Connect public, paid and private patent data with Google Patents Public Datasets

Analytical method for the detection and measurement of paracetamol

Info

Publication number
WO1994002842A1
WO1994002842A1 PCT/GB1993/001567 GB9301567W WO1994002842A1 WO 1994002842 A1 WO1994002842 A1 WO 1994002842A1 GB 9301567 W GB9301567 W GB 9301567W WO 1994002842 A1 WO1994002842 A1 WO 1994002842A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
electrode
membrane
paracetamol
method
blood
Prior art date
Application number
PCT/GB1993/001567
Other languages
French (fr)
Inventor
Pankaj Madganlal Vadgama
Ian Mcintyre Christie
Original Assignee
The Victoria University Of Manchester
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by the preceding groups
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483Physical analysis of biological material
    • G01N33/487Physical analysis of biological material of liquid biological material
    • G01N33/48707Physical analysis of biological material of liquid biological material by electrical means
    • G01N33/48714Physical analysis of biological material of liquid biological material by electrical means for determining substances foreign to the organism, e.g. drugs or heavy metals
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00Investigating or analysing materials by the use of electric, electro-chemical, or magnetic means
    • G01N27/26Investigating or analysing materials by the use of electric, electro-chemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28Electrolytic cell components
    • G01N27/40Semi-permeable membranes or partitions

Abstract

Method and electrode for electrolytic analysis/assay of paracetamol in liquids, especially in biological fluids (e.g. blood and serum), using a working metal electrode (especially of platinum) surrounded by two membranes -- an 'inner' perm-selective one and an 'outer' one of diffusion-limiting microporous material. The inner membrane is preferably a cellulose ester (especially cellulose acetate) or plasticised PVC, and is preferably 0.1 to 1.0 νm thick. The outer membrane is a polycarbonate, less than 10 microns thick, with a porosity less than 2 %, and is preferably first treated with a silane to increase its hydrophobic properties. The electrodes can be calibrated by treatment in a buffer solution (preferably isotonic phosphate buffer) before addition of the liquid under assay. Most conveniently, the electrode is set centrally in a polymer and surrounded by a silver ring as a reference electrode. Rapid measurement of paracetamol can be obtained from readings of the rate of current increase with time, shortly after contact with the analyte.

Description

ANALYTICAL METHOD FOR THE DETECTION AND MEASUREMENT OF PARACETAMOL

This invention relates to an improved analyt ical method , more particularly to an improved analyt ical method useful for detect ion and measurement of the compound paracetamol in biological fluids, especial ly blood and serum.

Paracetamol is a valuable drug in widespread use which has potentially dangerous properties because it can, in an overdose, produce fatal effects quite quickly . Also, its mode of action of not yet ful ly understood . It is therefore very desirable to have an analytical technique available for the speedy measurement of its presence in blood and serum samples from a patient . It can therefore be especially important to be able to determine whether or not a patient has consumed paracetamol in any amount which could be dangerous , and most of al l when the patient cannot be relied upon to give the relevant information. The estimation of paracetamol plays a vital role in the management of the patient with a suspected overdose.

A variety of methods have been proposed for such measurement , but none are entirely satisfactory, and there is a need for a simple method which can be used quickly and without need for any complex chemicals or equipment .

It has been proposed to detect the presence of paracetamol and measure it by chemical assay methods , for example treatment of the sample under test with a chemical reagent which produces colour , and then to measure the intensity of the colour so produced , to obtain a measure of the amount of paracetamol . It has also been proposed to use e lectrochemical methods , as paracetamol is electrochemical ly act ive at modest polarising potentials of approximately +0.6 v versus si lver/si lver chloride, and indeed is wel l recognised as an interferent at enzyme electrodes where the hydrogen peroxide product of an oxidase enzyme system is detected at a polarised working metal electrode.

We have now found that the problem can be overcome, and a satisfactory electrochemical method for analysing blood can be based on a form of electrode in which the metal electrode is surrounded by two membranes which can exclude interfering materials from the electrode surface whi le al lowing the paracetamol to reach the electrode.

Thus according to our invent ion we provide an improved electrode for use in the electrolyt ic analysis of l iquid media containing paracetamol , which comprises a working metal electrode surrounded by two membranes, one (nearer to the metal electrode and termed the "inner membrane") being a perm-selective membrane and the other (outside the first membrane and termed the "outer membrane") being a diffusion-limiting microporous membrane.

