WO2018222750A1 - Integrated devices for rapid detection of benzodiazepines or other drugs in solution - Google Patents

Integrated devices for rapid detection of benzodiazepines or other drugs in solution Download PDF

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Publication number
WO2018222750A1
WO2018222750A1 PCT/US2018/035187 US2018035187W WO2018222750A1 WO 2018222750 A1 WO2018222750 A1 WO 2018222750A1 US 2018035187 W US2018035187 W US 2018035187W WO 2018222750 A1 WO2018222750 A1 WO 2018222750A1
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WO
WIPO (PCT)
Prior art keywords
pad
test device
reaction
sample
disposed
Prior art date
Application number
PCT/US2018/035187
Other languages
French (fr)
Inventor
Danya SHERMAN
Edward Cheesman
Paul Vernucci
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Knonap Llc
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Publication date
Application filed by Knonap Llc filed Critical Knonap Llc
Publication of WO2018222750A1 publication Critical patent/WO2018222750A1/en

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Classifications

    • 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
    • G01N33/02—Food
    • G01N33/14—Beverages
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N31/00—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods
    • G01N31/22—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators
    • 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
    • G01N33/528—Atypical element structures, e.g. gloves, rods, tampons, toilet paper
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour

Definitions

  • Embodiments of the present disclosure relate to screening beverages for surreptitious drugs, and more specifically, to integrated devices for rapid detection of benzodiazepines or other drugs in solution.
  • a test device comprises a reaction chamber having an input port and an output port, the reaction chamber having translucent walls having a thickness; a hydrophilic sample pad disposed at the input port; an acidic layer disposed within the reaction chamber and in fluid communication with the sample pad; an ion exchange resin layer disposed within the reaction chamber and in fluid
  • a hydrophilic reaction pad disposed within the reaction chamber and in fluid communication with the ion exchange resin layer, the hydrophilic reaction pad being infused with a hydrolyzing and/or reducing reagent; a viewing pad disposed at the output port and in fluid communication with the reaction pad, the viewing pad extending along the thickness of the reaction chamber walls, the viewing pad being infused with at least one colorimetric reagent.
  • the reaction chamber comprises silicone or plastic.
  • the test device is disposed between napkin layers.
  • the sample pad, reaction pad, and/or viewing pad comprise chromatography paper.
  • the acidic layer comprises silica.
  • the acidic layer comprises sulphuric acid, hydrochloric acid, phosphoric acid, or sulphonic acid.
  • the test device further comprises a mixing pad disposed between the acidic layer and the ion exchange resin layer.
  • the test device further comprises a mixing pad disposed between the ion exchange resin layer and the reaction pad.
  • the hydrolyzing and/or reducing reagent comprises stannous chloride, cobalt powder, or iron powder.
  • the at least one colorimetric reagent comprises p-dimethylaminocinnamaldehyde.
  • a test device comprises a laminated envelope comprising an upper surface and a lower surface, the upper surface having an inlet port and at least one translucent area; a hydrophilic sample pad disposed within the laminated envelope and aligned with the inlet port; a viewing pad disposed within the laminated envelope and aligned with one of the at least one translucent areas, the viewing pad being infused with at least one colorimetric reagent; one more hydrophilic components disposed within the laminated envelope and in fluid communication with the sample pad and the viewing pad, at least one of the one more hydrophilic components comprising a hydrolyzing and/or reducing reagent.
  • the laminated envelope comprises polypropylene film. In various embodiments, the laminate envelope is disposed between napkin layers. In various embodiments, the sample pad, viewing pad, and/or one more hydrophilic components comprise chromatography paper. In various embodiments, the one more hydrophilic components comprise a reaction pad and one or more transfer pads. In various embodiments, the hydrolyzing and/or reducing reagent comprises stannous chloride, cobalt powder, or iron powder. In various embodiments, the at least one colorimetric reagent comprises p-dimethylaminocinnamaldehyde.
  • a test device comprises: a reaction chamber having an input port and an output port; a hydrophilic sample pad disposed at the input port; a hydrophilic reaction pad disposed at the output port, the hydrophilic reaction pad being infused with a hydrolyzing and/or reducing reagent; an acidic layer disposed within the reaction chamber and in fluid communication with the sample pad and the reaction pad; a viewing pad disposed outside the reaction chamber and in fluid communication with the reaction pad, the viewing pad being infused with at least one colorimetric reagent.
  • the reaction chamber comprises silicone or plastic.
  • the test device is disposed between napkin layers.
  • the sample pad, reaction pad, and/or viewing pad comprise chromatography paper.
  • the acidic layer comprises silica.
  • the acidic layer comprises sulphuric acid, hydrochloric acid, phosphoric acid, or sulphonic acid.
  • test device further comprises a mixing pad disposed between the acidic layer and the reaction pad.
  • the hydrolyzing and/or reducing reagent comprises stannous chloride, cobalt powder, or iron powder.
  • the at least one colorimetric reagent comprises p-dimethylaminocinnamaldehyde.
  • the test device further comprises an ion exchange resin layer disposed between the acidic layer and the reaction pad.
  • FIG. 1 is an exploded view of a first exemplary test device according to embodiments of the present disclosure.
  • FIG. 2A is a perspective view of a second exemplary test device according to
  • Fig. IB is a is a top view of a second exemplary test device according to embodiments of the present disclosure.
  • Fig. 2C is a side view of a second exemplary test device according to embodiments of the present disclosure.
  • Fig. 2D is an exploded view of a second exemplary test device according to embodiments of the present disclosure.
  • FIG. 3A is a perspective view of a third exemplary test device according to embodiments of the present disclosure.
  • FIG. 3B is a top view of a third exemplary test device according to embodiments of the present disclosure.
  • Fig. 3C is a side view of a third exemplary test device according to embodiments of the present disclosure.
  • Fig. 3D is a cross-sectional view of a third exemplary test device according to
  • Fig. 3E is an exploded view of a third exemplary test device according to embodiments of the present disclosure.
  • Fig. 3F is an exploded view of a third exemplary test device according to embodiments of the present disclosure.
  • FIG. 4A is a perspective view of a fourth exemplary test device according to
  • Fig. 4B is a top view of a fourth exemplary test device according to embodiments of the present disclosure.
  • Fig. 4C is a side view of a fourth exemplary test device according to embodiments of the present disclosure.
  • Fig. 4D is an exploded view of a fourth exemplary test device according to embodiments of the present disclosure.
  • FIG. 5A is a perspective view of a fifth exemplary test device according to embodiments of the present disclosure.
  • Fig. 5B is a top view of a fifth exemplary test device according to embodiments of the present disclosure.
  • Fig. 5C is a side view of a fifth exemplary test device according to embodiments of the present disclosure.
  • Fig. 5D is an exploded view of a fifth exemplary test device according to embodiments of the present disclosure.
  • Fig. 6A is a perspective view of a sixth exemplary test device according to embodiments of the present disclosure.
  • Fig. 6B is a top view of a sixth exemplary test device according to embodiments of the present disclosure.
  • Fig. 6C is a bottom view of a sixth exemplary test device according to embodiments of the present disclosure.
  • Fig. 6D is a side view of a sixth exemplary test device according to embodiments of the present disclosure.
  • Fig. 6E is a cross-sectional view of a sixth exemplary test device according to embodiments of the present disclosure.
  • Fig. 6F is an exploded view of a sixth exemplary test device according to embodiments of the present disclosure.
  • Fig. 7 is a flowchart illustrating an assay process according to embodiments of the present disclosure.
  • Benzodiazepines are a class of psychoactive drugs causing sedative, hypnotic (sleep- inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties. High doses of many shorter-acting benzodiazepines may also cause anterograde amnesia and dissociation. Benzodiazepines in overdoses can cause dangerous deep unconsciousness. When combined with other central nervous system (CNS) depressants such as alcoholic drinks and opioids, the potential for toxicity and fatal overdose increases.
  • CNS central nervous system
  • Fast-onset benzodiazepines include diazepam, flunitrazepam, and midazolam.
  • fast-onset benzodiazepines pose a particular danger when administered surreptitiously. They are widely referred to as date rape drugs due to their prevalence in drug- facilitated sexual assault.
  • the present disclosure provides a variety of integrated test devices for rapid detection of benzodiazepines or other drugs, for example in a beverage.
