WO2013013103A1 - Analyse d'échantillon pour détecter la fidélité au traitement du patient et/ou une surveillance de santé - Google Patents

Analyse d'échantillon pour détecter la fidélité au traitement du patient et/ou une surveillance de santé Download PDF

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Publication number
WO2013013103A1
WO2013013103A1 PCT/US2012/047493 US2012047493W WO2013013103A1 WO 2013013103 A1 WO2013013103 A1 WO 2013013103A1 US 2012047493 W US2012047493 W US 2012047493W WO 2013013103 A1 WO2013013103 A1 WO 2013013103A1
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WIPO (PCT)
Prior art keywords
test device
test
medication
sample
location
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PCT/US2012/047493
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English (en)
Inventor
Josiah SEALE
Brian Belmont
Angela KILBY
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Adherean, Inc.
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Publication of WO2013013103A1 publication Critical patent/WO2013013103A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54386—Analytical elements
    • G01N33/54387—Immunochromatographic test strips
    • G01N33/54388—Immunochromatographic test strips based on lateral flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4833—Assessment of subject's compliance to treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4845—Toxicology, e.g. by detection of alcohol, drug or toxic products
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/558—Immunoassay; Biospecific binding assay; Materials therefor using diffusion or migration of antigen or antibody
    • 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
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/585—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with a particulate label, e.g. coloured latex
    • 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
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/9446—Antibacterials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0295—Strip shaped analyte sensors for apparatus classified in A61B5/145 or A61B5/157

Definitions

  • the present invention relates to devices, kits, instruments, and methods to detect patient compliance, overmedication, undermedication, and/or untreated conditions.
  • the device detects medication metabolites, unmetabolized medication, indicators of treatment failure such as hepatotoxicity, and/or markers of undertreated or untreated disease in a sample provided by the patient.
  • Medication adherence and the lack thereof is a global problem of significant magnitude. For example, a large portion of hospitalizations are attributable to patients failing to fully complete their medication regimens as prescribed.
  • Pill boxes that count, register, and/or transmit the occasions on which they have been opened and closed, for example, use opening and closing the pill box as a proxy for the patient having taken the medication.
  • Another proposed solution is to tag medications with a substance, compound, or digestible device that can be detected by some other means.
  • the present invention addresses this and the related need in the art by providing an easy to use, often disposable, direct measure that can be used to convey information corresponding to the presence, absence, or amount of medication indicator present in a subject. Because it provides a direct measure, it can further be more effectively used in a program to incentivize or encourage patients to submit their results and/or take their medication as prescribed.
  • the present invention is directed to a test device for assessing medication status in a subject, which device comprises a porous matrix that comprises a test reagent at a test location on said porous matrix, wherein a liquid sample derived from a subject flows laterally along said test device and passes said test location to form a detectable signal to indicate presence, absence and/or amount of a medication indicator in said subject that can be used to assess medication status in said subject.
  • the present invention is directed to a method for assessing medication status in a subject, which method comprises: a) contacting a liquid sample derived from a subject with the above test device, wherein the liquid sample is applied to a site of the test device upstream of the test location; b) transporting a medication indicator, if present in the liquid sample, and a labeled reagent to the test location; and c) assessing a detectable
  • Docket 699302000240 signal at the test location that indicates presence, absence and/or amount of the medication indicator in the subject to assess medication status in the subject.
  • the principles of the present test devices and methods can be applied, or can be adapted to apply, to the lateral flow test devices and assays known in the art.
  • the principles of the present test devices and methods can be applied, or can be adapted to apply, to the lateral flow test devices and assays disclosed and/or claimed in the U.S. patent Nos. 3,641,235, 3,959,078, 3,966,897, 4,094,647, 4,168,146, 4,299,916,
  • Figure 1 shows a top view of an exemplary test device.
  • the rectangular portion of the drawing marked as "A” represents a hydrophobic or hydrophilic membrane in the exemplary test device.
  • the portion of the drawing marked as "B” represents the first location as described in connection with the exemplary test device.
  • the portion of the drawing marked as "C” represents the second location as described in connection with the exemplary test device.
