Membrane system with sufficient buffering capacity

• US 8,721,870 B2
• Filed: 03/16/2010
• Issued: 05/13/2014
• Est. Priority Date: 03/19/2009
• Status: Active Grant

• Current Assignee: Edwards Lifesciences Corporation
• Original Assignee: Edwards Lifesciences Corporation
• Inventors: Petisce, James, Mooney, Charles, Oviatt, Henry Jr.
• Primary Examiner(s): Noguerola, Alex
• Application Number:
  US12/724,583
• Publication Number:
  US 20100236923A1
• Time in Patent Office: 1,519 Days
• Field of Search: 204/400, 20440309-40315, 205/775, 205/777.5
• US Class Current: 205/777.5
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: A61B 5/1495 Calibrating or testing of in-vivo probes
• CPC Class Codes: A61B 5/415 the glands, e.g. tonsils, adenoids or thymus
• CPC Class Codes: C12Q 1/001 Enzyme electrodes
• CPC Class Codes: C12Q 1/002 Electrode membranes
• CPC Class Codes: G01N 27/3271 Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood amperometry per se G01N27/49; aspects concerning the enzyme reagent C12Q1/001

Abstract

Electrochemical sensors for measurement of an analyte comprising an analyte sensing membrane comprising at least one salt of acetate ion, carbonate ion, bicarbonate ion, or mixtures thereof. Sensor testing methods comprising contacting an electrochemical sensor with an aqueous solution comprising at least one salt of acetate ion, carbonate ion, bicarbonate ion, or mixtures thereof and contacting the electrochemical sensor with one or more concentrations of analyte, the one or more concentrations of analyte being in the clinical concentration range of the analyte.

Claims

1. An electrochemical analyte sensor comprising:

at least one electrode having an electroactive surface;

an analyte sensing membrane, at least a portion of the membrane covering the electroactive surface, the membrane comprising;

an optional interference layer;

an enzyme layer;

an optional hydrophilic polymer layer positioned (i) between the electroactive surface and the optional interference layer and/or (ii) between the optional interference layer and the enzyme layer; and

at least one buffering agent associated with the analyte sensing membrane, wherein the buffering agent comprises a polycation salt, the polycation salt comprising at least one of acetate ion, carbonate ion, bicarbonate ion, or combinations thereof.

2. The sensor of claim 1, wherein the buffering agent is (i) a dried layer between the electroactive surface and the optional interference layer;

(ii) a dried layer between the optional interference layer and the enzyme layer;

(iii) associated with the optional hydrophilic polymer layer, the optional hydrophilic layer positioned (a) between the electroactive surface and the optional interference layer and/or (b) between the optional interference layer and the enzyme layer;

or (iv) any or combinations of (i)-(iii).

3. The sensor of claim 1, wherein the buffering agent provides a signal drift at 400 mg/dL, glucose or more of 10% or less over a time period up to 8 hours or more.

4. The sensor of claim 1, wherein the at least one buffering agent is present in an amount sufficient to neutralize at least one of an acidic, electrochemically produced by-product of the enzyme layer over the clinical concentration range of analyte.

5. The sensor of claim 1, wherein the interference layer is cellulose acetate butyrate.

6. The sensor of claim 1, wherein the enzyme layer comprises an enzyme and a material selected from the group consisting of poly-N-vinylpyrrolidone, poly-N-vinyl-3-ethyl-2-pyrrolidone, poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole, poly-N-N-dimethylacrylamide, polyacrylamide, polyurethanes, and copolymers thereof.

7. The sensor of claim 1, wherein the optional hydrophilic polymer is poly-N-vinylpyrrolidone.

8. The sensor of claim 1, wherein the optional hydrophilic polymer excludes an enzyme.

9. The sensor of claim 1, further comprising a flux-limiting membrane, wherein the flux-limiting layer is a sealant or encapsulant of the analyte sensing membrane.

10. The sensor of claim 1, wherein the flux-limiting membrane is selected from the group consisting of vinyl polymers, polysilicones, polyurethanes, and copolymers or blends thereof.

