Method for capturing therapeutic agents into an analyte sensor

Abstract

This disclosure provides a method for depositing a therapeutic agent onto an analyte sensor (for example, to reduce signal inaccuracies or in vivo sensor failures due to foreign body reactions (FBRs)). In certain embodiments, this disclosure relates to a process for obtaining an analyte sensor containing a therapeutic agent by coating (e.g., immersion coating) an analyte sensor with a therapeutic agent-containing polymer composition. This disclosure further relates to a sharp instrument coated with a therapeutic agent.

Description

Description of related applications

[0001] This application claims priority to and benefit from U.S. Provisional Patent Application No. 63 / 504114, filed on 24 May 2023, and U.S. Provisional Patent Application No. 63 / 504097, filed on 24 May 2023, the entire contents of which are fully referenced herein. [Technical Field]

[0002] This disclosure relates to a process for depositing therapeutic agents onto analyte sensors to reduce signal inaccuracies or in vivo sensor failures, for example, due to foreign body reactions (FBRs). In certain embodiments, this disclosure relates to a process for obtaining an analyte sensor containing a therapeutic agent by coating (e.g., immersion coating) an analyte sensor in a therapeutic agent-containing polymer composition. This disclosure further relates to a sharp instrument coated with a therapeutic agent. [Background technology]

[0003] Detecting one or more appropriate analytes in individuals who need it can sometimes be crucial for monitoring their health, because deviations from normal analyte levels may indicate some physiological condition. For example, monitoring blood glucose levels allows diabetic patients to take appropriate corrective measures, including medication administration or the consumption of certain foods and beverages, to avoid serious physiological harm. Monitoring other analytes may also be desirable to monitor other physiological conditions. In some cases, particularly in patients with comorbid conditions where two or more analytes interact and cause simultaneous dysregulation, monitoring multiple analytes may be desirable to monitor multiple physiological conditions.

[0004] Analyte monitoring in individuals can be performed periodically or continuously over a period of time. Periodic analyte monitoring can be carried out by taking bodily fluid samples, such as blood or urine, at predetermined intervals and analyzing them in vitro. Periodic in vitro analyte monitoring is sufficient to determine the physiological state of many individuals. However, in vitro analyte monitoring can sometimes be inconvenient or painful. Furthermore, if analyte measurements are not obtained at a reasonable or appropriate time, there is no means to recover the lost data. Continuous analyte monitoring can be carried out using one or more sensors that remain at least partially implanted in an individual's tissue, such as intracutaneously, subcutaneously, or intravenously, thereby enabling in vivo analysis. Implantable sensors can collect analyte data on demand, on a set schedule, or continuously, depending on an individual's specific health needs and / or previously measured analyte levels. Analyte monitoring with in vivo implantable sensors may be a more desirable approach for individuals with severe analyte malregulation and / or rapidly fluctuating analyte levels, but it may also be beneficial for other individuals.

[0005] However, long-term implantable sensors (e.g., those that can be worn for 30 days) suffer from a shortened lifespan due to late sensor attenuation (LSA) that occurs when implanted in the body. The loss of sensor function and / or decreased sensitivity observed in long-term implantable sensors, i.e., late sensor attenuation, is thought to be primarily the result of certain biological reactions (e.g., xenobiotic reactions) occurring in the tissue surrounding (e.g., the surrounding) the implanted sensor tail of the analyte sensor, including immune responses, inflammation, fibrosis, and vasorespiration. These tissue reactions may result from tissue trauma caused by inserting the sensor tail into the skin, or they may be the result of the tissue reacting to the sensor tail as a foreign body. Anti-inflammatory drugs, such as dexamethasone, can be used to prevent or mitigate the xenobiotic reactions that cause this effect. [Overview of the project] [Problems that the invention aims to solve]

[0006] To allow controlled or selective release of the drug during long-term wear, the drug can be dissolved in a biocompatible polymer later applied to the sensor. However, the location of the therapeutic agent-containing polymer composition may affect the detection chemistry system of the analyte sensor. For example, it may interfere with the active chemical reactions of the analyte sensor or affect the thickness of the sensor around the detection spot. Therefore, there is a need in the art to develop a process for manufacturing analyte sensors in which the therapeutic agent-containing polymer film / composition is mounted in areas that do not affect the detection chemistry system, such as the non-detection areas of the analyte sensor.

[0007] Furthermore, the application method of the polymer composition should be efficient, produce minimal waste, and be adaptable to mass production facilities for analyte sensors. However, optimal polymers for controlled or selective drug elution, which can be combined with drugs, may not be suitable or compatible for covering the detection chemistry system of the analyte sensor, such as glucose detection systems. In addition, the complex and microscopic structure and shape of the sensor tail of the analyte sensor, as well as the relatively large deposition volume required, pose challenges to deposition technology. Therefore, the development of deposition methods that are compatible with drug-eluting polymer compositions and can be adopted in current mass production processes is also needed in this field. [Means for solving the problem]

[0008] The objectives and merits of the disclosed subject matter are described and evident in the following description and will be understood through the implementation of the disclosed subject matter. Additional merits of the disclosed subject matter are realized and achieved from the compositions, apparatus, and methods specifically indicated in the description and claims, as well as from the accompanying drawings.

[0009] Other embodiments are described in part in the following description, some of which become apparent from that description, or are understood by carrying out the embodiments presented.

[0010] This disclosure provides a method for manufacturing an analyte sensor containing a therapeutic agent. In a particular embodiment, the method includes providing an analyte sensor comprising an internal part that is made to be located beneath the surface of the subject's skin and in contact with the subject's interstitial fluid, the internal part having a second region containing an active area and a first region distal to the second region; preparing a first polymer solution containing a first polymer; preparing a second polymer solution containing a second polymer and a therapeutic agent; immersing the internal part in the first polymer solution to coat the first and second regions to form a first polymer film; and immersing the first region in the second polymer solution to coat the first region rather than the second region to form a second polymer film containing the therapeutic agent on top of the first polymer film.

[0011] In a particular embodiment, a method is provided for manufacturing an analyte sensor containing a therapeutic agent, the method comprising: providing an analyte sensor comprising an internal part having a second region containing an active area and a first region distal to the second region, which is made to be located beneath the surface of the skin of a subject and in contact with the interstitial fluid of the subject; preparing a first polymer solution containing a first polymer; preparing a second polymer solution containing a second polymer and a therapeutic agent; immersing the first region in the second polymer solution to coat the first region rather than the second region, thereby generating a second polymer film containing the therapeutic agent; and immersing the internal part in the first polymer solution to coat the first and second regions, thereby generating a first polymer film on top of the second polymer film.

[0012] In a particular embodiment, the therapeutic agent is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof. In a particular embodiment, the therapeutic agent is an anti-inflammatory agent. In a particular embodiment, the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, its derivatives, its salt forms, and combinations thereof.

[0013] In certain embodiments, the anti-inflammatory agent is dexamethasone, its derivatives, or salts thereof.

[0014] In a particular embodiment, the second polymer solution comprises the polymer, the therapeutic agent, and a solvent. In a particular embodiment, the solvent comprises an alcohol, a buffer, or a combination thereof. In a particular embodiment, the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 2,2-dimethyl-1-propanol, 1-butanol, 2-butanol, isobutanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2-methyl-1-pentanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, triphenylmethanol, and combinations thereof. In a particular embodiment, the second polymer solution further comprises a crosslinking agent. In certain embodiments, the therapeutic agent is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the second polymer solution. In certain embodiments, the polymer is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the second polymer solution. In certain embodiments, the crosslinking agent is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the second polymer solution. In certain embodiments, the second polymer solution has a viscosity of about 20 centipoise to about 250 centipoise. In certain embodiments, the second polymer solution has a viscosity of about 10 centipoise to about 150 centipoise. In certain embodiments, the second polymer solution has a viscosity of about 20 centipoise to about 80 centipoise. In a particular embodiment, the second polymer of the second polymer solution is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyetherurethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof.In certain embodiments, the polyvinylpyridine polymer is a polyvinylpyridine copolymer. In certain embodiments, the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer.

[0015] In a particular embodiment, the first region is immersed in a second polymer solution for a period of about 1 second to about 5 seconds. In a particular embodiment, the method further includes a step of drying the second polymer solution for a period of about 1 to about 20 minutes after immersion. In a particular embodiment, the first region of the analyte sensor is immersed in the second polymer solution one or more times to produce a polymer film having a thickness of about 5 μm to about 40 μm. In a particular embodiment, the first region of the analyte sensor is immersed in the second polymer solution at least three times. In a particular embodiment, the first region is ablated or planed before immersing the first region in the second polymer solution. In a particular embodiment, the length of the second region is about 5 μm to about 50 μm. In a particular embodiment, the length of the first region is about 5 μm to about 50 μm. In a particular embodiment, the length of the first region is about 5 μm to about 20 μm.

[0016] In certain embodiments, the active area includes a plurality of detection regions. In certain embodiments, at least one of the plurality of detection regions is a spot.

[0017] In certain embodiments, the first polymer of the first polymer solution is different from the second polymer. In certain embodiments, the first polymer of the first polymer solution is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyetherurethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof. In certain embodiments, the polyvinylpyridine polymer is a polyvinylpyridine copolymer. In certain embodiments, the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer. In certain embodiments, the internal portion of the analyte sensor is immersed in the first polymer solution for a period of about 1 second to about 5 seconds. In certain embodiments, the method further includes a step of drying the first polymer solution for a period of about 1 to about 20 minutes after immersion. In certain embodiments, the internal portion of the analyte sensor is immersed in the first polymer solution one or more times to generate a first polymer film having a thickness of about 5 μm to about 40 μm. In a particular embodiment, the internal portion of the analyte sensor is immersed in the first polymer solution at least five times. In a particular embodiment, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.9.

[0018] In certain embodiments, a method of manufacturing an analyte sensor that includes a therapeutic agent includes providing an analyte sensor having a body portion configured to be beneath the skin surface of a subject and in contact with the interstitial fluid of the subject, the body portion having a second region that includes an active region and a first region distal to the second region; preparing or providing a first polymer solution that includes a first polymer; preparing or providing a second polymer solution that includes a second polymer and a therapeutic agent; contacting the body portion with the first polymer solution to coat the first region and the second region and form a first polymer membrane; and contacting the first region with the second polymer solution to coat the first region but not the second region and form a second polymer membrane that includes the therapeutic agent.

[0019] In certain embodiments, contacting the body portion with the first polymer solution includes a screen printing, rotary printing, jet printing, aerosol deposition, spray coating, dip coating, drop casting, spin coating, or brush coating process. In certain embodiments, contacting the first region with the second polymer solution includes a screen printing, rotary printing, jet printing, aerosol deposition, spray coating, dip coating, drop casting, spin coating, or brush coating process.

[0020] In certain embodiments, the therapeutic agent is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anti-cancer agents, antiplatelet agents, anticoagulants, coagulants, anti-glycolytic agents, and combinations thereof. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, its derivatives, its salt forms, and combinations thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone, its derivatives, or its salt forms.

[0021] In a particular embodiment, the second polymer solution comprises the polymer, the therapeutic agent, and a solvent. In a particular embodiment, the solvent comprises an alcohol, a buffer, or a combination thereof. In a particular embodiment, the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 2,2-dimethyl-1-propanol, 1-butanol, 2-butanol, isobutanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2-methyl-1-pentanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, triphenylmethanol, and combinations thereof. In a particular embodiment, the second polymer solution further comprises a crosslinking agent. In certain embodiments, the therapeutic agent is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution. In certain embodiments, the polymer is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution. In certain embodiments, the crosslinking agent is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution. In certain embodiments, the second polymer solution has a viscosity of about 20 centipoise to about 250 centipoise. In certain embodiments, the second polymer solution has a viscosity of about 10 centipoise to about 150 centipoise. In certain embodiments, the second polymer solution has a viscosity of about 20 centipoise to about 80 centipoise.

[0022] In a particular embodiment, the second polymer of the second polymer solution is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyether urethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof. In a particular embodiment, the polyvinylpyridine polymer is a polyvinylpyridine copolymer. In a particular embodiment, the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer.

[0023] In a particular embodiment, the first region is in contact with the second polymer solution for a period of about 1 second to about 5 seconds. In a particular embodiment, the method further includes a step of drying the second polymer solution for a period of about 1 to about 20 minutes after contact. In a particular embodiment, the first region of the analyte sensor is in contact with the second polymer solution one or more times to produce a second polymer film having a thickness of about 5 μm to about 40 μm. In a particular embodiment, the first region of the analyte sensor is in contact with the second polymer solution at least three times. In a particular embodiment, the first region is ablated or planed before being in contact with the second polymer solution. In a particular embodiment, the length of the second region is about 5 μm to about 50 μm. In a particular embodiment, the length of the first region is about 5 μm to about 50 μm. In a particular embodiment, the length of the first region is about 5 μm to about 20 μm.

[0024] In certain embodiments, the active area includes a plurality of detection regions. In certain embodiments, at least one of the plurality of detection regions is a spot.

[0025] In certain embodiments, the step of bringing the internal portion into contact with the first polymer solution is performed before the step of bringing the first region into contact with the second polymer solution. In certain embodiments, the second polymer film at least partially covers the first polymer film. In certain embodiments, the step of bringing the first region into contact with the second polymer solution is performed before the step of bringing the internal portion into contact with the first polymer solution. In certain embodiments, the first polymer film at least partially covers the second polymer film.

[0026] In a particular embodiment, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.9.

[0027] In certain embodiments, the total amount of therapeutic agent in the second polymer membrane is approximately 0.01 μg to approximately 500 μg. In certain embodiments, the total amount of therapeutic agent in the second polymer membrane is less than approximately 5 μg.

[0028] In a particular embodiment, a method for manufacturing an analyte sensor containing a therapeutic agent includes the steps of: providing an analyte sensor comprising (i) a working electrode, (ii) a pair and / or reference electrode, and (iii) an active area; preparing or providing a first polymer solution comprising a first polymer; preparing or providing a second polymer solution comprising a second polymer and a therapeutic agent; depositing the second polymer solution onto at least a portion of the pair and / or reference electrode to produce a therapeutic agent-containing polymer composition; and depositing the first polymer solution onto a body portion to produce a first polymer film on at least a portion of the therapeutic agent-containing polymer composition. In a particular embodiment, the step of depositing the second polymer solution onto at least a portion of the pair and / or reference electrode includes screen printing, rotary printing, jet printing, aerosol deposition, spray coating, immersion coating, drop casting, spin coating, or brush coating processes. In certain embodiments, the step of depositing a first polymer solution onto a body part includes screen printing, rotary printing, jet printing, aerosol deposition, spray coating, immersion coating, drop casting, spin coating, or brush coating processes.

[0029] In a particular embodiment, the step of depositing a second polymer solution on at least a portion of a pair and / or reference electrode includes the step of depositing the second polymer solution on the pair and / or reference electrode as two or more spots of the therapeutic agent-containing polymer composition. In a particular embodiment, at least one of those spots is circular, elliptical, regular polygonal, or irregular polygonal. In a particular embodiment, at least two of the two or more spots contain the same amount of therapeutic agent. In a particular embodiment, at least two of the two or more spots contain different amounts of therapeutic agent. In a particular embodiment, the difference in the amount of therapeutic agent between at least two of the two or more spots is about 10% or more. In a particular embodiment, at least two of the two or more spots have the same thickness. In a particular embodiment, at least two of the two or more spots have different thicknesses. In a particular embodiment, the difference in thickness between two spots is about 10% or more.

[0030] The disclosure further provides a method for manufacturing an analyte sensor containing a therapeutic agent, the method comprising the steps of: patterning a plurality of first conductive layers on a substrate to generate a plurality of working electrodes; patterning a plurality of second conductive layers on a substrate to generate a plurality of pairs and / or reference electrodes; forming one or more spots of a therapeutic agent-containing polymer composition comprising a polymer and a therapeutic agent on each of the plurality of pairs and / or reference electrodes; and framing individual analyte sensors from the substrate, each of which individual analyte sensors comprises at least one working electrode and at least one pair and / or reference electrode. In certain embodiments, one or more spots have a circular, elliptical, regular polygonal, or irregular polygonal shape.

[0031] In a particular embodiment, two or more spots are formed on a pair and / or reference electrode, and at least two of these spots contain the same amount of therapeutic agent. In a particular embodiment, two or more spots are formed on a pair and / or reference electrode, and at least two of these spots contain different amounts of therapeutic agent. In a particular embodiment, the difference in the amount of therapeutic agent between the two or more spots is about 10% or more. In a particular embodiment, two or more spots are formed on a pair and / or reference electrode, and at least two of these spots have the same thickness. In a particular embodiment, two or more spots are formed on a pair and / or reference electrode, and at least two of these spots have different thicknesses. In a particular embodiment, the difference in thickness between the two or more individual areas is about 10% or more.

[0032] In a particular embodiment, the step of forming one or more spots of a therapeutic agent-containing polymer composition on each of a plurality of pairs and / or reference electrodes includes the step of distributing two or more layers of a polymer solution containing the therapeutic agent. In a particular embodiment, at least one of the two or more spots of the therapeutic agent-containing polymer composition is formed by distributing two layers of the polymer composition, and a second spot of the two or more spots of the therapeutic agent-containing polymer composition is formed by distributing three layers of the polymer solution.

[0033] In a particular embodiment, the therapeutic agent is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof. In a particular embodiment, the therapeutic agent is an anti-inflammatory agent. In a particular embodiment, the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, its derivatives, its salt forms, and combinations thereof. In a particular embodiment, the anti-inflammatory agent is dexamethasone, its derivatives, or its salt forms.

[0034] In certain embodiments, the second polymer solution or polymer solution comprises the polymer, the therapeutic agent, and a solvent. In certain embodiments, the solvent comprises an alcohol, a buffer, or a combination thereof. In certain embodiments, the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 2,2-dimethyl-1-propanol, 1-butanol, 2-butanol, isobutanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2-methyl-1-pentanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, triphenylmethanol, and combinations thereof. In certain embodiments, the second polymer solution or polymer solution further comprises a crosslinking agent. In certain embodiments, the therapeutic agent is present in the second polymer solution or polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution. In certain embodiments, the polymer is present in the second polymer solution or polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution. In certain embodiments, the crosslinking agent is present in the second polymer solution or polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution. In certain embodiments, the second polymer solution or polymer solution has a viscosity of about 20 centipoise to about 250 centipoise. In certain embodiments, the second polymer solution or polymer solution has a viscosity of about 20 centipoise to about 80 centipoise. In a particular embodiment, the second polymer solution or the polymer of the polymer solution is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyetherurethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof.In certain embodiments, the polyvinylpyridine polymer is a polyvinylpyridine copolymer. In certain embodiments, the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer.

[0035] In a particular embodiment, the method further includes the step of forming an active region on each of a plurality of working electrodes. In a particular embodiment, the active region includes a plurality of detection regions. In a particular embodiment, at least one of the plurality of detection regions is a detection spot. In a particular embodiment, the method further includes the step of forming a film covering at least a portion of the therapeutic agent-containing polymer composition of individual analytes. In a particular embodiment, the film is made of a polymer selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyetherurethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof.

[0036] This disclosure further provides analyte sensors. In certain embodiments, the analyte sensor comprises a sensor tail including a non-detection region and an activity detection region including a plurality of detection spots, wherein the non-detection region is located around the activity detection region and constitutes a drug loading structure filled with a therapeutic agent-containing polymer composition. In certain embodiments, the drug loading structure includes at least one selected from slots, holes, pores, grooves, and depressions. In certain embodiments, the drug loading structure includes two slots arranged symmetrically along a plurality of detection spots. In certain embodiments, the drug loading structure includes a plurality of holes arranged symmetrically around a plurality of detection spots. In certain embodiments, the slots are elliptical, polygonal, or irregular in shape. In certain embodiments, the holes are circular, regular polygonal, or irregular in shape. In certain embodiments, the therapeutic agent-containing polymer composition includes a polymer matrix and a therapeutic agent. In certain embodiments, the polymer matrix is ​​made from a copolymer selected from the group consisting of polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyetherurethane copolymers, silicone copolymers, their derivatives, and combinations thereof. In certain embodiments, the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer or a derivative thereof. In certain embodiments, the polyvinylpyridine / polystyrene copolymer may contain 1 to 50 monomer% of styrene units. In certain embodiments, the therapeutic agent is at least one selected from the group consisting of anti-inflammatory agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, antibiotics, antiviral agents, and combinations thereof. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In a particular embodiment, the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, its derivatives, its salt forms, and combinations thereof. In a particular embodiment, the anti-inflammatory agent is dexamethasone, its derivatives, or its salt forms.In certain embodiments, the therapeutic agent is in the range of 0.01% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition. In certain embodiments, the analyte sensor is a subcutaneous sensor. In certain embodiments, the analyte sensor is configured to detect glucose.

[0037] This disclosure further provides a method for preparing an analyte sensor, comprising the steps of (i) providing a sensor tail including an activity detection region including a non-detection region and a plurality of detection spots, (ii) cutting off at least a portion of the non-detection region of the sensor tail to form a drug loading structure, and (iii) loading a therapeutic agent-containing polymer composition into the drug loading structure. In certain embodiments, the drug loading structure includes at least one selected from slots, holes, pores, grooves, and depressions. In certain embodiments, the drug loading structure includes two slots arranged symmetrically along a plurality of detection spots. In certain embodiments, the drug loading structure includes a plurality of holes arranged symmetrically around a plurality of detection spots. In certain embodiments, the slots are elliptical, polygonal, or irregular in shape. In certain embodiments, the holes are circular, regular polygonal, or irregular polygonal. In certain embodiments, the therapeutic agent-containing polymer composition includes a polymer and a therapeutic agent. In certain embodiments, the polymer is made from a copolymer selected from the group consisting of polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyether urethane copolymers, silicone copolymers, their derivatives, and combinations thereof. In certain embodiments, the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer or a derivative thereof. In certain embodiments, the polyvinylpyridine / polystyrene copolymer may contain 1 to 50 monomer% of styrene units. In certain embodiments, the therapeutic agent is at least one selected from the group consisting of anti-inflammatory agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, antibiotics, antiviral agents, and combinations thereof. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In a particular embodiment, the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, its derivatives, its salt forms, and combinations thereof.In certain embodiments, the anti-inflammatory agent is dexamethasone, its derivatives, or a salt thereof. In certain embodiments, the therapeutic agent is in the range of 0.01% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition.

[0038] This disclosure further provides an insertion device. In certain embodiments, the insertion device comprises an insertion tip configured to penetrate the skin and coated with a therapeutic agent-containing polymer composition comprising a therapeutic agent and a polymer; and an analyte sensor comprising a working electrode, an active area positioned on the working electrode, and a film coating at least the active area. In certain embodiments, the insertion tip is retractable. In certain embodiments, the therapeutic agent-containing polymer composition coating the insertion tip is detachably attached to the insertion tip. In certain embodiments, the therapeutic agent-containing polymer composition is designed to remain within the subject's tissue when the sharp instrument is retracted. In certain embodiments, the therapeutic agent-containing polymer composition is designed to release the therapeutic agent into an area surrounding the insertion site of the analyte sensor. In certain embodiments, the therapeutic agent is selected from the group consisting of antibiotics, antivirals, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, antiglycolytic agents, and combinations thereof. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In a particular embodiment, the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, and combinations thereof. In a particular embodiment, the anti-inflammatory agent is dexamethasone. In a particular embodiment, the polymer of the therapeutic agent-containing polymer composition is a bioabsorbable polymer. In a particular embodiment, the polymer is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane copolymers, polyether urethane polymers, silicone polymers, polycaprolactone polymers, polylactide polymers, polyglycolide polymers, polyethylene glycol polymers, derivatives thereof, and combinations thereof.

[0039] In certain embodiments, the therapeutic agent is covalently bonded to the polymer.

[0040] In certain embodiments, the therapeutic agent is not bound to the polymer.

[0041] In certain embodiments, the membrane is made of poly(4-vinylpyridine).

[0042] In certain embodiments, the active region comprises one or more enzymes configured to detect an analyte. In certain embodiments, the analyte is selected from the group consisting of glutamic acid, glucose, ketones, lactate, oxygen, glycated hemoglobin (HbA1c), albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartic acid, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, and combinations thereof. In certain embodiments, the active region further comprises an electron transfer agent. In certain embodiments, the electron transfer agent comprises a transition metal complex. In certain embodiments, the analyte sensor further comprises albumin and, optionally, a pH buffer. In certain embodiments, the analyte sensor further comprises a reference electrode, a counter electrode, or both a reference electrode and a counter electrode. In certain embodiments, the analyte sensor further includes a second active region that reacts with a second analyte. In certain embodiments, the second analyte is glucose, lactate, or a ketone. In certain embodiments, the therapeutic agent-containing polymer composition is configured to release the therapeutic agent at a predetermined release rate. In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug delivery rate of about 0.01 μg / day to about 1 mg / day. In certain embodiments, the therapeutic agent is in the range of 0.01% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition, and / or the therapeutic agent-containing polymer composition contains about 0.01 μg to about 100 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition further includes a crosslinking agent.

[0043] This disclosure further provides a method for suppressing an immune response at an insertion site of a sharp instrument. In a particular embodiment, the method includes the steps of introducing an analyte sensor made from a therapeutic polymer composition comprising a polymer and an effective amount of therapeutic agent suitable for suppressing an immune response at the insertion site into tissue at an insertion site using a sharp instrument, wherein the therapeutic polymer composition coats the insertion tip; and retaining the therapeutic polymer composition in the tissue after the sharp instrument has been retracted. In a particular embodiment, the therapeutic polymer composition coating the insertion tip of the sharp instrument is detachably attached to the insertion tip. In a particular embodiment, the therapeutic agent is selected from the group consisting of antibiotics, antivirals, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, antiglycolytic agents, and combinations thereof. In a particular embodiment, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, and combinations thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone. In certain embodiments, the polymer of the therapeutic agent-containing polymer composition is a bioabsorbable polymer. In certain embodiments, the polymer is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane copolymers, polyether urethane polymers, silicone polymers, polycaprolactone polymers, polylactide polymers, polyglycolide polymers, polyethylene glycol polymers, derivatives thereof, and combinations thereof. In certain embodiments, the therapeutic agent is covalently bonded to the polymer composition. In certain embodiments, the therapeutic agent is not bonded to the polymer composition.