This has the advantage of al lowing the electrolytic system to respond to the paracetamol whi le avoiding the electrode surface foul ing caused by excess paracetamol reaching the electrode surface, typically at approximately 2 mM or higher . The electrode itse l f may be any electrode having the properties of a working metal electrode appropriate for the analyte components and the electrolytic conditions used, and many are known in the art . It is preferably plat inum metal , conveniently in any of the conventional forms. For example, it may be conveniently in the form of a 2mm diameter platinum disc mounted in Perspex (poly-methyl methacrylate) surrounded by a silver ring of 2 cm diameter as a reference electrode.

The inner membrane may be made of a variety of avai lable materials , which may be used individual ly or as mixtures of materials . Preferably , it is made of a cel lulose ester , and especially any form of cellulose acetate. The invention is not necessarily l imited to the use of cel lulose acetate, however , and other cel lulose esters derived from other lower alkanoic acids than acetic acid may be used if desired, or mixtures thereof , but a cellulose acetate is strongly preferred as the cellulose ester.

Other materials may be used if desired. These are usually polymer materials.

Thus , another preferred material found to be part icularly suitable i s PVC (polyv iny l ch l or ide) , especi al ly when in plasticised form. The plasticiser in such plasticised PVC may be any of the conventional products known or used for this purpose, for example esters, of which di-octyl phthalate is a commercially available and appropriate example.

The membrane is preferably made of a thickness in the range 0.1 to 1.0^im. This may be made by conventional methods, for example by casting from solution.

In the case of a cellulose acetate membrane, this can be done for example by casting a 2% (weight/volume) acetone solution of cellulose acetate polymer on to an inert solid or liquid surface of 25 cm area, using a polymer with 35% acetyl content. Similarly, for a plasticised PVC membrane, this can be done by casting a solution of 0.06 gms of PVC (MW. 200,000) and 150 ιl of plasticiser (e.g. di-octyl phthalate) dissolved in 10 mis of tetrahydrofuran in similar manner to form a membrane about 9.4 cm diameter. Additives may be used if desired, for example by inclusion in the casting solution, to modify the properties of the resulting cast film or to facilitate the casting process.

The outer membrane may be made of any form of microporous membrane with low permeability. Especially, it is composed of a polycarbonate. It is preferably made of a thickness less than 10 microns. Such membranes are typically made by conventional methods, for example by rolling, cutting from a mass, casting from solution, or combinations of such techniques. The desired microporosity should be such as to provide pores in the membrane which are of the order of 0.05 to 0.01 microns in size. Such porosity may be achieved by known methods, for example by etching techniques — especially the technique known as "track etching" using a neutron beam. Such products are obtainable commercially under the name "Nuclepore" from Nuclepore, Pleasanton, California. The polymer itself is impermeable to paracetamol, and may even be highly hydrophobic (for example PTFE, for example "Goretex") but has pore diameter and pore density sufficient to reduce the porosity to less than 2%.

In order to improve the efficiency of the electrode still further, it is preferred to treat the outer (especially polycarbonate) membrane with a silane to increase its hydrophobic properties. Such a treatment (which may be referred to as "silanating," or by a variety of other terms such as. "silylating" or "silanising") comprises application of a reactive si lane (usually a chlorosilane) to the membrane material, so that it hydrolyses on the surface to form a coating of hydrophobic polysilane. This coating improves the efficiency of the membrane by reducing porosity in a controlled manner and also imparts better bio-compatibility.

The methods of silylating and the reagents used are well known in the art. For example the treatment may comprise applying a solution of dimethyl-di chlorosilane in an inert organic solvent (for example in a halogenated hydrocarbon so 1 vent , very conven i ent ly 1,1,1-trichl or oet hane ) and t hen evaporating the solvent and allowing the membrane thus treated to be exposed to moist air, to complete the silanisation process.

The principal advantage of our electrodes is that they can be used in the reagent less analysis of blood or serum without dilution to detect amounts of paracetamol without interference from conjugates of paracetamol (e.g. the sulphate or the gluoonuride conjugates) , and endogenous or exogenous agents which may be present in a patient's blood. It also avoids any necessity for the use of an enzyme-based system. The special attraction for medical use is the potential for reagent less assay in an optically opaque solution, and for a quantitative read-out of either e.m.f. or current, with equipment at a fraction of the cost of most reflectance-based systems.