  • Various compact form factors are provided, integrating test devices into, for example, a napkin.
  • a napkin 100 includes a plurality of layers
  • Top and bottom layer 101, 104 comprise tissue paper. Sandwiched between top and bottom layer 101, 104 is test zone 102, and impermeable layer 103. In some embodiments, an additional test zone (not pictured) is included between impermeable layer 103 and bottom layer 104. In some embodiments, additional test zone and impermeable layer pairs are included between top and bottom layer 101, 104, for example at each of the four corners of the napkin.
  • impermeable layer 103 comprises polylactic acid (PLA), and prevents the flow of fluid from bottom to top through napkin 100. In embodiments having multiple test zones, impermeable layer 103 prevents fluid flow between upper and lower test zones.
  • Test zone 102 may include a region infused with a colorimetric compound. Test zone 102 may also include a fluid flow path, with one or more reaction zones, as for example as described in further detail below.
  • test zone 102 comprises porous paper capable of absorbing an aliquot of a beverage.
  • the porous paper includes color-changing compounds for detecting benzodiazepines or other drugs such as gamma-Hydroxybutyric acid (GHB) or ketamine.
  • GLB gamma-Hydroxybutyric acid
  • test zone 102 is marked on upper surface 101 by a perforated region. In embodiments having multiple test zones, each test zone may be marked with a perforated region (for example on both top and bottom layers 101, 104). If a beverage contains one or more of the drug components that the napkin tests for, the saturated testing region will undergo a color change.
  • a napkin is provided in a kit with a stir-stick and instructions on how to discreetly and safely transfer the liquid to a testing region.
  • the stir-stick's role is to aid in transferring the liquid from the drink to the napkin.
  • the napkin form factor provides for discretion, as only the user is aware that the cocktail napkin includes an integrate test element. This form factor is portable, and provides for a one- step testing process, thereby increasing usability and safety for the user. As a single-use test, this form factor is also more hygienic than non-disposable alternatives.
  • FIG. 2A-D an exemplary test device according to the present disclosure is illustrated.
  • four test zones are provided within a single device.
  • Device 200 includes a napkin top and bottom 209, 201, between which are arranged the other components.
  • top and bottom layers 209, 201 comprise tissue paper.
  • a laminate bottom 202 is stacked on napkin bottom 201, and provides an impermeable layer preventing the flow of fluid from bottom to top through napkin 200.
  • laminate bottom 202 comprises clear polypropylene film.
  • laminate bottom 202 is affixed by acrylic adhesive.
  • other adhesives such as gum rubber, PVA, acrylates, epoxies, or urethanes are used.
  • Each test zone includes a sample pad 203 and a viewing pad 204, connected to a reaction pad 205 by transfer strips 206, 207.
  • the sample pads comprise a hydrophilic material such as chromatography paper.
  • the sample pads comprise Whatman No. 1 chromatography paper.
  • the sample pads provide absorbent pads for collecting sample for testing.
  • Transfer pads 206, 207 provide wicks to transport the test sample from sample pad 203 to viewing pad 204 via reaction pad 205.
  • transfer pads 206, 207 comprise Whatman pads, however, a variety of hydrophilic materials are suitable for use as set out herein. As set out further below, transfer pads 206, 207 may be loaded with reagents for hydrolyzing and/or reducing the input sample.
  • Reaction pad 205 comprises a hydrophilic paper or polymer, for example a Whatman pad.
  • the reaction pad is loaded with reagents for hydrolyzing and/or reducing an input sample.
  • Viewing pad 204 is loaded with one or more reagents for colorimetric detection of a test substance.
  • viewing pad 204 is a Whatman pad, or other hydrophilic material such as a paper or polymer.
  • the viewing pad 204 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection.
  • DMACA p-Dimethylaminocinnamaldehyde
  • alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs.
  • Laminate top 208 is stacked on the various test components, and provides an
  • laminate top 208 comprises clear polypropylene film. In various embodiments, alternative polymer films are used. In various embodiments, laminate top 208 is affixed by acrylic adhesive. In various embodiments, other adhesives such as gum rubber, PVA, acrylates, epoxies, or urethanes are used. As pictured, in various embodiments laminate top 208 includes an input port aligned with sample pad 203, allowing fluid to contact sample pad 203. In embodiments where laminate top is transparent, there need not be an opening aligning with viewing pad 204. However, in embodiments where laminate top 208 is not transparent, a transparent window may be included in laminate top 208 to allow the color of viewing pad 204 to be seen.
  • Napkin top 209 includes ports aligning with sample pad 203 and viewing pad 204. These ports enable fluid to pass to reach sample pad 203, and allow the color change of viewing pad 204 to be seen.
  • a sample is introduced to sample pad 203 through the corresponding port in napkin face 209 and port in laminate top 208.
  • the sample wets sample pad 203 and the fluid laterally flows along transfer strip 206 to reaction pad 205. Hydrolysis and/or reduction reaction of the samples occurs at reaction pad 205.
  • the fluid flows laterally flows along transfer strip 207 to viewing pad 204.
  • the sample reacts with the colorimetric reagents loaded in viewing pad 204 to create a color change. The change in color is visible through the corresponding port in the napkin face 209 and through the transparent laminate film 208.
  • napkin 200 measures about 5 inches square, with sample pads being located about 3-4 inches apart measured from center-to-center. In an exemplary embodiment sample pads are about 5/8 inches in diameter. In an exemplary embodiment, napkin 200 is about 1/32 inch thick.
  • the test assembly 203...207 may be laminated separately from additional assemblies. In this way, modular test assemblies may be provided for integration into napkins or other form factors.
  • a sample well is positioned on top laminate 208 around the port corresponding to sample pad 203.
  • the sample well comprises polypropylene adhesive film.
  • alternative polymer films are used.
  • the sample well is affixed by acrylic adhesive, gum rubber, PVA, acrylates, epoxies, or urethanes.
  • FIG. 3A-F an exemplary test device according to the present disclosure is illustrated.
  • four test zones are provided, each separately laminated.
  • Device 300 includes a napkin top and bottom 307, 301, between which are arranged the other components.
  • top and bottom layers 307, 301 comprise tissue paper.
  • a laminate bottom 302 forms half of the laminated envelope for the test components, and provides an impermeable layer preventing the flow of fluid into those components except through an input port.
  • laminate bottom 302 comprises clear polypropylene film.
  • alternative polymer films are used.
  • laminate bottom 302 is affixed by acrylic adhesive. In various embodiments, other adhesives such as gum rubber, PVA, acrylates, epoxies, or urethanes are used.
  • Each test zone 303...304 includes a sample pad 308 and a viewing pad 309, connected to a reaction pad (as depicted in Fig. 2) or to each over by transfer strips 310.
  • the sample pads comprise a hydrophilic material such as chromatography paper.
  • the sample pads comprise Whatman No. 1 chromatography paper. The sample pads provide absorbent pads for collecting sample for testing.
  • Transfer strips 310 provide wicks to transport the test sample from sample pad 308 to viewing pad 309.
  • transfer pads 310 comprise Whatman pads, however, a variety of hydrophilic materials are suitable for use as set out herein. As set out further below, transfer pads 310 may be loaded with reagents for hydrolyzing and/or reducing the input sample.
  • Viewing pad 309 is loaded with one or more reagents for colorimetric detection of a test substance.
  • viewing pad 309 is a Whatman pad, or other hydrophilic material such as a paper or polymer.
  • the viewing pad 309 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection.
  • DMACA p-Dimethylaminocinnamaldehyde
  • alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs.
  • Laminate top 305...306 forms half of the laminated envelope for the test components, and provides an impermeable layer preventing the flow of fluid into test components except through an input port.
  • laminate top 305...306 comprises clear polypropylene film. In various embodiments, alternative polymer films are used. In various embodiments, laminate top 305...306 is affixed by acrylic adhesive. In various embodiments, other adhesives such as gum rubber, PVA, acrylates, epoxies, or urethanes are used. As pictured, in various embodiments laminate top 305...306 includes an input port aligned with sample pad 308, allowing fluid to contact sample pad 308.
  • laminate top is transparent
  • a transparent window may be included in laminate top 305...306 to allow the color of viewing pad 309 to be seen.
  • Napkin top 307 includes ports aligning with sample pad 308 and viewing pad 309. These ports enable fluid to pass to reach sample pad 308, and allow the color change of viewing pad 309 to be seen.