[0044] In certain embodiments, the analyte sensor includes a working electrode, an active region positioned on the working electrode, and at least a membrane coating the active region, the analyte sensor being isolated from the therapeutic agent. In certain embodiments, the membrane is made of poly(4-vinylpyridine). In certain embodiments, the active region includes one or more enzymes configured to detect the analyte. In certain embodiments, the analyte is selected from the group consisting of glutamic acid, glucose, ketones, lactate, oxygen, glycated hemoglobin (HbA1c), albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartic acid, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, and combinations thereof. In certain embodiments, the analyte is glucose, lactate, or ketone. In certain embodiments, the active region further includes an electron transfer agent. In certain embodiments, the electron transfer agent comprises a transition metal complex. In certain embodiments, the active region further comprises albumin and, optionally, a pH buffer. In certain embodiments, the analyte sensor further comprises a reference electrode, a counter electrode, or both a reference electrode and a counter electrode. In certain embodiments, the therapeutic agent-containing polymer composition is configured to release the active therapeutic agent into the region surrounding the insertion site of the sensor.

[0045] In certain embodiments, the therapeutic agent-containing polymer composition is configured to release the therapeutic agent at a predetermined release rate. In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug delivery rate of about 0.01 μg / day to about 1 mg / day. In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug delivery rate of about 0.001 μg / day to about 1 μg / day. In certain embodiments, the therapeutic agent is in the range of 0.01% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition, and / or the therapeutic agent-containing polymer composition contains about 0.01 μg to about 100 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition further contains a crosslinking agent. [Brief explanation of the drawing]

[0046] The patent or application document must include at least one color drawing. A color copy of this patent or patent application publication document will be provided by the Patent Office upon request and payment of the required fees.

[0047] The following drawings are included to illustrate specific aspects of the disclosure and should not be construed as exclusive embodiments. The disclosed subject matter can be substantially modified, altered, combined, and replaced with equivalents in form and function without departing from the scope of the disclosure. [Figure 1A] Cross-sectional view of an exemplary analyte sensor according to one or more embodiments of the present disclosure. [Figure 1B] Cross-sectional view of an exemplary analyte sensor according to one or more embodiments of the present disclosure. [Figure 2] Cross-sectional view of an exemplary analyte sensor according to one or more embodiments of the present disclosure. [Figure 3] Schematic plan view of an exemplary sensor tail with a drug loading structure according to one or more embodiments of the present disclosure [Figure 4] Schematic diagram of an exemplary analyte sensor according to one or more embodiments of the present disclosure. [Figure 5]Schematic diagram of an exemplary analyte sensor with a drug loading structure according to one or more embodiments of the present disclosure. [Figure 6] Flowchart of a method for preparing an exemplary analyte sensor according to one or more embodiments of the present disclosure. [Figure 7] Schematic diagram of an exemplary sensor tail according to one or more embodiments of the present disclosure. [Figure 8] A diagram illustrating an exemplary step, task, or action of a method for coating an analyte sensor according to one or more embodiments of the present disclosure. [Figure 9] Schematic diagram of an illustrated covered analyte sensor according to one or more embodiments of the present disclosure. [Figure 10] Schematic diagram of an exemplary sensor tail equipped with a substance transport limiting membrane and a drug elution membrane according to one or more embodiments of the present disclosure. [Figure 11] Schematic diagram of an exemplary sensor tail equipped with a substance transport limiting membrane and a drug elution membrane according to one or more embodiments of the present disclosure. [Figure 12A] A diagram showing an exemplary sensor tail having two dexamethasone-containing spots on the counter electrode, according to one or more embodiments of the present disclosure. [Figure 12B] A schematic diagram of an exemplary coated analyte sensor having two dexamethasone-containing spots on a counter electrode, according to one or more embodiments of the present disclosure, and a diagram showing the exemplary thickness of each spot. [Figure 13A] A figure showing an exemplary analyte sensor tail comprising a substance transport limiting membrane and a drug elution membrane disposed on the substance transport limiting membrane, according to one or more embodiments of the present disclosure. [Figure 13B] A figure showing an exemplary analyte sensor tail comprising a substance transport limiting membrane and a drug elution membrane disposed on the substance transport limiting membrane, according to one or more embodiments of the present disclosure. [Figure 14A] A diagram showing an exemplary analyte sensor tail comprising a substance transport limiting membrane and a drug elution membrane located beneath the substance transport limiting membrane, according to one or more embodiments of the present disclosure. [Figure 14B]A diagram showing an exemplary analyte sensor tail comprising a substance transport limiting membrane and a drug elution membrane located beneath the substance transport limiting membrane, according to one or more embodiments of the present disclosure. [Figure 14C] A diagram showing an exemplary sensor tail equipped with a drug-eluting membrane located on the sensor tail, according to one or more embodiments of the present disclosure. [Figure 15] A diagram illustrating an exemplary step, task, or action of a method for coating an analyte sensor according to one or more embodiments of this disclosure. [Figure 16] Schematic diagram of an exemplary detection system that can incorporate the analyte sensor of this disclosure. [Figure 17A] Cross-sectional view of an exemplary analyte sensor with one active region. [Figure 17B] Cross-sectional view of an exemplary analyte sensor with one active region. [Figure 18A] Cross-sectional view of an exemplary analyte sensor with two active regions on separate working electrodes. [Figure 18B] Cross-sectional view of an exemplary analyte sensor with two active regions on separate working electrodes. [Figure 18C] Cross-sectional view of an exemplary analyte sensor with two active regions on separate working electrodes. [Figure 19] Cross-sectional view of an exemplary analyte sensor with two active regions. [Figure 20A] Perspective view of an exemplary analyte sensor with two active regions on separate working electrodes. [Figure 20B] Perspective view of an exemplary analyte sensor with two active regions on separate working electrodes. [Figure 20C] Perspective view of an exemplary analyte sensor with two active regions on separate working electrodes. [Figure 21] Drug delivery profiles of exemplary drug elution membranes positioned above or below the substance transport limiting membrane of an analyte sensor according to specific embodiments of this disclosure. [Figure 22] Exemplary drug elution membrane thickness profiles positioned above or below the mass transport limiting membrane of an analyte sensor according to one or more embodiments of the present disclosure. [Figure 23A]A typical diagram of a sharp instrument coated with a therapeutic agent-containing polymer composition, illustrating a front view of the moment when the sensor tail of the sharp instrument, coated within the therapeutic agent-containing polymer composition loaded with the therapeutic agent, is inserted into the skin. [Figure 23B] A typical diagram of a sharp instrument coated with a therapeutic agent-containing polymer composition, illustrating that after insertion, the sharp instrument is retracted into the applicator and the therapeutic agent-containing polymer composition is maintained in the skin near the sensor. [Figure 24A] A top cross-sectional view of a sharp instrument coated with a therapeutic agent-containing polymer composition, showing the moment when the analyte sensor tail is inserted into the skin using the sharp instrument coated within the therapeutic agent-containing polymer composition loaded with the therapeutic agent. [Figure 24B] A schematic diagram showing a top cross-sectional view of a sharp instrument coated with a therapeutic agent-containing polymer composition, illustrating that after insertion, the sharp instrument is retracted into the applicator and the therapeutic agent-containing polymer composition is maintained in the skin near the sensor. [Modes for carrying out the invention]

[0048] As described herein, implanting an analyte sensor may trigger several physiological reactions that could adversely affect sensor function. For example, inflammation or immune responses at the site of tissue damage induced by the analyte sensor and its implantation may impair the sensor's functionality and sensitivity in the body.

[0049] To address the aforementioned needs, this disclosure provides an analyte sensor and a sharp instrument containing a therapeutic agent. This disclosure further provides a method for depositing the therapeutic agent and its composition onto an analyte sensor and a sharp instrument coated with the therapeutic agent for introducing the analyte sensor into a subject.

[0050] In certain embodiments, sustained release of a therapeutic agent, such as an anti-inflammatory agent, near the analyte sensor can prevent and / or reduce inflammation or immune responses in the tissue surrounding the implantation site. For example, without limitation, the lifespan of the implanted analyte sensor can be extended by preventing and / or reducing inflammation in the tissue surrounding the implantation site. In certain embodiments, the lifespan of the implanted analyte sensor can be extended by preventing and / or reducing immune responses to the analyte sensor. In certain embodiments, extending the lifespan of the implanted analyte sensor means maintaining the accuracy of the analyte sensor toward the end of its lifespan and / or minimizing, reducing, and / or eliminating inaccuracies in the analyte signal toward the end of its lifespan.

[0051] In certain embodiments, the lifespan of the analyte sensor disclosed herein can be extended to more than about 2 days, more than about 3 days, more than about 4 days, more than about 5 days, more than about 6 days, more than about 7 days, more than about 8 days, more than 9 days, more than about 10 days, more than about 11 days, more than about 12 days, more than about 13 days, more than about 14 days, more than about 15 days, more than about 16 days, more than about 17 days, more than about 18 days, more than 19 days, or more than about 20 days. In certain embodiments, an analyte sensor comprising a therapeutic agent-containing polymer composition of the Disclosure may have a lifespan of approximately 14 days or more, approximately 15 days or more, approximately 16 days or more, approximately 17 days or more, approximately 18 days or more, approximately 19 days or more, approximately 20 days or more, approximately 21 days or more, approximately 22 days or more, approximately 23 days or more, approximately 24 days or more, approximately 25 days or more, approximately 26 days or more, approximately 27 days or more, approximately 28 days or more, approximately 29 days or more, or approximately 30 days or more. In certain embodiments, the lifespan of the analyte sensor disclosed herein may be extended to obtain an analyte sensor having a lifespan of approximately 30 days or more.

[0052] Hereinafter, specific embodiments will be described in more detail so that those skilled in the art can easily implement them. For example, embodiments of the present disclosure will be described in more detail with reference to the drawings. However, the present disclosure can be embodied in many different forms and is not limited to the exemplary embodiments described herein.

[0053] Not intended to be limiting, but for clarity, the detailed description of the subject matter currently disclosed is divided into the following subsections: I. Definition; II. Therapeutic agents; III. Analytical substance sensors; IV. Polymer compositions containing therapeutic agents; V. Acquisition of therapeutic agents into analytes; VI. Manufacturing method; VII. Charging device: and VIII. Exemplary Embodiments.

[0054] I. Definition The terms used in this disclosure generally have the common meanings in the art in the context of this disclosure and in the specific context in which each term is used. Similar reference numbers may indicate similar elements throughout this disclosure. Certain terms are described below or elsewhere in the specification to provide additional guidance to those skilled in the art in describing the compositions and methods of this disclosure, and how they are manufactured and used.

[0055] The technical terms used herein are for illustrative purposes only and are not intended to limit the disclosure. In this disclosure, terms such as “first,” “second,” etc., may be used herein to describe one or more elements, components, regions, and / or layers, but these elements, components, regions, and / or layers should not be limited by these terms. These terms are used solely to distinguish one component from another.

[0056] In this specification, nouns are interpreted as including multiple subjects unless the context clearly indicates otherwise. Furthermore, when "can" is used to describe embodiments of this disclosure, it refers to "one or more embodiments of this disclosure."

[0057] The terms “comprise,” “include(s),” “having,” and “contain(s)” as used herein, and their variations, are intended to be open transitional phrases, terms, or words that do not preclude additional actions or structures. This disclosure also envisions other embodiments, whether expressly described or not, that “comprising,” “consisting of,” or “consisting essentially of” the embodiments or elements presented herein.

[0058] In this specification, “or” should not be interpreted as having an exclusive meaning; for example, “A or B” should be interpreted as including A, B, A+B, and / or. Furthermore, the term “and / or” as used herein encompasses any and all combinations of one or more of the relevant enumeration items. Expressions such as “at least one of,” “one of,” and “selected from” that follow a list of elements modify the entire list of elements, not the individual elements within the list.

[0059] The terms "approximately" or "about" may refer to a range of tolerance for a particular value as determined by those skilled in the art, which depends in part on the measurement method and determination method, i.e., the limits of the measurement system. For example, "approximately" may refer to within or beyond three standard deviations, according to the practice of the art. Alternatively, "approximately" may refer to a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Or, particularly with respect to biological systems and processes, the term may refer to a range within the number of decimal places of the value, for example, within five times or up to two times.

[0060] In this specification, “analyte sensor” or “sensor” can refer to any device capable of receiving sensor information from a user, including, but not limited to, body temperature sensors, blood pressure sensors, pulse or heart rate sensors, blood glucose sensors, analyte sensors, physical activity sensors, body motion sensors, or any other sensors that collect physical or biological information. Examples of analytes measured by an analyte sensor include, without limitation, glutamate, glucose, ketones, lactate, oxygen, hemoglobin A1c, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartic acid, asparagine, magnesium, pH, phosphorus, potassium, sodium, total protein, uric acid, and others.

[0061] As used herein, the term “biological fluid” refers to any bodily fluid or bodily fluid-derived substance in which an analyte can be measured. Non-limiting examples of biological fluids include skin fluid, interstitial fluid, plasma, blood, lymph, synovial fluid, cerebrospinal fluid, saliva, bronchoalveolar lavage fluid, amniotic fluid, sweat, and tears. In certain embodiments, the biological fluid is skin fluid or interstitial fluid. In certain embodiments, the biological fluid is interstitial fluid.

[0062] As used herein, the term “covalent bond” refers to a chemical bond in which electron pairs are shared between atoms. Similarly, “covalently bonded” refers to a chemical bond in which electron pairs are shared between atoms.

[0063] As used herein, the term "multicomponent membrane" refers to a membrane made from two or more different membrane polymers.

[0064] As used herein, the term “non-covalent” or similar refers to a chemical interaction that does not involve the sharing of electrons, but rather involves more broadly dispersed electromagnetic interactions between molecules or within molecules.

[0065] As used herein, the term "polyvinylpyridine polymer" may refer to a polymer (e.g., copolymer) comprising polyvinylpyridine (e.g., poly(2-vinylpyridine) or poly(4-vinylpyridine)) or a derivative thereof.

[0066] As used herein, the term “reference electrode” can refer to either a reference electrode or an electrode that functions as both a reference electrode and a counter electrode. Similarly, as used herein, the term “counter electrode” can refer to both a counter electrode and a counter electrode that also functions as a reference electrode. In certain embodiments, the term “counter / reference electrode” can refer to both a counter electrode and a counter electrode that also functions as a reference electrode.

[0067] As used herein, the term “single-component membrane” refers to a membrane made from a single type of membrane polymer.

[0068] II. Therapeutic Agents This disclosure provides an analyte sensor containing therapeutic agents. In certain embodiments, the analyte sensor of this disclosure may contain two or more therapeutic agents.

[0069] This disclosure further provides sharp instruments coated with therapeutic agents. In certain embodiments, the sharp instruments of this disclosure may be coated with two or more therapeutic agents.

[0070] In certain embodiments, the therapeutic agent to be delivered pursuant to this disclosure may be effective in reducing, minimizing, preventing and / or suppressing the tissue response to the implantation of an analyte sensor. For example, but not limited to, the therapeutic agent to be delivered pursuant to this disclosure may be effective in reducing, minimizing, preventing and / or suppressing inflammation in tissue. In certain embodiments, the therapeutic agent to be delivered pursuant to this disclosure may be effective in maintaining the accuracy of the analyte sensor toward the end of its lifespan and / or minimizing, reducing and / or eliminating inaccuracies in the analyte signal toward the end of its lifespan.

[0071] In certain embodiments, the therapeutic agent used in this disclosure comprises at least one selected from the group consisting of antibiotics, antivirals, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof. In certain embodiments, the therapeutic agent is an antibiotic. In certain embodiments, the therapeutic agent is an antiviral agent. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the therapeutic agent is an anticancer agent. In certain embodiments, the therapeutic agent is an antiplatelet agent. In certain embodiments, the therapeutic agent is an anticoagulant. In certain embodiments, the therapeutic agent is a coagulant. In certain embodiments, the therapeutic agent is an antiglycolytic agent.

[0072] In certain embodiments, the therapeutic agent is an antiviral agent. In certain embodiments, the antiviral agent may include, but is not limited to, umifenovir, baloxavir marboxil, darunavir, nitazoxanide, peramivir, and tipranavir.

[0073] In certain embodiments, the therapeutic agent is an antibiotic. In certain embodiments, the antibiotic may include, but is not limited to, rifaximin, ertapenem, doripenem, cefadroxil, clindamycin, amoxicillin, and penicillin.

[0074] In certain embodiments, the therapeutic agent is an anticancer agent. In certain embodiments, the anticancer agent may include, but is not limited to, gilteritinib, glasdevib, ivosidenib, enasidenib, midostaurin, venetoclax, alpelisib, and others.

[0075] In certain embodiments, the therapeutic agent used in this disclosure may be an immunosuppressant. Non-limiting examples of immunosuppressants include anti-inflammatory agents, anticancer agents, anti-rejection agents, and combinations thereof.

[0076] In certain embodiments, the therapeutic agent may be an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent is a steroidal anti-inflammatory agent, such as a corticosteroid. In certain embodiments, the anti-inflammatory agent may be one or more selected from triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, and their derivatives or salt forms. Non-limiting salt forms include pharmaceutically acceptable salts including acetates and phosphates. In certain embodiments, the anti-inflammatory agent is a salt of dexamethasone.

[0077] In certain embodiments, the anti-inflammatory agent is dexamethasone.

[0078] In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt thereof.

[0079] In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone acetate.

[0080] In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone sodium phosphate.

[0081] III. Analytical Sensors A. Overall structure of the analyte sensor system This disclosure relates to the uptake of therapeutic agents into analyte sensors, such as in vivo analyte sensors, and / or delivery of therapeutic agents to the vicinity of analyte sensors (e.g., by the use of a sharp instrument coated with a therapeutic agent).

[0082] Before describing these embodiments in detail, it is desirable to first describe, for example, examples of devices that may be present in an in vivo analyte monitoring system, and examples of their operation (all of which can be used in the embodiments described herein).

[0083] There are various types of in vivo analyte monitoring systems. For example, a "continuous analyte monitoring" system (or "continuous glucose monitoring" system) can continuously transmit data from a sensor control unit to a reader device automatically, for example, according to a schedule, without prompting. Another example is a "flash analyte monitoring" system (or "flash glucose monitoring" system, or simply a "flash" system) which can transmit data from a sensor control unit in response to scanning or data requests by a reader device, using protocols such as Near Field Communication (NFC) or Radio Frequency Identification (RFID). In vivo analyte monitoring systems can also operate without requiring calibration by finger prick.

[0084] In vivo analyte monitoring systems are distinguished from "in vivo" systems, which come into contact with biological samples outside the body (i.e., "extra vivo") and typically include measuring devices with ports for receiving analyte test pieces that carry the user's bodily fluids (which can be analyzed to determine the user's blood analyte levels).

[0085] An in vivo monitoring system may include sensors that, while placed within the body, come into contact with the user's bodily fluids and sense the levels of analytes contained therein. These sensors may be part of a sensor control unit that resides on the user's body and houses electronic equipment and power supply to enable and control analyte detection. Sensor control units, and variations thereof, may also be referred to, to some extent, as "sensor control units," "wearable electronic equipment" devices or units, "wearable" devices or units, or "sensor data communication" devices or units.

[0086] In vivo monitoring systems may also include devices that receive analyte data detected from sensor control devices and processes, and / or display the detected analyte data to the user in any format. These devices, and variations thereof, may also be referred to, to some extent, as “portable reader devices,” “reader devices” (or simply “readers”), “portable electronic devices” (or simply “portable devices”), “small data processing” devices or units, “data receivers,” “receiving” devices or units (or simply “receivers”), or “remote” devices or units. Other devices, such as personal computers, may also be used in or incorporated into in vivo and in vivo monitoring systems.

[0087] Figure 16 provides a schematic diagram of a detection system useful for illustrating how the analyte sensor of this disclosure may be incorporated. As shown in the figure, the detection system 100 includes a sensor control unit 102 and a reader device 120 configured to communicate with each other via a local communication path or link 140, which may be wired or wireless, unidirectional or bidirectional, and encrypted or unencrypted. The reader device 120 may, according to a particular embodiment, constitute an output medium for displaying the concentration of the analyte determined by the sensor 104 or an associated processor and for displaying alarms or notifications, and may also allow one or more user inputs. The reader device 120 may be a multipurpose smartphone or a dedicated electronic reader device. Although only one reader device 120 is shown, multiple reader devices 120 may be present in a particular situation. The reader devices 120 are capable of communicating with remote terminals 170 and / or trusted computer systems 180, respectively, via communication paths / links 141 and / or 142, which may be wired or wireless, unidirectional or bidirectional, and encrypted or unencrypted. The reader device 120 is also capable of communicating with a network 150 (e.g., a cellular network, the internet, or a cloud server) via a communication path / link 151. The network 150 is further capable of communicating with a remote terminal 170 via a communication path / link 152 and / or a trusted computer system 180 via a communication path / link 153. Alternatively, the sensor 104 may communicate directly with the remote terminal 170 and / or the trusted computer system 180 in the absence of the intervening reader device 120. For example, according to certain embodiments, but not limited to, as described in U.S. Patent Application Publication No. 2011 / 0213225, which is incorporated herein by reference in its entirety, the sensor 104 may communicate with the remote terminal 170 and / or the trusted computer system 180 via a direct communication link to the network 150.Each communication path or link may use any suitable electronic communication protocol, such as Near Field Communication (NFC), Radio Frequency Identification (RFID), Bluetooth® or the "Bluetooth" Low Energy protocol, or Wi-Fi. According to certain embodiments, the remote terminal 170 and / or trusted computer system 180 are accessible to individuals other than the primary user who are interested in the user's analyte level. The reader device 120 may include a display 122 and an optional input component 121. According to certain embodiments, the display 122 may include a touchscreen interface.

[0088] The sensor control device 102 includes a sensor housing 103 capable of housing the circuitry and power supply for operating the sensor 104. The power supply and / or active circuitry may be omitted if necessary. A processor (not shown) is communicatively connected to the sensor 104, and the processor is physically located within the sensor housing 103 or within the reader device 120. According to a particular embodiment, the sensor 104 protrudes from the bottom surface of the sensor housing 103 and penetrates an adhesive layer 105, which is adapted to adhere the sensor housing 103 to a tissue surface such as skin.

[0089] B. Body part of the analyte sensor The sensor 104 in Figure 16 is configured to be at least partially inserted into the tissue of interest, such as within the dermis or subcutaneous layer of the skin. The sensor 104 may include an internal portion (also referred to herein as the sensor tail) that is long enough to be inserted into the given tissue to a desired depth. The internal portion is located beneath the surface of the subject's skin and is configured to be in contact with the subject's fluids (e.g., interstitial fluid). The internal portion may include at least one working electrode. In certain embodiments, the internal portion may include two working electrodes. In certain configurations, the internal portion may include, for example, an active area on the working electrode for detecting an analyte. A counter electrode may be present in combination with at least one working electrode. Specific electrode configurations on the internal portion are described in more detail below.

[0090] The active region can be configured to detect specific analytes, as further detailed below. For example, but are not limited to, analytes may include glucose, ketones, lactate, alcohol, glutamate, creatine, creatinine, sarcosine, ascorbic acid, and combinations thereof. Additional non-limiting examples of analytes detectable by the analyte sensors of this disclosure are disclosed in Section III.B.ii of this specification. For example, but are not limited to, a glucose-responsive active region may include a glucose-responsive enzyme, a ketone-responsive active region may include a ketone-responsive enzyme, a lactate-responsive active region may include a lactate-responsive enzyme, an alcohol-responsive active region may include an alcohol-responsive enzyme, a glutamate-responsive active region may include a glutamate-responsive enzyme, a creatine-responsive active region may include a creatine-responsive enzyme system, a creatinine-responsive active region may include a creatinine-responsive enzyme system, a sarcosine-responsive active region may include a sarcosine-responsive enzyme system, and an ascorbic acid-responsive active region may include an ascorbic acid-responsive enzyme system.

[0091] The membrane can overlay the active region, as described in more detail below. In certain embodiments, the membrane overlaying the analyte-responsive active region can function as a mass transport limiting membrane and / or improve biocompatibility. The mass transport limiting membrane can function as a diffusion limiting barrier that reduces the mass transport rate of the analyte. For example, but not limited to, limiting the reach of the analyte to the analyte-responsive active region with a mass transport limiting membrane can help avoid sensor overloading (saturation), thereby improving detection performance and accuracy.

[0092] In certain embodiments of the Disclosure, one analyte can be monitored in any biological fluid of interest, such as skin fluid, interstitial fluid, plasma, blood, lymph, synovial fluid, cerebrospinal fluid, saliva, bronchoalveolar lavage fluid, or amniotic fluid. In certain embodiments, the analyte sensor of the Disclosure can be applied to analyze skin fluid or interstitial fluid to determine the concentration of one analyte in the body. In certain embodiments, the biological fluid is interstitial fluid.

[0093] Referring again to Figure 16, the sensor 104 can automatically transfer data to the reader device 120. For example, (but not limited to) analyte concentration data can be automatically and periodically communicated at a specific frequency when data is acquired, or after a certain period of time has elapsed, and the data is stored in memory until it is transmitted (e.g., every minute, every 5 minutes, or at other predetermined time intervals). In certain embodiments, the sensor 104 can communicate with the reader device 120 in a non-automatic manner, without following a set schedule. For example, (but not limited to) data can be communicated from the sensor 104 using RFID technology when the electronic equipment of the sensor 104 enters the communication range of the reader device 120. The data can remain stored in the sensor 104's memory until it is communicated to the reader device 120. Therefore, the user does not need to constantly stay near the reader device 120 and can upload data at their convenience. In certain embodiments, a combination of automatic and non-automatic data transfer can be implemented. For example, (but not limited to) data transfer can continue on an automatic basis until the reader device 120 is out of the communication range of the sensor 104.