Thus according to our invention we also provide a method for the electrolytic analysis of biological fluids which comprises applying them to an electrode system in which the anode is an electrode as defined above.

In use, the electrode of our invention can be used to carry out the method of our invention in several ways. One way is by immersion (together with an associated cathode) in a predetermined volume of a buffer solution to be analysed, and applying a polarising voltage so that the measurements (e.g. amperometric measurements) can be made and compared before and after the addition of the blood or serum sample under test . The procedure may also be cal ibrated by use of solutions containing known amounts of the paracetamol , and its accuracy thus checked and confirmed. An alternative procedure, often to be preferred to adding a sample to a buffer , comprises f irst obtaining a "basel ine" or reference measurement for the sensor , for example in a buffer solution, and then contacting the sensor with a separate liquid sample and taking further amperometric measurements. A similar technique can also be used for calibrating solutions.

Likewise , the procedure may be carried out using known amounts of compounds which are considered to be potent ial ly troublesome by their expected abi l ity to interfere with the measurement of the paracetamol , so that the degree of interference (if any) can be established. Conventional apparatus may be used, for the cel l , electrodes and the measurement and recording of the current -volt age rela ionships for the samples under est . Measurements may be made cont inuous ly or intermittently , as desired. Particularly useful measurements are those of the "steady state" current achieved after contact of the sensor with the sample under examination, and the "current versus time" readings prior to achieving the "steady state. " Both types of measurement are of value, but "steady state" readings do require a period of waiting unti l the "steady state" is reached.

As an alternative to using the "steady state" reading , we have found that a reading of the rate of current increase with time shortly after contact of the sensor with the analyte also provides a valuable mode for measurement of paracetamol . This has the advantage of shortening the t ime required to obtain a measure of the amount of paracetamol in a sample , so that more rapid measurements can be made. This shortening of the time for obtaining a useful measurement can be of considerable importance i n pract ical terms , especi al l y when one bears in mi nd the toxicity of paracetamol and the importance of the t ime factor when seeking a measure of the paracetamol present in cases of paracetamol poisoning.

In operating the procedure, it is convenient to use a polarising voltage in the range + 0.4 to 0.8 volts (preferably at approximately + 0.65 volt) against a silver/silver chloride electrode. The liquid medium may be at a pH which can vary over a considerable range, but is especially in the pH range 6 to 8 and preferably at approximately 7.4 (for physiological use).

The sample under examination may be stirred or unstirred, as desired or convenient. The procedure may be carried out over a considerable range of temperatures, for example in the range 20 to 40 C.. It is usually important that the temperature used for calibration is within approximately 4 degrees C. of the assay temperature.

For calibration, an isotonic or other other buffer may be used, but it is preferable to use one which has an ionic strength similar to blood (i.e. approximately 0.15 M).

The medium is commonly aqueous, but need not necessarily be so, and an organic solvent may be used if desired (as such, or in admixture with each other and/or water) provided it is an electrolyte and dissolves paracetamol, but is not medically relevant to the assay carried out.

Typically, a procedure for calibration uses a treatment in isotonic phosphate buffer at pH 7.4. Following this, the buffer is removed, the serum or blood is added, and the response is awaited; this illustrates how much the procedure can become a simplified analysis.

For this purpose, the electrode may be immersed in a sample of the fluid (e.g. blood) and then linked with a suitable reference electrode (for example a silver electrode or a calomel electrode) in conventional manner. It is preferred to enclose both the electrodes of the detector cell (the anode and the cathode) under the membrane, as this arrangement provides for the protection of both electrodes from contact with the sample itself. Alternatively, the reference/cathode electrode can be situated outside the membrane but this arrangement exposes it to the risk of fouling by contact with the sample; this form of construction can be used if the degree of fouling does not interfere with satisfactory operation for the samples involved. Measurement of the voltage, current and the like may be taken and the measurements taken and recorded as desired, intermittently or continuously. For this, conventional apparatus may be used.

The sample of the blood or serum for examination may be obtained by standard methods. The quantity of the blood/serum should be sufficient to cover the electrode and the current measured at a fixed time or after a stable response has been achieved.

The membrane and/or anode may be prepared for use in the analytical process of the invention by soaking it , when it is in place around the anode , in a solut ion corresponding to the electrolyte medium before the blood/serum sample is added. The invention is illustrated but not limited by the following

Examples .