  • the portion of the drawing marked as "D” represents the optional control location downstream from the second location as described in connection with the exemplary test device.
  • Figure 2 illustrates construction of a lateral flow strip.
  • Figure 3 illustrates an exemplary kanamycin test. Two identical lateral flow strips, with a capture line containing Kanamycin-BSA conjugate, were used to detect the
  • binding reagent refers to any substance that binds to an analyte with desired affinity and/or specificity.
  • Non-limiting examples of the binding reagent include cells, cellular organelles, viruses, particles, microparticles, molecules, or an aggregate or complex thereof, or an aggregate or complex of molecules.
  • Exemplary binding reagents can be an amino acid, a peptide, a protein, e.g., an antibody or receptor, a nucleoside, a nucleotide, an oligonucleotide, a nucleic acid, e.g., DNA or RNA, a vitamin, a
  • the term “specifically binds” refers to the specificity of a binding reagent, e.g., an antibody, such that it preferentially binds to a defined analyte.
  • a binding reagent that specifically binds to an analyte avoids binding to other interfering moiety or moieties in the sample to be tested.
  • binding reagents e.g., antibodies or antibody fragments.
  • Binding reagents, antibodies or antibody fragments that avoid binding to a particular moiety generally contain a specificity such that a large percentage of the particular moiety would not be bound by such binding reagents, antibodies or antibody fragments. This percentage generally lies within the acceptable cross reactivity percentage with interfering moieties of assays utilizing the binding reagents or antibodies directed to detecting a specific target.
  • the binding reagents, antibodies or antibody fragments of the present disclosure avoid binding greater than about 90% of an interfering moiety, although higher percentages are clearly
  • binding reagents, antibodies or antibody fragments of the present disclosure avoid binding about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, and about 99% or more of an interfering moiety. Less occasionally, binding reagents, antibodies or antibody fragments of the present disclosure avoid binding greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85% of an interfering moiety.
  • an "antibody” is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule, and can be an immunoglobulin of any class, e.g., IgG, IgM, IgA, IgD and IgE.
  • IgY which is the major antibody type in avian species such as chicken, is also included within the definition.
  • the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain (ScFv), mutants thereof, naturally occurring variants, fusion proteins comprising an antibody portion with an antigen recognition site of the required specificity, humanized antibodies, chimeric sd-595478 6 P A T E N T
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the antibodies comprising the population are identical except for possible naturally occurring mutations that are present in minor amounts. As used herein, a “monoclonal antibody” further refers to functional fragments of monoclonal antibodies.
  • the term "antigen" refers to a target molecule that is specifically bound by an antibody through its antigen recognition site.
  • the antigen may be monovalent or polyvalent, i.e., it may have one or more epitopes recognized by one or more antibodies.
  • Examples of kinds of antigens that can be recognized by antibodies include polypeptides, oligosaccharides, glycoproteins, polynucleotides, lipids, etc.
  • mammal refers to any of the mammalian class of species. Frequently, the term “mammal,” as used herein, refers to humans, human subjects or human patients. Also frequently, the term “mammal,” as used herein, refers to non-human mammalian subjects.
  • the term “subject” is not limited to a specific species or sample type.
  • the term “subject” may refer to a patient, and frequently a human patient. However, this term is not limited to humans and thus encompasses a variety of mammalian or non-mammal species.
  • sample refers to anything which may contain an analyte for which an analyte assay is desired.
  • the sample may be a biological sample, such as a biological fluid or a biological tissue.
  • biological fluids include urine, blood, plasma, serum, saliva, semen, stool, sputum, cerebral spinal fluid, tears, mucus, amniotic fluid or the like.
  • Biological tissues are aggregate of cells, usually of a particular kind together with their intercellular substance that form one of the structural materials of a human, animal, plant, bacterial, fungal or viral structure, including connective, epithelium, muscle sd-595478 7 P A T E N T
  • isolated refers to material removed from its original environment, and/or is altered from its natural state.
  • an isolated polypeptide could be coupled to a carrier, and still be “isolated” because that polypeptide is not in its original environment.