[0094] To facilitate the introduction of the sensor 104 into the tissue, an introducer may be temporarily present. In certain exemplary embodiments, the introducer may include a needle or a similar sharp instrument. As will be readily apparent to those skilled in the art, in alternative embodiments, other types of introducers may be present, such as a sheath or blade. More specifically, the needle or other introducer is temporarily placed near the sensor 104 before tissue insertion and then withdrawn. While placed, the needle or other introducer can facilitate the insertion of the sensor 104 into the tissue by opening an access path that the sensor 104 follows. For example, according to one or more embodiments, but not limited to, the needle facilitates puncture of the epidermis as an access path to the dermis, thereby enabling the implantation of the sensor 104. After opening the access path, the needle or other introducer can be withdrawn without creating a hazard from the sharp instrument. In certain embodiments, a suitable needle may be solid or hollow, oblique or non-oblique, and / or have a circular or non-circular cross-section. In more specific embodiments, a suitable needle may have a cross-sectional diameter and / or tip design equivalent to that of an acupuncture needle, with a cross-sectional diameter of approximately 250 micrometers. However, a suitable needle may have a larger or smaller cross-sectional diameter if required depending on the specific application. As disclosed herein, the needle or injector may be at least partially coated with a therapeutic agent.

[0095] In certain embodiments, the tip of the needle (if present) can be angled at the end of the sensor 104 so that the needle first penetrates the tissue and opens an access path for the sensor 104. In certain embodiments, the sensor 104 can be placed in the lumen or groove of the needle, which in turn opens an access path for the sensor 104. In either case, the needle is withdrawn after facilitating the insertion of the sensor.

[0096] i. Electrode configuration Sensor configurations with a single active region configured for the detection of a single corresponding analyte can employ two-electrode or three-electrode detection configurations, as further described herein with reference to Figures 1A-1B, Figure 2, and Figures 17A-17B. Sensor configurations with two different active regions intended for the detection of the same or different analytes, located on separate or identical working electrodes, are described separately later with reference to Figures 2 and 18A-20C. Sensor configurations with multiple working electrodes may be particularly advantageous for incorporating two different active regions within the same body portion (e.g., the sensor tail) because the signal contribution from each active region can be more easily determined.

[0097] When an analyte sensor has one working electrode, a three-electrode sensor configuration may include a working electrode, a counter electrode, and a reference electrode. A related two-electrode sensor configuration may include a working electrode and a second electrode, which can function as both a counter electrode and a reference electrode (i.e., a counter / reference electrode). The various electrodes may be at least partially stacked (layered) on the sensor tail and / or spaced laterally apart from each other. A suitable sensor configuration may be substantially flat, substantially cylindrical, or any suitable shape. In any of the sensor configurations disclosed herein, the various electrodes may be electrically insulated from each other by a dielectric material or similar insulator.

[0098] An analyte sensor with multiple working electrodes may similarly include at least one additional electrode. If one additional electrode is present, that one additional electrode can function as a pair / reference electrode for each of the multiple working electrodes. If two additional electrodes are present, one of the additional electrodes can function as a pair electrode for each of the multiple working electrodes, and the other additional electrode can function as a reference electrode for each of the multiple working electrodes.

[0099] Figure 1A shows a schematic diagram of an exemplary two-electrode analyte sensor configuration adapted for use in this disclosure. As shown in the figure, the analyte sensor 200 includes a substrate 212 positioned between a working electrode 214 and a pair / reference electrode 216. Alternatively, the working electrode 214 and the pair / reference electrode 216 may be positioned on the same plane of the substrate 212 with a dielectric material placed between them (such configuration is not shown). An active area 218 is positioned as at least one layer on at least a portion of the working electrode 214. The active area 218 may include a plurality of spots or a single spot configured to detect analytes at low working electrode potentials, as further described herein. In certain embodiments, the active area 218 may include electron transfer agents as described herein.

[0100] Referring further to Figure 1A, the film 220 covers at least the active region 218. In certain embodiments, the film 220 is made from a copolymer of the present disclosure. For example, but not limited to, the film 220 is made from a copolymer comprising a first monomer, e.g., styrene, and a second monomer having a heterocyclic component, e.g., vinylpyridine, e.g., 4-vinylpyridine.

[0101] In certain embodiments, the film 220 may also coat some or all of the working electrode 214 and / or the pair / reference electrode 216, or the entire analyte sensor 200. One or both sides of the analyte sensor 200 may be covered with the film 220. The film 220 may comprise one or more polymer film materials having the ability to restrict the flux of analyte into the active area 218 (i.e., the film 220 is a mass transport restriction film having some degree of permeability to the analyte of interest). The composition and thickness of the film 220 may be varied to facilitate the flux of a desired analyte into the active area 218, thereby providing a desired signal intensity and stability. The analyte sensor 200 may be operated to analyze the analyte by any of the electrochemical detection techniques of coulometry, amperometry, electrocoulometry, or potentiometry.

[0102] Figures 17A and 17B show schematic diagrams of exemplary three-electrode analyte sensor configurations adapted for use in the present disclosure. The three-electrode analyte sensor configurations may be similar to those shown in analyte sensor 200 in Figure 1A, except that analyte sensors 201 and 202 (Figures 17A and 17B) include an additional electrode 217. With the addition of the additional electrode 217, the pair / reference electrode 216 can function as either the pair electrode or the reference electrode, and the additional electrode 217 complements functions not performed by the other electrodes. The reference electrode 214 continues to perform its original function. The additional electrode 217 may be positioned between the reference electrode 214 or electrode 216, with a dielectric material isolation layer in between. For example, but not limited to, as shown in Figure 17A, dielectric layers 219a, 219b, and 219c isolate electrodes 214, 216, and 217 from each other and provide electrical shielding. Alternatively, at least one of electrodes 214, 216, and 217 may be positioned on the opposite side of the substrate 212, as shown in Figure 17B. Thus, in certain embodiments, electrodes 214 (working electrode) and 216 (counter electrode) may be positioned on the opposite side of the substrate 212, and electrode 217 (reference electrode) may be positioned on one of electrodes 214 or 216, spaced therefrom by a dielectric material. A reference material layer 230 (e.g., Ag / AgCl) may be present on electrode 217, and the position of the reference material layer 230 is not limited to the positions shown in Figures 17A and 17B. With respect to the sensor 200 shown in Figure 1A, the active area 218 of analyte sensors 201 and 202 may include multiple spots or a single spot. In certain embodiments, the active area 218 may include redox mediators disclosed herein. In addition, the analyte sensors 201 and 202 may be operated to analyze the analyte using any of the following electrochemical detection techniques: coulometry, current measurement, electrocoulometry, or potentiometry.

[0103] As in the analyte sensor 200, the film 220 can coat the active area 218 and other sensor components in the analyte sensors 201 and 202, thereby functioning as a material transport restriction film. In certain embodiments, an additional electrode 217 can be coated with film 220. Figures 17A and 17B show electrodes 214, 216, and 217 coated with film 220, but it should be noted that in certain embodiments, only the working electrode 214 may be coated. Furthermore, the thickness of film 220 on each of electrodes 214, 216, and 217 may be the same or different. As in the two-electrode analyte sensor configuration (Figure 1A), one or both sides of the analyte sensors 201 and 202 can be coated with film 220 in the sensor configurations of Figures 17A and 17B, or both of the analyte sensors 201 and 202 can be coated. Therefore, the three-electrode sensor configurations shown in Figures 17A and 17B should not be understood as limiting the embodiments disclosed herein, and alternative electrode and / or layer configurations are included within the scope of this disclosure.

[0104] Figure 18A shows an exemplary configuration of a sensor 203 having a working electrode with two different active regions positioned on top of it. Figure 18A is similar to Figure 1A except that there are two active regions on the working electrode 214: a first active region 218a and a second active region 218b. These active regions react to the same or different analytes and are spaced laterally apart from each other on the surface of the working electrode 214. The active regions 218a and 218b may contain multiple spots or single spots configured for the detection of each analyte. The composition of the film 220 may be different or compositionally the same in the active regions 218a and 218b. The first active region 218a and the second active region 218b may be configured to detect their respective corresponding analytes at different working electrode potentials, as will be further described below.

[0105] Figures 18B and 18C show cross-sectional views of exemplary three-electrode sensor configurations of sensors 204 and 205, respectively, each featuring one working electrode having a first active region 218a and a second active region 218b on top of it. Figures 18B and 18C are otherwise similar to Figures 17A and 17B and can be better understood by referring to them. As with respect to Figure 18A, the composition of the film 220 may be different or compositionally the same in the active regions 218a and 218b. In certain embodiments, either one of the active regions 218a and 218b may contain the redox mediators described herein. In certain embodiments, only one of the active regions 218a and 218b may contain the redox mediators described herein. For example, but not limited to, only active region 218a may contain the redox mediators described herein. In certain embodiments, only active region 218b may contain the redox mediators described herein. In certain embodiments, both active regions 218a and 218b contain the redox mediators described herein. In certain embodiments, the electron transfer agent present in active region 218a is different from the redox mediator present in 218b. Alternatively, the electron transfer agent present in active region 218a is the same as the redox mediator present in 218b.

[0106] Exemplary sensor configurations having multiple working electrodes, specifically two working electrodes, will be described in more detail with reference to Figures 19-20C. While the following description primarily focuses on sensor configurations with two working electrodes, it will be recognized that three or more working electrodes can be incorporated by extending this disclosure. Additional working electrodes can be used to provide the analyte sensor with further detection capabilities, not limited to only the first and second analytes.

[0107] Figure 19 shows a cross-sectional view of an exemplary analyte sensor configuration having two working electrodes, one reference electrode, and one counter electrode, suitable for use in the present disclosure. As shown in the figure, the analyte sensor 300 comprises working electrodes 304 and 306 located on opposite sides of a substrate 302. A first active area 310a is located on the surface of the working electrode 304, and a second active area 310b is located on the surface of the working electrode 306. The counter electrode 320 is electrically isolated from the working electrode 304 by a dielectric layer 322, and the reference electrode 321 is electrically isolated from the working electrode 306 by a dielectric layer 323. Outer dielectric layers 330 and 332 are located on the reference electrode 321 and the counter electrode 320, respectively. According to various embodiments, the film 340 can coat at least the active areas 310a and 310b together with other components of the analyte sensor 300, or the entire analyte sensor 300. In certain embodiments, the film 340 is made from the copolymer of the present disclosure. For example, but not limited to, the film 340 is made from a copolymer comprising a first monomer, for example, styrene, and a second monomer having a heterocyclic component, for example, vinylpyridine, for example, 4-vinylpyridine.

[0108] In certain embodiments, the film 340 may be continuous but compositionally different on the active areas 310a and / or 310b to obtain different permeability values ​​to differently regulate the analytical flux at each location. For example, but not limited to, one or more electrodes may be coated with a first polymer film portion 340a and / or a second polymer film portion 340b. In certain embodiments, different film formulations may be sprayed and / or printed on the opposite side of the analyte sensor 300. Immersion coating techniques may also be suitable, in particular, to deposit at least a portion of a two-layer film on one of the active areas 310a and 310b. In certain embodiments, the film 340 may be the same or compositionally different on the active areas 310a and 310b. For example, but not limited to, the film 340 may include two layers that overcoat the active area 310a and a homogeneous film that overcoats the active area 310b, or the film 340 may include two layers that overcoat the active area 310b and a homogeneous film that overcoats the active area 310a. In a particular embodiment, one of the first polymer film portion and the second polymer film portion may be a two-layer film, and according to a particular embodiment of the present disclosure, the other of the first polymer film portion and the second polymer film portion may consist of a single-layer polymer. In a particular embodiment, the analyte sensor may include a plurality of films 340, for example, two or more films. For example, but not limited to, the analyte sensor may include films covering one or more active areas, for example, 310a and 310b, and an additional film covering the entire sensor as shown in Figure 19. In such a configuration, the two-layer film can be formed on one or more active areas, for example, 310a and 310b. In certain embodiments, the two films may have different polymer compositions. For example, the first polymer film may contain the copolymer of the Disclosure, and the second polymer film may contain a different polymer. In certain embodiments, either active region 310a or 310b may contain the electron transfer agent described herein. In certain embodiments, only one of active regions 310a or 310b may contain the redox mediator described herein. For example, only active region 310a may contain the redox mediator described herein.In certain embodiments, only the active region 310b contains the redox mediator described herein. In certain embodiments, both active regions 310a and 310b contain the redox mediator described herein. In certain embodiments, the redox mediator present in active region 310a is different from the electron transfer agent present in 310b. Alternatively, the redox mediator present in active region 310a is the same as the electron transfer agent present in 310b.

[0109] Alternative sensor configurations having multiple working electrodes, different from the configuration shown in Figure 19, may include separate counter electrodes and counter / reference electrodes instead of the reference electrodes 320, 321, and / or may have different layer and / or film arrangements than those explicitly shown. For example, but not limited to, the arrangement of the counter electrode 320 and the reference electrode 321 may be reversed from that shown in Figure 19. In addition, the working electrodes 304 and 306 do not necessarily have to be on the opposite side of the substrate 302 in the manner shown in Figure 19.

[0110] While a suitable sensor configuration may include substantially planar electrodes, it should be understood that sensor configurations with non-planar electrodes are advantageous and particularly suitable for use in this disclosure. In particular, substantially cylindrical electrodes arranged concentrically can facilitate the deposition of a material transport limiting film, as will be discussed later. For example, but not limited to, concentric working electrodes spaced apart longitudinally along the sensor tail can facilitate film deposition by sequential immersion coating in a manner similar to that previously described for substantially planar sensor configurations. Figures 20A-20C show perspective views of an analyte sensor with two concentrically arranged working electrodes. It should be understood that sensor configurations with concentrically arranged electrodes but lacking a second working electrode are also possible in this disclosure.

[0111] Figure 20A shows a perspective view of an exemplary sensor configuration in which multiple electrodes are substantially cylindrical and arranged concentrically around a central base. As shown in the figure, the analyte sensor 400 comprises a central base 402 around which all electrodes and dielectric layers are arranged concentrically. Specifically, the working electrode 410 is located on the surface of the central base 402, and the dielectric layer 412 is located on the portion of the working electrode 410 distal to the sensor tip 404. The working electrode 420 is located on the dielectric layer 412, and the dielectric layer 422 is located on the portion of the working electrode 420 distal to the sensor tip 404. The counter electrode 430 is located on the dielectric layer 422, and the dielectric layer 432 is located on the portion of the counter electrode 430 distal to the sensor tip 404. The reference electrode 440 is located on the dielectric layer 432, and the dielectric layer 442 is located on the portion of the reference electrode 440 distal to the sensor tip 404. Thus, the exposed surfaces of the working electrode 410, the working electrode 420, the counter electrode 430, and the reference electrode 440 are spaced apart from each other along the vertical axis B of the analyte sensor 400.

[0112] Referring further to Figure 20A, a first active area 414a and a second active area 414b, which react to different analytes, are positioned on the exposed surfaces of the working electrodes 410 and 420, respectively, thereby enabling detection by contact with the fluid. Although the active areas 414a and 414b are shown as three separate spots in Figure 20A, it will be recognized that fewer or more spots, including a continuous layer of active areas, may instead be present in the sensor configuration. In certain embodiments, either active area 414a or 414b may contain an electron transfer agent as described herein. In certain embodiments, only one of active areas 414a or 414b may contain a redox mediator as described herein. For example, but not limited to, only active area 414a may contain a redox mediator as described herein. In certain embodiments, only active area 414b may contain a redox mediator as described herein. In certain embodiments, both active regions 414a and 414b contain the redox mediators described herein. In certain embodiments, the redox mediator present in active region 414a is different from the electron transfer agent present in 414b. Alternatively, the redox mediator present in active region 414a is the same as the electron transfer agent present in 414b.

[0113] In Figure 20A, the sensor 400 is partially covered by a film 450 over the working electrodes 410 and 420 and the active areas 414a and 414b located thereon. Figure 20B shows an alternative sensor configuration in which substantially the entire sensor 401 is covered by the film 450. The film 450 may be the same as or different in composition from the active areas 414a and 414b. For example, the film 450 may consist of two layers overcoating the active area 414a and a homogeneous film overcoating the active area 414b. In certain embodiments, the film 450 is composed of a copolymer of the present disclosure. For example, but not limited to, the film 450 is made of a copolymer comprising a first monomer, e.g., styrene, and a second monomer having a heterocyclic component, e.g., vinylpyridine, e.g., 4-vinylpyridine.

[0114] It will be further recognized that the positioning of the various electrodes in Figures 20A and 20B may differ from those explicitly shown. For example, the positions of the counter electrode 430 and the reference electrode 440 can be reversed from the configuration shown in Figures 20A and 20B. Similarly, the positions of the working electrodes 410 and 420 are not limited to those explicitly shown in Figures 20A and 20B. Figure 20C shows an alternative sensor configuration to that shown in Figure 20B, where the sensor 405 comprises the counter electrode 430 and the reference electrode 440 positioned more proximal to the sensor tip 404, and the working electrodes 410 and 420 positioned more distal to the sensor tip 404. A sensor configuration in which the working electrodes 410 and 420 are positioned more distal to the sensor tip 404 may be advantageous by providing a larger surface area for depositing the active areas 414a and 414b (the five individual detection spots shown as an example in Figure 20C), thereby easily increasing the signal intensity in some cases. Similarly, the central substrate 402 can be omitted in any concentric sensor configuration disclosed herein, in which case the innermost electrodes can instead support later deposited layers.

[0115] In certain embodiments, the analyte sensor of the present disclosure comprises one or more detection spots (e.g., two or more, three or more, four or more, five or more, or six or more) on a body portion, as described herein. For example, but not limited to, Figure 1B shows a cross-sectional view of an exemplary analyte sensor according to one or more embodiments of the present disclosure. As shown in Figure 1B, the analyte sensor may comprise a sensor tail 100 including (i) a substrate 102, (ii) a first working electrode 104 on the substrate 102, (iii) detection spots 108 disposed on the surface of the first working electrode for detecting analyte, (iv) a film 110 overlaying at least the detection spots 108, and (v) a pair / reference electrode 106 on the substrate 102. In certain embodiments, the substrate 102 may be positioned between the first working electrode 104 and the pair / reference electrode 106. In certain embodiments, the first working electrode 104 and the pair / reference electrode 106 may be positioned on the same side of the substrate 102 with a dielectric material placed between them. In certain embodiments, the detection spot 108 may be positioned as at least one layer on at least a portion of the first working electrode 104. The detection spot 108 may include an active area configured to detect an analyte by a detection chemistry system (also referred herein as an activation chemistry system). In certain embodiments, the film 110 covers the detection spot 108. In certain embodiments, the film 110 may overcoat some or all of the first working electrode 104 and / or the pair / reference electrode 106, or all of the sensor tail 100 of the analyte sensor. One or both sides of the sensor tail 100 of the analyte sensor may be covered with the film 110. In certain embodiments, the membrane 110 may include one or more polymer membrane materials having the ability to restrict the analytical flux to the detection spot 108 (i.e., the membrane 110 is a material transport restriction membrane having some permeability to the analyte of interest). In certain embodiments, the membrane 110 may be branched with a branching crosslinking agent in certain sensor configurations. The composition and thickness of the membrane 110 can facilitate a desired analytical flux to the detection spot 108, thereby providing a desired signal intensity and stability.The analyte sensor may be operated to analyze the analyte using any of the following electrochemical detection techniques: coulometry, current measurement, electrocoulometry, or potentiometry.

[0116] Figure 2 shows a cross-sectional view of an analyte sensor 200 according to one or more embodiments of the present disclosure. Figure 2 is similar to Figure 1B except that there are a plurality of detection spots 108a to 108f (first detection spot 108a to sixth detection spot 108f) on the first working electrode 104. Figure 7 further shows a schematic diagram of an exemplary sensor tail according to one or more embodiments of the present disclosure. As shown in Figure 7, the analyte sensor comprises a sensor tail 300 including (i) a substrate 102, (ii) a first working electrode 104 on the substrate 102, (iii) a plurality of detection spots 108a to 108f arranged on the surface of the first working electrode 104 for detecting analytes, and (iv) a pair / reference electrode (not shown in Figure 7, on the opposite side of the substrate). The plurality of detection spots 108a to 108f can react to different analytes and are arranged on the surface of the first working electrode 104 spaced laterally from each other. In certain embodiments, at least some of the detection spots 108a to 108f can react to the same analyte, while the remainder can react to different analytes. In certain embodiments, a membrane (e.g., 110 in Figure 2) can cover at least some of the detection spots 108a to 108f, or all of them. The composition of the membrane (e.g., 110 in Figure 2) may differ or be the same for the detection spots 108a to 108f. The detection spots 108a to 108f can be configured to detect the corresponding analytes at different working electrode potentials.

[0117] In certain embodiments, one or more electrodes of the analyte sensor described herein are working electrodes, such as permeable wire electrodes. In certain embodiments, the sensor tail includes a working electrode and a reference electrode helically wound around the working electrode. In certain embodiments, an insulator is placed between the working electrode and the reference electrode. In certain embodiments, multiple portions of the electrode are exposed to allow the reaction of one or more enzymes with an analyte on the electrode. In certain embodiments, each electrode is formed from a thin wire with a diameter of about 0.001 inches (about 0.025 mm) or less and about 0.010 inches (about 0.25 mm) or more. In certain embodiments, the diameter of the working electrode is from about 0.001 inches (about 0.025 mm) or less to about 0.010 inches (about 0.25 mm) or more, for example, from about 0.002 inches (about 0.050 mm) to about 0.008 inches (about 0.225 mm), or from about 0.004 inches (about 0.100 mm) to about 0.005 inches (about 0.050 mm). In certain embodiments, the electrode is formed from a plated insulator, plated wire, or conductive bulk material. In certain embodiments, the working electrode is made from a wire formed from a conductive material such as platinum, platinum-iridium, palladium, graphite, gold, carbon, conductive polymer, or alloy. In certain embodiments, the conductive material is a permeable conductive material. In certain embodiments, electrodes can be formed by various manufacturing techniques (e.g., bulk metal processing, metal deposition on a substrate, etc.), and electrodes can be formed from plated wire (e.g., platinum on steel wire) or bulk metal (e.g., platinum wire). In certain embodiments, electrodes can be formed from, for example, platinum-coated tantalum wire.

[0118] In certain embodiments, the reference electrode, which can function as a reference electrode alone or as a dual reference-counter electrode, is formed from silver, silver / silver chloride, or the like. In certain embodiments, the reference electrode is positioned alongside and / or entangled with or wound around the working electrode. In certain embodiments, the reference electrode is helically wound around the working electrode. In certain embodiments, the wire assembly can be coated or bonded with an insulating material to provide an insulated connection.

[0119] In certain embodiments, additional electrodes may be included in the in-vivo portion of the analyte sensor. For example, but not limited to, the analyte sensors of this disclosure may include a three-electrode system (working electrode, reference electrode, and counter electrode) and / or additional working electrodes (e.g., an electrode for detecting a second analyte). In certain embodiments where the sensor has two working electrodes, the two working electrodes are arranged adjacent to each other, with a reference electrode positioned around them (e.g., spirally wound around two or more working electrodes). In certain embodiments, two or more working electrodes may extend parallel to each other. In certain embodiments, the reference electrode is coiled around the working electrodes and extends toward the distal end of the sensor tail (i.e., the in-vivo end). In certain embodiments, the reference electrode extends (e.g., spirally) to the exposed region of the working electrodes.

[0120] In certain embodiments, one or more working electrodes are helically wound around a reference electrode. In certain embodiments where two or more working electrodes are provided, the working electrodes can be formed in a double, triple, quadruple or more helical configuration along the longitudinal direction of the sensor tail (for example, surrounding a reference electrode, insulating rod, or other support structure). In certain embodiments, electrodes, for example, two or more working electrodes, are formed coaxially. For example, but not limited to, all electrodes share the same central axis.

[0121] In certain embodiments, the working electrode constitutes a tube in which a reference electrode is located inside or wound in a coil, including an insulator placed between them. Alternatively, the reference electrode constitutes a tube in which the working electrode is located inside or wound in a coil, including an insulator placed between them. In certain embodiments, a polymer (e.g., insulating) rod is provided, on which one or more electrodes (e.g., one or more electrode layers) are located (e.g., by electroplating). In certain embodiments, a metal (e.g., steel or tantalum) rod or wire coated with an insulating material (as described herein) is provided, on which one or more working and reference electrodes are located. For example, but not limited to, the Disclosure provides a sensor including one or more tantalum wires, e.g., a sensor tail, on which a conductive material is located on a portion of the one or more tantalum wires to function as a working electrode. In certain embodiments, a platinum-clad tantalum wire is covered with an insulating material, the insulating material is partially covered with a silver / silver chloride composition to function as a reference and / or counter electrode.

[0122] In certain embodiments where the insulator is placed on a working electrode (e.g., on the platinum surface of the electrode), a portion of the insulator may be stripped or otherwise removed to expose the electroactive surface of the working electrode. For example, but not limited to, a portion of the insulator may be removed by manual work, excimer laser, chemical etching, laser ablation, grit blasting, etc. Alternatively, a portion of the electrode may be masked before the insulator is deposited, leaving the electroactive surface area exposed. In certain embodiments, the length of the portion of the insulator to be stripped and / or removed may range from about 0.1 mm or less to about 2 mm or more, for example, from about 0.5 mm to about 0.75 mm. In certain embodiments, the insulator is a non-conductive polymer. In certain embodiments, the insulator is composed of parylene, fluorinated polymers, polyethylene terephthalate, polyvinylpyrrolidone, polyurethane, polyimide, and other non-conductive polymers. In certain embodiments, glass or glass ceramic may also be used for the insulator layer. In certain embodiments, the insulator is composed of parylene. In certain embodiments, the insulator is made of polyurethane. In certain embodiments, the insulator is made of polyurethane and polyvinylpyrrolidone.

