Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/54—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving glucose or galactose
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
  • G01N33/521—Single-layer analytical elements
  • G01N33/523—Single-layer analytical elements the element being adapted for a specific analyte
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/60—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving cholesterol
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/61—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving triglycerides
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/62—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving uric acid
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/84—Systems specially adapted for particular applications
  • G01N21/8483—Investigating reagent band

Definitions

• This invention relates generally to formulations used in determining the amount of an analyte in biological fluids.
• the invention is applied to measuring the glucose content of blood or other fluids.
• the quantitative determination of analytes in biological fluids such as whole blood is of great importance in the diagnosing and treating of certain medical conditions. For example s determining the glucose level in the blood of diabetic individuals, who must frequently check the glucose level in their blood to regulate their diets and medication. Measuring the glucose content of blood can be done by several methods. One method employs an electrochemical biosensor that relates glucose content to a measured electrical current. Another method provides a visual indication of the glucose content, such as by developing a color by reaction of an indicator. While the present invention is particularly useful in optical measurements, it also has application to electrochemical biosensors.
• Various indicators have been employed in glucose sensors, such as benzidine-type indicators and heterocyclic azines. For example, 3,3',5,5'-tetramethylbenzidine and syringaldazine, luminol, o-tolidine, o-dianisitine, among others.
• Another family of indicators is tetrazolium dye precursors. Examples of patents describing such indicators include U.S. Patents 5,126,275, 5,322,680, 5,300,637, 5,290,536, 5,360,595 and 6,586,199. Tetrazolium indicators are used in a preferred embodiment of the invention to be described below. [0006] Of particular interest with regard to the present invention is the method described in U.S.
• a test of the glucose content of blood employs glucose dehydrogenase, as a cofactor NAD or PQQ or their derivatives, a tetrazolium dye precursor, a diaphorase enzyme or an analog, and a nitrite salt.
• Figure 5 of the '773 patent is a diagram of the process by which glucose is detected by development of color from the reduction of the tetrazolium dye precursor to formazan.
• An early patent relating to the use of enzymes to determine the amount of glucose in blood is U.S. Patent 3,630,957.
• Glucose oxidise and peroxidase were uniformly distributed in a water-resistant polymer film to react with glucose and to produce a color.
• the film could be supported on a substrate, e.g. a polymer film.
• fillers including chalk, titanium dioxide, colloidal silicic acid (used in the examples) and the like could be added and that pigments could be included to make the films opaque.
• Blood was applied to the reagent- containing film and then wiped off before reading the developed color. The use of opaque fillers to reduce interference with glucose measurements by red blood cells was also discussed in U.S. Patent 5,968,765.
• U.S. Patent 4,312,834 describes the use of a water- resistant film including fine insoluble particles, which provide access to the reagents while blocking access of large components.
• the film could be supported on carriers, such as films, foils, etc.
• film openers were concerned with access of certain molecules, stating that the amount of the fine particles (termed “film openers") should be with certain limits.
• Various types of particles were suggested, such as kieselguhr gel, silica gel, and gypsum, and the like. Titanium dioxide was suggested, both as a firm opener and as a way to improve the remission properties of the film.
• test strips have been described in many patents, since they are widely used for detection of analytes in biological samples. Each test strip application has its unique problems which must be overcome if accurate and consistent results are to be obtained. Testing whole blood requires that the red blood cells not interfere with the color which is developed to indicate the presence of glucose, or with electrochemical measurements. In some instances specific components are included in the test strips so that the red blood cells are filtered from the sample.
• the sample is wiped off after a period of time has elapsed so that the developed color can be measured.
• Another problem encountered when testing whole blood relates to the concentration of red blood cells in the sample. They are commonly measured by their volume in the sample and referred to as the hematocrit value. Since the hematocrit may vary from 20 to 60% in blood samples, the glucose measurement may be affected. Also, movement of the blood plasma carrying glucose to the reagents to develop color (or an electrochemical response), may be retarded or incomplete.