  • high-throughput screening refers to processes that test a large number of samples, such as samples of diverse chemical structures against disease targets to identify "hits" (see, e.g., Broach, et al., High throughput screening for drug discovery, Nature, 384: 14-16 (1996); Janzen, et al., High throughput screening as a discovery tool in the pharmaceutical industry, Lab Robotics Automation: 8261-265 (1996); Fernandes, P.B., Letter from the society president, /. Biomol. Screening, 2: 1 (1997); Burbaum, et al., New technologies for high-throughput screening, Curr. Opin. Chem. Biol., 7:72-78 (1997)).
  • HTS operations are highly automated and computerized to handle sample preparation, assay procedures and the subsequent processing of large volumes of data.
  • polypeptide oligopeptide
  • peptide protein
  • polymers of amino acids of any length e.g., at least 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 1,000 or more amino acids.
  • the polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
  • the terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component.
  • polypeptides containing one or more analogs of an amino acid including, for example, unnatural amino acids, etc.
  • polynucleotide oligonucleotide
  • nucleic acid nucleic acid molecule
  • Docket 699302000240 any length, e.g., at least 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 1,000 or more nucleotides, and may comprise ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof.
  • This term refers only to the primary structure of the molecule.
  • the term includes triple-, double- and single- stranded deoxyribonucleic acid ("DNA”), as well as triple-, double- and single- stranded ribonucleic acid (“RNA"). It also includes modified, for example by alkylation, and/or by capping, and unmodified forms of the polynucleotide.
  • polynucleotide examples include polydeoxyribonucleotides (containing 2-deoxy-D-ribose), polyribonucleotides (containing D-ribose), including tRNA, rRNA, hRNA, and mRNA, whether spliced or unspliced, any other type of polynucleotide which is an N- or C-glycoside of a purine or pyrimidine base, and other polymers containing normucleotidic backbones, for example, polyamide ⁇ e.g. , peptide nucleic acids (“PNAs”)) and polymorpholino
  • PNAs peptide nucleic acids
  • nucleobases in a configuration which allows for base pairing and base stacking, such as is found in DNA and RNA.
  • these terms include, for example, 3'-deoxy-2',5'-DNA, oligodeoxyribonucleotide N3' to P5' phosphoramidates, 2'-0-alkyl-substituted RNA, hybrids between DNA and RNA or between PNAs and DNA or RNA, and also include known types of modifications, for example, labels, alkylation, "caps," substitution of one or more of the nucleotides with an analog, intemucleotide modifications such as, for example, those with uncharged linkages ⁇ e.g. , methyl phosphonates, phosphotriesters, phosphoramidates, carbamates, etc.), with negatively charged linkages ⁇ e.g. , phosphorothioates,
  • aminoalkylphosphoramidates, aminoalkylphosphotriesters those containing pendant moieties, such as, for example, proteins (including enzymes ⁇ e.g. nucleases), toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators ⁇ e.g., acridine, psoralen, etc.), those containing chelates (of, e.g. , metals, radioactive metals, boron, oxidative sd-595478 9 P A T E N T
  • nucleoside and nucleotide will include those moieties which contain not only the known purine and pyrimidine bases, but also other heterocyclic bases which have been modified. Such modifications include methylated purines or pyrimidines, acylated purines or pyrimidines, or other heterocycles. Modified nucleosides or nucleotides can also include modifications on the sugar moiety, e.g. , wherein one or more of the hydroxyl groups are replaced with halogen, aliphatic groups, or are functionalized as ethers, amines, or the like.
  • the term “nucleotidic unit” is intended to encompass nucleosides and nucleotides.
  • Nucleic acid probe and “probe” are used interchangeably and refer to a structure comprising a polynucleotide, as defined above, that contains a nucleic acid sequence that can bind to a corresponding target.
  • the polynucleotide regions of probes may be composed of DNA, and/or RNA, and/or synthetic nucleotide analogs.
  • complementary or matched means that two nucleic acid sequences have at least 50% sequence identity. Preferably, the two nucleic acid sequences have at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of sequence identity. “Complementary or matched” also means that two nucleic acid sequences can hybridize under low, middle and/or high stringency condition(s).