[0123] ii. Detection chemistry system The analytic sensor of this disclosure may include one or more enzymes for detecting one or more analytic compounds. In certain embodiments, for example, an active region of the currently disclosed analytic sensor, located on a working electrode, may be configured to detect one analytic compound. In certain embodiments, the active region includes one or more enzymes for detecting the analytic compound. In certain embodiments, the analytic sensor of this disclosure may have multiple active regions, each configured to detect the same or different analytic compounds. In certain embodiments, the sensor does not include enzymes, and the analytic compound is oxidized directly at the working electrode.

[0124] In certain embodiments, the active area of ​​the sensor of the Disclosure is not limited to, but includes, glucose, lactate, ketones (e.g., ketone bodies), glutamine, alcohol, aspartic acid, asparagine, glutamic acid, creatinine, hematocrit, acetoacetate, fructosamine, amylase, bilirubin, cholesterol, chorionic gonadotropins, creatine kinase (e.g., CK-MB), creatine, DNA, RNA, growth factors, growth hormone, hormones (e.g., thyroid-stimulating hormone), steroids, vitamins (e.g., ascorbic acid), uric acid, neurochemicals (e.g., acetylcholine, norepinephrine, and dopamine), oxygen, albumin, hemoglobin A1c, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, blood urea nitrogen, sarcosine, The analytes may include one or more enzymes for detecting analytes containing prostate-specific antigen, prothrombin, thrombin, troponin, pyruvate, acetaldehyde, ascorbic acid, galactose, L-xylono-1,4-lactone, glutathione disulfide, hydrogen peroxide, linoleic acid, 1,3-bisphosphoglycerate, 6-phospho-D-glucono-1,5-lactone, hemoglobin, pharmaceuticals (e.g., antibiotics (e.g., gentamicin, vancomycin, etc.), digitoxin, digoxin, theophylline, insulin, and warfarin), abused drugs (e.g., analgesics, sedatives, stimulants, and hallucinogens), metal ions (e.g., potassium, sodium, calcium, magnesium, manganese, iron, cobalt, molybdenum, zinc, and chlorine), pH, carbonates, phosphates, sulfates, fatty acids, and antibodies.

[0125] In certain embodiments, the analytes are glucose, lactic acid, ketones, glutamic acid, creatinine, sarcosine, and / or ascorbic acid.

[0126] In certain embodiments, the analyte is glucose.

[0127] In certain embodiments, the analyte is a ketone.

[0128] In certain embodiments, the analyte is lactic acid.

[0129] In certain embodiments, the analyte is glutamic acid.

[0130] In certain embodiments, one or more enzymes in the active area of ​​the sensor of the present disclosure can be used to detect glutamate, glucose, ketones, lactate, oxygen, hemoglobin A1c, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartic acid, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, and uric acid.

[0131] In certain embodiments, enzymes for use in detecting glucose, lactic acid, ketones, creatinine, alcohols such as ethanol, may be included in one or more active areas and / or one or more detection spots of the analyte sensor disclosed herein, for example, as shown in Figures 1A and 1B. In certain embodiments, enzymes for use in detecting glucose, lactic acid, ketones, creatinine, alcohols such as ethanol, may be included in two or more detection spots of the analyte sensor disclosed herein, for example, as shown in Figure 2. In certain embodiments, one or more enzymes may include multiple enzymes, such as an enzyme system, that react cooperatively with the analyte.

[0132] In certain embodiments, the enzyme may be an oxidoreductase. In certain embodiments, the oxidoreductase may be an enzyme belonging to enzyme classification 1. For example, but not limited to, the enzyme may belong to enzyme classification 1.1 (e.g., 1.1.1 or 1.1.3), enzyme classification 1.4 (e.g., 1.4.3), or enzyme classification 1.5. In certain embodiments, the enzyme may be an NAD(P)+-dependent dehydrogenase. In certain embodiments, the enzyme may be a flavin adenine dinucleotide (FAD)-dependent oxidoreductase. In certain embodiments, the enzyme may be a hydrolase. In certain embodiments, the hydrolase may be an enzyme belonging to enzyme classification 3. For example, but not limited to, the enzyme may belong to enzyme classification 3.5, e.g., 3.5.2 or 3.5.3.

[0133] In certain embodiments, the active area of ​​the sensor of the Disclosure (e.g., one or more detection spots in the active area of ​​the analytic sensor of the Disclosure) may include one or more enzymes that can be used to detect glucose. For example, but not limited to, the analytic sensor of the Disclosure may include one or more detection spots containing one or more enzymes for detecting glucose, e.g., detection spot 108a, detection spot 108b, detection spot 108c, etc. In certain embodiments, the analytic sensor may include one or more detection spots containing glucose oxidase and / or glucose dehydrogenase for detecting glucose. In certain embodiments, the analytic sensor may include one or more detection spots containing glucose oxidase. In certain embodiments, the glucose dehydrogenase may be pyrroloquinoline quinone (PQQ) or cofactor-dependent glucose dehydrogenase, e.g., flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenase or nicotinamide adenine dinucleotide (NAD)-dependent glucose dehydrogenase. In certain embodiments, the active region (e.g., one or more detection spots) may further include a diaphorase. In certain embodiments, the enzyme for detecting glucose is FAD-dependent glucose oxidase.

[0134] In certain embodiments, the active area of ​​the sensor of the Disclosure (e.g., one or more detection spots in the active area of ​​the analytic sensor of the Disclosure) may include one or more enzymes that can be used to detect ketones. For example, but not limited to, the analytic sensor of the Disclosure may include one or more detection spots, e.g., detection spot 108d, that include one or more enzymes for detecting ketones, e.g., an enzyme system. In certain embodiments, the ketone-responsive active area may include an enzyme system comprising multiple enzymes that can act in coordination to facilitate ketone detection, as described in U.S. Patent Application Publication No. 2020 / 0237275, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the analytic sensor may include one or more detection spots that include β-hydroxybutyrate dehydrogenase. In certain embodiments, the analytic sensor may include one or more detection spots that include β-hydroxybutyrate dehydrogenase and diaphorase for detecting ketones. In certain embodiments, the active area (e.g., one or more detection spots) may further include diaphorase.

[0135] In certain embodiments, the active area of ​​the sensor of the Disclosure (e.g., one or more detection spots in the active area of ​​the analytic sensor of the Disclosure) may include one or more enzymes that can be used to detect lactic acid. For example, but not limited to, the analytic sensor of the Disclosure may include one or more detection spots, e.g., detection spot 108e, that include one or more enzymes for detecting lactic acid, e.g., an enzyme system. In certain embodiments, the lactic acid-responsive active area (e.g., one or more detection spots) may include an enzyme system comprising multiple enzymes that can act in coordination to facilitate the detection of lactic acid, as described in U.S. Patent Application Publication No. 2019 / 0320947, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the analytic sensor may include one or more detection spots that include lactate dehydrogenase. In certain embodiments, the analytic sensor may include one or more detection spots that include lactate oxidase. In certain embodiments, the active area (e.g., one or more detection spots) may further include diaphorase.

[0136] In certain embodiments, the active area of ​​the sensor of the Disclosure (e.g., one or more detection spots in the active area of ​​the analytic sensor of the Disclosure) may include one or more enzymes that can be used to detect alcohol. For example, but not limited to, the analytic sensor of the Disclosure may include one or more detection spots, e.g., detection spot 108e, that include one or more enzymes for detecting alcohol, e.g., an enzyme system. In certain embodiments, the ethanol-responsive active area may include an enzyme system comprising multiple enzymes that can work together to facilitate the detection of ethanol, as described in U.S. Patent Application Publication 2020 / 0237277 (the contents of which are incorporated herein by reference in their entirety). In certain embodiments, the analytic sensor may include one or more detection spots that include alcohol dehydrogenase or keto reductase.

[0137] In certain embodiments, the active area of ​​the sensor of the Disclosure (e.g., one or more detection spots in the active area of ​​the analytic sensor of the Disclosure) may include one or more enzymes that can be used to detect creatinine. For example, but not limited to, the analytic sensor of the Disclosure may include one or more detection spots, e.g., detection spot 108e, that include one or more enzymes for detecting creatinine, e.g., an enzyme system. In certain embodiments, the creatinine-responsive active area (e.g., one or more detection spots) may include an enzyme system that includes multiple enzymes capable of working together to facilitate the detection of creatinine, e.g., as described in U.S. Patent Application Publication No. 2020 / 0241015, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the analytic sensor may include one or more detection spots that include amide hydrolase, creatine amidino hydrolase, and / or sarcosine oxidase.

[0138] In certain embodiments, the active area of ​​the sensor of the Disclosure (e.g., one or more detection spots in the active area of ​​the analytic sensor of the Disclosure) may include one or more enzymes that can be used to detect glutamate. For example, but not limited to, the analytic sensor of the Disclosure may include one or more detection spots, e.g., detection spot 108e, that include one or more enzymes for detecting glutamate, e.g., an enzyme system. In certain embodiments, the analytic sensor may include one or more detection spots that include glutamate dehydrogenase or glutamate oxidase.

[0139] In certain embodiments, the active region of the Disclosure may include one or more detection spots, each detection spot may include one or more enzymes for detecting an analyte. For example, but not limited to, an analyte sensor disclosed herein may include two or more detection spots, e.g., detection spots 108a to 108f, each detection spot may include at least one enzyme for detecting an analyte. In certain embodiments, each active region (e.g., each detection spot) may be configured to detect the same analyte or different analytes. For example, but not limited to, an analyte sensor of the Disclosure may include a first detection spot containing a first enzyme (or first enzyme system) for detecting a first analyte, and a second detection spot containing a second enzyme (or second enzyme system) for detecting a second analyte, and so on. In certain embodiments, the first and second detection spots may be used to detect the same analyte, in which case the first and second detection spots may include different enzymes (or enzyme systems) or the same enzyme (or enzyme system) for detecting the analyte.

[0140] In certain embodiments, the active region (e.g., analyte responsiveness detection spot) may further contain stabilizers for stabilizing, for example, one or more enzymes. For example, the stabilizer may be albumin, such as serum albumin. Non-limited examples of serum albumin include bovine serum albumin and human serum albumin. In certain embodiments, the stabilizer may be human serum albumin. In certain embodiments, the stabilizer may be bovine serum albumin.

[0141] In certain embodiments, the active region (e.g., analyte-responsive detection spot) may further include cofactors or coenzymes for one or more enzymes present within the analyte-responsive detection spot. In certain embodiments, the cofactor may be nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP). In certain embodiments, the coenzyme may be NAD.

[0142] In certain embodiments, the sensors of the Disclosure do not include an analyte-responsive active area containing an enzyme. In certain embodiments, the sensors of the Disclosure include a working electrode on which no enzyme is located, or a working electrode on which an inactive enzyme, e.g., an enzyme lacking enzymatic activity (e.g., with respect to the analyte of interest), is located. In certain embodiments, such sensors can be used to detect analytes that can be directly oxidized on the working electrode. For example, but not limited to, a sensor of the Disclosure for detecting ascorbic acid does not include an enzyme on the working electrode. In certain embodiments, ascorbic acid is directly oxidized on the working electrode, producing a signal that correlates with the level of ascorbic acid in a biological fluid in contact with the sensor.

[0143] In certain embodiments, a working electrode that does not contain enzymes or contains inactive enzymes may be used to detect background signals. In certain embodiments, background signals include signals caused by chemical species other than the target analyte present in the sample, such as signals caused by interfering substances. In certain embodiments, background signals are signals caused by one or more interfering substances. Non-limiting examples of interfering substances include acetaminophen, ascorbates, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylates, tetracycline, trazamide, tolbutamide, triglycerides, urea, and uric acid. In certain embodiments, background signals may be used to calibrate, filter, and / or normalize signals obtained from a second working electrode (configured to detect the analyte) located on the same analyte sensor. In certain embodiments, the signal from a working electrode that does not contain an enzyme (or contains an inactive enzyme) can be subtracted from the signal obtained from a working electrode configured to detect the analyte to determine the signal contribution from the analyte.

[0144] In certain embodiments, the analyte sensors disclosed herein may include an electron transfer agent. For example, but not limited to, an active area (e.g., one or more detection spots of the analyte sensor) may include an electron transfer agent. In certain embodiments, the analyte sensor may include one detection spot containing an electron transfer agent and a second detection spot not containing an electron transfer agent. In certain embodiments, the analyte sensor may include a plurality of detection spots, the plurality of detection spots may contain electron transfer agents. In certain embodiments, the presence of an electron transfer agent in a detection spot may depend on the composition of the enzyme or enzyme system and / or working electrode used to detect the analyte.

[0145] The electron transfer agents currently disclosed, suitable for use in analyte sensors, can facilitate the transfer of electrons to an adjacent working electrode after the analyte has undergone an enzymatic redox reaction within the corresponding detection spot, thereby generating a current that indicates the presence of that particular analyte. The amount of current generated is proportional to the amount of analyte present.

[0146] In certain embodiments, suitable electron transfer agents may include electroreducible and electrooxidizing ions, complexes, or molecules (e.g., quinones) having redox potentials several hundred millivolts higher or lower than the redox potential of a standard calomel electrode. In certain embodiments, redox mediators may include osmium complexes and other transition metal complexes, such as those described in U.S. Patents No. 6,134461 and No. 6,605200, which are incorporated herein by reference in their entirety. Additional examples of suitable redox mediators include those described in U.S. Patents No. 6,736957, No. 7501053 and No. 7754093, whose respective disclosures are also incorporated herein by reference in their entirety. Other examples of suitable redox mediators include, for example, metal compounds or complexes of ruthenium, osmium, iron (e.g., polyvinylferrocene or hexacyanoferrate), or cobalt, including their metallocene compounds. Examples of suitable ligands for metal complexes include bipyridine, biimidazole, phenanthroline, or pyridyl(imidazole), which are bidentate or polydentate ligands. Other examples of suitable bidentate ligands include amino acids, oxalic acid, acetylacetone, diaminoalkanes, or o-diaminoarenes. Metal complexes, such as osmium complexes, can have any combination of monodentate, bidentate, tridentate, quaternate, or more polydentate ligands to form a complete coordination sphere. In certain embodiments, the electron transfer agent is an osmium complex. In certain embodiments, the electron transfer agent is osmium complexed with a bidentate ligand. In certain embodiments, the electron transfer agent is osmium complexed with a tridentate ligand.

[0147] In certain embodiments, the electron transfer agents disclosed herein may include suitable functional groups that promote covalent bonding with the polymer (also referred to herein as the polymer backbone) in the active region, as further described below. For example, but not limited to, electron transfer agents used in this disclosure may include polymer-bound electron transfer agents, such as redox polymers. Suitable non-limiting examples of polymer-bound electron transfer agents include those described in U.S. Patents No. 8,444,834, No. 8,268,143, and No. 6,605,201, and U.S. Patent Application Publication No. 2022 / 0202326, whose disclosures are incorporated herein by reference as a whole. In certain embodiments, the electron transfer agent is an osmium complex having a bidentate ligand bonded to the polymer described herein, for example, the polymer backbone described in Section 4 below. In certain embodiments, the electron transfer agent is an osmium complex having a tridentate ligand bonded to the polymer described herein, for example, the polymer backbone described in Section 4 below. In certain embodiments, a polymer-bound electron transfer agent (referred to as "X7") shown in Figure 3 of U.S. Patent No. 8,444,834 may be used in the sensor of this disclosure.

[0148] In certain embodiments, one or more working electrodes of the analyte sensor of the present disclosure do not have a redox mediator disposed on the working electrode. In certain embodiments, one or more working electrodes of the analyte sensor of the present disclosure do not have a redox mediator or enzyme disposed on the working electrode. In certain embodiments, such working electrodes can be used to detect analytes (or reaction products) that can be directly oxidized on the working electrode. For example, a working electrode having an activator that does not contain a redox mediator can be used to detect an analyte, such as glucose, by oxidation of hydrogen peroxide on the working electrode.

[0149] iii. Membrane In certain embodiments, the analyte sensor of the present disclosure further includes a film covering at least a portion of the detection layer. For example, but not limited to, the film may function as a material transport restriction film and / or to improve biocompatibility. In certain embodiments, the film 110 may overlay at least a portion of the active area as shown in Figure 1A. In certain embodiments, the film may overlay at least a portion of a plurality of detection spots, for example, a plurality of detection spots 108a to 108f, as shown in Figure 2.

[0150] A mass transport limiting membrane can function as a diffusion limiting membrane to reduce the rate of mass transport of an analyte, such as glucose, alcohol, ketone, or lactic acid, during sensor use. For example, but not limited to, restricting access to the detection spot of an analyte, such as glucose, with a mass transport limiting membrane can help prevent sensor overload (saturation), thereby improving detection performance and accuracy. In certain embodiments, a mass transport limiting layer can limit the flux of the analyte to the working electrode in an electrochemical sensor so that the sensor responds linearly over a wide concentration range of the analyte.

[0151] In certain embodiments, the mass transport restriction membrane can be homogeneous and single-component (containing a single membrane polymer). In certain embodiments, the mass transport restriction membrane can be multi-component (containing two or more different membrane polymers). In certain embodiments, the multi-component membrane can exist as a two-layer membrane or as a homogeneous mixture of two or more membrane polymers. The homogeneous mixture can be deposited by mixing two or more membrane polymers in a solution and depositing the solution onto the working electrode, for example, by immersion coating.

[0152] In certain embodiments, the material transport restriction membrane may consist of two or more layers, for example, a two-layer or three-layer membrane. In certain embodiments, each layer may contain a different polymer, or the same polymer with different concentrations or thicknesses.

[0153] In certain embodiments, the mass transport restriction membrane may include a polymer containing heterocyclic nitrogen groups. In certain embodiments, the mass transport restriction membrane may include a polyvinylpyridine polymer. Non-limiting examples of polyvinylpyridine polymers are disclosed in U.S. Patent Application Publication 2003 / 0042137, the contents of which are incorporated herein by reference in whole. In certain embodiments, the molecular weight of the polyvinylpyridine polymer is about 50 kD to about 500 kD, for example, about 50 kD to about 200 kD.

[0154] In certain embodiments, the material transport restriction membrane may include polyvinylpyridine (e.g., poly(2-vinylpyridine) or poly(4-vinylpyridine)), polyvinylimidazole, polyvinylpyridine copolymers (e.g., copolymers of vinylpyridine and styrene), polyacrylates, polyurethanes, polyether urethanes, silicones, polytetrafluoroethylenes, polyethylene / tetrafluoroethylene copolymers, polyolefins, polyesters, polycarbonates, biostable polytetrafluoroethylenes, homopolymers, copolymers or terpolymers of polyurethanes, polypropylenes, polyvinyl chlorides, polyvinylidene fluoride, polybutylene terephthalate, polymethyl methacrylates, polyether ether ketones, cellulosonic polymers, polysulfones, and block copolymers thereof (e.g., including 2-block, 3-block, alternating, random, and graft copolymers), or chemically related materials.

[0155] In certain embodiments, the material transport restriction membrane may include polyvinylpyridine (e.g., poly(4-vinylpyridine) and / or poly(2-vinylpyridine)). In certain embodiments, the material transport restriction membrane may include poly(4-vinylpyridine). In certain embodiments, the material transport restriction membrane may include a copolymer of vinylpyridine and styrene. In certain embodiments, the material transport restriction membrane may include a polyvinylpyridine / styrene copolymer. For example, but not limited to, the polyvinylpyridine / styrene copolymer may include a polyvinylpyridine / styrene copolymer in which some of the nitrogen atoms of pyridine are functionalized with non-crosslinked polyethylene glycol ends and some of the nitrogen atoms of pyridine are functionalized with alkyl sulfonic acid groups, such as propyl sulfonic acid. In certain embodiments, the derivatized polyvinylpyridine / styrene copolymer used as the membrane polymer may be the 10Q5 polymer described in U.S. Patent No. 8,761,857, the contents of which are incorporated herein by reference in whole.

[0156] In certain embodiments, a suitable copolymer of vinylpyridine and styrene can have a styrene content ranging from about 0.01 mol% (monomer%), or from about 0.05 mol% to about 45 mol%, or from about 0.1 mol% to about 40 mol%, or from about 0.5 mol% to about 35 mol%, or from about 1 mol% to about 30 mol%, or from about 2 mol% to about 25 mol%, or from about 5 mol% to about 20 mol%. In certain embodiments, a suitable copolymer of vinylpyridine and styrene can have a styrene content ranging from about 2 mol% to about 25 mol%. Substituted styrene can be used in similar amounts.

[0157] In certain embodiments, a suitable copolymer of vinylpyridine and styrene may have a weight-average molecular weight of 5 kD or more, or about 10 kD or more, or about 15 kD or more, or about 20 kD or more, or about 25 kD or more, or about 30 kD or more, or about 40 kD or more, or about 50 kD or more, or about 75 kD or more, or about 90 kD or more, or about 100 kD or more, or about 110 kD or more. Non-limiting examples include a suitable copolymer of vinylpyridine and styrene having a weight-average molecular weight ranging from about 5 kD to about 150 kD, or about 10 kD to about 125 kD, or about 15 kD to about 100 kD, or about 20 kD to about 80 kD, or about 25 kD to about 75 kD, or about 30 kD to about 60 kD. In certain embodiments, the vinylpyridine-styrene copolymer may have a weight-average molecular weight ranging from about 10 kD to about 125 kD.

[0158] In certain embodiments, the material transport restriction membrane may further comprise a silicone polymer, such as polydimethylsiloxane (PDMS). For example, but not limited to, the material transport restriction membrane may comprise a polyvinylpyridine / styrene copolymer (e.g., a derivatized polyvinylpyridine / styrene copolymer) and a silicone polymer (e.g., polydimethylsiloxane (PDMS)).

[0159] iv. Interference area In certain embodiments, the analyte sensor of the present disclosure may further include an interference region. For example, the sensor tail (i.e., the internal portion) 100 or 200 of the analyte sensor may further include an interference region. In certain embodiments, the interference region may include, for example, a polymer region that restricts the flow of one or more interfering substances to the surface of the working electrode. In certain embodiments, the interference region can function as a molecular sieve that allows the analyte to be measured by the working electrode and other substances to pass through, while preventing the passage of other substances, such as interfering substances. In certain embodiments, interfering substances may affect the signal obtained at the working electrode. Non-limiting examples of interfering substances include acetaminophen, ascorbates, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylates, tetracycline, trazamide, tolbutamide, triglycerides, urea, and uric acid.

[0160] In certain embodiments, the interference region is located between the working electrode and the active area, for example, one or more detection spots. In certain embodiments, non-limiting examples of polymers that can be used for the interference region include polyurethanes, polymers having pendant ion groups, and polymers having controlled pore sizes. In certain embodiments, the interference region may be formed from one or more cellulose derivatives.

[0161] Non-limiting examples of cellulose derivatives include polymers such as cellulose acetate, cellulose butyrate acetate, 2-hydroxyethylcellulose, cellulose phthalate acetate, cellulose propionate acetate, and cellulose trimephosphate acetate.

[0162] In certain embodiments, the interference region is part of the mass transport restriction membrane and is not a separate membrane. In certain embodiments, the interference region is located between one or more detection spots and the mass transport restriction membrane.

[0163] In certain embodiments, the interference region may include a non-swelling, thin-film hydrophobic membrane that restricts the diffusion of high molecular weight species. For example, but not limited to, the interference region may be permeable to relatively low molecular weight substances such as hydrogen peroxide, while restricting the passage of high molecular weight substances such as ketones, glucose, acetaminophen, and / or ascorbic acid.

[0164] IV. Polymer compositions containing therapeutic agents This disclosure provides therapeutic agent-containing polymer compositions that can be incorporated into analyte sensors described herein, such as implantable analyte sensors. For example, but not limited to, the sensor tail 100 or 200 (i.e., the in vivo portion) of an analyte sensor according to this disclosure, such as an analyte sensor described herein, comprises a therapeutic agent-containing polymer composition. One or more therapeutic agents are released in vivo near the analyte sensor. By incorporating the therapeutic agent into the analyte sensor itself, or by delivering the therapeutic composition near the sensor at the in vivo location of the sensor, it is possible to target the therapeutic agent to the tissue surrounding the implantation site and the analyte sensor (e.g., the surrounding tissue).

[0165] In certain embodiments, the therapeutic substance-containing polymer composition is also referred to herein as the drug-eluting membrane and the second polymer membrane.

[0166] Furthermore, this disclosure provides a sharp instrument for inserting an analyte sensor into a subject. For example, but not limited to, this disclosure provides a sharp instrument coated with a therapeutic agent-containing polymer composition described herein.

[0167] In certain embodiments, the therapeutic agent to be delivered in accordance with this disclosure is an effective therapeutic agent for reducing, minimizing, preventing and / or suppressing the tissue response to the implantation and / or tissue infection of the analyte sensor, and thus can prevent and / or reduce late sensor decay.

[0168] In certain embodiments, the therapeutic agent to be delivered in accordance with this disclosure is an effective therapeutic agent for reducing, minimizing, preventing and / or suppressing the tissue response to the implantation and / or tissue infection of the analyte sensor, and thus can reduce and / or minimize, for example, inaccuracies in sensor signals or failures of in vivo sensors caused by FBR.

[0169] Non-limiting examples of therapeutic agents that may be included in the therapeutic agent-containing polymer compositions of the present disclosure are disclosed in Section II. For example, the therapeutic agent may be an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent may be a non-steroidal anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent may be a steroidal anti-inflammatory agent, such as a corticosteroid. Non-limiting examples of anti-inflammatory agents include triamcinolone, betamethasone, dexamethasone, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid or its derivatives, and / or salts thereof or prodrugs thereof. Non-limiting salt forms include pharmaceutically acceptable salts, including acetates and phosphates.

