# US 11,112,377 B2 · Enzyme immobilized adhesive layer for analyte sensors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,112,377 B2 - Document ID: US11112377B2 - Status: Granted - Kind: B2 - Application number: 15/394,520 - Filed: 2016-12-29 - Published: 2017-07-06 - Granted: 2021-09-07 - Earliest claimed: 2015-12-30 - Assignees: DexCom, Inc. - Applicants: DexCom, Inc. - Inventors: Shanger Wang; Ted Tang Lee; Jiong Zou - Web page: https://patentgrep.com/patent/US11112377B2 ## CPC - G01N 27/3273: {Devices therefor, e.g. test element readers, circuitry (details not specific to biochemical electrodes G01N33/4875)} - A61B 5/0004: {characterised by the type of physiological signal transmitted} - A61B 5/14532: {for measuring glucose, e.g. by tissue impedance measurement} - A61B 5/14546: {for measuring analytes not otherwise provided for, e.g. ions, cytochromes} - A61B 5/1473: invasive, e.g. introduced into the body by a catheter - A61B 5/1486: using enzyme electrodes, e.g. with immobilised oxidase - A61B 5/14865: {invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors} - A61K 31/045: Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates - A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} - A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine - A61K 31/465: Nicotine; Derivatives thereof - A61K 31/485: Morphinan derivatives, e.g. morphine, codeine - A61K 31/515: Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital - A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids - A61K 33/00: Medicinal preparations containing inorganic active ingredients - A61K 36/185: Magnoliopsida (dicotyledons) - A61K 38/28: Insulins - C08G 18/0828: {containing sulfonate groups or groups forming them} - C08G 18/12: using two or more compounds having active hydrogen in the first polymerisation step - C08G 18/3857: {having nitrogen in addition to sulfur} - C08G 18/4018: {Mixtures of compounds of group C08G18/42 with compounds of group C08G18/48} - C08G 18/44: Polycarbonates - C08G 18/4833: {Polyethers containing oxyethylene units} - C08G 18/755: {and at least one isocyanate or isothiocyanate group linked to a secondary carbon atom of the cycloaliphatic ring, e.g. isophorone diisocyanate} - C08L 39/06: Homopolymers or copolymers of N-vinyl-pyrrolidones - C08L 69/00: Compositions of polycarbonates; Compositions of derivatives of polycarbonates - C08L 75/04: Polyurethanes - C12N 11/08: the carrier being a synthetic polymer - C12N 11/089: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds - C12N 11/093: Polyurethanes - C12Q 1/002: {Electrode membranes} - C12Q 1/006: {for glucose} - G01N 27/40: Semi-permeable membranes or partitions - G01N 33/66: involving blood sugars, e.g. galactose - A61B 5/002: {Monitoring the patient using a local or closed circuit, e.g. in a room or building (A61B5/0017 takes precedence)} - A61B 2562/12: Manufacturing methods specially adapted for producing sensors for in-vivo measurements - G01N 27/3275: {Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction} - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) - A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS - C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES ## Abstract Disclosed are devices for determining an analyte concentration (e.g., glucose). The devices comprise a sensor configured to generate a signal associated with a concentration of an analyte and a sensing membrane located over the sensor. The sensing membrane comprises an enzyme layer, wherein the enzyme layer comprises an enzyme and a polymer comprising polyurethane and/or polyurea segments and one or more zwitterionic repeating units. The enzyme layer protects the enzyme and prevents it from leaching from the sensing membrane into a host or deactivating. ## Claims ### Claim 1 A device for measurement of an analyte concentration, the device comprising: a sensor configured to generate a signal associated with a concentration of an analyte; a sensing membrane located over the sensor, the sensing membrane comprising an enzyme layer, wherein the enzyme layer comprises an enzyme and an enzyme-layer polymer that retains at least 80% of initial enzyme loading when contacted with an aqueous solution for 1 hour at about 25° C., and wherein the enzyme-layer polymer comprises polyurethane and/or polyurea segments and one or more zwitterionic repeating units, and wherein at least one of the zwitterionic repeating units is an internal zwitterionic repeating unit in a backbone of the enzyme-layer polymer and the at least one of the zwitterionic repeating units compromises a betaine compound or a precursor thereof; and a biointerface membrane positioned over the sensing membrane and configured to interface with a biological fluid. ### Claim 2 (depends on 1) The device of claim 1, wherein the enzyme-layer polymer further comprises one or more ionic or non-ionic emulsion stabilizing agents selected from carboxylic acid diols, polyethyleneoxide diol, polyoxazoline. ### Claim 3 (depends on 1) The device of claim 1, wherein the one or more zwitterionic repeating units comprise at least one moiety selected from the group consisting of a carboxyl betaine, a sulfo betaine, a phosphor betaine, and derivatives thereof. ### Claim 4 (depends on 1) The device of claim 1, wherein the one or more zwitterionic repeating units are derived from a monomer selected from the group consisting of: where Z is branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl; R1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R2 is selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R3 is selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heteroncycloalkyl, aryl, and heteroaryl; R4 is selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and