EXAMPLES:

Reagents .

Aqueous isotonic phosphate buffer (pH 7.4) was constituted using AnalaR grade Na2HP04 (52.8 mM) and K2 EDTA (0.15 mM) . (K2 EDTA * the di-potassium salt of ethylenediamine tetracetic acid. ) Stock standard (10 mM) was made up by dissolving paracetamol in the buffer . BSA (bovine serum albumin) was obtained from Sigma Chemical Co . , and used as a 5% (w/v) solut ion in buffer . Dimethyldlchlorosi lane obtained from BDH as a 25% solut ion in 1 ,1 ,1-trichloroethane, was di luted 1 in 10 in the solvent before use . Therapeutic drug monitoring equipment was obtained from Bio-Rad, Anaheim, California. Assigned values for paracetamol in low , medium and high controls were 43-86/um , 203-365um and 560- 1135ιιm respect ively . Neutron track etched poly-carbonate membranes (pore size 0.03^, 0.015jum, O .Oljim) were obtained from Nuclepore, Pleasanton , California . Cel lulose nitrate membranes (0.45pm) were purchased from Mi l l ipore , Croxley Green , Herts . U .K. , and cellulose acetate powder from BDH, Poole, Dorset , U .K. Apparatus .

A commercial two-electrode oxygen system (Rank Brothers,

Bottisham, Cambridge, U.K.) comprising a 2 mm diameter platinum working electrode set in Perspex, and an outer annular 10 mm diameter silver reference was used for electrochemical detection.

Electrodes were polarised between + 0.4 and + 0.9 V, using a variable voltage source, and changes in current with time during the measurements were recorded by means of an output to a strip chart recorder.

Membrane fabrication.

Nuclepore membranes were cut to 12 mm squares and either used as received or first dip-coated with dimethyldichlorosilane.

Coating was by 10-30 seconds immersion in silane solution followed by 2 minutes rinsing in a jet of distilled water.

Cellulose acetate membranes were cast from 1% (w/v) solutions in acetone by the application of 1 ml onto 5 cm plate glass squares. Slow rotation of the plates enabled uniform films to be formed.

Experimental Procedure.

A 12 mm square cut from the cast cellulose acetate was placed over the platinum working electrode, followed by a Nuclepore membrane. The loose membrane laminate was clamped into place by means of a screw-fit adapter, which also secured a sample well over the working electrode surface. Single membranes were secured in the same way. Concentrated stock solutions were added to buffer to give a final sample volume of 0.5 ml. A similar procedure was adopted for "spiking" samples of plasma from different patients or of pooled blood, resulting in minimum dilution of the sample (2% v/v). Results were obtained as the difference between a constant baseline and the plateau produced following the step change on paracetamol addition. Fouling and drug control studies were conducted by replacing buffer in the cell with undiluted BSA or control serum. Measurements were carried out without st irring , at room temperature (21 +2 -degrees C ) ; studies without, membranes required samples to becs-tEirred.

Results .

Increas ing the polar is ing voltage at a bare plat inum electrode up to the l imit for aqueous solut ions resulted in progressively increased , rapid «10 seconds) responses to paracetamol . While an adequate signal size (sensit ivity l imit 0.01 mM paracetamol ) was readi ly achieved , appropriate for cl inical measurement , at high concentrat ions ( 0.5 mM) a rapid decay in steady state signals was evident , with halving of the signal size in 3-10 minutes .

The super imposition of a Mi l l ipore microporous membrane (0.45 urn pore) on the electrode not only reduced signal size but also altered the current -voltage relationship curve which now had a plateau at polarising voltages above +0.75 V. When cellulose acetate was used, a plateau was retained and had shifted to lower voltages , albeit with lower current . A polarising voltage of +0.65 V was chosen as suitable for subsequent studies, because of the zero-order relationship between current and voltage.

With cel lulose acetate as a covering membrane , the l inear range was restricted to £2 mM paracetamol in buffer, but extended up to 5 mM when a polycarbonate membrane was superimposed over the cel lulose acetate , though at the expense of reduced signal size . The steady state signal was achieved in 3-5 minutes , showed no decay, was st i r- independent , and pH variations between 6.5 and 8.0 had no effect on signal size.

The response ratios (paracetamol -. interferent) obtained with a range of serum ant i ferents showed the high degree of selectivity for paracetamol imparted by the inclusion of a cellulose acetate membrane.