[0170] In certain embodiments, the anti-inflammatory agent is dexamethasone.

[0171] In certain embodiments, the anti-inflammatory agent may be a salt of dexamethasone.

[0172] In certain embodiments, the anti-inflammatory agent may be a derivative of dexamethasone.

[0173] In certain embodiments, the dexamethasone derivative and / or dexamethasone salt form may be dexamethasone acetate.

[0174] In certain embodiments, the dexamethasone derivative and / or dexamethasone salt form may be dexamethasone sodium phosphate.

[0175] In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from 0.01% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from 0.01% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from 1% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from 5% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from 10% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from 20% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from 30% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from about 5% to 20% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from about 5% to 10% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount ranging from about 1% to 10% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof.In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from about 1% to 20% by mass based on the total mass of the therapeutic agent-containing polymer composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from about 1% to 30% by mass based on the total mass of the therapeutic agent-containing polymer composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from about 10% to 20% by mass based on the total mass of the therapeutic agent-containing polymer composition.

[0176] In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from 0.01% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition.

[0177] In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from about 1% to 10% by mass based on the total mass of the therapeutic agent-containing polymer composition.

[0178] In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 50% by mass or less based on the total mass of the polymer (e.g., copolymer) in the composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 45% by mass or less based on the total mass of the polymer (e.g., copolymer) in the composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 40% by mass or less based on the total mass of the polymer (e.g., copolymer) in the composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 35% by mass or less based on the total mass of the polymer (e.g., copolymer) in the composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 30% by mass or less based on the total mass of the polymer (e.g., copolymer) in the composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 25% by mass or less based on the total mass of the polymer (e.g., copolymer) in the composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 20% by mass or less based on the total mass of the polymer (e.g., copolymer) in the composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 15% by mass or less based on the total mass of the polymer (e.g., copolymer) in the composition. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 10% by mass or less based on the total mass of the polymer (e.g., copolymer) in the composition.

[0179] In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone, in an amount of about 0.0005 mg to about 0.2 mg, or any value in between. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone, in an amount of about 0.0005 mg, about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, or about 0.2 mg. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent, such as dexamethasone, in an amount of about 0.0005 mg to about 0.1 mg, about 0.0005 mg to about 0.05 mg, about 0.0005 mg to about 0.01 mg, about 0.0005 mg to about 0.005 mg, or about 0.0005 mg to about 0.001 mg. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.0005 mg to about 0.1 mg. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.0005 mg to about 0.01 mg. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.001 mg to about 0.1 mg. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.001 mg to about 0.01 mg. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.001 mg to about 0.005 mg. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.001 mg to about 0.003 mg.In a particular embodiment, the therapeutic agent-containing polymer composition contains about 0.1 μg to about 200 μg of therapeutic agent, for example, about 0.5 μg to about 200 μg, about 1 μg to about 200 μg, about 1.5 μg to about 200 μg, about 2.0 μg to about 200 μg, about 2.5 μg to about 200 μg, about 3 μg to about 200 μg, about 4 μg to about 200 μg, about 5 μg to about 200 μg, about 10 μg to about 200 μg, about 15 μg to about 200 μg, about From 20 μg to approximately 200 μg, from approximately 25 μg to approximately 200 μg, from approximately 30 μg to approximately 200 μg, from approximately 35 μg to approximately 200 μg, from approximately 40 μg to approximately 200 μg, from approximately 45 μg to approximately 200 μg, from approximately 50 μg to approximately 200 μg, from approximately 55 μg to approximately 200 μg, from approximately 60 μg to approximately 200 μg, from approximately 65 μg to approximately 200 μg, from approximately 70 μg to approximately 200 μg, from approximately 75 μg to approximately 200 μg, from approximately 80 μg to approximately 200 μg, from approximately 85 μg to approximately 20 0 μg, approximately 90 μg to approximately 200 μg, approximately 95 μg to approximately 200 μg, approximately 100 μg to approximately 200 μg, approximately 110 μg to approximately 200 μg, approximately 120 μg to approximately 200 μg, approximately 130 μg to approximately 200 μg, approximately 140 μg to approximately 200 μg, approximately 150 μg to approximately 200 μg, approximately 160 μg to approximately 200 μg, approximately 170 μg to approximately 200 μg, approximately 180 μg to approximately 200 μg, approximately 190 μg to approximately 200 μg, approximately 0.1 μg to approximately The composition may contain 190 μg, approximately 0.1 μg to approximately 180 μg, approximately 0.1 μg to approximately 170 μg, approximately 0.1 μg to approximately 160 μg, approximately 0.1 μg to approximately 150 μg, approximately 0.1 μg to approximately 140 μg, approximately 0.1 μg to approximately 130 μg, approximately 0.1 μg to approximately 120 μg, approximately 0.1 μg to approximately 110 μg, approximately 0.1 μg to approximately 100 μg, approximately 1 μg to approximately 150 μg, approximately 5 μg to approximately 150 μg, or approximately 5 μg to approximately 120 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain approximately 0.1 μg to approximately 20 μg of the therapeutic agent.In a particular embodiment, the therapeutic agent-containing polymer composition contains about 1 μg to about 100 μg of therapeutic agent, for example, about 1 μg to about 95 μg, about 1 μg to about 90 μg, about 1 μg to about 85 μg, about 1 μg to about 80 μg, about 1 μg to about 75 μg, about 1 μg to about 70 μg, about 1 μg to about 65 μg, about 1 μg to about 60 μg, about 1 μg to about 55 μg, about 1 μg to about 50 μg, about 1 μg to about 45 μg, about 1 μg to about 40 μg, about 1 μg to about 35 μg, about 1 μg to about 30 μg, about 1 μg Approximately 25 μg, approximately 1 μg to approximately 20 μg, approximately 1 μg to approximately 15 μg, approximately 1 μg to approximately 14 μg, approximately 1 μg to approximately 13 μg, approximately 1 μg to approximately 12 μg, approximately 1 μg to approximately 11 μg, approximately 1 μg to approximately 10 μg, approximately 1 μg to approximately 9 μg, approximately 2 μg to approximately 100 μg, approximately 3 μg to approximately 100 μg, approximately 4 μg to approximately 100 μg, approximately 5 μg to approximately 100 μg, approximately 6 μg to approximately 100 μg, approximately 7 μg to approximately 100 μg, approximately 8 μg to approximately 100 μg, approximately 9 μg to approximately 100 μg, approximately 10 μg to approximately 100 μg, approximately 1 Approximately 100 μg from 1 μg, approximately 100 μg from 12 μg, approximately 100 μg from 13 μg, approximately 100 μg from 14 μg, approximately 100 μg from 15 μg, approximately 100 μg from 16 μg, approximately 100 μg from 17 μg, approximately 100 μg from 18 μg, approximately 100 μg from 19 μg, approximately 100 μg from 20 μg, approximately 100 μg from 25 μg, approximately 100 μg from 30 μg, approximately 100 μg from 35 μg, approximately 100 μg from 40 μg, approximately 100 μg from 45 μg, approximately 100 μg from 50 μg, The composition may contain approximately 55 μg to 100 μg, approximately 60 μg to 100 μg, approximately 65 μg to 100 μg, approximately 70 μg to 100 μg, approximately 75 μg to 100 μg, approximately 80 μg to 100 μg, approximately 85 μg to 100 μg, approximately 90 μg to 100 μg, approximately 95 μg to 100 μg, approximately 5 μg to 50 μg, approximately 5 μg to 45 μg, approximately 5 μg to 40 μg, approximately 5 μg to 35 μg, approximately 5 μg to 30 μg, approximately 5 μg to 25 μg, or approximately 5 μg to 20 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain approximately 1 μg to 20 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 5 μg to about 20 μg of the therapeutic agent.In certain embodiments, the therapeutic agent-containing polymer composition may contain about 1 μg to about 30 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 5 μg to about 30 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.1 μg to about 15 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.1 μg to about 10 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.1 μg to about 5 μg of the therapeutic agent.

[0180] In certain embodiments, the therapeutic agent-containing polymer composition may contain about 0.01 μg to about 5 μg of the therapeutic agent.

[0181] In certain embodiments, the therapeutic agent-containing polymer composition may contain less than approximately 50 μg of therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain less than approximately 40 μg of therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain less than approximately 30 μg of therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain less than approximately 20 μg of therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain less than approximately 10 μg of therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition may contain less than approximately 5 μg of therapeutic agent.

[0182] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a set or predetermined drug release rate to reduce and / or minimize, for example, inaccuracies in sensor signals or failures of in vivo sensors caused by FBR. In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a set or predetermined drug release rate to achieve desirable therapeutic effects, such as minimizing and / or reducing LSA.

[0183] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.001 μg / day to about 1 mg / day, or any value in between.

[0184] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.001 μg / day to about 5 μg / day, or any value in between.

[0185] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.001 μg / day to about 1 μg / day, or any value in between.

[0186] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.001 μg / day to about 0.1 μg / day, or any value in between.

[0187] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.01 μg / day to about 100 μg / day, or any value in between.

[0188] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.01 μg / day to about 10 μg / day, or any value in between.

[0189] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.01 μg / day to about 1 mg / day, or any value in between.

[0190] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate of less than approximately 1 mg / day, or less than approximately 0.5 mg / day, for example, dexamethasone (e.g., average drug release rate).

[0191] In a particular embodiment, the therapeutic agent-containing polymer composition is available in doses of approximately 0.1 μg / day, approximately 0.2 μg / day, approximately 0.3 μg / day, approximately 0.4 μg / day, approximately 0.5 μg / day, approximately 0.6 μg / day, approximately 0.7 μg / day, approximately 0.8 μg / day, approximately 0.9 μg / day, approximately 1 μg / day, approximately 2 μg / day, approximately 3 μg / day, approximately 4 μg / day, approximately 5 μg / day, approximately 6 μg / day, approximately 7 μg / day, approximately 8 μg / day, approximately 9 μg / day, approximately 10 μg / day, approximately 20 μg / day, approximately 30 μg / day, and approximately 40 μg / The therapeutic agent can be continuously released at a drug release rate (e.g., average drug release rate) of the therapeutic agent, such as dexamethasone, at a dose of approximately 50 μg / day, 60 μg / day, 70 μg / day, 800 μg / day, 90 μg / day, 100 μg / day, 200 μg / day, 300 μg / day, 400 μg / day, 500 μg / day, 600 μg / day, 700 μg / day, 800 μg / day, 900 μg / day, or approximately 1 mg / day, or any value in between. In a particular embodiment, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a dose of approximately 0.2 μg / day to approximately 5 μg / day, such as dexamethasone, at a drug release rate (e.g., average drug release rate). In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of approximately 0.2 μg / day to approximately 2 μg / day of the therapeutic agent, for example, dexamethasone. In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of approximately 0.2 μg / day to approximately 1 μg / day of the therapeutic agent, for example, dexamethasone. In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug release rate set or predetermined to achieve desired therapeutic outcomes such as reduction, minimization, prevention, and / or suppression of inflammation and / or infection.

[0192] In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a set or predetermined drug release rate over a set or predetermined number of days, such as at least 20 days. In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a set or predetermined drug release rate over a set or predetermined number of days, such as at least 20 days. In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a set or predetermined drug release rate over a set or predetermined number of days, such as at least 25 days. In certain embodiments, the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a set or predetermined drug release rate for a set or predetermined number of days, such as at least 30 days.

[0193] In certain embodiments, the therapeutic agent-containing polymer composition of the Disclosure releases about 1% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded into the composition) within a period of about 30 to 31 days (e.g., when implanted in a subject). In certain embodiments, the therapeutic agent-containing polymer composition of the Disclosure releases about 30% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded into the composition) within a period of about 30 to 31 days (e.g., when implanted in a subject). In certain embodiments, the therapeutic agent-containing polymer composition of the Disclosure releases about 50% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded into the composition) within a period of about 30 to 31 days (e.g., when implanted in a subject). In certain embodiments, the therapeutic agent-containing polymer composition of the Disclosure releases about 30% to about 90% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded into the composition) within a period of about 30 to 31 days (e.g., when implanted in a subject). In certain embodiments, the therapeutic agent-containing polymer composition of the Disclosure releases about 30% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded into the composition) within a period of about 30 to 31 days (e.g., when implanted in a subject). In certain embodiments, the therapeutic agent-containing polymer composition of the Disclosure releases about 30% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded into the composition) within a period of about 30 to 31 days (e.g., when implanted in a subject). In certain embodiments, the period of about 30 to 31 days is the wearing time of the sensor described herein. In certain embodiments, the period of about 30 to 31 days is the lifespan of the sensor described herein.

[0194] In certain embodiments, approximately 90% or less of the therapeutic agent present in the therapeutic agent-containing polymer composition (e.g., the total amount of therapeutic agent loaded into the composition) is released, for example, within a period of approximately 30 to 31 days. In certain embodiments, approximately 70% or less of the therapeutic agent present in the therapeutic agent-containing polymer composition (e.g., the total amount of therapeutic agent loaded into the composition) is released, for example, within a period of approximately 30 to 31 days.

[0195] In certain embodiments, about 30% or less, about 35% or less, about 40% or less, about 45% or less, about 50% or less, about 55% or less, about 65% or less, about 70% or less, or 75% or less of the therapeutic agent present in the therapeutic agent-containing polymer composition (e.g., the total amount of therapeutic agent loaded into the composition) is released during the first 5, 6, or 7 days after insertion of the composition.

[0196] In certain embodiments, approximately 30% or less of the therapeutic agent present in the therapeutic agent-containing polymer composition (e.g., the total amount of therapeutic agent loaded into the composition) is released during the first 5, 6, or 7 days after insertion of the composition. In certain embodiments, approximately 40% or less of the therapeutic agent present in the therapeutic agent-containing polymer composition (e.g., the total amount of therapeutic agent loaded into the composition) is released during the first 5, 6, or 7 days after insertion of the composition. In certain embodiments, approximately 50% or less of the therapeutic agent present in the therapeutic agent-containing polymer composition (e.g., the total amount of therapeutic agent loaded into the composition) is released during the first 5, 6, or 7 days after insertion of the composition. In certain embodiments, approximately 60% or less of the therapeutic agent present in the therapeutic agent-containing polymer composition (e.g., the total amount of therapeutic agent loaded into the composition) is released during the first 5, 6, or 7 days after insertion of the composition. In certain embodiments, approximately 70% or less of the therapeutic agent present in the therapeutic agent-containing polymer composition (e.g., the total amount of therapeutic agent loaded into the composition) is released during the first 5, 6, or 7 days after insertion of the composition.

[0197] In certain embodiments, the therapeutic agent-containing polymer compositions of the present disclosure comprise one or more polymers. Non-limiting examples of polymers used in the therapeutic agent-containing polymer compositions of the present disclosure are disclosed in U.S. Patent Application Publication 2003 / 0042137, International Patent Application PCT / US2022 / 011058, and International Patent Application PCT / US2024 / 010088, the contents of which are fully incorporated herein. For example, but not limited to, polymers (e.g., copolymers) that can be used in the therapeutic agent-containing polymer compositions of the present disclosure are disclosed on pages 82–84, 102–104, and 112 of International Patent Application PCT / US2022 / 011058, and on pages 22–32 of International Patent Application PCT / US2024 / 010088.

[0198] In certain embodiments, the polymer in the therapeutic agent-containing polymer composition may include polymers selected from polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyether urethane polymers, silicone polymers, their derivatives, their copolymers, and combinations thereof.

[0199] In a particular embodiment, the polymer of the therapeutic agent-containing polymer composition includes an acrylate.

[0200] In a particular embodiment, the polymer in the therapeutic agent-containing polymer composition is a polyurethane polymer containing acrylate.

[0201] In a particular embodiment, the polymer in the therapeutic agent-containing polymer composition is a polyacrylate-based polymer.

[0202] In a particular embodiment, the polymer in the therapeutic agent-containing polymer composition is a polyacrylate-based polymer.

[0203] In a particular embodiment, the polymer of the therapeutic agent-containing polymer composition is poly(2-hydroxyethyl methacrylate).

[0204] In a particular embodiment, the polymer in the therapeutic agent-containing polymer composition is a polyvinylpyridine polymer.

[0205] In a particular embodiment, the polymer in the therapeutic agent-containing polymer composition is a polyurethane polymer.

[0206] In a particular embodiment, the polymer in the therapeutic agent-containing polymer composition is a polyurethane polyurea polymer.

[0207] In a particular embodiment, the polymer in the therapeutic agent-containing polymer composition is a polyurethane polymer containing silicone.

[0208] In a particular embodiment, the polymer in the therapeutic agent-containing polymer composition is a polymer comprising a polyurethane block polymer and a polysiloxane.

[0209] The polymer in the therapeutic agent-containing polymer composition may include copolymers selected from polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyether urethane copolymers, silicone copolymers, their derivatives, and combinations thereof.

[0210] The polymer in the therapeutic agent-containing polymer composition may include copolymers selected from polyvinylpyridine copolymers, polyvinylimidazole copolymers, and combinations thereof.

[0211] In certain embodiments, the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer. In certain embodiments, the polyvinylpyridine / polystyrene copolymer may be a poly(N-vinylimidazole) / polystyrene copolymer, a poly(1-vinylimidazole) / polystyrene copolymer, or a derivative thereof.

[0212] In certain embodiments, the polyvinylpyridine copolymer may be a copolymer of vinylpyridine and styrene, or a derivative thereof.

[0213] In certain embodiments, the polymer in the therapeutic agent-containing polymer composition may include a polyvinylpyridine / polystyrene copolymer.

[0214] In certain embodiments, the polyvinylpyridine / polystyrene copolymer may be a poly(4-vinylpyridine)polystyrene copolymer, a poly(2-vinylpyridine) / polystyrene copolymer, or a derivative thereof.

[0215] In certain embodiments, the polymer in the therapeutic agent-containing polymer composition may include a poly(4-vinylpyridine / styrene) copolymer.

[0216] In a particular embodiment, the polyvinylpyridine / polystyrene copolymer may contain about 1 to 50 monomer% of styrene units, about 1 to 40 monomer% of styrene units, about 1 to 30 monomer% of styrene units, about 1 to 20 monomer% of styrene units, or about 1 to 15 monomer% of styrene units. In a particular embodiment, the polyvinylpyridine / polystyrene copolymer may contain about 1 to 50 monomer% of styrene units. In a particular embodiment, the polyvinylpyridine / polystyrene copolymer may contain about 10 to 50 monomer% of styrene units. In a particular embodiment, the polyvinylpyridine / polystyrene copolymer may contain about 10 to 40 monomer% of styrene units. In a particular embodiment, the polyvinylpyridine / polystyrene copolymer may contain about 10 to 30 monomer% of styrene units. In a particular embodiment, the polyvinylpyridine / polystyrene copolymer may contain about 1 to 40 monomer% of styrene units. In a particular embodiment, the polyvinylpyridine / polystyrene copolymer may contain about 1 to 30 monomer% of styrene units. In certain embodiments, the polyvinylpyridine / polystyrene copolymer may contain about 1 to 20 monomer% of styrene units. In certain embodiments, the polyvinylpyridine / polystyrene copolymer may contain about 1 to 15 monomer% of styrene units.

[0217] In certain embodiments, the polyvinylpyridine / polystyrene copolymer may contain about 5 to 25 monomer% of styrene units. In certain embodiments, the polyvinylpyridine / polystyrene copolymer may contain about 5 to 20 monomer% of styrene units.

[0218] In certain embodiments, the polyvinylpyridine / polystyrene copolymer may contain about 5 to 15 monomer% of styrene units.

[0219] In certain embodiments, the polymer of the therapeutic agent-containing polymer composition may be a biodegradable or bioabsorbable polymer such as polycaprolactone (PCL), poly(glycolic acid) (PGA), poly(lactic acid) (PLA), or poly(D,L-lactic acid-coglycolic acid) (PLGA), but is not limited to the following. In certain embodiments, the polymer may be a polylactide, polyglycolide, or polyethylene glycol polymer. In certain embodiments, the polymer may be a blend of two or three of these polymer portions as a block copolymer, for example, a diblock copolymer or a triblock copolymer. Non-limiting embodiments of such block copolymers include poly(D,L-lactic acid-coglycolic acid) (PLGA) and the triblock copolymer polylactic acid-block-poly(ethylene glycol)-block-polylactic acid (PLA-PEG-PLA). Additional non-limiting examples of block copolymers include PEO-PPO diblock copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock copolymers, alternating PEO-PPO block copolymers, random copolymers of ethylene oxide and propylene oxide, and PEO-PPO copolymers such as blends thereof.

[0220] In a particular embodiment, the weight-average molecular weight of the polymer (e.g., copolymer) is approximately 5kD to 1,000kD, approximately 5kD to 900kD, approximately 5kD to 800kD, approximately 5kD to 700kD, approximately 5kD to 600kD, approximately 5kD to 500kD, approximately 5kD to 400kD, approximately 5kD to 300kD, approximately 10kD to 300kD, approximately 20kD to 300kD, approximately 30kD to The molecular weight is in any range defined between any two of the above values, such as 300kD, approximately 40kD-300kD, approximately 50kD-300kD, approximately 60kD-300kD, approximately 70kD-300kD, approximately 80kD-300kD, approximately 90kD-300kD, approximately 100kD-300kD, or approximately 100kD-200kD, or approximately 100kD-400kD. In certain embodiments, the weight-average molecular weight of the polymer (e.g., copolymer) is in the range of approximately 100kD-250kD. In certain embodiments, the molecular weight of the polymer (e.g., copolymer) can be determined by a suitable method such as gel permeation chromatography.

[0221] In certain embodiments, the polymer (e.g., copolymer) used in the Disclosure may absorb about 5% to about 95% of its mass in water. For example, but not limited to, the polymer (e.g., copolymer) used in the Disclosure may absorb about 5% to about 95%, about 5% to about 90%, about 5% to about 85%, about 10% to about 95%, about 15% to about 95%, about 20% to about 95%, about 25% to about 95%, about 30% to about 95%, about 5% to about 30%, about 5% to about 35%, about 5% to about 25%, or about 5% to about 20%. In certain embodiments, the polymer (e.g., copolymer) may absorb at least about 5% of its mass in water. In certain embodiments, the polymer (e.g., copolymer) may absorb at least about 10% of its mass in water. In certain embodiments, the polymer (e.g., copolymer) may absorb at least about 20% of its mass in water. In certain embodiments, a polymer (e.g., a copolymer) can absorb at least about 30% of its mass in water. In certain embodiments, a polymer (e.g., a copolymer) can absorb at least about 40% of its mass in water. In certain embodiments, a polymer (e.g., a copolymer) can absorb at least about 50% of its mass in water. In certain embodiments, a polymer (e.g., a copolymer) can absorb at least about 60% of its mass in water. In certain embodiments, a polymer (e.g., a copolymer) can absorb at least about 70% of its mass in water. In certain embodiments, a polymer (e.g., a copolymer) can absorb at least about 80% of its mass in water. In certain embodiments, a polymer (e.g., a copolymer) can absorb at least about 90% of its mass in water. In certain embodiments, a polymer (e.g., a copolymer) can absorb at least about 95% of its mass in water. In certain embodiments, the polymer (e.g., copolymer) used in this disclosure can absorb about 5% to about 25% of its mass in water.

[0222] In certain embodiments, the polymers (e.g., copolymers) used in the Disclosure may have hardnesses ranging from about 20 to about 100 Shore A. For example, but not limited to, polymers (e.g., copolymers) used in the Disclosure may have hardnesses ranging from about 20 to about 90 Shore A, about 20 to about 80 Shore A, about 20 to about 70 Shore A, about 20 to about 60 Shore A, about 20 to about 50 Shore A, about 20 to about 40 Shore A, about 20 to about 30 Shore A, about 30 to about 100 Shore A, about 40 to about 100 Shore A, about 50 to about 100 Shore A, and about 60 to about The polymer may have a hardness of 100 Shore A, about 70 to about 100 Shore A, about 80 to about 100 Shore A, about 90 to about 100 Shore A, about 70 to about 95 Shore A, about 70 to about 90 Shore A, about 70 to about 85 Shore A, about 70 to about 80 Shore A, about 75 to about 95 Shore A, about 80 to about 95 Shore A, about 85 to about 95 Shore A, about 80 to about 93 Shore A, or about 80 to about 90 Shore A. In certain embodiments, the polymer (e.g., copolymer) used in the disclosure may have a hardness of about 80 Shore A. In certain embodiments, the polymer (e.g., copolymer) used in the disclosure may have a hardness of about 90 Shore A. In certain embodiments, the polymer (e.g., copolymer) used in the disclosure may have a hardness of about 93 Shore A. In certain embodiments, the polymer (e.g., copolymer) used in the Disclosure may have a hardness of about 80 to about 100 Shore A before being implanted in a subject or before hydration. In certain embodiments, the polymer (e.g., copolymer) used in the Disclosure may have a hardness of about 20 to about 60 Shore A when, for example, it is implanted in a subject or after hydration.

[0223] In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 10% to about 200%. For example, but not limited to, the linear expansion of polymers (e.g., copolymers) used in this disclosure is approximately 10% to approximately 190%, approximately 10% to approximately 180%, approximately 10% to approximately 170%, approximately 10% to approximately 160%, approximately 10% to approximately 150%, approximately 10% to approximately 140%, approximately 10% to approximately 130%, approximately 10% to approximately 120%, approximately 10% to approximately 110%, approximately 10% to approximately 100%, approximately 25% to approximately 100%, approximately 30% to approximately 100%, approximately 35% to approximately 100%, approximately 40% to approximately 100%, approximately 45% to approximately 100%, approximately 50% to approximately 100%, approximately 55% to approximately 100%, approximately 60% to approximately 100%, approximately 65% ​​to approximately 100%, and approximately 70%. It could be approximately 100%, 75% to 100%, 80% to 100%, 85% to 100%, 90% to 100%, 95% to 100%, 20% to 95%, 20% to 90%, 20% to 85%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 30%, 30% to 60%, 40% to 50%, 40% to 60%, 20% to 30%, or 50% to 70%. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 25%. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 40%. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 45%. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 50%. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 60%. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 100%.In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 110% or more, about 100% or more, about 90% or more, about 80% or more, about 70% or more, about 60% or more, about 50% or more, about 40% or more, about 30% or more, about 20% or more, or about 10% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 110% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 100% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 90% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 80% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in this disclosure is about 70% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in the disclosure is about 60% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in the disclosure is about 50% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in the disclosure is about 40% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in the disclosure is about 30% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in the disclosure is about 20% or more. In certain embodiments, the linear expansion of the polymer (e.g., copolymer) used in the disclosure is about 10% or more.

