MEASUREMENT OF GLUCOSE NEAR AN INSULIN DELIVERY CATHETER BY MINIMIZING THE ADVERSE EFFECTS OF INSULIN PRESERVATIVES: ALTERNATIVE LIGANDS AND REDOX MEDIATOR METALS
A device for delivery of an insulin or insulin analog formulation and measurement of subcutaneous glucose concentration may comprise a hollow tube, and an amperometric glucose sensor located proximal to a distal end of the hollow tube. The amperometric glucose sensor may comprise a redox mediator and an enzyme comprising glucose oxidase or glucose dehydrogenase. An applied bias potential may allow an electrode layer of the amperometric glucose sensor to undergo substantially no electropolymerization of an excipient of the insulin or insulin analog formulation during continuous operation of amperometric glucose sensor. A sensitivity of the amperometric glucose sensor to the subcutaneous glucose concentration may be maintained in presence of the insulin or insulin analog formulation.
1 . (canceled)
2 . A device for delivery of an insulin or insulin analog formulation and measurement of subcutaneous glucose concentration, comprising:
a hollow tube comprising a distal end configured to deliver the insulin or insulin analog formulation subcutaneously into a subject, wherein the subject comprises a human or an animal, wherein the insulin or insulin analog formulation comprises an excipient; and
an amperometric glucose sensor located no more than a pre-determined distance away from the distal end, wherein the amperometric glucose sensor comprises:
an electrode layer comprising at least one indicating electrode, wherein the electrode layer underlies a redox-catalytic layer comprising:
(1) a redox mediator comprising a metal compound, wherein the metal compound comprises a metal selected from the group consisting of: ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper, and
(2) an enzyme;
wherein the redox mediator and the enzyme allow electron transfer from subcutaneous glucose to the at least one indicating electrode sufficient to cause a response of the amperometric glucose sensor to a subcutaneous glucose concentration at an applied bias potential of no more than +250 millivolts (mV) relative to a reference electrode;
wherein the applied bias potential of no more than +250 m V relative to the reference electrode allows the electrode layer to undergo substantially no electrochemical reaction of the excipient during continuous operation of at least one hour of the amperometric glucose sensor, thereby maintaining a sensitivity of the amperometric glucose sensor to the subcutaneous glucose concentration in a presence of the insulin or insulin analog formulation.
3 . The device of claim 2 , wherein the excipient comprises a phenol or cresol.
4 . The device of claim 3 , further comprising a filter configured to remove the phenol or the cresol from the insulin or insulin analog formulation.
5 . The device of claim 2 , wherein the metal compound is covalently bound to a pyridine-based or imidazole-based ligand.
6 . The device of claim 5 , wherein the pyridine-based ligand is 4,4′-dimethyl-2,2′-bipyridine.
7 . The device of claim 5 , wherein the pyridine-based ligand is poly (4-vinyl pyridine).
8 . The device of claim 5 , wherein the imidazole-based ligand is poly (1-vinyl imidazole).
9 . The device of claim 2 , wherein the reference electrode comprises silver (Ag) or silver chloride (AgCl).
10 . The device of claim 2 , wherein the electrode layer comprises a film having a thickness of no more than about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm.
11 . The device of claim 2 , wherein the amperometric glucose sensor is disposed on a second hollow tube comprising a second distal end, wherein the second distal end is configured to be inserted subcutaneously.
12 . The device of claim 2 , further comprising a housing comprising an upper accessible surface and a lower surface configured to be adhered to a skin surface.
13 . The device of claim 2 , wherein the pre-determined distance is about 15 millimeters (mm), 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm.
14 . The device of claim 2 , wherein the amperometric sensor further comprises an insulating layer and a metal layer, wherein the insulating layer is coupled to the metal layer, and wherein the metal layer is coupled to the electrode layer.
15 . The device of claim 14 , wherein the insulating layer comprises a polyimide or liquid crystal polymer.
16 . The device of claim 2 , wherein the applied bias potential is no more than about +200 mV, +150 mV, +100 mV, or +50 mV relative to the reference electrode.
17 . The device of claim 16 , wherein the applied bias potential of no more than about +200 mV, +150 mV, +100 mV, or +50 mV relative to the reference electrode allows the electrode layer to undergo substantially no electrochemical reaction of the excipient during continuous operation of at least one hour of the amperometric glucose sensor.
18 . The device of claim 2 , wherein the ligand comprises a heterocyclic nitrogen compound, a pyridine ring combined with an imidazole ring, a non-nitrogen element substituted into a heterocycle ring, or an accessory “R” group bound to a heterocyclic ring.
19 . The device of claim 2 , wherein the metal compound comprises ruthenium.
20 . The device of claim 2 , wherein the enzyme comprises glucose oxidase or glucose dehydrogenase.
21 . The device of claim 2 , wherein the at least one indicating electrode comprises one or more of gold, carbon, graphite, platinum, or iridium.