• Patent 5,306,623 a coating capable of separating whole blood was selected from a group of polymers including polyvinyl sulfonic acid, polyethylene glycol, polystyrene sulfonic acid, hydroxypropyl cellulose, polypropylene glycol, polyvinyl pyrrolidone and polyacrylic acid.
• the separating coating was deposited on a porous matrix along with reagents for testing blood.
• the invention generally relates to size self-limiting reagent formulations used in optical or electrochemical methods to measure analytes in biological fluids and test strips containing the reagent formulation.
• glucose is an analyte of particular interest, other analytes in other biological fluids are considered to be within the scope of the present invention.
• the inventive formulation in general includes a water-soluble swellable polymer matrix containing water-insoluble particles having a nominal size of about 0.05 to 20 ⁇ m, preferably about 1 to 10 ⁇ m, and an enzyme system for reacting with an analyte.
• the weight ratio of water-insoluble particles to the water-soluble swellable polymer matrix is about 1/2 to 2/1.
• the reagent formulation of the invention includes as reactants an enzyme system for reaction with glucose and an indicator.
• the enzyme system includes glucose dehydrogenase and a co-factor for the enzyme, e.g. NAD, a tetrazolium salt indicator, and the enzyme diaphorase as a mediator in a particularly preferred embodiment.
• the reagents are combined with a water-soluble swellable polymer matrix containing small water- insoluble particles, preferably titanium dioxide and calcium carbonate.
• the polymer matrix preferably is chosen from among polyacrylic acid, polyvinyl alcohol, polystyrene sodium sulfuric acid, polyacrylic latexes, polyethyleneglycol, styrene acrylates, and their co-polymers.
• the weight ratio of the particles to the polymer matrix preferably is about 1/2 to 2/1.
• the formulation of the invention is cast as a membrane with a thickness of about 6 to 16 ⁇ m, preferably about 7 to 10 ⁇ m on a non-porous substrate.
• the membrane is covered with an adhesive layer including a capillary passageway and a protective top to complete the test strip.
• the cover may be clear or opaque.
• the invention is a method of testing by optical or electrochemical methods for an analyte in a biological fluid, e.g. glucose in whole blood, that provides a rapid and stable response and is insensitive to the amount of the sample.
• the method of the invention employs a test strip in which a thin membrane is cast on a non-porous substrate, the membrane including water-insoluble particles having a nominal size of 0.05 to 20 ⁇ m, preferably 1-10 ⁇ m, in a water-soluble swellable polymer matrix.
• the thin membrane preferably has a thickness of about 6 to 16 ⁇ m, more preferably about 7 to 10 ⁇ m and the weight ratio of reflective particles to the polymer matrix preferably is about 1/2 to 2/1.
• Fig. 1 a, b are plots of the results of Example 1.
• Fig. 2 a, b are plots of the results of Example 2.
• Fig. 3 a, b, c are plots of the results of Example 3.
• Fig. 4 a, b, c are plots of the results of Example 4.
• the invention generally relates to formulations for measuring analytes in biological fluids, including but not limited to glucose, lactate, cholesterol, triglycerides, free fatty acids, bilirubin, ascorbate, hydrogen peroxide, and uric acid.
• analytes in biological fluids including but not limited to glucose, lactate, cholesterol, triglycerides, free fatty acids, bilirubin, ascorbate, hydrogen peroxide, and uric acid.
• One important application of the invention is measuring the glucose content of whole blood, which is described in more detail below. It will be evident to those skilled in the art that the formulations may substitute other reagents for those used to measure glucose.
• Glucose in blood may be determined by reagent systems that employ enzymes to oxidize glucose, including without limitation hexolinase, glucose-6-phosphate dehydrogenase, glucose dehydrogenase, glucose dehydrogenase-PQQ, and glucose oxidase.
• glucose oxidase In the methods which employ glucose oxidase, those enzymes react with glucose, producing oxidized glucose and hydrogen peroxide.
• the hydrogen peroxide oxidizes an indicator compound in the presence of a peroxidase.
• the oxidized indicator produces a color which is correlated with the glucose content of the blood sample.