  • sample pad 308 When used, a sample is introduced to sample pad 308 through the corresponding port in napkin face 307 and port in laminate top 305...306.
  • the sample wets sample pad 308 and the fluid laterally flows along transfer strip 310 to viewing pad 309. Hydrolysis and/or reduction reaction of the samples occurs in transfer strip 310.
  • the sample reacts with the colorimetric reagents loaded in viewing pad 309 to create a color change. The change in color is visible through the corresponding port in the napkin face 307 and through the transparent laminate film 305...306.
  • napkin 300 measures about 5 inches square. Each laminated test zone measures about 1 5/8 inches square. In an exemplary embodiment, sample pads are about 0.6 inches in diameter and viewing pads are about 0.35 inches in diameter. In various embodiments, the pads 308...310 are about 13/16 inches thick. In various embodiments, the bottom laminate is about 0.005 inches thick and the top laminate is about 0.001 inches thick. Other exemplary laminates have a thickness about 0.001 inches to about 0.010 inches. In various embodiment a tissue ply has a thickness of about 0.008 inches. However, it will be appreciated that these dimensions are merely exemplary, and a variety of dimensions may be adopted for various devices according to the present disclosure.
  • pads 308...310 may be cut out from a single larger pad.
  • pads 308...310 are defined by printing on a larger pad with a hydrophobic ink or wax to define a hypdophilic pathway.
  • the reagents are loaded in different areas in the hydrophilic sub-regions.
  • each test zone 303...304 is laminated separately from additional assemblies.
  • modular test assemblies may be provided for integration into napkins or other form factors.
  • test module is provided that may be integrated into a variety of form factors, for example a napkin such as described above.
  • Device 400 includes a sample pad 402.
  • the sample pad comprises a hydrophilic material such as chromatography paper.
  • the sample pad comprises Whatman No. 1 chromatography paper.
  • the sample pad provides an absorbent pad for collecting sample for testing.
  • Beneath sample pad 402 is a silica gel wafer 404, which is loaded with sulfuric acid. It will be appreciated that a variety of alternative porous materials may be used in place of silica.
  • Beneath silica gel wafer 404 is outlet pad 403.
  • the outlet pad comprises a hydrophilic material such as chromatography paper.
  • the sample pad comprises Whatman No. 1 chromatography paper.
  • the outlet pad wicks the sample from silica gel wafer 404 to reaction pad 405.
  • Silica gel wafer 404 and outlet pad 403 are set inside ring 401. Ring 401 forms a chamber, within which the sample undergoes acidification.
  • ring 401 comprises silicone or plastic.
  • reaction pad 405 comprises a hydrophilic paper or polymer, for example a Whatman pad.
  • the reaction pad is loaded with reagents for hydrolyzing and/or reducing an input sample.
  • Transfer strip 406 connects reaction pad 405 to viewing pad 407.
  • transfer pad 406 comprises Whatman pads, however, a variety of hydrophilic materials are suitable for use as set out herein. As set out further below, transfer pad 406 may be loaded with reagents for hydrolyzing and/or reducing the input sample.
  • Viewing pad 407 is loaded with one or more reagents for colorimetric detection of a test substance.
  • viewing pad 407 is a Whatman pad, or other hydrophilic material such as a paper or polymer.
  • the viewing pad 407 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection.
  • DMACA p-Dimethylaminocinnamaldehyde
  • alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs.
  • sample pad 402. When used, a sample is introduced to sample pad 402. The sample flows downward through SiC bed 404, which is loaded with strong acid and contained in chamber 401. Acidified fluid flows down through outlet pad 403, which acts as a boundary material for the
  • test device 400 may be embedded in a device such as the napkins described above. Test device 400 may also be used in a standalone configuration.
  • test module is provided that may be integrated into a variety of form factors, for example a napkin such as described above.
  • Device 500 includes a sample pad 502.
  • the sample pad comprises a hydrophilic material such as chromatography paper.
  • the sample pad comprises Whatman No. 1 chromatography paper.
  • the sample pad provides an absorbent pad for collecting sample for testing.
  • Beneath sample pad 502 is a silica gel wafer 508, which is loaded with sulfuric acid. It will be appreciated that a variety of alternative porous materials may be used in place of silica.
  • Beneath silica gel wafer 508 is outlet pad 509.
  • the outlet pad comprises a hydrophilic material such as chromatography paper.
  • the sample pad comprises Whatman No. 1 chromatography paper.
  • the outlet pad wicks the sample from silica gel wafer 508 to ion exchange resin 504 and provides a barrier between these two chemistries.
  • Ion exchange resin 504 removes interfering substances from the sample, and in some embodiments comprises amberlite IRA 400.
  • Beneath ion exchange resin 504 is outlet pad 503.
  • the outlet pad comprises a hydrophilic material such as chromatography paper.
  • the sample pad comprises Whatman No. 1 chromatography paper.
  • the outlet pad wicks the sample from ion exchange resin 504 to reaction pad 505 and provides a barrier between these two chemistries.
  • Silica gel wafer 508, ion exchange resin 504, and outlet pads 509, 503 are set inside ring 501. Ring 501 forms a reaction chamber.
  • ring 401 comprises silicone or plastic.
  • reaction pad 505 comprises a hydrophilic paper or polymer, for example a Whatman pad.
  • the reaction pad is loaded with reagents for hydrolyzing and/or reducing an input sample.
  • Transfer strip 506 connects reaction pad 505 to viewing pad 507.
  • transfer pad 506 comprises Whatman pads, however, a variety of hydrophilic materials are suitable for use as set out herein. As set out further below, transfer pad 506 may be loaded with reagents for hydrolyzing and/or reducing the input sample.
  • Viewing pad 507 is loaded with one or more reagents for colorimetric detection of a test substance.
  • viewing pad 507 is a Whatman pad, or other hydrophilic material such as a paper or polymer.
  • the viewing pad 507 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection.
  • DMACA p-Dimethylaminocinnamaldehyde
  • alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs.
  • test device 500 When used, a sample is introduced to sample pad 502. The sample flows downward through SiC bed 508, which is loaded with strong acid and contained in chamber 501. Acidified fluid flows down through outlet pad 509 into ion exchange resin 504. From there, it flows down through outlet pad 503, which acts as a boundary material for the hydrolysis/reduction pad 505. After hydrolysis/reduction, the sample flows laterally down transfer strip 506 to viewing pad 507. The sample reacts with the colorimetric reagents loaded in viewing pad 507 to generate a color change. [0086] In various embodiments, test device 500 may be embedded in a device such as the napkins described above. Test device 500 may also be used in a standalone configuration.
  • test module is provided that may be integrated into a variety of form factors, for example a napkin such as described above.
  • Device 600 includes cover 611, which includes a chamber inlet. As pictured, in some embodiments, cover 611 is shared such that a inlet well is formed. In such embodiments, the well is sized to hold a sample, and expose the sample to the layers described below. In some embodiments, the well is sized to receive a cocktail straw containing a sample. In some embodiment, cover 611 comprises molded plastic. However, it will be appreciated that a variety of polymers are suitable for use as described herein.
  • Device 600 includes a sample pad 602.
  • the sample pad comprises a hydrophilic material such as chromatography paper.
  • the sample pad comprises Whatman No. 1 chromatography paper.
  • the sample pad provides an absorbent pad for collecting sample for testing.
  • Beneath sample pad 602 is a silica gel wafer 603, which is loaded with sulfuric acid. It will be appreciated that a variety of alternative porous materials may be used in place of silica.
  • Beneath silica gel wafer 603 is mixing pad 604.
  • mixing pad provides a time delay to the sample flow to allow reaction to take place.
  • the mixing pad comprises a hydrophilic material such as chromatography paper.
  • the sample pad comprises Whatman No. 1 chromatography paper.
  • the outlet pad wicks the sample from silica gel wafer 603 to ion exchange resin 605 and provides mixing of the sample while separating chemistries.
  • mixing pad 604 is loaded with a hydrolysis reagent.
  • Ion exchange resin 605 removes interfering substances from the sample, and in some embodiments comprises amberlite IRA 400.
  • Beneath ion exchange resin 605 is mixing pad 612.
  • mixing pad provides a time delay to the sample flow to allow reaction to take place
  • the mixing pad comprises a hydrophilic material such as chromatography paper.