[0224] In a particular embodiment, the polymer (e.g., copolymer) has a linear expansion of about 45% and can absorb about 70% of its mass in water. In a particular embodiment, the polymer (e.g., copolymer) has a linear expansion of about 25% and can absorb about 55% of its mass in water. In a particular embodiment, the polymer (e.g., copolymer) has a linear expansion of about 40% and can absorb about 60% of its mass in water. In a particular embodiment, the polymer (e.g., copolymer) has a linear expansion of about 50% and can absorb about 50% of its mass in water. In a particular embodiment, the polymer (e.g., copolymer) has a linear expansion of about 60% and can absorb about 80% of its mass in water. In a particular embodiment, the polymer (e.g., copolymer) has a linear expansion of about 100% and can absorb about 90% of its mass in water. In a particular embodiment, the polymer (e.g., copolymer) has a linear expansion of about 10% and can absorb about 30% of its mass in water. In a particular embodiment, the polymer (e.g., copolymer) has a linear expansion of about 180% and can absorb about 95% of its mass in water.

[0225] In certain embodiments, the therapeutic agent-containing polymer composition of the present disclosure may further comprise a crosslinking agent. In certain embodiments, the polyvinylpyridine / polystyrene copolymer may be further crosslinked with a suitable crosslinking agent. In certain embodiments, the crosslinking agent may be a diglycidyl or triglycidyl functional epoxy.

[0226] In certain embodiments, the crosslinking agent may include polyepoxide, carbodiimide, cyanuryl chloride, triglycidylglycerol (Gly3), N-hydroxysuccinimide, imide ester, epichlorohydrin, or derivatives thereof. In certain embodiments, the crosslinking agent is polyethylene glycol diglycidyl ether.

[0227] In certain embodiments, the crosslinking agent can be selected from the group consisting of diglycidyl-PEG(200-1000), glycerol triglycidyl ether, and combinations thereof. For example, but not limited to, the crosslinking agent is diglycidyl-PEG(200-1000) having a molecular weight of 200 g / mol to 1000 g / mol. The term "diglycidyl-PEG" as used in this disclosure may refer to polyethylene glycol diglycidyl ether.

[0228] In a particular embodiment, the crosslinking agent can be selected from the group consisting of diglycidyl-PEG200, diglycidyl-PEG400, glycerol triglycidyl ether, and combinations thereof. In a particular embodiment, the crosslinking agent may be diglycidyl-PEG200. In a particular embodiment, the crosslinking agent may be diglycidyl-PEG400. In a particular embodiment, the crosslinking agent may be glycerol triglycidyl ether.

[0229] In a particular embodiment, the therapeutic agent-containing polymer composition contains a crosslinking agent that crosslinks a polymer, e.g., copolymer, present in the therapeutic agent-containing polymer composition by a specific molar percentage (e.g., a specific amount of crosslinking agent). In a particular embodiment, the degree of crosslinking by molar percentage of the polymer, e.g., copolymer, can be in the range of about 0.1 mol% to 50 mol%. In a particular embodiment, the degree of crosslinking by molar percentage of the polymer, e.g., copolymer, can be in the range of about 1 mol% to 50 mol%. In a particular embodiment, the degree of crosslinking by molar percentage of the polymer, e.g., copolymer, can be in the range of about 0.1 mol% to 40 mol%. In a particular embodiment, the degree of crosslinking by molar percentage of the polymer, e.g., copolymer, can be in the range of about 1 mol% to 40 mol%. In a particular embodiment, the degree of crosslinking by molar percentage of the polymer, e.g., copolymer, can be in the range of about 0.1 mol% to 30 mol%. In a particular embodiment, the degree of crosslinking by molar percentage of the polymer, e.g., copolymer, can be in the range of about 0.2 mol% to 30 mol%. In certain embodiments, the degree of crosslinking by mole percent of a polymer, for example, a copolymer, can be in the range of about 1 mol% to 30 mol%. In certain embodiments, the degree of crosslinking by mole percent of a polymer, for example, a copolymer, can be in the range of about 0.1 mol% to 25 mol%. In certain embodiments, the degree of crosslinking by mole percent of a polymer, for example, a copolymer, can be in the range of about 1 mol% to 25 mol%. In certain embodiments, the degree of crosslinking by mole percent of a polymer, for example, a copolymer, can be in the range of about 0.1 mol% to 20 mol%. In certain embodiments, the degree of crosslinking by mole percent of a polymer, for example, a copolymer, can be in the range of about 1 mol% to 20 mol%. In certain embodiments, the degree of crosslinking by mole percent of a polymer, for example, a copolymer, can be in the range of about 0.1 mol% to 15 mol%. In certain embodiments, the degree of crosslinking by mole percent of a polymer, for example, a copolymer, can be in the range of about 1 mol% to 15 mol%. In certain embodiments, the degree of crosslinking by mol% of a polymer, e.g., a copolymer, can be in the range of about 0.1 mol% to 10 mol%. In certain embodiments, the degree of crosslinking by mol% of a polymer, e.g., a copolymer, can be in the range of about 0.5 mol% to 10 mol%.In certain embodiments, the degree of crosslinking by mol% of the polymer, for example, the copolymer, can be in the range of about 1 mol% to 10 mol%.

[0230] In a particular embodiment, the therapeutic agent-containing polymer composition of the present disclosure includes a crosslinking agent, and the amount of the crosslinking agent in the therapeutic agent-containing polymer composition is about 20 mol% or less of the crosslinking agent (e.g., a copolymer).

[0231] In a particular embodiment, the degree of crosslinking of the polymer in mole percent may be in the range of about 0.5 mol% to 10 mol%.

[0232] In a particular embodiment, the degree of crosslinking of the polymer in mole percent may be in the range of about 1 mole percent to 10 mole percent.

[0233] In a particular embodiment, the degree of crosslinking of the polymer in mole percent may be in the range of about 1 mol% to 25 mol%.

[0234] In a particular embodiment, the therapeutic agent-containing polymer composition may contain a crosslinking agent in an amount ranging from about 0.01% to 50% by mass based on the total mass of the polymer, for example, the copolymer (for example, in the therapeutic agent-containing polymer composition). In a particular embodiment, the therapeutic agent-containing polymer composition may contain a crosslinking agent in an amount ranging from about 0.01% to 40% by mass based on the total mass of the polymer, for example, the copolymer. In a particular embodiment, the therapeutic agent-containing polymer composition may contain a crosslinking agent in an amount ranging from about 0.01% to 30% by mass based on the total mass of the polymer, for example, the copolymer. In a particular embodiment, the therapeutic agent-containing polymer composition may contain a crosslinking agent in an amount ranging from about 0.01% to 20% by mass based on the total mass of the polymer, for example, the copolymer. In a particular embodiment, the therapeutic agent-containing polymer composition may contain a crosslinking agent in an amount ranging from about 0.01% to 15% by mass based on the total mass of the polymer, for example, the copolymer. In a particular embodiment, the therapeutic agent-containing polymer composition may contain a crosslinking agent in an amount ranging from about 0.01% to 10% by mass based on the total mass of the polymer, for example, the copolymer. In certain embodiments, the therapeutic agent-containing polymer composition may contain a crosslinking agent in an amount ranging from about 1% to 15% by mass based on the total mass of the polymer, for example, the copolymer. In certain embodiments, the therapeutic agent-containing polymer composition may contain a crosslinking agent in an amount ranging from about 1% to 10% by mass based on the total mass of the polymer, for example, the copolymer. In certain embodiments, the therapeutic agent-containing polymer composition may contain a crosslinking agent in an amount ranging from about 1% to 5% by mass based on the total mass of the polymer, for example, the copolymer.

[0235] In a particular embodiment, the crosslinking agent is triglycidylglycerol (Gly3), and the degree of crosslinking of the polymer can be in the range of about 1 mol% to 15 mol%.

[0236] In a particular embodiment, the therapeutic agent-containing polymer composition comprises (i) a polyvinylpyridine / polystyrene copolymer containing about 5 to 15 monomer% of styrene units, and (ii) a crosslinking agent, wherein the molar degree of crosslinking of the copolymer may be in the range of about 1 mol% to 15 mol%.

[0237] In a particular embodiment, the therapeutic agent-containing polymer composition comprises (i) a polyvinylpyridine / polystyrene copolymer containing about 5 to 15 monomer% of styrene units, and (ii) a triglycidylglycerol (Gly3) crosslinking agent, wherein the molar degree of crosslinking of the copolymer may be in the range of about 1 mol% to 15 mol%.

[0238] In certain embodiments, the therapeutic agent can be incorporated into the polymer of the therapeutic agent-containing polymer composition. For example, but not limited to, the therapeutic agent can be non-covalently mixed with and / or encapsulated within the polymer of the therapeutic agent-containing polymer composition.

[0239] In certain embodiments, the therapeutic agent can be non-covalently mixed with and / or encapsulated within a polymer of a therapeutic agent-containing polymer composition comprising a polyvinylpyridine / polystyrene copolymer.

[0240] In certain embodiments, the therapeutic agent can be bonded (e.g., covalently) to the polymer of the therapeutic agent-containing polymer composition. In certain embodiments, the therapeutic agent can be bonded (e.g., covalently) directly to one or more chains and / or monomers of the polymer, or via a linker.

[0241] In certain embodiments, the therapeutic agent can be reversibly bound to the polymer so that the therapeutic agent is dissociated from the polymer under specific conditions. In certain embodiments, the therapeutic agent can be dissociated from the polymer after insertion into a subject, depending on environmental conditions. In certain embodiments, the therapeutic agent can be dissociated from the polymer when exposed to an aqueous medium (e.g., interstitial fluid). In certain embodiments, the therapeutic agent can be dissociated from the polymer when exposed to glucose. In certain embodiments, the therapeutic agent can be dissociated from the polymer in response to changes in the pH of the environment in which the analyte sensor is inserted. In certain embodiments, the therapeutic agent can be dissociated from the polymer in response to changes in the temperature of the environment in which the analyte sensor is inserted. In certain embodiments, the therapeutic agent can be dissociated from the polymer in response to electrochemical stimuli, such as a voltage applied to the analyte sensor and / or a current within the analyte sensor. In certain embodiments, the therapeutic agent can be dissociated from the polymer by enzymes, reactive oxygen species such as hydrogen peroxide, temperature, ions, pH, etc.

[0242] In certain embodiments, the therapeutic agent can be bonded (e.g., covalently) to one or more chains and / or monomers of a polymer by hydrolyzable bonds, so that the therapeutic agent can be released with a delay after the analyte sensor has been inserted into the body.

[0243] In certain embodiments, the therapeutic agent can be bonded (e.g., covalently) to a polyvinylpyridine polymer present in the therapeutic agent-containing polymer composition by a hydrolyzable bond, so that the therapeutic agent can be released with a delay after the analyte sensor has been inserted into the body.

[0244] In certain embodiments, the therapeutic agent can be bonded (e.g., covalently) to a poly(2-hydroxyethyl methacrylate) polymer present in the therapeutic agent-containing polymer composition. In certain embodiments, the therapeutic agent can be bonded (e.g., covalently) to a poly(2-hydroxyethyl methacrylate) polymer present in the therapeutic agent-containing polymer composition via an acrylate moiety so that the therapeutic agent can be released later after insertion of the analyte sensor into the body. In certain embodiments, the therapeutic agent can be dissociated from the acrylate moiety, as previously described, for example, upon exposure to an aqueous medium (e.g., interstitial fluid), upon exposure to glucose, in response to a change in pH of the environment in which the analyte sensor is inserted, in response to a change in temperature of the environment in which the analyte sensor is inserted, and / or in response to electrochemical stimuli, such as a voltage applied to the analyte sensor and / or a current within the analyte sensor.

[0245] V. Integrating therapeutic agents into analyte sensors This disclosure further provides an analyte sensor comprising one or more therapeutic agents. For example, but not limited to, this disclosure provides an analyte sensor comprising one or more therapeutic agent-containing polymer compositions.

[0246] In certain embodiments, the therapeutic agent-containing polymer composition applied to the analyte sensor may be referred to herein as a drug-eluting membrane or a second polymer membrane.

[0247] By incorporating a therapeutic agent into the analyte sensor itself, it becomes possible to target the therapeutic agent to the implantation site and the tissue surrounding the analyte sensor, allowing the therapeutic agent to be released in vivo near the analyte sensor. In certain embodiments, the therapeutic agent delivered according to this disclosure is effective in reducing, minimizing, preventing and / or suppressing the tissue response to the implantation and / or tissue infection of the analyte sensor, thereby preventing and / or reducing late sensor attenuation (LSA). In certain embodiments, the therapeutic agent delivered according to this disclosure is effective in reducing, minimizing, preventing and / or suppressing the tissue response to the implantation and / or tissue infection of the analyte sensor, thereby preventing and / or reducing inaccuracy of the analyte signal towards the end of the sensor's lifespan.

[0248] Non-limiting examples of therapeutic agents that can be incorporated into the analyte sensors of this disclosure are disclosed in Section II of this specification. In certain embodiments, the therapeutic agent may be an antibiotic, an antiviral agent, an anti-inflammatory agent, an anticancer agent, an antiplatelet agent, an anticoagulant, a coagulant, an antiglycolytic agent, or a combination thereof. In certain embodiments, the anti-inflammatory agent may be a nonsteroidal anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent may be a steroidal anti-inflammatory agent, such as a corticosteroid. Non-limiting examples of anti-inflammatory agents include triamcinolone, betamethasone, dexamethasone, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid or its derivatives, salts thereof, or prodrugs thereof. Non-limiting salt forms include pharmaceutically acceptable salts, including acetates and phosphates. In certain embodiments, the anti-inflammatory agent may be a salt of dexamethasone. In certain embodiments, the anti-inflammatory agent may be a derivative of dexamethasone. In certain embodiments, the dexamethasone derivative or salt form may be dexamethasone acetate. In certain embodiments, the dexamethasone derivative or salt form may be dexamethasone sodium phosphate.

[0249] Non-limiting examples of analyte sensors that can be improved to incorporate therapeutic agents (e.g., in therapeutic agent-containing polymer compositions) are disclosed in Section III. In certain embodiments, the analyte sensor is a skin sensor. In certain embodiments, the analyte sensor is a subcutaneous sensor, such as a subcutaneous implantable sensor. In certain embodiments, the analyte sensor is an intravenous sensor, such as an intravenous implantable sensor. In certain embodiments, the analyte sensor is configured to detect glucose. In certain embodiments, the analyte sensor is configured to detect glucose and ketones. In certain embodiments, the analyte sensor is configured to detect lactate. In certain embodiments, the analyte sensor is configured to detect creatinine. In certain embodiments, the analyte sensor is configured to detect alcohol. In certain embodiments, the analyte sensor has a second working electrode for detecting a second analyte, as described in Section III.

[0250] This disclosure provides an analytic sensor, for example, a sensor tail (i.e., internal portion) 100 or 200, further comprising a therapeutic agent-containing polymer composition. Figures 1A–1B and 17A–17B show cross-sectional views of an exemplary analytic sensor according to a particular embodiment of this disclosure. As shown in Figure 1A, the analytic sensor may include (i) a sensor tail (i.e., internal portion) 200 comprising at least a first working electrode 214 on a substrate 212; (ii) an active area 218 positioned on the surface of the first working electrode to detect an analytic; (iii) a substance transport limiting membrane 220 that allows analytic material to pass through and covers at least the active area; (iv) a pair / reference electrode 216 on the substrate 212; and (v) a therapeutic agent-containing polymer composition. As shown in Figure 1B, the analyte sensor may include a sensor tail (i.e., an internal part) 100 comprising (i) a substrate 102; (ii) a first working electrode 104 on the substrate 102; (ii) a detection spot 108 positioned on the surface of the first working electrode to detect the analyte; (iii) a film 110 coating at least the detection spot 108; (iv) a pair / reference electrode 106 on the substrate 102; and (v) a sensor tail (i.e., an internal part) 100 comprising a therapeutic agent-containing polymer composition. As shown in Figure 2, the analyte sensor may include a sensor tail (i.e., an internal part) 100 comprising (i) a substrate 102; (ii) a first working electrode 104 on the substrate 102; (ii) a plurality of detection spots 108a-108f positioned on the surface of the first working electrode to detect the analyte; (iii) a film 110 coating at least the detection spot 108; (iv) a pair / reference electrode 106 on the substrate 102; and (v) a sensor tail (i.e., an internal part) 100 comprising a therapeutic agent-containing polymer composition.

[0251] In certain embodiments, the therapeutic agent-containing polymer composition may be placed on the structure or components of the internal portion (i.e., the sensor tail). In certain embodiments, the therapeutic agent-containing polymer composition may be placed on or incorporated into components of the analyte sensor (e.g., the internal portion of the analyte sensor). For example, but not limited to, the therapeutic agent-containing polymer composition may be placed on electrodes (e.g., pair / reference electrodes (e.g., 216 in Figure 18A)) and / or working electrodes (e.g., 214 in Figure 18A), insulating materials (e.g., insulating materials (219a-c in Figure 18A)), substrates (e.g., 212 in Figure 18A), mass transport limiting membranes (e.g., 220 in Figure 18A), and the surface of the distal tip of the analyte sensor (e.g., 412 in Figure 10 and 512 in Figure 11). In certain embodiments, the therapeutic agent-containing polymer composition may be placed on a substrate surrounding the active area and / or on a portion of the working electrode. For example, but not limited to, the therapeutic agent-containing polymer The composition can be placed on the non-detectable chemical system portion of the working electrode. In certain embodiments, the therapeutic agent-containing polymer composition can be placed on the non-detectable chemical system portion of the substrate. In certain embodiments, the therapeutic agent-containing polymer composition can be placed on a portion of the substrate and / or the working electrode distal to the active region. In certain embodiments, the therapeutic agent-containing polymer composition can be placed on a portion of the substrate and / or the working electrode proximal to the active region. In certain embodiments, the therapeutic agent-containing polymer composition can be placed on a portion of the substrate and / or the working electrode surrounding the active region.

[0252] In certain embodiments, the therapeutic agent-containing polymer composition can be placed on a pair / reference electrode. In certain embodiments where the analyte sensor includes a pair electrode and a reference electrode, the therapeutic agent-containing polymer composition can be placed on a pair / reference electrode. In certain embodiments, the therapeutic agent-containing polymer composition can be placed on a pair electrode, for example, as shown in Figures 12A and 12B. In certain embodiments, the therapeutic agent-containing polymer composition can be placed on a reference electrode. In certain embodiments where the analyte sensor includes a pair electrode and a reference electrode, the therapeutic agent-containing polymer composition can be placed on a pair electrode. In certain embodiments where the analyte sensor includes a pair electrode and a reference electrode, the therapeutic agent-containing polymer composition can be placed on a reference electrode, for example, as shown in Figures 12A and 12B.

[0253] In certain embodiments, the therapeutic agent-containing polymer composition can be arranged on the structure of the internal body portion (i.e., the sensor tail) (e.g., the pair / reference electrode) as a plurality of individual regions, as shown, for example, in Figures 12A and 12B. In certain embodiments, the therapeutic agent-containing polymer composition can be arranged on the structure of the internal body portion (i.e., the sensor tail) (e.g., the pair / reference electrode) as a plurality of spots, as shown, for example, in Figures 12A and 12B. For example, but not limited to, a therapeutic agent-containing polymer composition can be placed on a pair / reference electrode as one or more spots, two or more spots, three or more spots, four or more spots, five or more spots, six or more spots, seven or more spots, eight or more spots, nine or more spots, ten or more spots, eleven or more spots, twelve or more spots, thirteen or more spots, fourteen or more spots, fifteen or more spots, sixteen or more spots, seventeen or more spots, eighteen or more spots, nineteen or more spots, twenty or more spots, twenty-one or more spots, twenty-two or more spots, twenty-three or more spots, twenty-four or more spots, twenty-five or more spots, twenty-six or more spots, twenty-seven or more spots, twenty-eight or twenty-nine spots, or thirty or more spots. For example, but not limited to, a therapeutic agent-containing polymer composition can be placed on a pair / reference electrode (e.g., the pair electrode) as two or more spots, as shown in Figures 12A and 12B. In certain embodiments, a therapeutic agent-containing polymer composition can be placed as one or more spots, for example, two or more spots, on a substrate surrounding an active area and / or on a portion of the working electrode. In certain embodiments, the therapeutic agent-containing polymer composition can be placed on a substrate surrounding the active area and / or on a portion of the working electrode. For example, but not limited to, the therapeutic agent-containing polymer composition can be placed on the non-detection chemical system portion of the working electrode as one or more spots, e.g., two or more spots. In certain embodiments, the therapeutic agent-containing polymer composition can be placed on the non-detection chemical system portion of the substrate as one or more spots, e.g., two or more spots.In certain embodiments, the therapeutic agent-containing polymer composition can be arranged as one or more spots, for example, two or more spots, on a substrate and / or part of the working electrode distal to the active area. In certain embodiments, the therapeutic agent-containing polymer composition can be arranged as one or more spots, for example, two or more spots, on a substrate and / or part of the working electrode proximal to the active area. In certain embodiments, the therapeutic agent-containing polymer composition can be arranged as one or more spots, for example, two or more spots, on a substrate and / or part of the working electrode surrounding the active area.

[0254] In certain embodiments, one or more spots, for example, two or more spots, may have a circular, elliptical, regular polygonal, or irregular polygonal shape. In certain embodiments, each of the spots may have the same or similar shape. For example, but not limited to, each of the spots may have a circular or rounded shape. In certain embodiments, at least two or more spots may have different shapes. For example, one of the spots may be circular or elliptical, and another spot may have a regular polygonal or irregular polygonal shape.

[0255] In a particular embodiment, each spot contains the same or a similar amount of the therapeutic agent. Alternatively, at least one spot contains a different amount of the therapeutic agent compared to another spot. In a particular embodiment, at least two spots have a difference in the amount of the therapeutic agent of approximately 5% or more, approximately 10% or more, approximately 15% or more, approximately 20% or more, approximately 25% or more, approximately 30% or more, approximately 35% or more, approximately 40% or more, approximately 45% or more, approximately 50% or more, approximately 55% or more, approximately 60% or more, approximately 65% ​​or more, approximately 70% or more, approximately 75% or more, approximately 80% or more, approximately 85% or more, approximately 90% or more, and approximately 95%. The above are approximately 100% or more, approximately 105% or more, approximately 110% or more, approximately 115% or more, approximately 120% or more, approximately 125% or more, approximately 130% or more, approximately 135% or more, approximately 140% or more, approximately 145% or more, approximately 150% or more, approximately 155% or more, approximately 160% or more, approximately 165% or more, approximately 170% or more, approximately 180% or more, approximately 185% or more, approximately 190% or more, approximately 195% or more, or 200% or more. In a particular embodiment, at least two or more spots have a difference in the amount of therapeutic agent of approximately 50% or more. In a particular embodiment, at least two or more spots have a difference in the amount of therapeutic agent of approximately 60% or more. In a particular embodiment, at least two or more spots have a difference in the amount of therapeutic agent of approximately 70% or more. In a particular embodiment, at least two or more spots have a difference in the amount of therapeutic agent of approximately 80% or more. In certain embodiments, at least two or more spots have a difference in the amount of therapeutic agent of approximately 90% or more. In certain embodiments, at least two or more spots have a difference in the amount of therapeutic agent of approximately 100% or more.

[0256] In certain embodiments, each spot has the same or similar thickness. Alternatively, at least two or more spots have different thicknesses, as shown, for example, in FIGS. 12A and 12B. In certain embodiments, at least two or more spots have a thickness difference of about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 100% or more, about 105% or more, about 110% or more, about 115% or more, about 120% or more, about 125% or more, about 130% or more, about 135% or more, about 140% or more, about 145% or more, about 150% or more, about 155% or more, about 160% or more, about 165% or more, about 170% or more, about 180% or more, about 185% or more, about 190% or more, about 195% or more, or 200% or more. For example, without limitation, at least two or more spots have a thickness difference of about 50% or more. In certain embodiments, at least two or more spots have a thickness difference of about 60% or more. In certain embodiments, at least two or more spots have a thickness difference of about 70% or more. In certain embodiments, at least two or more spots have a thickness difference of about 80% or more. In certain embodiments, at least two or more spots have a thickness difference of about 90% or more. In certain embodiments, at least two or more spots have a thickness difference of about 100% or more.

[0257] In certain embodiments, the analyte sensor of the present disclosure may include: (i) a sensor tail (i.e., an in-body portion) including at least a first working electrode on a substrate; (ii) an active region disposed on the surface of the first working electrode for detecting an analyte; (iii) a mass transport limiting membrane that allows an analyte to permeate and at least covers the active region; (iv) a counter / reference electrode on the substrate; and (v) at least one spot (e.g., at least two spots) of a therapeutic agent-containing polymer composition on the structure of the sensor tail (i.e., the in-body portion). In certain embodiments, the mass transport limiting membrane also at least partially covers at least one spot (e.g., at least two spots) of the therapeutic agent-containing polymer composition.