• a glucose dehydrogenase is used, along with a co-factor, such as NAD, FAD or PQQ, a mediator, e.g. diaphorase, and an indicator, such as tetrazolium dye precursor to produce a visible response proportional to the glucose content of the sample.
• a co-factor such as NAD, FAD or PQQ
• mediator e.g. diaphorase
• an indicator such as tetrazolium dye precursor
• glucose is converted to gluconolactone while the dehydrogenase-co-factor is reduced and then reoxidized by a mediator for further reaction with available glucose.
• glucose dehydrogenase A dehydrogenase specific for reaction with glucose is termed a glucose dehydrogenase. They are commercially available from Toyobo, Kyowa, Amano, Genzyme,
• Biozyme and others are either native enzymes or recombinant enzymes produced by classic fermentation and/or recombinant methods, hi order to be effective, such dehydrogenases require a co-factor, such as NAD (nicotinamide adenine dinucleotide) and its derivatives, FAD (flavin adenine dinucleotide) and its derivatives, and PQQ (pyrroloquinoline quinone) and its derivatives.
• NAD nicotinamide adenine dinucleotide
• FAD flavin adenine dinucleotide
• PQQ pyrroloquinoline quinone
• a mediator is typically used to reoxidize the reduced dehydrogenase-co-factor after the reaction with glucose to form the corresponding lactone.
• mediators called a hydride extractor in US Patent 6,200,773 include diaphorase, PMS (phenazine niethosulfate),
• PES phenazine ethosulfate
• DCIP 2,6-dichlorophenolindophenol
• ferrocene A commonly used mediator in electrochemical sensors is ferricyanide.
• Tetrazolium indicators are generally described in U.S. Patent 5,360,595 and others mentioned above, hi U.S. Patent 6,200,773 certain tetrazolium dye precursors are listed as being particularly useful in reactions with dehydrogenase-co-factor combinations. Among them is the tetrazolium compound designated WST-4, used in the examples below. Supportive Substrates
• the reagent layer of the invention typically is placed on a substantially non-porous supporting substrate, typically a polymer strip or handle such as a polyester, polycarbonate or the like.
• a substantially non-porous supporting substrate typically a polymer strip or handle such as a polyester, polycarbonate or the like.
• Such strips will have dimensions suited for use with the instrument used to read the developed color.
• the strips described in the examples will be about 0.060 by 0.160 inches (1.5 by 4.1 mm) and have a thickness of about 0.002 in (51 ⁇ m).
• the substrates preferably will be optically clear and may contain one or more coatings applied during their manufacture to help with adhesion to other surfaces, such as the reagent-carrying layer.
• Electrodes in contact with a blood (or other) sample to produce an electrical current that is measured and correlated with the amount of the analyte (e.g. glucose) in the sample.
• the electrodes are in contact with a solid layer containing enzyme reagents that oxidize the analyte in the sample and mediators that reoxidize the reduced enzyme.
• the reactors may be described by the following steps:
• the reactive formulation used in electrochemical sensors will be similar to that used in optical methods, except that the indicators are not required.
• the reagent layer of the invention is a single very thin layer containing reagents which react with glucose in a blood sample and produce a quick and uniform response.
• the reagent layer may be characterized as being size self-limiting in that it blocks movement of large particles, such as red blood cells, and permits movement of desired components. It may be described generally as a water-soluble swellable polymer matrix containing water-insoluble particles, and an enzyme for reaction with glucose, such as a glucose dehydrogenase and its co- factor, a mediator and an indicator where optical detection is used. Additional components may include detergents, surfactants, and the like.
• the polymers may include polyacrylic acid, polyvinyl alcohol, polystyrene sodium sulfonic acid, polyacrylic latex, polyethylene glycol, styrene acrylates and their co-polymers.
• Such polymers are characterized by having relatively low molecular weight, for example 100 to 100,000 daltons, including low molecular weight oligomers.
• Such polymers will have high solubility in aqueous solutions and typically have low viscosity. They typically will be dissolved in a buffered solution to maintain a desired pH, e.g. about 7.5. The polymers will rapidly swell when rehydrated in neutral pH solutions such as whole blood. It is believed that such polymers provide the rapid access of the analyte (e.g. glucose) to the reagents.