  • the sample pad comprises Whatman No. 1 chromatography paper. The outlet pad wicks the sample from ion exchange resin 605 to reduction pad 606 and provides mixing of the sample while separating chemistries.
  • Reduction pad 606 comprises a hydrophilic material such as chromatography paper.
  • the reduction pad comprises Whatman No. 1 chromatography paper.
  • the reduction pad is loaded with a reducing reagent.
  • Beneath reduction pad 606 is mixing pad 613.
  • mixing pad provides a time delay to the sample flow to allow reaction to take place.
  • the mixing pad comprises a hydrophilic material such as chromatography paper.
  • the mixing pad comprises Whatman No. 1 chromatography paper. The mixing pad wicks the sample from reduction pad 606 to viewing pad 607 and provides mixing of the sample while separating chemistries.
  • Components 602, 603, 604, 605, 612, 606, 613 are set inside ring 601, thereby forming a reaction chamber.
  • ring 601 comprises silicone or plastic.
  • Viewing pad 607 is loaded with one or more reagents for colorimetric detection of a test substance.
  • viewing pad 607 is a Whatman pad, or other hydrophilic material such as a paper or polymer.
  • the viewing pad 607 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection.
  • DMACA p-Dimethylaminocinnamaldehyde
  • alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs.
  • viewing pad 607 has a larger radius than the components above it in the stack. Thus, the viewing pad may be seen from above through ring 601.
  • Beneath viewing pad 607 is chamber outlet layer 608.
  • Outlet layer 608 comprises a channel along the outer edge, which is adapted to draw sample from the middle of viewing pad 607 to the outer edge.
  • outlet layer comprises molded plastic.
  • Beneath outlet layer 608 is a sink pad 609.
  • the sink pad comprises a hydrophilic material such as chromatography paper.
  • the sink pad comprises Whatman No. 1 chromatography paper. The sink pad wicks the sample from the viewing pad through the channel in the outlet layer.
  • chamber bottom 610 couples to ring 601 and top 611 to form the overall exterior casing of the device.
  • a sample is introduced to sample pad 602 via the input port in cover 611.
  • the sample flows downward through SiC bed 603, which is loaded with strong acid and contained in chamber 601.
  • Hydrolyzed fluid flows down through mix pad 604 into ion exchange resin 605.
  • mix pad 612 which acts as a boundary material reduction pad 606.
  • the sample flows through mix pad 613 to the center of viewing pad 607.
  • the sample reacts with the colorimetric reagents loaded in viewing pad 607 to generate a color change.
  • Sink pad 609 draws the sample from the center of viewing pad 607 to its edges and through outlet holes in chamber outlet layer 608. This radial flow allows visualization of the viewing pad 607 through cover 611 and ring 601.
  • bottom 610 includes a center vent hole for air management.
  • mixing pads provides a time delay to the sample flow to allow reaction to take place.
  • a sample is exposed to a strong acid.
  • the strong acid is suspended in a shelf stable solid or gel.
  • sulphuric acid is suspended in a silica gel.
  • sulphuric acid, hydrochloric acid, phosphoric acid, or sulphonic acid is suspended in silica gel, ion exchange resin, polymer microbeads, or acidic membranes.
  • the sample is supplied to an ion exchange resin.
  • the ion exchange resin is a styrene/divinylbenzene resin such as amberlite IRA 400.
  • amberlite IRA 400 a variety of anion exchange resins are suitable for use according to the present disclosure.
  • the sample is reduced.
  • the reducing agent is loaded in a reactive pad.
  • the reducing agent comprises stannous chloride.
  • the reducing agent comprises cobalt powder.
  • the reducing agent comprises iron powder.
  • a reactive pad is loaded with a solution of the reducing agent.
  • the colorimetric reagent comprises p-dimethylaminocinnamaldehyde (DMACA).
  • DMACA p-dimethylaminocinnamaldehyde
  • a pink/red color is obtained with the presence of benzodiazepines.
  • Other colorimetric reagents are suitable for use in detection of other drugs. Variation in the reducing agent may result in a variation in the resulting color. For example, while stannous chloride yields a pink/red color, cobalt yields a darker fuchsia.

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Abstract

Integrated devices for rapid detection of benzodiazepines or other drugs in solution are provided. In various embodiments, a test device comprises a reaction chamber having an input port and an output port, the reaction chamber having translucent walls having a thickness; a hydrophilic sample pad disposed at the input port; an acidic layer disposed within the reaction chamber and in fluid communication with the sample pad; an ion exchange resin layer disposed within the reaction chamber and in fluid communication with the acidic layer; a hydrophilic reaction pad disposed within the reaction chamber and in fluid communication with the ion exchange resin layer, the hydrophilic reaction pad being infused with a hydrolyzing and/or reducing reagent; a viewing pad disposed at the output port and in fluid communication with the reaction pad, the viewing pad extending along the thickness of the reaction chamber walls, the viewing pad being infused with at least one colorimetric reagent.

Description

INTEGRATED DEVICES FOR RAPID DETECTION OF BENZODIAZEPINES OR OTHER
DRUGS IN SOLUTION
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 62/512,302, filed May 30, 2017, and U.S. Provisional Application No. 62/596,359, filed December 8, 2017, which are hereby incorporate by reference in their entirety.
BACKGROUND
[0002] Embodiments of the present disclosure relate to screening beverages for surreptitious drugs, and more specifically, to integrated devices for rapid detection of benzodiazepines or other drugs in solution.
BRIEF SUMMARY
[0003] According to embodiments of the present disclosure, rapid assay devices for detecting benzodiazepines or other drugs are provided. In various embodiments, a test device comprises a reaction chamber having an input port and an output port, the reaction chamber having translucent walls having a thickness; a hydrophilic sample pad disposed at the input port; an acidic layer disposed within the reaction chamber and in fluid communication with the sample pad; an ion exchange resin layer disposed within the reaction chamber and in fluid
communication with the acidic layer; a hydrophilic reaction pad disposed within the reaction chamber and in fluid communication with the ion exchange resin layer, the hydrophilic reaction pad being infused with a hydrolyzing and/or reducing reagent; a viewing pad disposed at the output port and in fluid communication with the reaction pad, the viewing pad extending along the thickness of the reaction chamber walls, the viewing pad being infused with at least one colorimetric reagent.
[0004] In various embodiments, the reaction chamber comprises silicone or plastic. In various embodiments, the test device is disposed between napkin layers. In various embodiments, the sample pad, reaction pad, and/or viewing pad comprise chromatography paper. In various embodiments, the acidic layer comprises silica. In various embodiments, the acidic layer comprises sulphuric acid, hydrochloric acid, phosphoric acid, or sulphonic acid. In various embodiments, the test device further comprises a mixing pad disposed between the acidic layer and the ion exchange resin layer. In various embodiments, the test device further comprises a mixing pad disposed between the ion exchange resin layer and the reaction pad. In various embodiments, the hydrolyzing and/or reducing reagent comprises stannous chloride, cobalt powder, or iron powder. In various embodiments, the at least one colorimetric reagent comprises p-dimethylaminocinnamaldehyde.
[0005] According to embodiments of the present disclosure, rapid assay devices for detecting benzodiazepines or other drugs are provided. In various embodiments, a test device comprises a laminated envelope comprising an upper surface and a lower surface, the upper surface having an inlet port and at least one translucent area; a hydrophilic sample pad disposed within the laminated envelope and aligned with the inlet port; a viewing pad disposed within the laminated envelope and aligned with one of the at least one translucent areas, the viewing pad being infused with at least one colorimetric reagent; one more hydrophilic components disposed within the laminated envelope and in fluid communication with the sample pad and the viewing pad, at least one of the one more hydrophilic components comprising a hydrolyzing and/or reducing reagent.
[0006] In various embodiments, the laminated envelope comprises polypropylene film. In various embodiments, the laminate envelope is disposed between napkin layers. In various embodiments, the sample pad, viewing pad, and/or one more hydrophilic components comprise chromatography paper. In various embodiments, the one more hydrophilic components comprise a reaction pad and one or more transfer pads. In various embodiments, the hydrolyzing and/or reducing reagent comprises stannous chloride, cobalt powder, or iron powder. In various embodiments, the at least one colorimetric reagent comprises p-dimethylaminocinnamaldehyde.