  • substantially complementary or substantially matched means that two nucleic acid sequences have at least 90% sequence identity. Preferably, the two nucleic acid sequences have at least 95%, 96%, 97%, 98%, 99% or 100% of sequence identity. Alternatively, “substantially complementary or substantially matched” means that two nucleic acid sequences can hybridize under high stringency condition(s).
  • the stability of a hybrid is a function of the ion concentration and temperature.
  • a hybridization reaction is performed under conditions of lower sd-595478 10 P A T E N T
  • Moderately stringent hybridization refers to conditions that permit a nucleic acid molecule such as a probe to bind a complementary nucleic acid molecule.
  • the hybridized nucleic acid molecules generally have at least 60% identity, including for example at least any of 70%, 75%, 80%, 85%, 90%, or 95% identity.
  • Moderately stringent conditions are conditions equivalent to hybridization in 50% formamide, 5x Denhardt' s solution, 5x SSPE, 0.2% SDS at 42°C, followed by washing in 0.2x SSPE, 0.2% SDS, at 42°C.
  • High stringency conditions can be provided, for example, by hybridization in 50% formamide, 5x Denhardt' s solution, 5x SSPE, 0.2% SDS at 42°C, followed by washing in 0. lx SSPE, and 0.1% SDS at 65°C.
  • Low stringency hybridization refers to conditions equivalent to hybridization in 10% formamide, 5x
  • Denhardt' s solution 6x SSPE, 0.2% SDS at 22°C, followed by washing in lx SSPE, 0.2% SDS, at 37°C.
  • Denhardt' s solution contains 1% Ficoll, 1% polyvinylpyrolidone, and 1% bovine serum albumin (BSA).
  • 20x SSPE sodium chloride, sodium phosphate, ethylene diamide tetraacetic acid (EDTA) contains 3M sodium chloride, 0.2M sodium phosphate, and 0.025 M EDTA.
  • RNA or DNA strand will hybridize under selective hybridization conditions to its complement.
  • selective hybridization will occur when there is at least about 65% complementary over a stretch of at least 14 to 25 nucleotides, preferably at least about 75%, more preferably at least about 90% complementary. See Kanehisa (1984) Nucleic Acids Res. 12:203-215.
  • biological sample refers to any sample obtained from a living or viral source or other source of macromolecules and biomolecules, and includes any cell type or tissue of a subject from which nucleic acid or protein or other macromolecule can sd-595478 ⁇ P A T E N T
  • the biological sample can be a sample obtained directly from a biological source or a sample that is processed.
  • isolated nucleic acids that are amplified constitute a biological sample.
  • Biological samples include, but are not limited to, body fluids, such as blood, plasma, serum, cerebrospinal fluid, synovial fluid, urine and sweat, tissue and organ samples from animals and plants and processed samples derived therefrom. Also included are soil and water samples and other environmental samples, viruses, bacteria, fungi, algae, protozoa and components thereof.
  • the present disclosure provides for a test device for assessing medication status in a subject, which device comprises a porous matrix that comprises a test reagent at a test location on said porous matrix, wherein a liquid sample derived from a subject flows laterally along said test device and passes said test location to form a detectable sd-595478 12 P A T E N T
  • Docket 699302000240 signal to indicate presence, absence and/or amount of a medication indicator in said subject that can be used to assess medication status in said subject.
  • the medication indicator to be detected comprises or is an antigen
  • the binding reagent on the test device comprises or is an antibody.
  • the antibody specifically binds to the medication indicator.
  • the test device is used in a sandwich assay format, in which a binding reagent, e.g. , an antibody, is used as a reagent at the test location, and another binding reagent having a detectable label is also used to form a labeled binding reagent- medication indicator - binding reagent or antibody sandwich at the test location to generate readout signals.
  • a binding reagent is used as a reagent at the test location, and an antibody having a detectable label is also used to form a labeled antibody- medication indicator - binding reagent sandwich at the test location to generate readout signals.
  • the sandwich assay uses two antibodies, one as the capture reagent and the other as the labeled reagent.
  • the test device can also be used in a competition assay format.