The gluconuride conjugate of paracetamol gave responses at a bare electrode which were 7% of those of the equi molar parent compound, but this interference became undetectable when a cellulose acetate covering membrane was included. A guide to the discrimination of the electrode for paracetamol was given by exposure to the drug control sera. A calibrated paracetamol electrode comprising silanised 0.03 yum polycarbonate over a cellulose acetate membrane gave responses corresponding to 110, 345 and 900 uM paracetamol for assigned values of 43-86, 203-365 and 560-1135 iM respectively. The measured value was higher than the assigned range for the low concentration control, but within the assigned ranges of the medium and high concentration control tests. The other drugs present in the control sera had assigned values at three therapeutic levels and were:- amikacin, amitriptyline, caffeine, carbamazepine, chloramphenicol , cloanazepam, cortisol, cyclosporine, desipramine, digoxin, disopyramide, estriol , ethosuximide, gentamicin, haloperidol , imipramine, kanamycin, lidocaine, lithium, methotrexate, NAPA, netilmicin, nortriptyline, phenobarbital , phenytoin, primidone, procainamide, propranolol, quinidine, sal icy late, streptomycin, theophylline, TSH, T3, T4, tobramycin, valproic acid and vancomycin.

Repeated exposure of the un-silanised electrode (0,03 um polycarbonate over cellulose acetate) to BSA resulted in a lowering of the electrode response to 3.0 mM aqueous paracetamol standards. After the 17 hours exposure, the responses to paracetamol in buffer had become reduced to the following extent:- by 40% (1 mM); by 30% (2 mM); and by 29% (3 mM). Problems of signal attenuation were avoided by use of organo-silane treated polycarbonate membranes covering the cellulose acetate. Signals in response to 3.0 mM aqueous paracetamol showed no decrease after 70 minutes exposure to 5% BSA. A calibrated electrode with the silanised membranes was found to give a reliable estimation of paracetamol up to 2.0 mM in samples of different patients' plasma, "spiked" with small quantities (<2% v/v) of paracetamol stock solution.

Similar "spiking" of pooled blood at 2.0, 3.0 and 4.0 mM paracetamol resulted in a silanised, pre-calibrated electrode giving 95%, 81% and 79% recovery of the expected paracetamol signal .