[0007] According to embodiments of the present disclosure, rapid assay devices for detecting benzodiazepines or other drugs are provided. In various embodiments a test device comprises: a reaction chamber having an input port and an output port; a hydrophilic sample pad disposed at the input port; a hydrophilic reaction pad disposed at the output port, the hydrophilic reaction pad being infused with a hydrolyzing and/or reducing reagent; an acidic layer disposed within the reaction chamber and in fluid communication with the sample pad and the reaction pad; a viewing pad disposed outside the reaction chamber and in fluid communication with the reaction pad, the viewing pad being infused with at least one colorimetric reagent.
[0008] In various embodiments, the reaction chamber comprises silicone or plastic. In various embodiments, the test device is disposed between napkin layers. In various embodiments, the sample pad, reaction pad, and/or viewing pad comprise chromatography paper. In various embodiments, the acidic layer comprises silica. In various embodiments, the acidic layer comprises sulphuric acid, hydrochloric acid, phosphoric acid, or sulphonic acid. In various embodiments, test device further comprises a mixing pad disposed between the acidic layer and the reaction pad. In various embodiments, the hydrolyzing and/or reducing reagent comprises stannous chloride, cobalt powder, or iron powder. In various embodiments, the at least one colorimetric reagent comprises p-dimethylaminocinnamaldehyde. In various embodiments, the test device further comprises an ion exchange resin layer disposed between the acidic layer and the reaction pad.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0009] Fig. 1 is an exploded view of a first exemplary test device according to embodiments of the present disclosure.
[0010] Fig. 2A is a perspective view of a second exemplary test device according to
embodiments of the present disclosure.
[0011] Fig. IB is a is a top view of a second exemplary test device according to embodiments of the present disclosure.
[0012] Fig. 2C is a side view of a second exemplary test device according to embodiments of the present disclosure.
[0013] Fig. 2D is an exploded view of a second exemplary test device according to embodiments of the present disclosure.
[0014] Fig. 3A is a perspective view of a third exemplary test device according to embodiments of the present disclosure.
[0015] Fig. 3B is a top view of a third exemplary test device according to embodiments of the present disclosure.
[0016] Fig. 3C is a side view of a third exemplary test device according to embodiments of the present disclosure. [0017] Fig. 3D is a cross-sectional view of a third exemplary test device according to
embodiments of the present disclosure.
[0018] Fig. 3E is an exploded view of a third exemplary test device according to embodiments of the present disclosure.
[0019] Fig. 3F is an exploded view of a third exemplary test device according to embodiments of the present disclosure.
[0020] Fig. 4A is a perspective view of a fourth exemplary test device according to
embodiments of the present disclosure.
[0021] Fig. 4B is a top view of a fourth exemplary test device according to embodiments of the present disclosure.
[0022] Fig. 4C is a side view of a fourth exemplary test device according to embodiments of the present disclosure.
[0023] Fig. 4D is an exploded view of a fourth exemplary test device according to embodiments of the present disclosure.
[0024] Fig. 5A is a perspective view of a fifth exemplary test device according to embodiments of the present disclosure.
[0025] Fig. 5B is a top view of a fifth exemplary test device according to embodiments of the present disclosure.
[0026] Fig. 5C is a side view of a fifth exemplary test device according to embodiments of the present disclosure.
[0027] Fig. 5D is an exploded view of a fifth exemplary test device according to embodiments of the present disclosure. [0028] Fig. 6A is a perspective view of a sixth exemplary test device according to embodiments of the present disclosure.
[0029] Fig. 6B is a top view of a sixth exemplary test device according to embodiments of the present disclosure.
[0030] Fig. 6C is a bottom view of a sixth exemplary test device according to embodiments of the present disclosure.
[0031] Fig. 6D is a side view of a sixth exemplary test device according to embodiments of the present disclosure.
[0032] Fig. 6E is a cross-sectional view of a sixth exemplary test device according to embodiments of the present disclosure.
[0033] Fig. 6F is an exploded view of a sixth exemplary test device according to embodiments of the present disclosure.
[0034] Fig. 7 is a flowchart illustrating an assay process according to embodiments of the present disclosure.
DETAILED DESCRIPTION
[0035] Benzodiazepines are a class of psychoactive drugs causing sedative, hypnotic (sleep- inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties. High doses of many shorter-acting benzodiazepines may also cause anterograde amnesia and dissociation. Benzodiazepines in overdoses can cause dangerous deep unconsciousness. When combined with other central nervous system (CNS) depressants such as alcoholic drinks and opioids, the potential for toxicity and fatal overdose increases.
[0036] Fast-onset benzodiazepines include diazepam, flunitrazepam, and midazolam. [0037] Such fast-onset benzodiazepines pose a particular danger when administered surreptitiously. They are widely referred to as date rape drugs due to their prevalence in drug- facilitated sexual assault.
[0038] Given the danger and prevalence of surreptitious administration of benzodiazepines and other drugs, there is a need for an effective portable test allowing a user to test a beverage for the presence of benzodiazepines or other drugs. Such a test kit should be easy to interpret, easy to use, discrete, and reliable.
[0039] The present disclosure provides a variety of integrated test devices for rapid detection of benzodiazepines or other drugs, for example in a beverage. Various compact form factors are provided, integrating test devices into, for example, a napkin.
[0040] With reference now to Fig. 1, an exemplary test device according to the present disclosure is illustrated. In this embodiment, a napkin 100 includes a plurality of layers
101...104. Top and bottom layer 101, 104 comprise tissue paper. Sandwiched between top and bottom layer 101, 104 is test zone 102, and impermeable layer 103. In some embodiments, an additional test zone (not pictured) is included between impermeable layer 103 and bottom layer 104. In some embodiments, additional test zone and impermeable layer pairs are included between top and bottom layer 101, 104, for example at each of the four corners of the napkin. In various embodiments, impermeable layer 103 comprises polylactic acid (PLA), and prevents the flow of fluid from bottom to top through napkin 100. In embodiments having multiple test zones, impermeable layer 103 prevents fluid flow between upper and lower test zones. Test zone 102 may include a region infused with a colorimetric compound. Test zone 102 may also include a fluid flow path, with one or more reaction zones, as for example as described in further detail below.
[0041] In some embodiments, test zone 102 comprises porous paper capable of absorbing an aliquot of a beverage. The porous paper includes color-changing compounds for detecting benzodiazepines or other drugs such as gamma-Hydroxybutyric acid (GHB) or ketamine. In some embodiments, test zone 102 is marked on upper surface 101 by a perforated region. In embodiments having multiple test zones, each test zone may be marked with a perforated region (for example on both top and bottom layers 101, 104). If a beverage contains one or more of the drug components that the napkin tests for, the saturated testing region will undergo a color change.
[0042] In various embodiments, a napkin is provided in a kit with a stir-stick and instructions on how to discreetly and safely transfer the liquid to a testing region. The stir-stick's role is to aid in transferring the liquid from the drink to the napkin.
[0043] The napkin form factor provides for discretion, as only the user is aware that the cocktail napkin includes an integrate test element. This form factor is portable, and provides for a one- step testing process, thereby increasing usability and safety for the user. As a single-use test, this form factor is also more hygienic than non-disposable alternatives.
[0044] Referring now to Figs. 2A-D, an exemplary test device according to the present disclosure is illustrated. In this embodiment, four test zones are provided within a single device.
[0045] Device 200 includes a napkin top and bottom 209, 201, between which are arranged the other components. In various embodiments top and bottom layers 209, 201 comprise tissue paper. A laminate bottom 202 is stacked on napkin bottom 201, and provides an impermeable layer preventing the flow of fluid from bottom to top through napkin 200. In various embodiments, laminate bottom 202 comprises clear polypropylene film. In various
embodiments, alternative polymer films are used. In various embodiments, laminate bottom 202 is affixed by acrylic adhesive. In various embodiments, other adhesives such as gum rubber, PVA, acrylates, epoxies, or urethanes are used.
[0046] Each test zone includes a sample pad 203 and a viewing pad 204, connected to a reaction pad 205 by transfer strips 206, 207. In various embodiments, the sample pads comprise a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pads comprise Whatman No. 1 chromatography paper. The sample pads provide absorbent pads for collecting sample for testing.
[0047] Transfer pads 206, 207 provide wicks to transport the test sample from sample pad 203 to viewing pad 204 via reaction pad 205. In some embodiments, transfer pads 206, 207 comprise Whatman pads, however, a variety of hydrophilic materials are suitable for use as set out herein. As set out further below, transfer pads 206, 207 may be loaded with reagents for hydrolyzing and/or reducing the input sample.