• analyte e.g. glucose
• Particles may include titanium dioxide, calcium carbonate, bentonite clay, silica, barium sulfate, powdered metals, latex and the like. Suitable particles are essentially insoluble in water and have a nominal size of about 0.05 to 20 ⁇ m, but preferably are in the 1 to 10 ⁇ m range.
• the particles should not have pores that permit undesirable migration of reagents or sample components.
• Detergents and surfactants may include proprietary materials, such as Silwet L-7600
• additives which may be included are emulsifiers, wetting agents, thickeners, pigments, and similar additives.
• the weight ratio of the reflective particles to the polymer matrix is typically between about 1/2 to 2/1.
• the coating may be from 6 to 16 ⁇ m thick, preferably about 7 to 10 ⁇ m.
• Such coatings are much thinner than those commonly used in the art. It was surprising to find that such thin layers could provide rapid and stable response, as will be illustrated in the examples below.
• the reagent layer is prepared by blending the components described above into a uniform aqueous coating, which is applied to a substrate using techniques familiar to those skilled in the art, such as gravure or Mayer-rod coating, and dried. Other coating methods may be used, since the method of applying the coating is not considered essential to success.
• a protective top preferably a hydrophilic-coated polyester, which may be transparent or opaque. An additional opaque layer may also be added.
• an adhesive layer that joins the other two layers and also forms a capillary passageway for introducing blood samples.
• the test strips of the invention are not sensitive to the dimensions of the capillary. That is, the test strips do not require that a fixed amount of blood (or other biological fluid) be applied.
• the reagent layer excluding the optical indicator, will be applied to electrodes to produce an electrochemical sensor, such as those described for example in U.S. Published Application 2001/0042683.
• a reagent layer was prepared by blending the components listed in Table A, applying them to a substrate, and completing the test strip as described above.
• the performance of the test strips was measured by adding a small sample of whole blood (about 600 nL) containing a known amount of glucose to the reagent layer, placing the strip in a small read area (e.g. 0.75 mm diameter) diffuse reflectance measuring instrument and reading the color developed over a period of about 60 seconds.
• the results are reported as K/S, the Kubelka-Munk function (1-R) 2 /2R where R is the measured reflectance.
• the measured color intensity remained constant over the period for each of the glucose concentrations tested.
• the response of the glucose meter was plotted versus the glucose content, as shown in Fig Ib. It will be clear that the response time was rapid and that the results for 12 second and 52 seconds were very similar. Thus, one can conclude that the test strips of the invention provide a rapid response and are not unduly sensitive to the time of reading.
• Another reagent layer was prepared by blending the components listed in Table B, applying them to a substrate and completing the test strip as described above. A series of tests were carried out as in Example 1 with whole blood samples containing known amounts of glucose. The results of the tests are shown in Figs 2a-b. It will be seen that the color developed was substantially constant over a 60 second period of time, except that some additional color was developed at higher concentrations. Table B
• Titanium dioxide (2) 5.3% TiO 2
• a reagent layer was prepared by blending the components listed in Table C, applying them to a substrate, and completing the test strip as described above.
• the reagent layer was tested as in Examples 1 and 2. The results are shown in Fig 3a, b, c. Fig. 3a and 3b report results similar to those of Examples 1 and 2. The additional color development at higher glucose concentrations noted in Figs. 2a and b does not appear in this example.
• Titanium dioxide ⁇ 8% TiO 2
• Rhodasurf-ON870 (6) 1.0%
• a reagent layer was prepared by blending the components listed in Table D, applying them to a substrate, and completing the test strip as described above.
• the resulting test strip was tested as in the previous examples. The results are shown in Fig 4 a,b,c. The consistency of measured color development is even greater than found with previous examples. That is, one can conclude that color development is substantially complete within the first few seconds.
• Fig. 4c shows another advantage of test strips of the invention. Two test strips designs were compared. The first had a 50 ⁇ m capillary gap through which the blood sample entered, while the second type had an 80 ⁇ m capillary gap. Fig 4c shows that this difference in capillary gap height and the resulting change in sample volume has no significant effect on the results.