[0258] In certain embodiments, the analyte sensor of the present disclosure may include: (i) a sensor tail including at least a first working electrode on a substrate; (ii) an active region disposed on the surface of the first working electrode for detecting an analyte; (iii) a mass transport limiting membrane that allows an analyte to permeate and at least covers the active region; (iv) a counter / reference electrode on the substrate; and (v) at least one spot (e.g., at least two spots) of a therapeutic agent-containing polymer composition on the surface of the counter / reference electrode. In certain embodiments, the mass transport limiting membrane also at least partially covers at least one spot (e.g., at least two spots) of the therapeutic agent-containing polymer composition. In certain embodiments, the analyte sensor includes two or more spots on the surface of the counter / reference electrode, and at least two of the two or more spots have different thicknesses, e.g., at least two of the two or more spots have a thickness difference of more than about 50% (e.g., more than about 70%). In certain embodiments, the mass transport limiting membrane can be disposed on at least one spot (e.g., at least two spots) of the therapeutic agent-containing polymer composition on the surface of the counter / reference electrode (e.g., an Ag / AgCl material).

[0259] In certain embodiments, the therapeutic agent-containing polymer composition may be located in the most distal region of the sensor tail (e.g., the internal portion of the analyte sensor). For example, but not limited to, the distal tip of the analyte sensor, e.g., the distal tip of the internal portion of the analyte sensor, may be coated with the therapeutic agent-containing polymer composition.

[0260] In certain embodiments, the therapeutic agent-containing polymer composition may be located in the region between the tip of the sensor tail (e.g., 300 in Figure 7) and the starting end of the detection layer (e.g., the end of the first detection spot (e.g., spot 108a in Figure 7)), for example, above or below the material transport restriction membrane. In certain embodiments, the region between the tip of the sensor tail and the starting end of the detection layer may have a length, for example, referred to as d3 in Figure 7. In certain embodiments, as shown in Figure 7, the exemplary sensor tail 300 may include a first region having a first length d3 between the tip of the sensor tail 300 and the end of the first detection spot 108a, and a second region having a second length d4 extending away from the end of the first detection spot 108a and including a plurality of detection spots 108a-108f. The first region may not include any detection spots (e.g., exclude detection spots) and may be a non-detection region. The second region may be a detection region (for example, including a plurality of detection spots 108a to 108f). In certain embodiments, the therapeutic agent-containing polymer composition can be deposited on the first region (for example, without contact with the second region) by, for example, immersion.

[0261] In certain embodiments, the region between the tip of the sensor tail and the beginning of the sensing layer may have a length ranging from about 0.1 mm to about 1 mm, for example, about 0.2 mm to about 1 mm, about 0.3 mm to about 1 mm, about 0.4 mm to about 1 mm, about 0.5 mm to about 1 mm, about 0.6 mm to about 1 mm, or about 0.7 mm to about 1 mm (e.g., d3 in Figure 7). In certain embodiments, the region between the tip of the sensor tail and the beginning of the sensing layer may have a length ranging from about 0.5 mm to about 1 mm (e.g., d3 in Figure 7). In certain embodiments, the region between the tip of the sensor tail and the beginning of the sensing layer may have a length ranging from about 0.5 mm to about 1 mm (e.g., d3 in Figure 7). In certain embodiments, the region between the tip of the sensor tail and the beginning of the sensing layer may have a length of about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, or about 1 mm (e.g., d3 in Figure 7). In certain embodiments, the first length of the first region may be the length between the tip of the sensor tail and the end of the first sensing spot 108a that is proximal to the tip of the sensor tail among the plurality of sensing spots. In certain embodiments, the first length of the first region may be in the range of about 0.1 mm to about 1 mm, for example, about 0.2 mm to about 1 mm, about 0.3 mm to about 1 mm, about 0.4 mm to about 1 mm, about 0.5 mm to about 1 mm, about 0.6 mm to about 1 mm, or about 0.7 mm to about 1 mm. In certain embodiments, the first length of the first region may be about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, or about 1 mm. However, embodiments of the present disclosure are not limited to these.

[0262] In a particular embodiment, the second region including the detection layer (e.g., multiple detection spots) has a length referred to as d4 in Figure 7. For example, the second length of the second region may be the length of the second region including the detection layer (e.g., multiple detection spots). In a particular embodiment, the second length of the second region may be in the range of about 1 mm to about 3 mm, for example, about 1 mm to about 2.9 mm, about 1 mm to about 2.8 mm, about 1 mm to about 2.7 mm, about 1 mm to about 2.6 mm, about 1 mm to about 2.5 mm, about 1 mm to about 2.5 mm, about 1 mm to about 2.4 mm, about 1 mm to about 2.3 mm, about 1 mm to about 2.2 mm, about 1 mm to about 2.1 mm, or about 1 mm to about 2 mm. In certain embodiments, the second length of the second region may be about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, or about 3 mm. However, embodiments of the present disclosure are not limited to these.

[0263] In certain embodiments, the therapeutic agent-containing polymer composition may be placed on a mass transport restriction membrane. In certain embodiments, the therapeutic agent-containing polymer composition may be placed on a portion of the mass transport restriction membrane. For example, but not limited to, therapeutic agent-containing polymer compositions 512 and 412 may be placed on mass transport restriction membranes 510 and 410 located at the distal tip of the sensor tail, for example, as shown in Figures 9 and 10. In certain embodiments, the therapeutic agent-containing polymer composition may be placed on a mass transport restriction membrane located in the most distal region of the sensor tail (i.e., the body portion), in which case the therapeutic agent-containing polymer composition is not located on and / or covers the analyte detection layer, for example, as shown in Figures 9 and 10. In certain embodiments, the therapeutic agent-containing polymer composition may be present on a portion of the mass transport restriction membrane placed over a region of the sensor tail located between the tip of the sensor tail and the beginning of the detection layer.

[0264] In certain embodiments, the therapeutic agent-containing polymer composition may be located beneath a mass transport restriction membrane. For example, but not limited to, the therapeutic agent-containing polymer composition may be located at the distal tip of the sensor tail beneath the mass transport restriction membrane 510, as shown in Figure 11. In certain embodiments, the therapeutic agent-containing polymer composition may be located beneath the mass transport restriction membrane in the most distal region of the sensor tail (i.e., the internal body portion), in which case the therapeutic agent-containing polymer composition is not located on and / or covers the analyte detection layer, as shown in Figure 11, for example. In certain embodiments, the therapeutic agent-containing polymer composition may be located on a substrate, for example, 502 in Figure 11, and / or on the substrate and on portions of the working electrode 504 adjacent to but not covering the analyte detection layer, as shown in Figure 11, for example, 508a-508f. In certain embodiments, the therapeutic agent-containing polymer composition may be located on the distal region of the sensor tail between the tip of the sensor tail and the beginning of the detection layer, and beneath the mass transport restriction membrane.

[0265] In a particular embodiment, the exemplary analyte sensor includes an internal portion configured to be in contact with the interstitial fluid of the subject and located beneath the surface of the subject's skin, the internal portion including a second region having an active area and a first region distal to the second region. In a particular embodiment, the first and second regions are coated with a first polymer film, the first region being coated with a second polymer film containing a therapeutic agent, while the second region is not coated.

[0266] In a particular embodiment, the exemplary analyte sensor is configured to be located beneath the surface of the subject's skin and includes an internal portion that comes into contact with the subject's interstitial fluid, and this internal portion is (i) A substrate comprising (a) a second region having an active region and (b) a first region distal to this second region, (ii) Working electrode on a substrate including the active region, (iii) Pair / reference electrode on the substrate, (iv) A first polymer film coated on a second region having a first region and an active region, and (v) A second polymer film coated on a first polymer film in a first region, not in a second region, the second polymer film containing a therapeutic agent, Includes.

[0267] In a particular embodiment, the exemplary analyte sensor includes an internal part configured to be in contact with the interstitial fluid of the subject and located beneath the surface of the subject's skin, and this internal part is (i) A substrate comprising (a) a second region having an active region and (b) a first region distal to this second region, (ii) Working electrode on a substrate including the active region, (iii) Pair / reference electrode on the substrate, (iv) A second polymer film coated on the first region, rather than the second region, the second polymer film containing a therapeutic agent, and (v) a first polymer film coated on a second region having a first region and an active region, Includes.

[0268] Figure 10 shows an exemplary sensor tail (i.e., internal portion) comprising a substance transport restriction membrane and a membrane containing a therapeutic agent, according to one or more embodiments of the present disclosure. As shown in Figure 10, according to one or more embodiments of the present disclosure, the analyte sensor is (i) Base 402, (ii) working electrode 404, (iii) Pair / reference electrode 406 on substrate 402, (iv) Multiple detection spots 408a to 408f on the surface of the working electrode 404, including the first detection spot 408a which is located proximal to the tip of the sensor tail, among the multiple detection spots 408a to 408f, (v) A first region located between the tip of the sensor tail 400 and the end of the first detection spot 408a, having a first length and not including any detection spot, (vi) A second region having a second length, extending distally from the end of the first detection spot 408a away from the tip of the sensor tail, and including a plurality of detection spots 408a to 408f (vii) A first polymer film 410 covering the sensor tail 400 in a first region and a second region including a plurality of detection spots 408a to 408f, and (viii) Unlike the first polymer film 410, the second polymer film 412 is coated on the first polymer film 410 in the first region, not in the second region, and the second polymer film 412 contains a therapeutic agent. It may include a sensor tail 400 (i.e., an internal part) that includes the sensor tail.

[0269] In certain embodiments, the first length of the first region of the sensor tail 400 may be in the range of about 0.1 mm to about 1 mm, for example, about 0.2 mm to about 1 mm, about 0.3 mm to about 1 mm, about 0.4 mm to about 1 mm, about 0.5 mm to about 1 mm, about 0.6 mm to about 1 mm, or about 0.7 mm to about 1 mm. In certain embodiments, the first length of the first region may be about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, or about 1 mm. However, embodiments of the present disclosure are not limited to these.

[0270] In a particular embodiment, the second length of the second region of the sensor tail 400 may be in the range of about 1 mm to about 3 mm, for example, about 1 mm to about 2.9 mm, about 1 mm to about 2.8 mm, about 1 mm to about 2.7 mm, about 1 mm to about 2.6 mm, about 1 mm to about 2.5 mm, about 1 mm to about 2.5 mm, about 1 mm to about 2.4 mm, about 1 mm to about 2.3 mm, about 1 mm to about 2.2 mm, about 1 mm to about 2.1 mm, or about 1 mm to about 2 mm. In certain embodiments, the second length of the second region may be about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, or about 3 mm. However, embodiments of the present disclosure are not limited to these.

[0271] In certain embodiments, the first polymer film 410 (e.g., of FIG. 10) can be made from a first polymer selected from the group consisting of polyvinylpyridine-based polymers, polyvinylimidazole-based polymers, polyacrylate-based polymers, polyurethane-based polymers, polyetherurethane-based polymers, silicone-based polymers, derivatives thereof, and combinations thereof. In certain embodiments, the first polymer film 410 can be made from a first polymer comprising a first copolymer selected from the group consisting of polyvinylpyridine-based copolymers, polyvinylimidazole-based copolymers, and combinations thereof. In certain embodiments, the polyvinylpyridine-based copolymer can be a polyvinylpyridine / polystyrene copolymer. In certain embodiments, the first polymer film 410 can be made from a polyvinylpyridine / polystyrene copolymer, and the polyvinylpyridine / polystyrene copolymer includes a charged pyridine moiety. In certain embodiments, the first polymer film 410 can be made from a polyvinylpyridine / polystyrene copolymer in which some of the nitrogen atoms of the pyridine are functionalized with non-crosslinked polyethylene glycol tails and some of the nitrogen atoms of the pyridine are functionalized with an alkali sulfonic acid group, e.g., propylsulfonic acid. In certain embodiments, the derivatized polyvinylpyridine / polystyrene copolymer for use in the first polymer film 410 can be the 10Q5 polymer described in U.S. Patent No. 8,761,857, the content of which is hereby incorporated by reference in its entirety.

[0272] In certain embodiments, the first polymer film 410 (e.g., of FIG. 10) can have a thickness (e.g., dry film thickness) in the range of from about 0.1 μm to about 1,000 μm, such as from about 1 μm to about 500 μm, from about 10 μm to about 300 μm, or from about 10 μm to about 100 μm.

[0273] In certain embodiments, the second polymer film 412 (e.g., in Figure 10) may have the composition of the therapeutic agent-containing polymer composition described herein. In certain embodiments, the second polymer film 412 may include a second polymer selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyether urethane polymers, silicone polymers, their derivatives, and combinations thereof. In certain embodiments, the second polymer film 412 may include a second copolymer selected from the group consisting of polyvinylpyridine copolymers, polyvinylimidazole copolymers, and combinations thereof. In certain embodiments, the polyvinylpyridine copolymer may be a copolymer of vinylpyridine and styrene, or a derivative thereof. In certain embodiments, the second polymer film 412 may include a polyvinylpyridine / polystyrene copolymer.

[0274] In certain embodiments, the second polymer film 412 (e.g., in Figure 10) may comprise a poly(4-vinylpyridine / styrene) copolymer. In certain embodiments, the poly(4-vinylpyridine / styrene) copolymer may comprise 1 to 50 monomer% of styrene units. In certain embodiments, the poly(4-vinylpyridine / styrene) copolymer may comprise 1 to 30 monomer% of styrene units.

[0275] In certain embodiments, the second polymer film 412 containing the therapeutic agent (e.g., in Figure 10) may have a thickness (e.g., dry film thickness) ranging from about 0.1 μm to about 1,000 μm, for example, about 1 μm to about 500 μm, about 10 μm to about 500 μm, about 10 μm to about 400 μm, about 10 μm to about 300 μm, about 10 μm to about 200 μm, or about 10 μm to about 100 μm. In certain embodiments, the second polymer film 412 containing the therapeutic agent may have a thickness ranging from about 1 μm to about 500 μm. In certain embodiments, the second polymer film 412 containing the therapeutic agent may have a thickness ranging from about 1 μm to about 400 μm. In certain embodiments, the second polymer film 412 containing the therapeutic agent may have a thickness ranging from about 1 μm to about 300 μm. In certain embodiments, the second polymer film 412 containing the therapeutic agent may have a thickness in the range of about 1 μm to about 200 μm. In certain embodiments, the second polymer film 412 containing the therapeutic agent may have a thickness in the range of about 10 μm to about 200 μm. In certain embodiments, the second polymer film 412 containing the therapeutic agent may have a thickness in the range of about 10 μm to about 300 μm. In certain embodiments, the second polymer film 412 containing the therapeutic agent may have a thickness in the range of about 50 μm to about 300 μm.

[0276] Figure 11 shows an exemplary sensor tail equipped with a substance transport limiting membrane and a drug elution membrane according to one or more embodiments of the present disclosure. As shown in Figure 11, the analyte sensor is (i) Base 502, (ii) working electrode 504, (iii) Pair / reference electrode 506 on substrate 502, (iv) Multiple detection spots 508a to 508f on the surface of the working electrode 504, including the first detection spot 508a which is located proximal to the tip of the sensor tail, among the multiple detection spots 508a to 508f, (v) A first region located between the tip of the sensor tail 500 and the end of the first detection spot 508a, having a first length and not including any detection spot, (vi) A second region having a second length, extending distally from the end of the first detection spot 508a away from the tip of the sensor tail, and including a plurality of detection spots 508a to 508f (vii) A first polymer film 510 covering the sensor tail 500 in a first region and a second region including a plurality of detection spots 508a to 508f, and covering the second polymer film 512, and (viii) A second polymer film 512 that differs from the first polymer film 510 in the first region and is located beneath the first polymer film 510 and does not cover the second region, and the second polymer film 512 contains a therapeutic agent. It may include a sensor tail 500 (i.e., an internal part) that includes the following.

[0277] In certain embodiments, the first length of the first region of the sensor tail 500 may be in the range of about 0.1 mm to about 1 mm, for example, about 0.2 mm to about 1 mm, about 0.3 mm to about 1 mm, about 0.4 mm to about 1 mm, about 0.5 mm to about 1 mm, about 0.6 mm to about 1 mm, or about 0.7 mm to about 1 mm. In certain embodiments, the first length of the first region may be about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, or about 1 mm. However, embodiments of the present disclosure are not limited to these.

[0278] In a particular embodiment, the second length of the second region of the sensor tail 500 may be in the range of about 1 mm to about 3 mm, for example, about 1 mm to about 2.9 mm, about 1 mm to about 2.8 mm, about 1 mm to about 2.7 mm, about 1 mm to about 2.6 mm, about 1 mm to about 2.5 mm, about 1 mm to about 2.5 mm, about 1 mm to about 2.4 mm, about 1 mm to about 2.3 mm, about 1 mm to about 2.2 mm, about 1 mm to about 2.1 mm, or about 1 mm to about 2 mm. In certain embodiments, the second length of the second region may be about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, or about 3 mm. However, embodiments of the present disclosure are not limited to these.

[0279] In a particular embodiment, the first polymer film 510 can be made from a first polymer selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyetherurethane polymers, silicone polymers, their derivatives, and combinations thereof. In a particular embodiment, the first polymer film 510 can be made from a first polymer comprising a first copolymer selected from the group consisting of polyvinylpyridine copolymers, polyvinylimidazole copolymers, and combinations thereof.

[0280] In certain embodiments, the polyvinylpyridine copolymer may be a polyvinylpyridine / polystyrene copolymer. In certain embodiments, the first polymer film 510 may be made from a polyvinylpyridine / polystyrene copolymer, the polyvinylpyridine / polystyrene copolymer containing a charged pyridine moiety. In certain embodiments, the first polymer film 510 may be made from a polyvinylpyridine / polystyrene copolymer in which some of the nitrogen atoms of the pyridine are functionalized with non-crosslinked polyethylene glycol tails, and some of the nitrogen atoms of the pyridine are functionalized with alkali sulfonic acid groups, such as propyl sulfonic acid. In certain embodiments, the derivatized polyvinylpyridine / polystyrene copolymer for use in the first polymer film 510 may be the 10Q5 polymer described in U.S. Patent No. 8,761,857, the contents of which are incorporated herein by full reference.

[0281] In a particular embodiment, the first polymer film 510 may have a thickness (e.g., dry film thickness) ranging from about 0.1 μm to about 1,000 μm, for example, from about 1 μm to about 500 μm, from about 10 μm to about 300 μm, or from about 10 μm to about 100 μm.

[0282] In certain embodiments, the second polymer film 512 may have the composition of the therapeutic agent-containing polymer composition described herein. In certain embodiments, the second polymer film 512 may include a second polymer selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyether urethane polymers, silicone polymers, their derivatives, and combinations thereof. In certain embodiments, the second polymer film 512 may include a second polymer selected from the group consisting of polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyether urethane copolymers, silicone copolymers, their derivatives, and combinations thereof. In certain embodiments, the second polymer film 512 may include a second copolymer selected from the group consisting of polyvinylpyridine copolymers, polyvinylimidazole copolymers, and combinations thereof. In certain embodiments, the polyvinylpyridine copolymer may be a copolymer of vinylpyridine and styrene, or a derivative thereof.

[0283] In certain embodiments, the second polymer film 512 may include a polyvinylpyridine / polystyrene copolymer. In certain embodiments, the second polymer film 512 may include a poly(4-vinylpyridine / styrene) copolymer.

[0284] In certain embodiments, the poly(4-vinylpyridine / styrene) copolymer may contain 1 to 50 monomer% of styrene units. In certain embodiments, the poly(4-vinylpyridine / styrene) copolymer may contain 1 to 30 monomer% of styrene units.

[0285] In certain embodiments, the second polymer film 512 containing the therapeutic agent may have a thickness (e.g., dry film thickness) ranging from about 0.1 μm to about 1,000 μm, for example, about 1 μm to about 500 μm, about 10 μm to about 500 μm, about 10 μm to about 400 μm, about 10 μm to about 300 μm, about 10 μm to about 200 μm, or about 10 μm to about 100 μm. In certain embodiments, the second polymer film 512 containing the therapeutic agent may have a thickness ranging from about 1 μm to about 500 μm. In certain embodiments, the second polymer film 512 containing the therapeutic agent may have a thickness ranging from about 1 μm to about 400 μm. In certain embodiments, the second polymer film 512 containing the therapeutic agent may have a thickness ranging from about 1 μm to about 300 μm. In certain embodiments, the second polymer film 512 containing the therapeutic agent may have a thickness in the range of about 1 μm to about 200 μm. In certain embodiments, the second polymer film 512 containing the therapeutic agent may have a thickness in the range of about 10 μm to about 200 μm. In certain embodiments, the second polymer film 512 containing the therapeutic agent may have a thickness in the range of about 10 μm to about 300 μm. In certain embodiments, the second polymer film 512 containing the therapeutic agent may have a thickness in the range of about 50 μm to about 300 μm.

[0286] In certain embodiments, the second polymer film may have a variable thickness (e.g., over the length of the second polymer film). As shown in Figure 22, the more distal region of the second polymer film (e.g., about 0.3 mm from the tip of the sensor tail) is thicker than the more proximal region of the second polymer film (e.g., about 1.5 mm from the tip of the sensor tail). In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is about 0.9 or less. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is about 0.85 or less. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is about 0.8 or less. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is about 0.75 or less. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is about 0.7 or less. In a particular embodiment, the ratio of the thinnest point to the thickest point of the second polymer film is approximately 0.65 or less. In a particular embodiment, the ratio of the thinnest point to the thickest point of the second polymer film is approximately 0.6 or less. In a particular embodiment, the ratio of the thinnest point to the thickest point of the second polymer film is approximately 0.55 or less. In a particular embodiment, the ratio of the thinnest point to the thickest point of the second polymer film is approximately 0.5 or less.

[0287] In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.9, as shown in Figure 22. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.85. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.8. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.75. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.7. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.65. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.6. In certain embodiments, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.55. In a particular embodiment, the ratio of the thinnest point to the thickest point of the second polymer film is less than approximately 0.5.

[0288] In certain embodiments, the first polymer film 410 or 510 may be a mass transport restriction film. In certain embodiments, the mass transport restriction film may be a gluten transport restriction film.

[0289] In certain embodiments, the second polymer membrane 412 or 512 may be a drug-eluting membrane containing a therapeutic agent. As disclosed herein, the terms “drug-eluting membrane” and “therapeutic agent-containing polymer composition” are used synonymously. Further details of the therapeutic agent-containing polymer composition, which may be the second polymer membrane, are described herein in Section IV.

[0290] This disclosure further provides the use of a drug loading structure for incorporating the therapeutic agents disclosed herein into an analyte sensor. In certain embodiments, because the subcutaneous space of the in vivo analyte sensor is limited, it is desirable to apply / add a therapeutic agent, such as dexamethasone, to a precise area that can minimize the immune response and thus improve sensor performance.

[0291] In certain embodiments, the Disclosure provides an analyte sensor comprising a sensor tail (i.e., a body portion) having a drug-loading structure filled with a therapeutic agent-containing polymer composition. In certain embodiments, the drug-loading structure filled with the therapeutic agent-containing polymer composition is located in a non-detection region of the sensor tail, thereby allowing for the gradual release of a therapeutic agent such as dexamethasone, without affecting the detection chemistry system of the active region (e.g., detection spots) or the thickness of the sensor around the active region (e.g., detection spots (also referred to as activation spots)). For example, one or more embodiments of the Disclosure may be directed to an analyte sensor, which comprises a sensor tail (i.e., a body portion) including a non-detection region and an activity-detection region (e.g., including a plurality of detection spots), the non-detection region surrounding the activity-detection region, and may include a drug-loading structure filled with a therapeutic agent-containing polymer composition.

[0292] In certain embodiments, the analytic sensor of the present disclosure includes one or more drug-loading structures. For example, but not limited to, the analytic sensor of the present disclosure may include (i) a sensor tail comprising at least a first working electrode on a substrate, (ii) an active region positioned on the surface of the first working electrode for detecting an analytic, (iii) a substance transport restriction membrane that allows the analytic to pass through and covers at least the active region, (iv) a pair / reference electrode on the substrate, and (v) one or more drug-loading structures.

[0293] Figure 3 shows a schematic diagram of an exemplary sensor tail (i.e., body portion) according to one or more embodiments of the present disclosure. As shown in Figure 3, the analyte sensor may include a sensor tail 300 having a non-detection region 302 and an activity-sensing region 304 including a sensing layer (e.g., including a plurality of detection spots 306), the non-detection region 302 may include a drug-loading structure such as 308a shown in Figure 3B, 308b shown in Figure 3C, or 308c shown in Figure 3D, which surrounds the activity-sensing region 304 and is filled with a therapeutic agent-containing polymer composition 310. In a particular embodiment, one or more drug-loading structures may be positioned on the substrate of the sensor tail.

[0294] In certain embodiments, one or more drug loading structures can be positioned on the base of the sensor tail, for example, as shown in Figures 3B to 3D.

[0295] In certain embodiments, the drug loading structure may include at least one selected from slots, holes, pores, grooves, recesses, or combinations thereof.

[0296] In certain embodiments, the drug loading structure may include at least one slot.

[0297] In certain embodiments, the drug loading structure may include at least one hole.

[0298] In certain embodiments, the drug loading structure may include at least one pore.

[0299] In certain embodiments, the drug loading structure may include at least one groove.

[0300] In certain embodiments, the drug loading structure may include at least one recess.

[0301] In certain embodiments, the drug loading structure may include, for example, two slots symmetrically arranged along a plurality of detection spots, as shown in Figure 3B.

[0302] In certain embodiments, the drug loading structure may include a plurality of holes arranged around a plurality of detection spots (e.g., symmetrically arranged), as shown in Figure 3C, for example. For example, the plurality of holes may include 1 or more holes, 2 or more holes, 3 or more holes, 4 or more holes, 5 or more holes, 6 or more holes, 7 or more holes, 8 or more holes, 9 or more holes, 10 or more holes, 11 or more holes, 12 or more holes, 13 or more holes, 14 or more holes, 15 or more holes, 16 or more holes, 17 or more holes, 18 or more holes, 19 or more holes, 20 or more holes, 21 or more holes, 22 or more holes, 23 or more holes, 24 or more holes, 25 or more holes, 26 or more holes, 27 or more holes, 28 or more holes, 29 or more holes, or 30 or more holes. In certain embodiments, the holes may be circular, regular polygonal, or irregular polygonal. In certain embodiments, the holes may be circular, regular polygonal, or rectangular, as shown in Figure 3D, for example. In certain embodiments, the hole is a through hole.