Claims

CLAIMS :-
1. A method, for the electrolytic analysis or assay of paracetamol in a liquid medium, which comprises using a working metal electrode surrounded by two membranes, one (nearer to the metal electrode and termed the "inner membrane") being a perm- selective membrane and the other (outside the first membrane and termed the "outer membrane") being a diffusion-limiting microporous membrane.
2. A method as claimed in Claim 1 wherein the liquid medium containing paracetamol is a biological fluid, especially blood or serum.
3. A method as claimed in Claim 1 or Claim 2 wherein the electrode is immersed in a sample of the liquid medium (e.g. blood) and then linked with a suitable reference electrode (for example a silver electrode or a calomel electrode).
4. A method as claimed in any of Claims 1 to 3 wherein the working metal electrode is made of platinum metal.
5. A method as claimed in any of Claims 1 to 4 wherein the inner membrane is made of a cellulose ester, especially a cellulose acetate.
6. A method as claimed in any of Claims 1 to 4 wherein the inner membrane is made of PVC, especially a plasticised PVC.
7. A method as claimed in any of Claims 1 to 6 wherein the outer membrane is composed of a polycarbonate.
8. A method as claimed in any of Claims 1 to 7 wherein the outer membrane is treated with a silane to increase its hydrophobic properties.
9. A method as claimed in any of Claims 1 to 8 wherein the quantity of the liquid medium under examination (e.g. blood or serum) is sufficient to cover the electrode and the current is measured at a fixed time or after a stable response has been achieved.
10. A method as claimed in any of Claims 1 to 8 wherein the quantity of the liquid medium under examination (e.g. blood or serum) is sufficient to cover the electrode and the rate of current increase with time shortly after contact with the analyte is measured.
11. A method as claimed in any of Claims 1 to 10 wherein the electrode is immersed (together with an associated cathode) in a predetermined volume of a buffer solution to be analysed, and applying a polarising voltage so that the amperometric measurements can be made and compared before and after the addition of the blood or serum sample under test.
12. A method as claimed in any of Claims 1 to 10 wherein the electrode is immersed (together with an associated cathode) in a liquid medium (e.g. a buffer) and applying a polarising voltage so that the amperometric measurements can be made to establish a "baseline" or reference measurement for the sensor, and then contacting the sensor with a separate liquid sample under examination and taking further amperometric measurements.
13. A method as claimed in any of Claims 1 to 12 wherein the liquid medium is at a pH in the pH range 6 to 8 and preferably at approximately pH 7.4.
14. A method as claimed in any of Claims 1 to 13 wherein the polarising voltage in the range + 0.4 to 0.8 volts (preferably at approximately + 0.65 volt) against a silver/silver chloride electrode.
15. A method as claimed in any of Claims 1 to 14 wherein the electrode assembly is calibrated by use of solutions containing known amounts of paracetamol and/or known amounts of compounds which are considered to be potentially troublesome by their expected ability to interfere with the measurement of the paracetamol.
16. A method as claimed in Claim 15 wherein the calibration is carried out at a temperature in the range 20 to 40 C. , especially at a temperature within approximately 4 degrees C. of the assay temperature.
17. A method as claimed in Claim 15 or Claim 16 wherein the calibration is carried out by treatment in a buffer solution (preferably an isotonic phosphate buffer at pH 7.4) followed by removal of the buffer, addition of the liquid medium to be examined (e.g. serum or blood) and the response is determined.
18. A method as claimed in any of Claims 1 to 17 .wherein the membrane and or anode are be prepared for use by soaking it , when the membrane is in place around the anode, in a solution corresponding to the electrolyte medium before the sample to be assayed (e.g. blood or serum) is added.
19. Method for detect ion and measurement of the compound paracetamol in f luids , especial ly biological f luids and most especial ly blood and serum, substantially as described.
20. An electrode, useful for the electrolytic analysis of liquid media containing paracetamol by a method claimed in any of Claims 1 to 19 , which comprises a working metal electrode surrounded by two membranes, one (nearer to the metal electrode and termed the " inner membrane" ) being a perm-select ive membrane and the other (outside the first membrane and termed the "outer membrane") being a diffusion-l imiting microporous membrane.
21. An electrode as claimed in Claim 20 wherein the inner membrane is made of a cellulose ester derived from one or more lower alkanoic acids , especial ly a cel lulose acetate , or PVC (preferably in plast icised form) and is preferably of a thickness in the range 0.1 to 1.0 yum.
22. An electrode as claimed in Claim 20 or Claim 21 wherein the outer membrane is a microporous membrane with low permeability, especially a polycarbonate, preferably of a thickness less than 10 microns.
23. An electrode as claimed in Claim 22 wherein the outer membrane has a pore diameter and pore density suff icient to reduce the porosity to less than 2% , for example with pores which are of the order of 0.05 to 0.01 microns in size.
24. An electrode as claimed in any of Claims 20 to 23 wherein the outer membrane , before use , is treated with a si lane to increase its hydrophobic properties, for example by application of a reactive si lane (usually a chlorosilane) to the membrane material so that it hydrolyses on the surface to form a coating of hydrophobic polysilane.
25. An electrode as claimed in any of Claims 20 to 24 wherein the working metal electrode is made of platinum metal.
26. An electrode as claimed in any of Claims 20 to 25 which comprises a platinum disc mounted in a polymer and surrounded by a silver ring as a reference electrode.
27. An electrode for detection and measurement of the compound paracetamol in fluids, especially biological fluids and most especially blood and serum, substantially as described.
PCT/GB1993/001567 1992-07-28 1993-07-23 Analytical method for the detection and measurement of paracetamol WO1994002842A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB9215972A GB9215972D0 (en) 1992-07-28 1992-07-28 Improved analytical method
GB9215972.2 1992-07-28

Publications (1)

Publication Number Publication Date
WO1994002842A1 true true WO1994002842A1 (en) 1994-02-03

Family

ID=10719392

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/001567 WO1994002842A1 (en) 1992-07-28 1993-07-23 Analytical method for the detection and measurement of paracetamol

Country Status (2)

