Glucose measurement near insulin delivery catheters by minimizing the adverse effects of insulin preservatives: Alternative ligands and redox mediator metals

Abstract

This invention provides a device in which a glucose sensor can be successfully integrated with an insulin cannula, as well as a method for using the same. [Solution] A device for the delivery of insulin or insulin analog formulations and for measuring subcutaneous glucose concentration may include a hollow tube and an amperometric glucose sensor positioned proximal to the distal end of the hollow tube. The amperometric glucose sensor may include an enzyme comprising a redox mediator and glucose oxidase or glucose dehydrogenase. The applied bias potential may ensure that the electrode layer of the amperometric glucose sensor substantially does not undergo electrolytic polymerization of the excipients of the insulin or insulin analog formulation during continuous operation of the amperometric glucose sensor. The sensitivity of the amperometric glucose sensor to subcutaneous glucose concentration may be maintained in the presence of insulin or insulin analog formulations.

Claims

1. A device for the delivery of insulin or insulin analog formulations and for measuring subcutaneous glucose concentration, the following: A hollow tube having a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of insulin or an insulin analog formulation, and the distal end is designed to deliver the insulin or insulin analog formulation subcutaneously, wherein the insulin or insulin analog formulation contains an excipient comprising phenol or cresol; and A current-measuring glucose sensor located at a distance not greater than a predetermined distance from the distal end, wherein the current-measuring glucose sensor includes the following: An electrode layer comprising at least one indicator electrode, wherein the electrode layer is located beneath a redox catalyst layer comprising (1) a redox mediator containing a metal compound covalently bonded to a ligand and (2) an enzyme comprising glucose oxidase or glucose dehydrogenase; A device that includes this.

2. A device according to claim 1, further comprising a housing including an upper accessible surface and a lower surface designed to adhere to a skin surface.

3. A device according to claim 1, wherein the current measuring glucose sensor is positioned on a second hollow tube including a second distal end, and the second distal end is designed to be inserted subcutaneously.

4. A device according to claim 1, wherein at least one indicator electrode comprises gold, carbon, graphite, platinum, or iridium.

5. A device according to claim 1, wherein the ligand is pyridine-based.

6. The device according to claim 5, wherein the ligand is 4,4'-dimethyl-2,2'-bipyridine.

7. A device according to claim 1, wherein the ligand is imidazole-based.

8. A device according to claim 1, wherein the redox mediator is bonded to poly(4-vinylpyridine).

9. A device according to claim 1, wherein the redox mediator is bonded to poly(1-vinylimidazole).

10. A device according to claim 1, wherein the excipient comprises phenol.

11. A device according to claim 1, wherein the excipient comprises cresol.

12. A device according to claim 1, wherein the predetermined distance is approximately 15 millimeters (mm), 14 mm, 13 mm, 12 mm, 10 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm.

13. A device according to claim 1, wherein the current measuring sensor further includes a reference electrode.

14. The device according to claim 13, wherein the reference electrode includes a silver / silver chloride (Ag / AgCl) reference electrode.

15. A device according to claim 1, wherein the current measuring sensor further comprises an insulating layer and a metal layer, the insulating layer being bonded to the metal layer and the metal layer being bonded to the electrode layer.

16. A device according to claim 15, wherein the insulating layer comprises a polyimide or a liquid crystal polymer.

17. A device according to claim 15, wherein the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm.

18. A device according to claim 17, wherein the metal layer comprises titanium, gold, or platinum.

19. A device according to claim 1, wherein the electrode layer comprises a thin film having a thickness not exceeding approximately 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm.

20. A device according to claim 1, wherein the redox mediator and the enzyme enable electron transfer from subcutaneous glucose to the at least one indicator electrode at an applied bias potential not exceeding about +250 millivolts (mV), +200 mV, +150 mV, +100 mV, or +50 mV compared to a reference electrode, thereby causing a response of the current-measuring glucose sensor to a subcutaneous glucose concentration.

21. A device according to claim 20, wherein the applied bias potential, which is not more than about +250 mV, +200 mV, +150 mV, +100 mV, or +50 mV compared to the reference electrode, prevents the electrode layer from substantially undergoing electropolymerization of the excipient during at least one hour of continuous operation of the current-measuring glucose sensor, thereby maintaining the sensitivity of the current-measuring glucose sensor to subcutaneous glucose concentration in the presence of the insulin or insulin analog formulation.

22. A device according to any one of claims 1 to 21, wherein the metal compound comprises a metal selected from the group consisting of osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

23. A device according to claim 22, wherein the metal compound comprises a metal selected from the group consisting of ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

24. A device according to any one of claims 1 to 23, wherein the ligand comprises a heterocyclic nitrogen compound, a pyridine ring combined with an imidazole ring, a non-nitrogen element substituted in a heterocyclic ring, or an accessory "R" group bonded to a heterocyclic ring.