[0048] Reaction pad 205 comprises a hydrophilic paper or polymer, for example a Whatman pad. In some embodiments, the reaction pad is loaded with reagents for hydrolyzing and/or reducing an input sample.
[0049] Viewing pad 204 is loaded with one or more reagents for colorimetric detection of a test substance. In some embodiments, viewing pad 204 is a Whatman pad, or other hydrophilic material such as a paper or polymer. In some embodiments, the viewing pad 204 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection. In various alternative embodiments, alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs.
[0050] Laminate top 208 is stacked on the various test components, and provides an
impermeable layer preventing the flow of fluid into napkin 200 except through sample pads. In various embodiments, laminate top 208 comprises clear polypropylene film. In various embodiments, alternative polymer films are used. In various embodiments, laminate top 208 is affixed by acrylic adhesive. In various embodiments, other adhesives such as gum rubber, PVA, acrylates, epoxies, or urethanes are used. As pictured, in various embodiments laminate top 208 includes an input port aligned with sample pad 203, allowing fluid to contact sample pad 203. In embodiments where laminate top is transparent, there need not be an opening aligning with viewing pad 204. However, in embodiments where laminate top 208 is not transparent, a transparent window may be included in laminate top 208 to allow the color of viewing pad 204 to be seen.
[0051] Napkin top 209 includes ports aligning with sample pad 203 and viewing pad 204. These ports enable fluid to pass to reach sample pad 203, and allow the color change of viewing pad 204 to be seen.
[0052] When used, a sample is introduced to sample pad 203 through the corresponding port in napkin face 209 and port in laminate top 208. The sample wets sample pad 203 and the fluid laterally flows along transfer strip 206 to reaction pad 205. Hydrolysis and/or reduction reaction of the samples occurs at reaction pad 205. The fluid flows laterally flows along transfer strip 207 to viewing pad 204. The sample reacts with the colorimetric reagents loaded in viewing pad 204 to create a color change. The change in color is visible through the corresponding port in the napkin face 209 and through the transparent laminate film 208. [0053] In an exemplary embodiment, napkin 200 measures about 5 inches square, with sample pads being located about 3-4 inches apart measured from center-to-center. In an exemplary embodiment sample pads are about 5/8 inches in diameter. In an exemplary embodiment, napkin 200 is about 1/32 inch thick.
[0054] In various embodiments, the test assembly 203...207 may be laminated separately from additional assemblies. In this way, modular test assemblies may be provided for integration into napkins or other form factors. In some such embodiments, a sample well is positioned on top laminate 208 around the port corresponding to sample pad 203. In some embodiment, the sample well comprises polypropylene adhesive film. In various embodiments, alternative polymer films are used. In various embodiments, the sample well is affixed by acrylic adhesive, gum rubber, PVA, acrylates, epoxies, or urethanes.
[0055] Referring now to Figs. 3A-F, an exemplary test device according to the present disclosure is illustrated. In this embodiment, four test zones are provided, each separately laminated.
[0056] Device 300 includes a napkin top and bottom 307, 301, between which are arranged the other components. In various embodiments top and bottom layers 307, 301 comprise tissue paper. A laminate bottom 302 forms half of the laminated envelope for the test components, and provides an impermeable layer preventing the flow of fluid into those components except through an input port. In various embodiments, laminate bottom 302 comprises clear polypropylene film. In various embodiments, alternative polymer films are used. In various embodiments, laminate bottom 302 is affixed by acrylic adhesive. In various embodiments, other adhesives such as gum rubber, PVA, acrylates, epoxies, or urethanes are used. [0057] Each test zone 303...304 includes a sample pad 308 and a viewing pad 309, connected to a reaction pad (as depicted in Fig. 2) or to each over by transfer strips 310. In various embodiments, the sample pads comprise a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pads comprise Whatman No. 1 chromatography paper. The sample pads provide absorbent pads for collecting sample for testing.
[0058] Transfer strips 310 provide wicks to transport the test sample from sample pad 308 to viewing pad 309. In some embodiments, transfer pads 310 comprise Whatman pads, however, a variety of hydrophilic materials are suitable for use as set out herein. As set out further below, transfer pads 310 may be loaded with reagents for hydrolyzing and/or reducing the input sample.
[0059] Viewing pad 309 is loaded with one or more reagents for colorimetric detection of a test substance. In some embodiments, viewing pad 309 is a Whatman pad, or other hydrophilic material such as a paper or polymer. In some embodiments, the viewing pad 309 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection. In various alternative embodiments, alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs.
[0060] Laminate top 305...306 forms half of the laminated envelope for the test components, and provides an impermeable layer preventing the flow of fluid into test components except through an input port. In various embodiments, laminate top 305...306 comprises clear polypropylene film. In various embodiments, alternative polymer films are used. In various embodiments, laminate top 305...306 is affixed by acrylic adhesive. In various embodiments, other adhesives such as gum rubber, PVA, acrylates, epoxies, or urethanes are used. As pictured, in various embodiments laminate top 305...306 includes an input port aligned with sample pad 308, allowing fluid to contact sample pad 308. In embodiments where laminate top is transparent, there need not be an opening aligning with viewing pad 309. However, in embodiments where laminate top 305...306 is not transparent, a transparent window may be included in laminate top 305...306 to allow the color of viewing pad 309 to be seen.
[0061] Napkin top 307 includes ports aligning with sample pad 308 and viewing pad 309. These ports enable fluid to pass to reach sample pad 308, and allow the color change of viewing pad 309 to be seen.
[0062] When used, a sample is introduced to sample pad 308 through the corresponding port in napkin face 307 and port in laminate top 305...306. The sample wets sample pad 308 and the fluid laterally flows along transfer strip 310 to viewing pad 309. Hydrolysis and/or reduction reaction of the samples occurs in transfer strip 310. The sample reacts with the colorimetric reagents loaded in viewing pad 309 to create a color change. The change in color is visible through the corresponding port in the napkin face 307 and through the transparent laminate film 305...306.
[0063] In an exemplary embodiment, napkin 300 measures about 5 inches square. Each laminated test zone measures about 1 5/8 inches square. In an exemplary embodiment, sample pads are about 0.6 inches in diameter and viewing pads are about 0.35 inches in diameter. In various embodiments, the pads 308...310 are about 13/16 inches thick. In various embodiments, the bottom laminate is about 0.005 inches thick and the top laminate is about 0.001 inches thick. Other exemplary laminates have a thickness about 0.001 inches to about 0.010 inches. In various embodiment a tissue ply has a thickness of about 0.008 inches. However, it will be appreciated that these dimensions are merely exemplary, and a variety of dimensions may be adopted for various devices according to the present disclosure. [0064] In various embodiments, pads 308...310 may be cut out from a single larger pad. In other embodiments, pads 308...310 are defined by printing on a larger pad with a hydrophobic ink or wax to define a hypdophilic pathway. In such embodiments, the reagents are loaded in different areas in the hydrophilic sub-regions.
[0065] In various embodiments, each test zone 303...304 is laminated separately from additional assemblies. In this way, modular test assemblies may be provided for integration into napkins or other form factors.
[0066] Referring now to Figs. 4A-D, an exemplary test device according to the present disclosure is illustrated. In this embodiment, a test module is provided that may be integrated into a variety of form factors, for example a napkin such as described above.
[0067] Device 400 includes a sample pad 402. In various embodiments, the sample pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pad comprises Whatman No. 1 chromatography paper. The sample pad provides an absorbent pad for collecting sample for testing.
[0068] Beneath sample pad 402 is a silica gel wafer 404, which is loaded with sulfuric acid. It will be appreciated that a variety of alternative porous materials may be used in place of silica.
[0069] Beneath silica gel wafer 404 is outlet pad 403. In various embodiments, the outlet pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pad comprises Whatman No. 1 chromatography paper. The outlet pad wicks the sample from silica gel wafer 404 to reaction pad 405. [0070] Silica gel wafer 404 and outlet pad 403 are set inside ring 401. Ring 401 forms a chamber, within which the sample undergoes acidification. In various embodiments ring 401 comprises silicone or plastic.