  • a binding reagent e.g., an antibody
  • a medication indicator or a medication indicator analog having a detectable label either added in a liquid or previously dried on the test device and redissolved or resuspended by a liquid, will compete with a medication indicator in a sample to bind to the capture reagent at the test location.
  • a medication indicator or a medication indicator analog is used as a capture reagent at the test location.
  • a binding reagent e.g.
  • an antibody, having a detectable label is either added in a liquid or previously dried on the test device and redissolved or resuspended by a liquid.
  • a medication indicator in a sample will compete with the medication indicator or the medication indicator analog at the test location for binding to the binding reagent, e.g., an antibody, having a detectable label.
  • the test reagent can be any suitable substance.
  • the test reagent is capable of binding to a medication indicator or another binding reagent that is sd-595478 13 P A T E N T
  • the test reagent is capable of specifically binding to a medication indicator or another binding reagent that is capable of binding or specific binding to a medication indicator.
  • the test reagent is a medication indicator or a medication indicator analog that competes with a medication indicator in the liquid sample for binding to a binding reagent for the medication indicator.
  • the test reagent is an inorganic molecule, an organic molecule or a complex thereof.
  • organic molecules include an amino acid, a peptide, a protein, a nucleoside, a nucleotide, an oligonucleotide, a nucleic acid, a vitamin, a monosaccharide, an oligosaccharide, a carbohydrate, a lipid and a complex thereof.
  • the protein is an antigen or an antibody.
  • the matrix can comprise or be made of any suitable material.
  • the matrix comprises nitrocellulose, glass fiber, polypropylene, polyethylene (preferably of very high molecular weight), polyvinylidene flouride, ethylene vinylacetate, acrylonitrile and/or polytetrafluoro-ethylene. See e.g., U.S. patent No. 6,187,598. It can be advantageous to pre-treat the membrane with a surface-active agent during manufacture, as this can reduce any inherent hydrophobicity in the membrane and therefore enhance its ability to take up and deliver a moist sample rapidly and efficiently.
  • the matrix can also be made from paper or other cellulosic materials.
  • the matrix comprises or is made of nitrocellulose or glass fiber.
  • the matrix can also be in any suitable form or shape. In some embodiments,
  • the matrix is in the form a strip or a circle.
  • the matrix can also comprise or be made of any suitable number of element.
  • the matrix is a single element or comprises multiple elements.
  • test devices can comprise any suitable additional elements.
  • the test device can further comprise a sample application element upstream from and in fluid communication with the matrix.
  • the test device can further comprise a liquid absorption element downstream from and in fluid sd-595478 14 P A T E N T
  • test device can further comprise a control zone comprising means for indicating proper flow of the liquid sample and/or a valid test result.
  • control zone comprising means for indicating proper flow of the liquid sample and/or a valid test result.
  • at least a portion of the matrix is supported by a solid backing.
  • the entire matrix is supported by a solid backing.
  • a labeled reagent can be dried on the test device and the dried labeled reagent can be redissolved or resuspended by a liquid, e.g., a sample liquid and/or additional liquid, and transported laterally through the test device to generate readout, control and/or other signals.
  • a portion of the matrix, upstream from the test location can comprise a dried, labeled reagent, the labeled reagent capable of being moved by a liquid sample and/or a further liquid to the test location and/or a control location to generate a detectable signal.
  • the dried, labeled reagent can be located at any suitable places on the test device.
  • the dried, labeled reagent is located downstream from a sample or liquid application place on the test device.
  • the dried, labeled reagent is located upstream from a sample or liquid application place on the test device.
  • the type of the labeled reagent can be determined based on the intended assay formats. For example, if the test device is to be used in a sandwich assay, the labeled reagent should be capable of binding, and preferably capable of specifically binding, to the analyte or a target, or another substance that binds to the analyte or the target. The same labeled reagent can also be used for certain competitive binding assays. For other types of the competitive binding assays, the labeled reagent should be an analyte or an analyte analog linked to a detectable label.
  • a portion of the matrix, upstream from the test location comprises a dried, labeled reagent, the labeled reagent being capable of being moved by a liquid sample and/or a further liquid to the test location and/or a control location to generate a detectable signal.
