Chemistry: analytical and immunological testing – Hemoglobin – myoglobin – or occult blood
Reexamination Certificate
1994-08-26
2001-09-11
Warden, Jill (Department: 1743)
Chemistry: analytical and immunological testing
Hemoglobin, myoglobin, or occult blood
C436S169000, C436S170000, C422S051000
Reexamination Certificate
active
06287867
ABSTRACT:
The invention concerns the use of asymmetric porous membranes in analytical methods and test carriers for carrying out such methods.
The term test carrier denotes solid analytical agents, especially these which are in the form of flat strips or slides, that carry the reagents necessary for analyzes, in particular of biological liquids such as blood, plasma, serum, urine etc. The carrier materials themselves are solid and as a rule also contain the reagents in a solid form. Known carrier materials are for example fibrous structures such at paper, fleecess, woven and knitted fabrics, nets etc., films which are soluble or capable of swelling in the liquid to be examined or porous membranes The regents required for carrying out the determination of analytes in liquids such as body fluids can be manufactured by impregnating the carrier materials with appropriate solutions or coating them with appropriate spreadable pastes containing the reagents and subsequent drying. Alternatively, the required reagents can of course also be added to the carrier materials themselves during their manufacture. For example films or membranes can be manufactured from castable solutions or suspensions which already contain the reagents necessary for the determination of an analyte.
When a liquid which is to be examined is applied to such a test carrier a reaction takes place on or in the test carrier between the analyte to be determined in the sample liquid and the reagents located in the carrier material. The reaction products are determined and represent a measure of the amount of analyte in the sample liquid to be analysed.
The U.S. Pat. No. 3,607,093, for example, describes a test carrier for analysing biological liquids containing a membrane permeable to liquids which membrane contains, in at least parts, a diagnostic reagent in a solid form i.e. as a dry substance. The membrane itself should be made in such a way that at least a surface part is impermeable to larger particles such as erythrocytes. It may be gathered from the experimental section that the membrane is impregnated with a solution of the reagents necessary for analysing biological liquids and dried. When the liquid to be analysed is applied, and if desired after wiping off excess liquid, a chance in the colour of the membrane is observed if the analyte to be determined is present in the sample liquid.
EP-A 0 345 781 concerns a test carrier for analysing liquids. It contains an asymmetric porous membrane which carries one or several reagents that in the presence of the analyte to be determined produce a detectable substance. In order to determine an analyte in a liquid the sample liquid is applied to the large-pored surface of the membrane while the measurement is carried out from the fine-pored surface. The “BTS asymmetric membrane” from Filtrite (San Diego, Calif., USA) is described as being particularly advantageous since in this case cellular blood components are separated off and the reagent/analyte reaction proceeds in the entire membrane. In the selection of the reagents which generate a detectable substance on reaction with the analyte to be determined, importance is attached to the properties that are important for the detection such as colour, chemiluminescence etc, provided the reagent is sufficiently stable in the membrane.
EP-A 0 407 800 is directed towards a test strip for the analysis of substances in biological liquids. It contains an asymmetric porous membrane which is preferably manufactured from a polymer solution containing 1 to 4% by weight of an anionic surfactant. The membrane carries the reagents necessary for the analyte determination. In order to carry out the analysis, the liquid to be examined is applied to the large-pored side. The measurement of the reaction product takes place from the fine-pored side of the membrane.
None of the documents of the state of the art describe an enrichment of the detachable substance, whether it is coloured, chemiluminescent etc., on one surface of an asymmetric porous membrane containing by definition surfaces of different porosity. Surprisingly it has now been found that a substance can be concentrated and distributed evenly on the fine-pored side of an asymmetric porous membrane when this substance on the form of a membrane-wetting solution is brought into contact with the membrane and when the substance is not or not substantially adsorbed to the membrane.
The invention therefore concerns the use of an asymmetric porous membrane for the enrichment of a substance on a uniform distribution on the fine-pored side of the membrane, said substance being not or not substantially adsorbed to the membrane and brought into contact with the membrane in the form of a membrane-wetting solution.
The invention also concerns a process for the accumulation of a substance in an even distribution on one side of a membrane which is characterized in that a membrane-wetting solution of the substance is contacted with an asymmetric porous membrane on which the substance in not or not substantially adsorbed.
Finally the invention also concerns a method for the determination of a substance in a liquid sample means of a test carrier in which use is made of one of the process described above and in which a solution of the substance to be determined is contacted with an asymmetric porous membrane or the substance to be determined in the sample is formed or released by one or several of the substances present on the membrane and is determined from the fine-pored side which is characterized in that the substance to be determined is not or not substantially adsorbed to the membrane.
A particularly advantageous subject matter of the invention is a process as described above which is characterized in that the substance to be determined is haemoglobin and a suitable test carrier for this containing an asymmetric porous membrane which does not or does not substantially adsorb haemoglobin and which carries a haemolzying substance or such a substance in an additional layer located in front of it.
The term “asymmetric porous” is a conventional term generally known to a person skilled in the art (cf. for example EP-A 0 407 800 or EP-A 0 345 781). It is usually understood to be a polymer film which is porous throughout with two opposite surfaces in which the pores of one surface are larger than those of the opposite surface. Preferred asymmetric porous membranes according to the present invention are those which have an asymmetry factor of more than 10, particularly preferably of more than 100. The asymmetry factor in this case gives the ratio of the pore size on the large-pore surface to the pore size on the fine-pored surface according to the invention those asymmetric porous membranes are preferably used in which the pore size on the fine-pored side ie 0.003-3 &mgr;m.
Asymmetric porous membranes are known from the state of the art, for example from U.S. Pat. No. 4,774,039, U.S. Pat. No. 4,629,561 and also from EP-A 0 345 781. Asymmetric porous membranes can be manufactured by a person skilled in the art according to this state of the art. Asymmetric porous membranes are commercially available, for example the BTS 25 membrane of the Memtec Timonium Company, Maryland, USA has proven to be particularly advantageous according to the present invention. This membrane ie a porous polysulfone membrane. Polyethersulfone membranes alloyed with polyvinylpyrrolidone as described for example in EP-A 0 336 403 have also proven to be usable for the subject matter of the invention. Such membranes are for example cold by the X-Flow R.V. Company (Enschede, Netherlands) under the name PS 11 and PS 21.
In order to be used according to the present invention, the asymmetric porous membrane must be capable of being wetted with the liquid which contains the substance which is to be concentrated on the fine-pored side. In the case of aqueous liquids, such as body fluids like blood, plasma, serum, urine etc., the membrane must therefore be sufficiently hydrophilic. If the membrane material itself is not sufficiently hydrophilic, po
Harttig Herbert
Lange Hans
Merdes Hartmut
Zeiler Manfred
Fulbright & Jaworski LLP
Roche Diagnostics GmbH
Warden Jill
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