[0071] Beneath ring 401, a reaction pad is provided. Reaction pad 405 comprises a hydrophilic paper or polymer, for example a Whatman pad. In some embodiments, the reaction pad is loaded with reagents for hydrolyzing and/or reducing an input sample.
[0072] Transfer strip 406 connects reaction pad 405 to viewing pad 407. In some embodiments, transfer pad 406 comprises Whatman pads, however, a variety of hydrophilic materials are suitable for use as set out herein. As set out further below, transfer pad 406 may be loaded with reagents for hydrolyzing and/or reducing the input sample.
[0073] Viewing pad 407 is loaded with one or more reagents for colorimetric detection of a test substance. In some embodiments, viewing pad 407 is a Whatman pad, or other hydrophilic material such as a paper or polymer. In some embodiments, the viewing pad 407 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection. In various alternative embodiments, alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs.
[0074] When used, a sample is introduced to sample pad 402. The sample flows downward through SiC bed 404, which is loaded with strong acid and contained in chamber 401. Acidified fluid flows down through outlet pad 403, which acts as a boundary material for the
hydrolysis/reduction pad 405. After hydrolysis/reduction, the sample flows laterally down transfer strip 406 to viewing pad 407. The sample reacts with the colorimetric reagents loaded in viewing pad 407 to generate a color change. [0075] In various embodiments, test device 400 may be embedded in a device such as the napkins described above. Test device 400 may also be used in a standalone configuration.
[0076] Referring now to Figs. 5A-D, an exemplary test device according to the present disclosure is illustrated. In this embodiment, a test module is provided that may be integrated into a variety of form factors, for example a napkin such as described above.
[0077] Device 500 includes a sample pad 502. In various embodiments, the sample pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pad comprises Whatman No. 1 chromatography paper. The sample pad provides an absorbent pad for collecting sample for testing.
[0078] Beneath sample pad 502 is a silica gel wafer 508, which is loaded with sulfuric acid. It will be appreciated that a variety of alternative porous materials may be used in place of silica.
[0079] Beneath silica gel wafer 508 is outlet pad 509. In various embodiments, the outlet pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pad comprises Whatman No. 1 chromatography paper. The outlet pad wicks the sample from silica gel wafer 508 to ion exchange resin 504 and provides a barrier between these two chemistries. Ion exchange resin 504 removes interfering substances from the sample, and in some embodiments comprises amberlite IRA 400.
[0080] Beneath ion exchange resin 504 is outlet pad 503. In various embodiments, the outlet pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pad comprises Whatman No. 1 chromatography paper. The outlet pad wicks the sample from ion exchange resin 504 to reaction pad 505 and provides a barrier between these two chemistries. [0081] Silica gel wafer 508, ion exchange resin 504, and outlet pads 509, 503 are set inside ring 501. Ring 501 forms a reaction chamber. In various embodiments ring 401 comprises silicone or plastic.
[0082] Beneath ring 501, a reaction pad is provided. Reaction pad 505 comprises a hydrophilic paper or polymer, for example a Whatman pad. In some embodiments, the reaction pad is loaded with reagents for hydrolyzing and/or reducing an input sample.
[0083] Transfer strip 506 connects reaction pad 505 to viewing pad 507. In some embodiments, transfer pad 506 comprises Whatman pads, however, a variety of hydrophilic materials are suitable for use as set out herein. As set out further below, transfer pad 506 may be loaded with reagents for hydrolyzing and/or reducing the input sample.
[0084] Viewing pad 507 is loaded with one or more reagents for colorimetric detection of a test substance. In some embodiments, viewing pad 507 is a Whatman pad, or other hydrophilic material such as a paper or polymer. In some embodiments, the viewing pad 507 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection. In various alternative embodiments, alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs.
[0085] When used, a sample is introduced to sample pad 502. The sample flows downward through SiC bed 508, which is loaded with strong acid and contained in chamber 501. Acidified fluid flows down through outlet pad 509 into ion exchange resin 504. From there, it flows down through outlet pad 503, which acts as a boundary material for the hydrolysis/reduction pad 505. After hydrolysis/reduction, the sample flows laterally down transfer strip 506 to viewing pad 507. The sample reacts with the colorimetric reagents loaded in viewing pad 507 to generate a color change. [0086] In various embodiments, test device 500 may be embedded in a device such as the napkins described above. Test device 500 may also be used in a standalone configuration.
[0087] Referring now to Figs. 6A-F, an exemplary test device according to the present disclosure is illustrated. In this embodiment, a test module is provided that may be integrated into a variety of form factors, for example a napkin such as described above.
[0088] Device 600 includes cover 611, which includes a chamber inlet. As pictured, in some embodiments, cover 611 is shared such that a inlet well is formed. In such embodiments, the well is sized to hold a sample, and expose the sample to the layers described below. In some embodiments, the well is sized to receive a cocktail straw containing a sample. In some embodiment, cover 611 comprises molded plastic. However, it will be appreciated that a variety of polymers are suitable for use as described herein.
[0089] Device 600 includes a sample pad 602. In various embodiments, the sample pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pad comprises Whatman No. 1 chromatography paper. The sample pad provides an absorbent pad for collecting sample for testing.
[0090] Beneath sample pad 602 is a silica gel wafer 603, which is loaded with sulfuric acid. It will be appreciated that a variety of alternative porous materials may be used in place of silica.
[0091] Beneath silica gel wafer 603 is mixing pad 604. In various embodiments, mixing pad provides a time delay to the sample flow to allow reaction to take place. In various
embodiments, the mixing pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pad comprises Whatman No. 1 chromatography paper. The outlet pad wicks the sample from silica gel wafer 603 to ion exchange resin 605 and provides mixing of the sample while separating chemistries. In some embodiments, mixing pad 604 is loaded with a hydrolysis reagent.
[0092] Ion exchange resin 605 removes interfering substances from the sample, and in some embodiments comprises amberlite IRA 400.
[0093] Beneath ion exchange resin 605 is mixing pad 612. In various embodiments, mixing pad provides a time delay to the sample flow to allow reaction to take place In various embodiments, the mixing pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the sample pad comprises Whatman No. 1 chromatography paper. The outlet pad wicks the sample from ion exchange resin 605 to reduction pad 606 and provides mixing of the sample while separating chemistries.
[0094] Reduction pad 606 comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the reduction pad comprises Whatman No. 1 chromatography paper. The reduction pad is loaded with a reducing reagent.
[0095] Beneath reduction pad 606 is mixing pad 613. In various embodiments, mixing pad provides a time delay to the sample flow to allow reaction to take place. In various
embodiments, the mixing pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the mixing pad comprises Whatman No. 1 chromatography paper. The mixing pad wicks the sample from reduction pad 606 to viewing pad 607 and provides mixing of the sample while separating chemistries.
[0096] Components 602, 603, 604, 605, 612, 606, 613 are set inside ring 601, thereby forming a reaction chamber. In various embodiments, ring 601 comprises silicone or plastic.
[0097] Viewing pad 607 is loaded with one or more reagents for colorimetric detection of a test substance. In some embodiments, viewing pad 607 is a Whatman pad, or other hydrophilic material such as a paper or polymer. In some embodiments, the viewing pad 607 is loaded with p-Dimethylaminocinnamaldehyde (DMACA) for colorimetric detection. In various alternative embodiments, alternative colorimetric reaction chemistry is provided for detecting hydrolyzed and reduced benzodiazepines or other drugs. As pictured viewing pad 607 has a larger radius than the components above it in the stack. Thus, the viewing pad may be seen from above through ring 601.
[0098] Beneath viewing pad 607, is chamber outlet layer 608. Outlet layer 608 comprises a channel along the outer edge, which is adapted to draw sample from the middle of viewing pad 607 to the outer edge. In various embodiments, outlet layer comprises molded plastic. Beneath outlet layer 608 is a sink pad 609. In various embodiments, the sink pad comprises a hydrophilic material such as chromatography paper. For example, in some embodiments, the sink pad comprises Whatman No. 1 chromatography paper. The sink pad wicks the sample from the viewing pad through the channel in the outlet layer.
[0099] In various embodiments, chamber bottom 610 couples to ring 601 and top 611 to form the overall exterior casing of the device.