  • the dried, labeled reagent can be located downstream from a sd-595478 15 P A T E N T
  • the dried, labeled reagent can be located upstream from a sample application place on the test device.
  • the test can further comprise, upstream from the test location, a conjugate element that comprises a dried, labeled reagent, the labeled reagent being capable of moved by a liquid sample and/or a further liquid to the test location and/or a control location to generate a detectable signal.
  • the conjugate element can be located downstream from a sample application place on the test device. Alternatively, the conjugate element can be located upstream from a sample application place on the test device.
  • the labeled reagent binds, and preferably specifically binds, to a medication indicator in the liquid sample. In other embodiments, the labeled reagent competes with a medication indicator in the liquid sample for binding to a binding reagent for the medication indicator at the test location.
  • the label can be a soluble label, such as a colorimetric, radioactive, enzymatic, luminescent or fluorescent label.
  • the label can also be a particle or particulate label, such as a particulate direct label, or a colored particle label.
  • Exemplary particle or particulate labels include colloidal gold label, latex particle label, nanoparticle label and quantum dot label.
  • the labels such as colorimetric, radioactive, enzymatic, luminescent or fluorescent label, can be either a soluble label or a particle or particulate label.
  • the labeled reagent is dried in the presence of a material that stabilizes the labeled reagent, facilitates solubilization or resuspension of the labeled reagent in a liquid, and/or facilitates mobility of the labeled reagent.
  • a material that stabilizes the labeled reagent facilitates solubilization or resuspension of the labeled reagent in a liquid, and/or facilitates mobility of the labeled reagent.
  • the material can be a protein, e.g., a meta-soluble protein, a peptide, a polysaccharide, a sugar, e.g., sucrose, a polymer, a gelatin or a detergent. See e.g., U.S. patent Nos. 5,120,643 and 6,187,598.
  • the present test devices can be used with any suitable liquid.
  • a sample liquid alone is used to transport a medication indicator and/or the labeled sd-595478 16 P A T E N T
  • a developing liquid is used to transport a medication indicator and/or the labeled reagent to the test location.
  • the test device can further comprise a housing that covers at least a portion of the test device, wherein the housing comprises a sample or liquid application port to allow sample or liquid application upstream from or to the test location and an optic opening around the test location and/or the control location to allow signal detection at the test location and/or the control location.
  • the optic opening can be achieved in any suitable way.
  • the optic opening can simply be an open space.
  • the optic opening can be a transparent cover.
  • the housing can cover the entire test device. In still other embodiments, at least a portion of the sample receiving portion of the matrix or the sample application element is not covered by the housing and a sample or liquid is applied to the portion of the sample receiving portion of the matrix or the sample application element outside the housing and then transported to the test location and/or control location.
  • the housing can comprise any suitable material.
  • the housing can comprise a plastic material.
  • the present test devices can be used to assess medication status in any suitable subject.
  • the present test devices can be used to assess medication status in a human.
  • the present test devices can be used to assess medication status in an animal, e.g., a non-human mammal.
  • the present test devices can be used to assess medication status in a suitable subject by assessing any suitable medication indicator from the subject.
  • the medication indicator is a medication metabolite, an unmetabolized medication, or an indicator of over medication, under medication or medication failure.
  • the present test devices can be used to assess medication status in a subject of the exemplary medications listed in the Orange Book:
  • the present invention provides for a test device wherein the liquid or sample has moved laterally along the test device to generate a detectable signal at the test location.
  • the present disclosure provides for a method for assessing medication status in a subject, which method comprises: a) contacting a liquid sample derived from a subject with the test device described in above Section B, wherein the liquid sample is applied to a site of the test device upstream of the test location; b) transporting a medication indicator, if present in the liquid sample, and a labeled reagent to the test location; and c) assessing a detectable signal at the test location that indicates presence, absence and/or amount of the medication indicator in the subject to assess medication status in the subject.
  • the liquid and the labeled reagent are premixed to form a mixture and the mixture is applied to the test device.
  • the labeled reagent can be provided or stored in a liquid and then can be premixed with a sample to form a mixture and the mixture is applied to the test device.
