Measurement of glucose in an insulin delivery catheter by minimizing the adverse effects of insulin preservatives

Abstract

In an aspect, the present disclosure provides a combined drug delivery cannula and continuous glucose sensor that measures glucose without interference from the drug excipient, said cannula being a hollow tube, the outer wall of which includes: an electrode layer with at least one indicating electrode, said layer underlying a redox-catalytic layer that includes an osmium compound bound to a ligand, and either glucose oxidase or glucose dehydrogenase.

1 .- 34 . (canceled) 
     
     
         35 . A method for delivering an insulin or insulin analog formulation and measuring subcutaneous glucose concentration, comprising:
 (a) obtaining a device comprising:   a hollow tube comprising a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of the insulin or insulin analog formulation; and   an amperometric glucose sensor located no more than 7 millimeters (mm) 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) an osmium-based redox mediator comprising an osmium compound covalently bound to a pyridine-based or imidazole-based ligand, and (2) an enzyme comprising glucose oxidase or glucose dehydrogenase;   (b) delivering the insulin or insulin analog formulation to the subject subcutaneously via the distal end of the hollow tube, wherein the insulin or insulin analog formulation comprises an excipient comprising a phenol or cresol; and   (c) measuring the subcutaneous glucose concentration of the subject, at least in part by using the osmium-based redox mediator and the enzyme to allow electron transfer from subcutaneous glucose to the at least one indicating electrode sufficient to cause a response of the amperometric glucose sensor to the 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 mV relative to the reference electrode allows the electrode layer to undergo substantially no electropolymerization 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 presence of the insulin or insulin analog formulation.   
     
     
         36 . The method of  claim 35 , wherein the device further comprises a housing comprising an upper accessible surface and a lower surface, and wherein the method further comprises adhering the lower surface to a skin surface. 
     
     
         37 . The method of  claim 35 , wherein the amperometric glucose sensor is disposed on a second hollow tube comprising a second distal end, wherein the method further comprises inserting the second distal end subcutaneously. 
     
     
         38 . The method of  claim 35 , wherein the at least one indicating electrode comprises gold, carbon, graphite, platinum, or iridium. 
     
     
         39 . The method of  claim 35 , wherein the ligand is pyridine-based. 
     
     
         40 . The method of  claim 39 , wherein the ligand is 4,4′-dimethyl-2,2′-bipyridine. 
     
     
         41 . The method of  claim 35 , wherein the ligand is imidazole-based. 
     
     
         42 . The method of  claim 35 , wherein the osmium-based redox mediator is bound to poly (4- vinyl pyridine). 
     
     
         43 . The method of  claim 35 , wherein the osmium-based redox mediator is bound to poly (1-vinyl imidazole). 
     
     
         44 . The method of  claim 35 , wherein the excipient comprises the phenol. 
     
     
         45 . The method of  claim 35 , wherein the excipient comprises the cresol. 
     
     
         46 . The method of  claim 35 , wherein the amperometric sensor is located no more than 5 mm away from the distal end of the hollow tube. 
     
     
         47 . The method of  claim 35 , wherein the amperometric sensor is located no more than 3 mm away from the distal end of the hollow tube. 
     
     
         48 . The method of  claim 35 , wherein the reference electrode comprises a silver/silver chloride (Ag/AgCl) reference electrode. 
     
     
         49 . The method of  claim 35 , 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. 
     
     
         50 . The method of  claim 49 , wherein the insulating layer comprises a polyimide. 
     
     
         51 . The method of  claim 49 , wherein the metal layer has a thickness of at least 2 micrometers (μm). 
     
     
         52 . The method of  claim 49 , wherein the metal layer comprises titanium, gold, or platinum. 
     
     
         53 . The method of  claim 35 , wherein the electrode layer comprises a film having a thickness of less than 500 nanometers (nm).