[0100] When used, a sample is introduced to sample pad 602 via the input port in cover 611. The sample flows downward through SiC bed 603, which is loaded with strong acid and contained in chamber 601. Hydrolyzed fluid flows down through mix pad 604 into ion exchange resin 605. From there, it flows down through mix pad 612, which acts as a boundary material reduction pad 606. After reduction, the sample flows through mix pad 613 to the center of viewing pad 607. The sample reacts with the colorimetric reagents loaded in viewing pad 607 to generate a color change. Sink pad 609 draws the sample from the center of viewing pad 607 to its edges and through outlet holes in chamber outlet layer 608. This radial flow allows visualization of the viewing pad 607 through cover 611 and ring 601. In some embodiments, bottom 610 includes a center vent hole for air management. In various embodiments, mixing pads provides a time delay to the sample flow to allow reaction to take place.
[0101] Referring to Fig. 7, an assay process for detecting benzodiazepines or other drugs is illustrated according to embodiments of the present disclosure. At 701, a sample is exposed to a strong acid. In some embodiments, the strong acid is suspended in a shelf stable solid or gel. For example, in some embodiments, sulphuric acid is suspended in a silica gel. In other embodiments, sulphuric acid, hydrochloric acid, phosphoric acid, or sulphonic acid is suspended in silica gel, ion exchange resin, polymer microbeads, or acidic membranes.
[0102] At 702, the sample is supplied to an ion exchange resin. In various embodiments, the ion exchange resin is a styrene/divinylbenzene resin such as amberlite IRA 400. However, it will be appreciated that a variety of anion exchange resins are suitable for use according to the present disclosure.
[0103] At 703, the sample is reduced. In some embodiments, the reducing agent is loaded in a reactive pad. In some embodiments, the reducing agent comprises stannous chloride. In some embodiments, the reducing agent comprises cobalt powder. In some embodiments, the reducing agent comprises iron powder. In some embodiments a reactive pad is loaded with a solution of the reducing agent.
[0104] At 704, a colorimetric reaction is performed. In various embodiments, the colorimetric reagent comprises p-dimethylaminocinnamaldehyde (DMACA). In such embodiments, a pink/red color is obtained with the presence of benzodiazepines. Other colorimetric reagents are suitable for use in detection of other drugs. Variation in the reducing agent may result in a variation in the resulting color. For example, while stannous chloride yields a pink/red color, cobalt yields a darker fuchsia.
[0105] The descriptions of the various embodiments of the present disclosure have been presented for purposes of illustration, but are not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein was chosen to best explain the principles of the embodiments, the practical application or technical improvement over technologies found in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

CLAIMS What is claimed is:
1. A test device comprising:
a reaction chamber having an input port and an output port, the reaction chamber having translucent walls having a thickness;
a hydrophilic sample pad disposed at the input port;
an acidic layer disposed within the reaction chamber and in fluid communication with the sample pad;
an ion exchange resin layer disposed within the reaction chamber and in fluid communication with the acidic layer;
a hydrophilic reaction pad disposed within the reaction chamber and in fluid
communication with the ion exchange resin layer, the hydrophilic reaction pad being infused with a hydrolyzing and/or reducing reagent;
a viewing pad disposed at the output port and in fluid communication with the reaction pad, the viewing pad extending along the thickness of the reaction chamber walls, the viewing pad being infused with at least one colorimetric reagent.
2. The test device of claim 1 , wherein the reaction chamber comprises silicone or plastic.
3. The test device of claim 1, wherein the test device is disposed between napkin layers.
4. The test device of claim 1 , wherein the sample pad, reaction pad, and/or viewing pad comprise chromatography paper.
5. The test device of claim 1, wherein the acidic layer comprises silica.
6. The test device of claim 1 , wherein the acidic layer comprises sulphuric acid, hydrochloric acid, phosphoric acid, or sulphonic acid.
7. The test device of claim 1 , further comprising a mixing pad disposed between the acidic layer and the ion exchange resin layer.
8. The test device of claim 1, further comprising a mixing pad disposed between the ion exchange resin layer and the reaction pad.
9. The test device of claim 1 , wherein the hydro lyzing and/or reducing reagent comprises stannous chloride, cobalt powder, or iron powder.
10. The test device of claim 1, wherein the at least one colorimetric reagent comprises p- dimethylaminocinnamaldehyde.
11. A test device comprising:
a laminated envelope comprising an upper surface and a lower surface, the upper surface having an inlet port and at least one translucent area;
a hydrophilic sample pad disposed within the laminated envelope and aligned with the inlet port;
a viewing pad disposed within the laminated envelope and aligned with one of the at least one translucent areas, the viewing pad being infused with at least one colorimetric reagent;
one more hydrophilic components disposed within the laminated envelope and in fluid communication with the sample pad and the viewing pad, at least one of the one more hydrophilic components comprising a hydrolyzing and/or reducing reagent.
12. The test device of claim 11, wherein the laminated envelope comprises polypropylene film.
13. The test device of claim 11, wherein the laminate envelope is disposed between napkin layers.
14. The test device of claim 11, wherein the sample pad, viewing pad, and/or one more hydrophilic components comprise chromatography paper.
15. The test device of claim 11 , wherein the one more hydrophilic components comprise a reaction pad and one or more transfer pads.
16. The test device of claim 11, wherein the hydro lyzing and/or reducing reagent comprises stannous chloride, cobalt powder, or iron powder.
17. The test device of claim 11, wherein the at least one colorimetric reagent comprises p- dimethylaminocinnamaldehyde.
18. A test device comprising :
a reaction chamber having an input port and an output port;
a hydrophilic sample pad disposed at the input port;
a hydrophilic reaction pad disposed at the output port, the hydrophilic reaction pad being infused with a hydrolyzing and/or reducing reagent;
an acidic layer disposed within the reaction chamber and in fluid communication with the sample pad and the reaction pad;
a viewing pad disposed outside the reaction chamber and in fluid communication with the reaction pad, the viewing pad being infused with at least one colorimetric reagent.
19. The test device of claim 18, wherein the reaction chamber comprises silicone or plastic.
20. The test device of claim 18, wherein the test device is disposed between napkin layers.
21. The test device of claim 18, wherein the sample pad, reaction pad, and/or viewing pad comprise chromatography paper.
22. The test device of claim 18, wherein the acidic layer comprises silica.
23. The test device of claim 18, wherein the acidic layer comprises sulphuric acid, hydrochloric acid, phosphoric acid, or sulphonic acid.
24. The test device of claim 18, further comprising a mixing pad disposed between the acidic layer and the reaction pad.
25. The test device of claim 18, wherein the hydrolyzing and/or reducing reagent comprises stannous chloride, cobalt powder, or iron powder.
26. The test device of claim 18, wherein the at least one colorimetric reagent comprises p- dimethylaminocinnamaldehyde.
27. The test device of claim 18, further comprising an ion exchange resin layer disposed between the acidic layer and the reaction pad.
PCT/US2018/035187 2017-05-30 2018-05-30 Integrated devices for rapid detection of benzodiazepines or other drugs in solution WO2018222750A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201762512302P 2017-05-30 2017-05-30
US62/512,302 2017-05-30
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US62/596,359 2017-12-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021226305A1 (en) * 2020-05-06 2021-11-11 Syngenta Crop Protection Ag Colorimetric measurement of fludioxonil

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3598533A (en) * 1968-04-04 1971-08-10 Chugai Pharmaceutical Co Ltd Diagnostic paper strip
US6713306B1 (en) * 2001-09-05 2004-03-30 R. E. Davis Chemical Corporation Method for identification of flunitrazepam
US20100081188A1 (en) * 2003-12-19 2010-04-01 James Gordon Campbell Apparatus for detecting drugs in a beverage
US20150368691A1 (en) * 2013-01-23 2015-12-24 Anp Technologies, Inc. One-step Rapid Assay for the Detection of Inhibitors of Enzymes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3598533A (en) * 1968-04-04 1971-08-10 Chugai Pharmaceutical Co Ltd Diagnostic paper strip
US6713306B1 (en) * 2001-09-05 2004-03-30 R. E. Davis Chemical Corporation Method for identification of flunitrazepam
US20100081188A1 (en) * 2003-12-19 2010-04-01 James Gordon Campbell Apparatus for detecting drugs in a beverage
US20150368691A1 (en) * 2013-01-23 2015-12-24 Anp Technologies, Inc. One-step Rapid Assay for the Detection of Inhibitors of Enzymes

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021226305A1 (en) * 2020-05-06 2021-11-11 Syngenta Crop Protection Ag Colorimetric measurement of fludioxonil

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