  • the labeled reagent can be dried in a location or container not in fluid communication with the test device, e.g., in a test tube or well such as a microtiter plate well.
  • the sample liquid can be added to the container, e.g., the test tube or well, to form the mixture and the mixture can then be applied to the test device.
  • the test device comprises a dried labeled reagent before use and the dried labeled reagent is solubilized or resuspended, and transported to the test location by the liquid sample.
  • the dried labeled reagent can be located at any suitable sd-595478 18 P A T E N T
  • the dried labeled reagent can be located on the test device.
  • the dried labeled reagent can be located on the test device.
  • the dried labeled reagent can be located upstream from the sample application site, and the dried labeled reagent is solubilized or resuspended, and transported to the test location by another liquid.
  • the labeled reagent is solubilized or resuspended, and transported to the test location by the liquid sample alone.
  • the medication indicator and/or labeled reagent is solubilized or resuspended, and transported to the test location by another liquid.
  • the present methods can be used to assess medication status in a suitable subject by assessing a medication indicator in any suitable sample.
  • the liquid sample is a body fluid sample, e.g., a whole blood, a serum, a plasma and a urine sample.
  • the present methods can be used to assess medication status in a subject by assessing presence or absence of a medication indicator in a sample. In other embodiments, the present methods can be used to assess medication status in a subject by quantifying or semi-quantifying the amount of a medication indicator in a liquid sample. In still other embodiments, the present methods can be used to assess medication status in a subject by assessing multiple medication indicators in a liquid sample.
  • the present methods can be used to assess medication status in a subject of the exemplary medications listed in the Orange Book:
  • the present invention provides for devices to detect medication metabolites, unmetabolized medication, indicators of treatment failure such as hepatotoxicity, and/or markers of undertreated or untreated disease in a sample provided by the patient.
  • the present invention provides a device for detecting at least an analyte in a sample in the form of a competitive lateral flow assay, which device comprises: at least a naturally hydrophobic membrane comprising at least a first location and a second location, wherein said first location comprises a dried particle labeled binding reagent capable of binding to an analyte, if present in a sample to be tested, to form a first complex comprising said labeled binding reagent and said analyte; said second location, downstream from said first location, comprises an immobilized substance capable of competing with analyte that might be present in the sample, to form a second complex comprising said first labeled binding reagent and said immobilized substance; whereby the addition of a liquid, either as part of the sample or independently from it, for transporting said sample and said first labeled binding reagent to said second location to form said second complex allows the presence, absence and/or amount of said analyte in said sample to be
  • any suitable naturally hydrophobic membrane can be used.
  • the naturally hydrophobic membrane comprises nitrocellulose membrane.
  • the first and second locations can take any suitable form.
  • the first location, the second location or both locations can be in the form of a zone or zones.
  • any suitable label, or labeled particle can be used.
  • the labeled particle comprises a quantum dot or a colored particle.
  • the label, or labeled particle can be dried before use, either on the test device or on a location off the test device.
  • the label, or labeled particle can be dried in any suitable manner, e.g. , air dried or lyophilized.
  • the particle labeled binding reagent is dried in the presence of a material that: a) stabilizes the particle labeled binding reagent; b) facilitates resuspension of the particle labeled binding reagent in the liquid; and/or c) facilitates mobility of the particle labeled binding reagent.
  • exemplary material can be a protein, a peptide, a polysaccharide, a sugar, a polymer, a gelatin or a detergent.
  • the first labeled binding reagent binds specifically to the analyte.
  • the first labeled binding reagent can be any suitable substance, e.g. , an antibody to the analyte, and/or an aptamer, aptazyme, and/or ribozyme that specifically binds with the analyte.
  • the substance can be immobilized at the second location in any suitable manner.
  • the substance can be immobilized by absorption, adsorption, or covalent binding to the naturally hydrophobic membrane; or attached to another substance or particle that is immobilized to the naturally hydrophobic membrane.
  • the naturally hydrophobic membrane can be supported by a solid backing.
  • the device can further comprise a housing that covers at least the first and second locations on the membrane, wherein the housing comprises a sample application site to allow sample application upstream from or to the first location on the membrane and an opening around the second location to allow response detection at the second location.