11. The sensor of claim 1, wherein the flux-limiting membrane is poly(ethylene-vinylacetate).

12. An electrochemical analyte sensor comprising:

at least one working electrode having an electroactive surface;

an analyte sensing membrane comprising;

a hydrophilic layer;

an optional interference layer;

an enzyme layer; and

at least one buffering agent consisting of a polycation salt of any one of acetate ion, carbonate ion, bicarbonate ion, or mixtures thereof, the at least one buffering agent being;

(i) a dried layer between the electroactive surface and the optional interference layer;

(ii) a dried layer between the optional interference layer and the enzyme layer;

(iii) associated with the optional hydrophilic polymer layer, the hydrophilic layer positioned (a) between the electrode surface and the optional interference layer and/or (b) between the optional interference layer and the enzyme layer;

(iv) associated with the enzyme layer;

or (v) any or all combinations of (i)-(iv);

wherein the hydrophilic layer is positioned (i) between the electroactive surface and the optional interference layer or enzyme layer and/or (ii) between the optional interference layer and an enzyme layer, the hydrophilic layer comprising at least one hydrophilic polymer and excluding an enzyme.

13. The sensor of claim 12, wherein the at least one buffering agent is present in an amount sufficient to neutralize at least one of an acidic, electrochemically produced by-product of the enzyme layer over the clinical concentration range of analyte.

14. The sensor of claim 12, wherein the enzyme layer comprises an enzyme and a material selected from the group consisting of poly-N-vinylpyrrolidone, poly-N-vinyl-3-ethyl-2-pyrrolidone, poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole, poly-N-N-dimethylacrylamide, polyacrylamide, polyurethane, and copolymers thereof.

15. The sensor of claim 12, wherein the hydrophilic polymer is poly-N-vinylpyrrolidone.

16. The sensor of claim 12, further comprising a flux-limiting membrane covering the enzyme layer, the optional interference layer, the hydrophilic layer, and the at least one electrode wherein the flux-limiting membrane is selected from the group consisting of vinyl polymers, polysilicones, polyurethanes, and copolymers or blends thereof.

17. The sensor of claim 16, wherein the flux-limiting membrane is poly(ethylene-vinylacetate).

18. The sensor of claim 12, wherein the sensor is constructed on a flex circuit, wherein the flex circuit comprises at least one reference electrode and at least one working electrode, and at least one counter electrode, the flex circuit being (i) configurable to a catheter for intravenously measuring an analyte concentration in a subject;

and/or (ii) configurable to a continuous blood glucose monitor for continuously measuring the glucose concentration in a subject.

19. An in vitro, electrochemical analyte sensor testing method, the method comprising:

providing an electrochemical sensor;

contacting the electrochemical sensor to an aqueous solution comprising a buffering agent, wherein the buffering agent comprises acetate ion, carbonate ion, bicarbonate ion, phosphate buffered saline (PBS) of at least 0.030 molality Na₂HPO₄ and at least 0.006 molality KH₂PO₄, or any combination of acetate ion, carbonate ion, bicarbonate ion, and phosphate buffered saline (PBS), the buffering agent providing a signal drift at 400 mg/dL glucose or more of 10% or less over a time period of at least one hour;

contacting the electrochemical sensor with one or more concentrations of analyte, the one or more concentrations of analyte being in the clinical concentration range of the analyte; and

testing the electrochemical analyte sensor.

20. The method of claim 19, wherein the buffering agent is present in an amount sufficient to:

(i) neutralize acidic, electrochemically generated by-products of the electrochemical analyte sensor over the clinical concentration range of the analyte in vitro; and

/or

(ii) provide essentially a constant output current at the upper end of the clinical concentration range of the analyte for at least two hours when tested in vitro.

21. The method of claim 20, wherein the buffering agent comprises phosphate buffered saline (PBS) buffer, wherein the total molar amount of carbonate ion, bicarbonate ion, or mixture of carbonate and bicarbonate ions is at least 20 mM.

22. The method of claim 19, wherein the buffering agent provides a signal drift at 400 mg/dL glucose or more of 10% or less over a time period up to 8 hours or more.