Country Link
GB (1) GB9215972D0 (en)
WO (1) WO1994002842A1 (en)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000441A1 (en) * 1995-06-19 1997-01-03 Memtec America Corporation Electrochemical cell
WO1997018465A1 (en) * 1995-11-16 1997-05-22 Memtec America Corporation Electrochemical method
WO1997041427A1 (en) * 1996-04-30 1997-11-06 Medtronic, Inc. Sensor for detecting low concentrations of polyions
US5980709A (en) * 1995-04-12 1999-11-09 Usf Filtration And Separations Group Method of defining an electrode area
EP1017999A1 (en) * 1996-03-19 2000-07-12 Ysi Incorporated Processes for preparing barrier layer films for use in enzyme electrodes and films made thereby
US6413410B1 (en) 1996-06-19 2002-07-02 Lifescan, Inc. Electrochemical cell
US6521110B1 (en) 1995-11-16 2003-02-18 Lifescan, Inc. Electrochemical cell
US6652734B1 (en) 1999-03-16 2003-11-25 Lifescan, Inc. Sensor with improved shelf life
US6695345B2 (en) 1996-04-08 2004-02-24 Daicel Chemical Industries, Ltd. Airbag inflator and an airbag apparatus
US6863801B2 (en) 1995-11-16 2005-03-08 Lifescan, Inc. Electrochemical cell
US6878251B2 (en) 1998-03-12 2005-04-12 Lifescan, Inc. Heated electrochemical cell
WO2008032076A2 (en) * 2006-09-13 2008-03-20 Rtc North Limited Biological fluid analysis system
US8449740B2 (en) 2006-03-31 2013-05-28 Lifescan, Inc. Systems and methods for discriminating control solution from a physiological sample
US8916040B2 (en) 2008-01-17 2014-12-23 Lifescan, Inc. System and method for measuring an analyte in a sample
US9157110B2 (en) 2007-09-28 2015-10-13 Lifescan, Inc. Systems and methods of discriminating control solution from a physiological sample
US9784707B2 (en) 2008-06-09 2017-10-10 Lifescan, Inc. System and method for measuring an analyte in a sample

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2194843A (en) * 1986-09-08 1988-03-16 Cambridge Life Sciences Enzyme electrode membrane and method of making same
US4759828A (en) * 1987-04-09 1988-07-26 Nova Biomedical Corporation Glucose electrode and method of determining glucose
GB2216267A (en) * 1988-03-28 1989-10-04 Cubio Ltd Paracetamol sensor
EP0368474A2 (en) * 1988-10-07 1990-05-16 MediSense, Inc. Enhanced amperometric sensor
US4948727A (en) * 1984-10-12 1990-08-14 Medisense, Inc. Chemical sensor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4948727A (en) * 1984-10-12 1990-08-14 Medisense, Inc. Chemical sensor
GB2194843A (en) * 1986-09-08 1988-03-16 Cambridge Life Sciences Enzyme electrode membrane and method of making same
US4759828A (en) * 1987-04-09 1988-07-26 Nova Biomedical Corporation Glucose electrode and method of determining glucose
GB2216267A (en) * 1988-03-28 1989-10-04 Cubio Ltd Paracetamol sensor
EP0368474A2 (en) * 1988-10-07 1990-05-16 MediSense, Inc. Enhanced amperometric sensor