• a reactive formulation for measuring the amount of an analyte in a biological fluid comprising:
• the enzyme system includes a member of the group consisting of hexokinase, glucose-6- phosphate dehydrogenase, glucose dehydrogenase, glucose dehydrogenase-PQQ, and glucose oxidase.
• a reactive formulation of Alternate Embodiment A wherein said water-soluble swellable polymer matrix includes at least one member of the group consisting of polyacrylic acid, polyvinyl alcohol, polystyrene sodium sulfonic acid, polyacrylic latex, polyethylene glycol, styrene acrylates, and their co-polymers.
• test strip or electrochemical sensor comprising a non-porous substrate on which is deposited a thin film containing an enzyme system for reacting with said analyte in a formulation including a water-soluble swellable polymer matrix, and water-insoluble particles having a nominal size of about 0.05 to 20 ⁇ m;
• a method of Alternate Process K wherein said water-soluble swellable polymer matrix is a polymer matrix that includes at least one member of the group consisting of polyacrylic acid, polyvinyl alcohol, polystyrene sodium sulfuric acid, polyacrylic latex, polyethylene glycol, styrene acrylates and their co-polymers.
• a reactive formulation for measuring the glucose content of whole blood comprising
• said enzyme system includes a member of the group consisting of hexokinase; glucose-6-phosphate dehydrogenase, glucose dehydrogenase, glucose dehydrogenase-PQQ, and glucose oxidase.
• said enzyme system comprises glucose dehydrogenase, a co-factor for said glucose dehydrogenase, a tetrazolium salt indicator, and a mediator.
• a reactive formulation of Alternate Embodiment U wherein said water-soluble swellable polymer matrix includes at least one member of the group consisting of polyacrylic acid, polyvinyl alcohol, polystyrene sodium sulfuric acid, polyacrylic latex, polyethylene glycol, styrene acrylates, and co-polymers thereof.
• a reactive formulation of Alternate Embodiment U further comprising at least one surfactant, detergent, or thickener.
• a test strip for measuring the glucose content of whole blood samples comprising: (a) a substantially non-porous substrate; (b) a reagent layer disposed on said substrate, said reagent layer comprising;
• said enzyme system includes a member of the group consisting of hexokinase, glucose-6-phosphate dehydrogenase, glucose dehydrogenase, glucose dehydrogenase-PQQ, and glucose oxidase.
• a test strip of Alternate Embodiment FF wherein said water-soluble swellable polymer matrix is at least one member of the group consisting of polyacrylic acid, polyvinyl alcohol, polystyrene sodium sulfonic acid, polyacrylic latex, polyethylene glycol, styrene acrylates, and co-polymers thereof.
• said water-soluble swellable polymer matrix is at least one member of the group consisting of polyacrylic acid, polyvinyl alcohol, polystyrene sodium sulfonic acid, polyacrylic latex, polyethylene glycol, styrene acrylates, and co-polymers thereof.
• said water-insoluble particles are at least one member of the group consisting of titanium dioxide, calcium carbonate, silica, barium sulfate, powdered metals, and latex.
• a method of measuring the amount of glucose in a sample of whole blood by applying the blood sample to a test strip and obtaining a rapid and stable response that is not sensitive to the volume of the blood sample comprising:
• test strip comprising a non-porous substrate on which is deposited a thin film containing an enzyme system for reacting with said glucose in a formulation including a water-soluble swellable polymer matrix, water- insoluble particles having a nominal size of about 0.05 to 20 ⁇ m, and an indicator; and
• a method of Alternate Process RR wherein said water-soluble swellable polymer matrix includes at least one member of the group consisting of polyacrylic acid, polyvinyl alcohol, polystyrene sodium sulfuric acid, polyacrylic latex, polyethylene glycol, styrene acrylates, and co-polymers thereof.
• said particles are at least one member of the group consisting of titanium dioxide, calcium carbonate, silica, barium sulfate, powdered metals, and latex.

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