wherein one or more of R1, R2, R3, R4, and Z are substituted with a polymerization group. ### Claim 5 (depends on 1) The device of claim 1, wherein the one or more zwitterionic repeating units are derived from a monomer selected from the group consisting of: where Z is branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl; R1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R2 is selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R3 is selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein one or more of R1, R2, R3, and Z are substituted with a polymerization group. ### Claim 6 (depends on 1) The device of claim 1, wherein the one or more zwitterionic repeating units are derived from a monomer selected from the group consisting of: where Z is branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl; R1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R2 is selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R3 is selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein one or more of R1, R2, R3, and Z are substituted with a polymerization group. ### Claim 7 (depends on 4) The device of claim 4, wherein the polymerization group is selected from alkene, alkyne, epoxide, lactone, amine, hydroxyl, isocyanate, carboxylic acid, anhydride, silane, halide, aldehyde, and carbodiimide. ### Claim 8 (depends on 1) The device of claim 1, wherein the one or more zwitterionic repeating units are at least 10 wt. % based on the total weight of the enzyme-layer polymer. ### Claim 9 (depends on 1) The device of claim 1, wherein the polyurethane and/or polyurea segments excluding zwitterionic repeating units are from 15 wt. % to 99 wt. %, based on the total weight of the enzyme-layer polymer. ### Claim 10 (depends on 1) The device of claim 1, wherein the enzyme-layer polymer further comprises a polyethylene oxide segment. ### Claim 11 (depends on 10) The device of claim 10, wherein the polyethylene oxide segment is from 5 wt. % to 60 wt. %, based on the total weight of the enzyme-layer polymer. ### Claim 12 (depends on 1) The device of claim 1, wherein the enzyme-layer polymer has a molecular weight of from 10 kDa to 500,000 kDa. ### Claim 13 (depends on 1) The device of claim 1, wherein the enzyme is glucose oxidase. ### Claim 14 (depends on 1) The device of claim 1, wherein the enzyme is galactose oxidase, cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactate oxidase, or uricase. ### Claim 15 (depends on 1) The device of claim 1, further comprising a base polymer, wherein the base polymer comprises a polyurethane. ### Claim 16 (depends on 15) The device of claim 15, wherein the base polymer is a polyurethane copolymer chosen from a polyether-urethane-urea, polycarbonate-urethane, polyetherurethane, silicone-polyether-urethane, silicone-polycarbonate-urethane, and polyesterurethane. ### Claim 17 (depends on 1) The device of claim 1, further comprising a base polymer, wherein the base polymer comprises a polymer selected from silicone, epoxies, polyolefins, polystyrene, polyoxymethylene, polysiloxanes, polyethers, polyacrylics, polymethacrylic, polyesters, polycarbonates, polyamide, poly(ether ketone), poly(ether imide). ### Claim 18 (depends on 1) The device of claim 1, further comprising an enzyme stabilizing reagent. ### Claim 19 (depends on 18) The device of claim 18, wherein the enzyme stabilizing reagent comprises one or more zwitterions chosen from cocamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, caprylyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly(carboxybetaine), and poly(sulfobetaine). ### Claim 20 (depends on 18) The device of claim 18, wherein the enzyme stabilizing reagent comprises bioagents chosen from albumin, chitosan, and hyaluronate. ### Claim 21 (depends on 1) The device of claim 1, further comprising a crosslinker or several crosslinkers, where in the crosslinker or the several crosslinkers comprise a polymer or oligomer selected from polyfunctional isocynate, polyfunctional aziridine, and polyfunctional carbodiimide. ### Claim 22 (depends on 1) The device of claim 1, wherein the enzyme layer is from 0.01 μm to 250 μm thick. ### Claim 23 (depends on 1) The device of claim 1, wherein the sensor comprises an electrode. ### Claim 24 (depends on 1) The device of claim 1, wherein the device is configured for continuous measurement of an analyte concentration. ### Claim 25 (depends on 1) The device of claim 1, wherein the analyte is glucose. ### Claim 26 (depends on 8) The device of claim 8, wherein the one or more zwitterionic repeating units are at least 30 wt. % based on the total weight of the enzyme-layer polymer. ### Claim 27 (depends on 1) The device of claim 1, wherein the sensing membrane is configured to be free of direct contact with biological fluid. ### Claim 28 A device for measurement of an analyte concentration, the device comprising: a sensor configured to generate a signal associated with a concentration of an analyte; a sensing membrane located over the sensor, the sensing membrane comprising an enzyme layer, wherein the enzyme layer comprises an enzyme and an enzyme-layer polymer that retains at least 50% of initial sensor sensitivity when exposed to 70° C. and 95% relative humidity conditions for up to 24 hours treatment, and the enzyme-layer polymer comprises polyurethane and/or polyurea segments and one or more zwitterionic repeating units wherein at least one zwitterionic repeating unit is an internal zwitterionic repeating unit in a backbone of the enzyme-layer polymer, and the at least one zwitterionic repeating unit comprises betaine compound or a precursor thereof; and a biointerface membrane positioned over the sensing membrane and configured to interface with a biological fluid.