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5980709A (en) * 1995-04-12 1999-11-09 Usf Filtration And Separations Group Method of defining an electrode area
US6284125B1 (en) 1995-06-19 2001-09-04 Usf Filtration And Separations Group, Inc. Electrochemical cell
CN1325908C (en) * 1995-06-19 2007-07-11 利费斯坎公司 Electrochemical detector
WO1997000441A1 (en) * 1995-06-19 1997-01-03 Memtec America Corporation Electrochemical cell
US6521110B1 (en) 1995-11-16 2003-02-18 Lifescan, Inc. Electrochemical cell
US5942102A (en) * 1995-11-16 1999-08-24 Usf Filtration And Separations Group Inc. Electrochemical method
US6179979B1 (en) 1995-11-16 2001-01-30 Usf Filtration & Separations Group, Inc. Electrochemical cell
WO1997018465A1 (en) * 1995-11-16 1997-05-22 Memtec America Corporation Electrochemical method
US6863801B2 (en) 1995-11-16 2005-03-08 Lifescan, Inc. Electrochemical cell
EP1017999A4 (en) * 1996-03-19 2001-09-26 Ysi Inc Processes for preparing barrier layer films for use in enzyme electrodes and films made thereby
EP1017999A1 (en) * 1996-03-19 2000-07-12 Ysi Incorporated Processes for preparing barrier layer films for use in enzyme electrodes and films made thereby
US6695345B2 (en) 1996-04-08 2004-02-24 Daicel Chemical Industries, Ltd. Airbag inflator and an airbag apparatus
WO1997041427A1 (en) * 1996-04-30 1997-11-06 Medtronic, Inc. Sensor for detecting low concentrations of polyions
US6960289B2 (en) 1996-06-19 2005-11-01 Lifescan, Inc. Electrochemical cell
US6413410B1 (en) 1996-06-19 2002-07-02 Lifescan, Inc. Electrochemical cell
US9075004B2 (en) 1996-06-19 2015-07-07 Lifescan, Inc. Electrochemical cell
US6878251B2 (en) 1998-03-12 2005-04-12 Lifescan, Inc. Heated electrochemical cell
US7335292B2 (en) 1998-03-20 2008-02-26 Lifescan, Inc. Sensor with improved shelf life
US6652734B1 (en) 1999-03-16 2003-11-25 Lifescan, Inc. Sensor with improved shelf life
US9274078B2 (en) 2006-03-31 2016-03-01 Lifescan, Inc. Systems and methods of discriminating control solution from a physiological sample
US8449740B2 (en) 2006-03-31 2013-05-28 Lifescan, Inc. Systems and methods for discriminating control solution from a physiological sample
WO2008032076A2 (en) * 2006-09-13 2008-03-20 Rtc North Limited Biological fluid analysis system
WO2008032076A3 (en) * 2006-09-13 2008-07-03 Rtc North Ltd Biological fluid analysis system
US9157110B2 (en) 2007-09-28 2015-10-13 Lifescan, Inc. Systems and methods of discriminating control solution from a physiological sample
US8916040B2 (en) 2008-01-17 2014-12-23 Lifescan, Inc. System and method for measuring an analyte in a sample
US9739749B2 (en) 2008-01-17 2017-08-22 Lifescan, Inc. System and method for measuring an analyte in a sample
US9784707B2 (en) 2008-06-09 2017-10-10 Lifescan, Inc. System and method for measuring an analyte in a sample

Also Published As

Publication number Publication date Type
GB9215972D0 (en) 1992-09-09 grant

Similar Documents

Publication Publication Date Title
US7498132B2 (en) Electrochemical test strip kit for analyte determination
US6037178A (en) Method for quality control of an analyzing system
US5352348A (en) Method of using enzyme electrode
US5746898A (en) Electrochemical-enzymatic sensor
Zhang et al. Development and analytical application of an uric acid biosensor using an uricase-immobilized eggshell membrane
US5773270A (en) Three-layered membrane for use in an electrochemical sensor system
US4197852A (en) Catheter electrode for electrochemical analysis
US6652720B1 (en) Analytical instruments, biosensors and methods thereof
US5312590A (en) Amperometric sensor for single and multicomponent analysis
US6872297B2 (en) Analytical instruments, biosensors and methods thereof
US4919767A (en) Sensor and method for analyte determination
US6475372B1 (en) Electrochemical methods and devices for use in the determination of hematocrit corrected analyte concentrations
Guilbault et al. Enzyme electrodes based on the use of a carbon dioxide sensor. Urea and L-tyrosine electrodes
US20050233407A1 (en) Cross-linked enzyme matrix and uses thereof
US4655880A (en) Apparatus and method for sensing species, substances and substrates using oxidase
US20030036202A1 (en) Methods and devices for use in analyte concentration determination assays
US4897173A (en) Biosensor and method for making the same
US5437973A (en) Enzyme-electrode sensor
Hill et al. Flexible valinomycin electrodes for on-line determination of intravascular and myocardial K+
EP0286118B1 (en) Glucose electrode and method of determining glucose
US4388166A (en) Electrochemical measuring apparatus provided with an enzyme electrode
US4040908A (en) Polarographic analysis of cholesterol and other macromolecular substances
Wang et al. Cobalt phthalocyanine/cellulose acetate chemically modified electrodes for electrochemical detection in flowing streams. Multifunctional operation based upon the coupling of electrocatalysis and permselectivity
US20060121547A1 (en) Diffusion layer for an enzyme-based sensor application
US4127448A (en) Amperometric-non-enzymatic method of determining sugars and other polyhydroxy compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: CA

NENP Non-entry into the national phase in:

Ref country code: CA