to restrict the invention unnecessarily.

Examples

example 1

The Polybond S100 PET film with a thickness of 100 μm etched on one side with trichloroacetic acid from the company Polyfibra Spa is particularly good for use in medical applications Diagnostic strips suitable. This surface-modified film is characterized by a high blood transport speed and excellent bond strength. The Verbundfestig ke ^'rt can not be measured, since the adhesion to the etched surface of the PET film is greater than the adhesion to the support of the adhesive tape, so that the adhesive umspult. The film also shows good biocompatibility, which means that the reaction with the enzyme glucose oxidase / peroxidase is not adversely affected.

Example 2

The Kemafoil® HP100 PET film, etched on one side with trichloroacetic acid with the addition of silicon oxide particles, with a thickness of 100 μm from Coveme Spa is also particularly suitable for use in medical diagnostic strips. This surface-modified film is characterized by a very high blood transport speed and excellent bond strength. The bond strength cannot be measured here either, since the adhesion to the etched surface of the PET film is greater than the adhesion to the backing of the adhesive tape, so that the adhesive is rewound. The film also shows good biocompatibility, which means that the reaction with the enzyme glucose oxidase / peroxidase is not adversely affected.

Counterexamples Counterexample 1

As counter example 1, the commercial PET film Hostaphan® RN 100 is used, the surface of which is not modified. Counterexample 2

As counter example 3, the commercial product 3M® 9971 is used. This PET film is coated on one side with a surface-active substance. Counterexample 3

As counter example 4, a 100 μm thick PET film is coated with polyvinylpyrrolidone Luvitec K 60 (BASF) with a layer thickness of 0.5 μm.

Overview of the results

Claims

claims

1.Use of a film for medical diagnostic strips, by means of which biological liquids are examined, from a carrier material, the surface of which is hydrophilically modified on one or both sides by a chemical treatment and this treated surface has the following properties: - permanently hydrophilic properties - a surface tension of at least 58 mN / m - contact angle with water less than 50 °.

2. Use according to claim 1, characterized in that the surface thereof is modified by the action of trichloroacetic acid.

3. Use according to claims 1 or 2, characterized in that the surface treatment with trichloroacetic acid is carried out in the presence of silicon oxide particles.

4. Use according to at least one of claims 1 to 3, characterized in that in a capillary in which the modified surface of this film forms a wall, the transport of biological liquids such as blood at a speed of at least 1.0 mm / s, is preferably at least 1.5 mm / s and particularly preferably at least 2.0 mm / s.

5. Use according to at least one of the preceding claims, characterized in that the film consists of polyester, polyethylene, polypropylene, stretched polypropylene, polyvinyl chloride, preferably of polyethylene terephthalate (PET), and / or of laminates or coextrudates.

6. Use according to at least one of the preceding claims, characterized in that the thickness of the film is 25 microns to 150 microns. Use according to at least one of the preceding claims, characterized in that the hydrophilically modified surface is biocompatible, that is to say that the usual detection reactions with enzymes are not adversely affected or impaired.