25. A device according to claim 24, wherein the heterocyclic nitrogen compound comprises a pyridine or imidazole having one, two, three, or four rings.

26. Insulin or an insulin analog formulation is delivered, and subcutaneous glucose concentration is measured. The method involves the following steps: (a) Obtain a device for the delivery of insulin or an insulin analog formulation and for measuring subcutaneous glucose concentration, wherein the device includes: (i) a hollow tube having a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of insulin or an insulin analog formulation, and the distal end is designed to deliver the insulin or insulin analog formulation subcutaneously, wherein the insulin or insulin analog formulation comprises an excipient comprising phenol or cresol; and (ii) A current-measuring glucose sensor located at a distance not greater than a predetermined distance from the distal end, wherein the current-measuring glucose sensor includes: An electrode layer comprising at least one indicator electrode, wherein the electrode layer is located beneath a redox catalyst layer comprising (1) a redox mediator comprising a metal compound covalently bonded to a ligand and (2) an enzyme comprising glucose oxidase or glucose dehydrogenase; (b) Connect the proximal end of the hollow tube to a source of the insulin or insulin analog formulation; (c) Subcutaneous insertion of the distal end of the hollow tube into the target; and (d) Simultaneously (1) deliver the insulin or insulin analog formulation subcutaneously to the subject, and (2) measure the subcutaneous glucose concentration of the subject; A method that includes this.

27. A method according to claim 26, wherein the device comprises a housing further including an upper accessible surface and a lower surface, the method further including attaching the lower surface to the skin surface of the object.

28. A method according to claim 26, wherein the current measuring glucose sensor is positioned on a second hollow tube including a second distal end, and the second distal end is designed to be inserted subcutaneously.

29. A method according to claim 26, wherein at least one indicator electrode comprises gold, carbon, graphite, platinum, or iridium.

30. The method according to claim 26, wherein the ligand is pyridine-based.

31. A method according to claim 30, wherein the ligand is 4,4'-dimethyl-2,2'-bipyridine.

32. A method according to claim 26, wherein the ligand is imidazole-based.

33. The method according to claim 26, wherein the redox mediator is bonded to poly(4-vinylpyridine).

34. A method according to claim 26, wherein the redox mediator is bonded to poly(1-vinylimidazole).

35. A method according to claim 26, wherein the excipient comprises the phenol.

36. A method according to claim 26, wherein the excipient comprises the cresol.

37. The method according to claim 26, wherein the predetermined distance is approximately 15 millimeters (mm), 14 mm, 13 mm, 12 mm, 10 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 A method where the dimensions are mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm.

38. A method according to claim 26, wherein the current measuring sensor further includes a reference electrode.

39. The method according to claim 38, wherein the reference electrode comprises a silver / silver chloride (Ag / AgCl) reference electrode.

40. A method according to claim 26, wherein the current measuring sensor further comprises an insulating layer and a metal layer, the insulating layer being bonded to the metal layer and the metal layer being bonded to the electrode layer.

41. A method according to claim 40, wherein the insulating layer comprises a polyimide or a liquid crystal polymer.

42. A method according to claim 40, wherein the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm.

43. A method according to claim 42, wherein the metal layer comprises titanium, gold, or platinum.

44. A method according to claim 26, wherein the electrode layer comprises a thin film having a thickness not exceeding about 1,000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm.

45. A method according to claim 26, further comprising applying a bias potential not exceeding about +250 millivolts (mV), +200 mV, +150 mV, +100 mV, or +50 mV compared to a reference electrode, wherein the redox mediator and the enzyme enable electron transfer from subcutaneous glucose to at least one indicator electrode sufficient to cause a response of the current-measuring glucose sensor to subcutaneous glucose concentration at the applied bias potential.

46. A method according to claim 45, wherein the applied bias potential prevents the electrode layer from undergoing substantially electropolymerization of the excipient during at least one hour of continuous operation of the current-measuring glucose sensor, thereby maintaining the sensitivity of the current-measuring glucose sensor to subcutaneous glucose concentration in the presence of the insulin or insulin analog formulation.

47. A method according to any one of claims 26 to 46, wherein the metal compound comprises a metal selected from the group consisting of osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

48. A method according to claim 47, wherein the metal compound comprises a metal selected from the group consisting of ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

49. A method according to any one of claims 26 to 48, wherein the ligand comprises a heterocyclic nitrogen compound, a pyridine ring combined with an imidazole ring, a non-nitrogen element substituted in a heterocyclic ring, or an accessory "R" group bonded to a heterocyclic ring.

50. A method according to claim 49, wherein the heterocyclic nitrogen compound comprises a pyridine or imidazole having one, two, three, or four rings.

51. A method according to any one of claims 26 to 50, wherein the subject has type 1 diabetes.

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