  • the housing can be made of any suitable material.
  • the housing can comprise a plastic material.
  • the device can further comprise a control location downstream from, but in fluid communication with, the second location, wherein the control location comprises means for indicating a valid test result.
  • the present invention provides for a method for detecting an analyte in a sample, comprising a) contacting a sample with the above device, wherein the sample is applied to a site of the membrane upstream of the second site; b) transporting an analyte, if present in said sample, and the dried first particle labeled binding reagent capable of binding to an analyte, by a liquid to the second location to form the second complex comprising said first labeled binding reagent and the immobilized substance capable of competing with the analyte and binding with the first labeled binding reagent at the second location if the first labeled binding reagent has not bound with analyte that might be present in the sample; and c) determining the presence, absence and/or amount of said analyte in said sample by assessing behavior in said first labeled binding reagent in said second complex at said second location.
  • the sample can be applied to any suitable location of the test device.
  • the sample is applied to the first location of the membrane.
  • the sample is applied to a site of the membrane upstream of the first location of the membrane.
  • the present methods can be used to assess a medication indicator in any suitable sample.
  • the sample is whole blood, a serum, a plasma, or a urine sample.
  • medication indicators include medication metabolites, unmetabolized medication, ketones, glucose, transaminases, albumin, sarcosine, cancer markers,
  • the capture line was created by the immobilization of Kanamycin-BSA conjugate onto the lateral flow membrane.
  • the detection particles were composed of a gold nanoparticle conjugated to a DNA oligonucleotide containing a kanamycin-binding sequence.
  • a lateral flow assay strip was constructed using a cellulose sample pad (Millipore, # CFSP223000), conjugate pad (Millipore, # GFCP203000), HiFlow Plus HFB09004 membrane (Millipore, # HF09004XSS), absorbent pad (Millipore, #
  • kanamycin-binding aptamer sequence The oligonucleotide had sequence
  • the capture region of the lateral flow strip was prepared by dispensing 1 microliter of a 2 mg/mL solution of Kanamycin-B ovine Serum Albumin conjugate
  • Liquid sample (10 mM sodium phosphate, with or without 0.5 mg/mL kanamycin) was applied to two identical strips, and the tests were allowed to develop.

Abstract

La présente invention concerne des dispositifs, des nécessaires, des instruments et des procédés pour détecter la fidélité au traitement du patient, une surconsommation de médicaments, un manque de prise de médicaments et/ou des états non traités. Le dispositif détecte des métabolites de médicament, un médicament non métabolisé, des indicateurs d'échec de traitement, tels que l'hépatotoxicité, et/ou des marqueurs d'une maladie sous-traitée ou non traitée dans un échantillon fourni par le patient.
PCT/US2012/047493 2011-07-20 2012-07-19 Analyse d'échantillon pour détecter la fidélité au traitement du patient et/ou une surveillance de santé WO2013013103A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161509910P 2011-07-20 2011-07-20
US201161509929P 2011-07-20 2011-07-20
US61/509,929 2011-07-20
US61/509,910 2011-07-20

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656503A (en) * 1987-04-27 1997-08-12 Unilever Patent Holdings B.V. Test device for detecting analytes in biological samples
US20060040408A1 (en) * 2004-03-30 2006-02-23 Whatman, Inc. Lateral flow format, materials and methods
US7799554B2 (en) * 2006-03-16 2010-09-21 The Board Of Trustees Of The University Of Illinois Lateral flow devices
US20110171754A1 (en) * 2007-09-14 2011-07-14 Gareth Redmond Analysis system

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656503A (en) * 1987-04-27 1997-08-12 Unilever Patent Holdings B.V. Test device for detecting analytes in biological samples
US20060040408A1 (en) * 2004-03-30 2006-02-23 Whatman, Inc. Lateral flow format, materials and methods
US7799554B2 (en) * 2006-03-16 2010-09-21 The Board Of Trustees Of The University Of Illinois Lateral flow devices
US20110171754A1 (en) * 2007-09-14 2011-07-14 Gareth Redmond Analysis system

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