[0303] In certain embodiments, the slots are elliptical, polygonal, or irregularly shaped. In certain embodiments, the slots are through slots.

[0304] In certain embodiments, the depth of the groove or depression may be about 1 / 4 to 3 / 4 of the thickness of the sensor tail. In certain embodiments, the surface of the distal tip of the sensor tail is ablated (e.g., laser ablation) and / or planed to form a depression or groove. In certain embodiments, the surface of the distal tip of the sensor tail is ablated and / or planed down to the sensing layer (e.g., one or more sensing spots) to form a depression or groove. For example, but not limited to, the region between the tip of the sensor tail and the beginning of the sensing layer (indicated as d3 in Figure 7) is ablated and / or planed to create a depression or groove to generate a drug-loading structure that can be filled with and / or covered with a therapeutic polymer composition.

[0305] Figure 4 shows a schematic diagram of an exemplary analyte sensor according to one or more embodiments of the present disclosure. As shown in Figure 4, the analyte sensor is (i) Base 402, (ii) working electrode 404, (iii) Pair / reference electrode 406 on substrate 402, (iv) Multiple detection spots 408a to 408f on the surface of the working electrode 404, (v) A polymer film 410 covering multiple detection spots 408a to 408f, (vi) A drug loading structure 409 filled with a therapeutic agent-containing polymer composition 412 (for example, but not limited to therapeutic agent-containing polymer compositions), The sensor may be provided with a tail portion 400 (i.e., an internal portion) including the polymer film 410. In certain embodiments, the polymer film 410 may be a mass transport restriction membrane. In certain embodiments, the mass transport restriction membrane 410 may refer to a mass transport restriction membrane disclosed elsewhere in this specification (e.g., in Section III), which will not be repeated herein for the sake of brevity. In certain embodiments, the mass transport restriction membrane may be a glutamate transport restriction membrane. In certain embodiments, the polymer film 410 may have a thickness (e.g., dry film thickness) in the range of about 0.1 μm to about 1,000 μm, for example, about 1 μm to about 500 μm, about 10 μm to about 300 μm, about 10 μm to about 100 μm, or about 10 μm to about 500 μm.

[0306] In certain embodiments, the drug loading structure 409 may be a trace, mark, hole, or slot. In certain embodiments, the therapeutic agent-containing polymer composition 412 fills the drug loading structure 409. In certain embodiments, the therapeutic agent-containing polymer composition 412 can continuously release a therapeutic agent, such as dexamethasone, its derivatives, or salts thereof, at a predetermined drug delivery rate for a predetermined number of days, such as at least about 30 days. A more detailed description of the therapeutic agent-containing polymer composition 412 may refer to the therapeutic agent-containing polymer compositions disclosed elsewhere in this disclosure (e.g., in Section IV).

[0307] FIG. 5 shows a schematic diagram of an exemplary analyte sensor according to one or more embodiments of the present disclosure. FIG. 5A shows that the analyte sensor comprises a sensor tail including an active sensing region 502 and a non-sensing region 504 filled with a drug loading structure 508 containing a therapeutic agent-containing polymer composition. FIG. 5B is an enlarged version of FIG. 5A and shows the detailed structure of the sensor tail. FIG. 5C shows that the analyte sensor comprises a sensor tail including an active sensing region 502 (e.g., including a plurality of sensing spots 506) and a non-sensing region 504 filled with a drug loading structure 508 containing a therapeutic agent-containing polymer composition. A detailed description of the drug loading structure 508 filled (or loaded) with the therapeutic agent-containing polymer composition can refer to the drug loading structure and the therapeutic agent-containing polymer composition disclosed herein.

[0308] In certain embodiments, the drug loading structure is from about 0.01 mm 2 to about 3.0 mm 2 e.g., from about 0.01 mm 2 to about 2.0 mm 2 from about 0.01 mm 2 to about 1.0 mm 2 from about 0.01 mm 2 to about 0.5 mm 2 from about 0.01 mm 2 to about 0.3 mm 2 or from about 0.01 mm 2 to about 0.1 mm 2 and can have a total area of any value therebetween. In certain embodiments, the total area of the drug loading structure can refer to the sum of the areas of all sub-loading structures such as slots, holes, pores, grooves, and / or depressions. The area of the drug loading structure is the area of the drug loading structure in a plan view, e.g., the sum of the areas of all sub-loading structures in a plan view.

[0309] Examples of therapeutic agent-containing polymer compositions (also referred to as drug-eluting membranes and second polymer membranes) that can be incorporated into the analyte sensors of this disclosure, as described herein, are described in Section IV. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent in an amount ranging from 0.01% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent in an amount ranging from 0.01% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent in an amount ranging from 1% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent in an amount ranging from 5% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, for example, dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent in an amount ranging from 10% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, such as dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent in an amount ranging from 20% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, such as dexamethasone or a derivative thereof. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent in an amount ranging from 30% to 40% by mass based on the total mass of the therapeutic agent-containing polymer composition, such as dexamethasone or a derivative thereof.

[0310] In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from 1% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition.

[0311] In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent in an amount of about 0.0005 mg to about 0.2 mg, or any value in between, such as dexamethasone. In certain embodiments, the therapeutic agent-containing polymer composition may contain a therapeutic agent in an amount of about 0.0005 mg, about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, or about 0.2 mg, such as dexamethasone. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain a therapeutic agent in an amount of about 0.1 μg to about 20 μg.In a particular embodiment, the therapeutic agent-containing polymer composition incorporated into the analyte sensor is present in amounts ranging from approximately 0.1 μg to approximately 200 μg, for example, approximately 0.5 μg to approximately 200 μg, approximately 1 μg to approximately 200 μg, approximately 1.5 μg to approximately 200 μg, approximately 2.0 μg to approximately 200 μg, approximately 2.5 μg to approximately 200 μg, approximately 3 μg to approximately 200 μg, approximately 4 μg to approximately 200 μg, approximately 5 μg to approximately 200 μg, approximately 10 μg to approximately 200 μg, and approximately 15 μg to approximately 2 00μg, approximately 20μg to approximately 200μg, approximately 25μg to approximately 200μg, approximately 30μg to approximately 200μg, approximately 35μg to approximately 200μg, approximately 40μg to approximately 200μg, approximately 45μg to approximately 200μg, approximately 50μg to approximately 200μg, approximately 55μg to approximately 200μg, approximately 60μg to approximately 200μg, approximately 65μg to approximately 200μg, approximately 70μg to approximately 200μg, approximately 75μg to approximately 200μg, approximately 80μg to approximately 200μg, approximately 85μg to approximately 200 μg, approximately 90 μg to approximately 200 μg, approximately 95 μg to approximately 200 μg, approximately 100 μg to approximately 200 μg, approximately 110 μg to approximately 200 μg, approximately 120 μg to approximately 200 μg, approximately 130 μg to approximately 200 μg, approximately 140 μg to approximately 200 μg, approximately 150 μg to approximately 200 μg, approximately 160 μg to approximately 200 μg, approximately 170 μg to approximately 200 μg, approximately 180 μg to approximately 200 μg, approximately 190 μg to approximately 200 μg, approximately 0.1 μg to approximately 1 The formulation may contain 90 μg, approximately 0.1 μg to 180 μg, approximately 0.1 μg to 170 μg, approximately 0.1 μg to 160 μg, approximately 0.1 μg to 150 μg, approximately 0.1 μg to 140 μg, approximately 0.1 μg to 130 μg, approximately 0.1 μg to 120 μg, approximately 0.1 μg to 110 μg, approximately 0.1 μg to 100 μg, approximately 1 μg to 150 μg, approximately 5 μg to 150 μg, or approximately 5 μg to 120 μg of the therapeutic agent.In a particular embodiment, the therapeutic agent-containing polymer composition incorporated into the analyte sensor is approximately 1 μg to approximately 100 μg, for example, approximately 1 μg to approximately 95 μg, approximately 1 μg to approximately 90 μg, approximately 1 μg to approximately 85 μg, approximately 1 μg to approximately 80 μg, approximately 1 μg to approximately 75 μg, approximately 1 μg to approximately 70 μg, approximately 1 μg to approximately 65 μg, approximately 1 μg to approximately 60 μg, approximately 1 μg to approximately 55 μg, approximately 1 μg to approximately 50 μg, approximately 1 μg to approximately 45 μg, approximately 1 μg to approximately 40 μg, approximately 1 μg to approximately 35 μg, approximately 1 μg to approximately 30 μg, Approximately 1 μg to approximately 25 μg, approximately 1 μg to approximately 20 μg, approximately 1 μg to approximately 15 μg, approximately 1 μg to approximately 14 μg, approximately 1 μg to approximately 13 μg, approximately 1 μg to approximately 12 μg, approximately 1 μg to approximately 11 μg, approximately 1 μg to approximately 10 μg, approximately 1 μg to approximately 9 μg, approximately 2 μg to approximately 100 μg, approximately 3 μg to approximately 100 μg, approximately 4 μg to approximately 100 μg, approximately 5 μg to approximately 100 μg, approximately 6 μg to approximately 100 μg, approximately 7 μg to approximately 100 μg, approximately 8 μg to approximately 100 μg, approximately 9 μg to approximately 100 μg, approximately 10 μg to approximately 100 μg, Approximately 11 μg to approximately 100 μg, approximately 12 μg to approximately 100 μg, approximately 13 μg to approximately 100 μg, approximately 14 μg to approximately 100 μg, approximately 15 μg to approximately 100 μg, approximately 16 μg to approximately 100 μg, approximately 17 μg to approximately 100 μg, approximately 18 μg to approximately 100 μg, approximately 19 μg to approximately 100 μg, approximately 20 μg to approximately 100 μg, approximately 25 μg to approximately 100 μg, approximately 30 μg to approximately 100 μg, approximately 35 μg to approximately 100 μg, approximately 40 μg to approximately 100 μg, approximately 45 μg to approximately 100 μg, approximately 50 μg to approximately 100 μg, approximately The therapeutic agent may be included in amounts ranging from 55 μg to approximately 100 μg, approximately 60 μg to approximately 100 μg, approximately 65 μg to approximately 100 μg, approximately 70 μg to approximately 100 μg, approximately 75 μg to approximately 100 μg, approximately 80 μg to approximately 100 μg, approximately 85 μg to approximately 100 μg, approximately 90 μg to approximately 100 μg, approximately 95 μg to approximately 100 μg, approximately 5 μg to approximately 50 μg, approximately 5 μg to approximately 45 μg, approximately 5 μg to approximately 40 μg, approximately 5 μg to approximately 35 μg, approximately 5 μg to approximately 30 μg, approximately 5 μg to approximately 25 μg, or approximately 5 μg to approximately 20 μg. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may include approximately 1 μg to approximately 5 μg of the therapeutic agent.In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 1 μg to about 10 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 1 μg to about 15 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 1 μg to about 20 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 5 μg to about 20 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 1 μg to about 30 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 5 μg to about 10 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 5 μg to about 15 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 5 μg to about 20 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 5 μg to about 25 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 5 μg to about 30 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 0.1 μg to about 30 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 0.1 μg to about 20 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 0.1 μg to about 15 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 0.1 μg to about 10 μg of the therapeutic agent. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 0.1 μg to about 5 μg of the therapeutic agent.

[0312] In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor may contain about 0.01 μg to about 5 μg of the therapeutic agent.

[0313] In certain embodiments, the therapeutic agent-containing polymer composition may contain less than approximately 10 μg of the therapeutic agent.

[0314] In certain embodiments, the therapeutic agent-containing polymer composition may contain less than approximately 5 μg of the therapeutic agent.

[0315] In a particular embodiment, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate of approximately 0.001 μg / day to approximately 1 mg / day, or any value in between, for example, dexamethasone.

[0316] In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.001 μg / day to about 5 μg / day, or any value in between.

[0317] In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of approximately 0.001 μg / day to approximately 1 μg / day, or any value in between.

[0318] In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.001 μg / day to about 0.1 μg / day, or any value in between.

[0319] In a particular embodiment, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.01 μg / day to about 100 μg / day, or any value in between.

[0320] In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate (e.g., average drug release rate) of about 0.01 μg / day to about 10 μg / day, or any value in between.

[0321] In a particular embodiment, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate of approximately 0.01 μg / day to approximately 1 mg / day, or any value in between, for example, dexamethasone.

[0322] In a particular embodiment, the therapeutic agent-containing polymer composition incorporated into the analyte sensor is present in doses of approximately 0.1 μg / day, for example, approximately 0.2 μg / day, approximately 0.3 μg / day, approximately 0.4 μg / day, approximately 0.5 μg / day, approximately 0.6 μg / day, approximately 0.7 μg / day, approximately 0.8 μg / day, approximately 0.9 μg / day, approximately 1 μg / day, approximately 2 μg / day, approximately 3 μg / day, approximately 4 μg / day, approximately 5 μg / day, approximately 6 μg / day, approximately 7 μg / day, approximately 8 μg / day, approximately 9 μg / day, approximately 10 μg / day, approximately 20 μg / day, The therapeutic agent can be continuously released at a drug release rate of approximately 30 μg / day, approximately 40 μg / day, approximately 50 μg / day, approximately 60 μg / day, approximately 70 μg / day, approximately 80 μg / day, approximately 90 μg / day, approximately 100 μg / day, approximately 200 μg / day, approximately 300 μg / day, approximately 400 μg / day, approximately 500 μg / day, approximately 600 μg / day, approximately 700 μg / day, approximately 800 μg / day, approximately 900 μg / day, or approximately 1 mg / day, or any value in between, such as dexamethasone. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate of approximately 0.2 μg / day to approximately 5 μg / day, such as dexamethasone. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate of approximately 0.2 μg / day to approximately 2 μg / day, for example, dexamethasone. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate of approximately 0.2 μg / day to approximately 1 μg / day, for example, dexamethasone. In certain embodiments, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a drug release rate set to achieve desired therapeutic outcomes such as reduction, minimization, prevention, and / or suppression of inflammation and / or infection.

[0323] In a particular embodiment, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a predetermined drug release rate for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, or at least 30 days. In a particular embodiment, the therapeutic agent-containing polymer composition incorporated into the analyte sensor can continuously release the therapeutic agent at a predetermined drug release rate for a predetermined number of days, such as at least 30 days.

[0324] In certain embodiments, when incorporated into an analyte sensor, the therapeutic agent-containing polymer composition releases about 40% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded into the composition) within a period of about 30 to 31 days. For example, but not limited to, when incorporated into an analyte sensor, the compositions of the disclosure release about 45% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded into the composition), about 50% to about 80% of the therapeutic agent, about 55% to about 80% of the therapeutic agent, about 60% to about 80% of the therapeutic agent, about 65% to about 80% of the therapeutic agent, about 70% to about 80% of the therapeutic agent, or about 75% to about 80% of the therapeutic agent. , releasing approximately 40% to 75% of the therapeutic agent, releasing approximately 40% to 70% of the therapeutic agent, releasing approximately 40% to 65% of the therapeutic agent, releasing approximately 40% to 60% of the therapeutic agent, releasing approximately 40% to 55% of the therapeutic agent, releasing approximately 40% to 50% of the therapeutic agent, releasing approximately 40% to 45% of the therapeutic agent, releasing approximately 45% to 75% of the therapeutic agent, releasing approximately 50% to 75% of the therapeutic agent, releasing approximately 55% to 80% of the therapeutic agent, or releasing approximately 60% to 75% of the therapeutic agent.

[0325] In certain embodiments, approximately 90% or less of the therapeutic agent in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released, for example, within a period of approximately 30 to 31 days. In certain embodiments, approximately 95% or less of the therapeutic agent in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released, for example, within a period of approximately 30 to 31 days. In certain embodiments, approximately 80% or less of the therapeutic agent in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released, for example, within a period of approximately 30 to 31 days. In certain embodiments, approximately 75% or less of the therapeutic agent in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released, for example, within a period of approximately 30 to 31 days. In certain embodiments, approximately 70% or less of the therapeutic agent in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released, for example, within a period of approximately 30 to 31 days. In certain embodiments, approximately 65% ​​or less of the therapeutic agent in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released, for example, within a period of approximately 30 to 31 days. In certain embodiments, approximately 60% or less of the therapeutic agent in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released, for example, within a period of approximately 30 to 31 days. In certain embodiments, approximately 55% or less of the therapeutic agent in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released, for example, within a period of approximately 30 to 31 days. In a particular embodiment, approximately 50% or less of the therapeutic agent in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released, for example, within a period of approximately 30 to 31 days.

[0326] In certain embodiments, approximately 30% or less, approximately 35% or less, approximately 40% or less, approximately 45% or less, approximately 50% or less, approximately 55% or less, approximately 65% ​​or less, approximately 70% or less, or 75% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first 5, 6, or 7 days after insertion. In certain embodiments, approximately 30% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first 5 days after insertion. In certain embodiments, approximately 30% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first 6 days after insertion. In certain embodiments, approximately 30% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first 7 days after insertion. In certain embodiments, approximately 35% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first 5 days after insertion. In certain embodiments, approximately 35% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first 6 days after insertion. In certain embodiments, approximately 35% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first 7 days after insertion. In certain embodiments, approximately 40% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first 5 days after insertion. In certain embodiments, approximately 40% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first 6 days after insertion. In certain embodiments, approximately 40% or less of the therapeutic agent present in the composition incorporated into the analyte sensor (e.g., the total amount of therapeutic agent added to the composition) is released during the first seven days after insertion.

[0327] Further descriptions of therapeutic agent-containing polymer compositions (also referred to as drug-eluting membranes and second polymer membranes) that can be incorporated into analyte sensors are disclosed elsewhere in this disclosure, for example in Section IV, and are not repeated herein for the sake of brevity.

[0328] VI. Manufacturing method This disclosure further provides a method for preparing an analyte sensor comprising one or more therapeutic agents. For example, but not limited to, this disclosure provides a method for preparing an analyte sensor comprising one or more therapeutic agent-containing polymer compositions of this disclosure.

[0329] In certain embodiments, the Disclosure provides a method for preparing an analytic sensor containing one or more therapeutic agents, for example, present in a therapeutic agent-containing polymer composition, which are arranged in or incorporated into components of the analytic sensor (e.g., internal parts of the analytic sensor). For example, but not limited to, the method of the Disclosure includes the step of distributing the therapeutic agent-containing polymer composition onto the surface of electrodes (e.g., pair / reference electrodes (e.g., 216 in Figure 18A) and / or working electrodes (e.g., 214 in Figure 18A)), insulating materials (e.g., dielectric materials (e.g., 219a-c in Figure 18A)), a substrate (e.g., 212 in Figure 18A), a mass transport limiting membrane (e.g., 220 in Figure 18A), and the distal tip of the analytic sensor (e.g., 412 in Figure 10 and 512 in Figure 11). In certain embodiments, the therapeutic agent-containing polymer composition is not arranged on an active layer (e.g., multiple detection spots). In a particular embodiment, the therapeutic agent-containing polymer composition is placed on the structure or components of an analyte sensor adjacent to the active layer (e.g., multiple detection spots).

[0330] In certain embodiments, the therapeutic agent-containing polymer composition of the Disclosure is placed on or incorporated onto the structure or components of an analyte sensor (e.g., the internal part of the analyte sensor) by a screen printing, rotary printing, jet printing, aerosol deposition, microdispensing, spray coating, immersion coating, drop casting, spin coating, or brush coating process.

[0331] In certain embodiments, the step of depositing the therapeutic agent-containing polymer composition of the present disclosure onto the structure or components of the sensor tail (e.g., the internal part of the analyte sensor) can be carried out by immersion.

[0332] In certain embodiments, the step of depositing the therapeutic agent-containing polymer composition of the present disclosure onto the structure or components of the sensor tail (e.g., the internal part of the analyte sensor) can be carried out by drop casting.

[0333] In certain embodiments, the step of depositing the therapeutic agent-containing polymer composition of the present disclosure onto the structure or components of the sensor tail (e.g., the internal part of the analyte sensor) can be carried out by aerosol deposition.

[0334] In one embodiment, the present disclosure provides a method for preparing an analyte sensor containing one or more therapeutic agents, including the generation of a drug-loading structure. Figure 6 shows a flowchart illustrating an exemplary method for preparing an analyte sensor according to one or more embodiments of the present disclosure. As shown in Figure 6, an exemplary method for preparing an analyte sensor is: (602) A step to provide an analyte sensor having a sensor tail including a non-detection region and an activity detection region (e.g., including multiple detection spots), (604) A step of cutting off at least a portion of the non-detection area of ​​the sensor tail to form a drug loading structure, and (606) A step of filling (or loading) a therapeutic agent-containing polymer composition into a drug loading structure. It may include.

[0335] In certain embodiments, the activity detection region includes an analyte-responsive active area. In certain embodiments, the analyte-responsive active area includes two or more detection spots.

[0336] In certain embodiments, the step of cutting off at least a portion of the non-detection region of the sensor tail to form a drug loading structure may include the step of removing at least a portion of the non-detection region of the sensor tail by laser cutting, photolithography, ion beam lithography, etching (e.g., dry etching or wet etching), ablation, planing, etc., to form a drug loading structure.

[0337] In a particular embodiment, the step of cutting off at least a portion of the non-detection region of the sensor tail to form a drug loading structure may include the step of removing at least a portion of the non-detection region of the sensor tail by laser cutting.

[0338] In certain embodiments, the step of cutting off at least a portion of the non-detection region of the sensor tail to form a drug loading structure may include the step of removing at least a portion of the non-detection region of the sensor tail by ablation.

[0339] In a particular embodiment, the step of cutting off at least a portion of the non-detection area of ​​the sensor tail to form a drug loading structure may include the step of removing at least a portion of the non-detection area of ​​the sensor tail by planing.

[0340] In certain embodiments, the step of filling (or loading) a therapeutic agent-containing polymer composition into a drug loading structure may include filling the drug loading structure with the therapeutic agent-containing polymer composition by immersion, spraying, aerosol deposition, jet printing, drop casting, or the like.

[0341] In certain embodiments, the step of filling (or loading) the drug loading structure with a therapeutic polymer composition may include the step of filling (or loading) the drug loading structure with a therapeutic polymer composition by immersion.

[0342] In certain embodiments, the step of filling (or loading) a therapeutic agent-containing polymer composition into a drug-loading structure may include the step of filling (or loading) a therapeutic agent-containing polymer composition into the drug-loading structure by aerosol deposition.

[0343] In certain embodiments, the drug loading structure may include at least one selected from slots, holes, pores, grooves, marks, traces, and depressions. In certain embodiments, the drug loading structure may include at least one slot. In certain embodiments, the drug loading structure may include at least one hole. In certain embodiments, the drug loading structure may include at least one pore. In certain embodiments, the drug loading structure may include at least one groove. In certain embodiments, the drug loading structure may include at least one depression. Further details relating to the drug loading structure are described in Section V of this specification.

[0344] In a particular embodiment, the drug loading structure may include two slots symmetrically arranged along a plurality of detection spots.

[0345] In certain embodiments, the drug loading structure may include a plurality of holes symmetrically arranged around a plurality of detection spots. In certain embodiments, the holes may be circular, regular polygonal, or irregular polygonal in shape. In certain embodiments, the holes may be through holes.

[0346] In certain embodiments, the slots are elliptical, polygonal, or irregularly shaped. In certain embodiments, the slots are through slots.

[0347] In certain embodiments, the depth of the groove or recess may be about 1 / 4 to 3 / 4 of the thickness of the sensor tail.

[0348] In a particular embodiment, the drug loading structure is approximately 0.01 mm 2 From approximately 3.0 mm 2For example, approximately 0.01 mm 2 From approximately 2.0 mm 2 Approximately 0.01 mm 2 From approximately 1.0 mm 2 Approximately 0.01 mm 2 From approximately 0.5 mm 2 Approximately 0.01 mm 2 From approximately 0.3 mm 2 , or approximately 0.01 mm 2 From approximately 0.1 mm 2 The total area may be any value between these. The total area of ​​the drug loading structure may refer to the sum of the areas of all secondary loading structures such as slots, holes, pores, grooves, and / or recesses. The area of ​​the drug loading structure is the area of ​​the drug loading structure in a plan view, for example, the sum of the areas of all secondary loading structures in a plan view.

[0349] This disclosure further provides a method for depositing a therapeutic agent onto the distal region of a sensor tail (e.g., the internal portion of an analyte sensor). Figure 8 shows a step, task, or action of a method for coating an analyte sensor according to one or more embodiments of this disclosure. Figure 9 shows a schematic diagram of a coated analyte sensor according to one or more embodiments of this disclosure. Herein, the enumeration of steps, tasks, or actions described in a particular order does not necessarily mean that the invention or claims require that particular order. That is, the general principle applies that unless the steps, tasks, or actions of a method (e.g., claims of a method) actually specify an order, those steps, tasks, or actions should not be construed as requiring an order.

[0350] In a particular embodiment, the method for coating the analyte sensor of this disclosure is: (i) A step of providing an analyte sensor that is made to be located beneath the surface of the subject's skin and in contact with the subject's interstitial fluid, and includes an internal part having a second region containing an active area and a first region distal to the second region. (ii) A step of preparing a first polymer solution containing a first polymer, or providing a first polymer solution containing a first polymer. (iii) A step of preparing a second polymer solution comprising a second polymer and a therapeutic agent, or providing a second polymer solution comprising a second polymer and a therapeutic agent. (iv) A step of bringing the internal portion into contact with the first polymer solution to coat the first region and the second region and generate a first polymer film, and (v) A step of bringing the first region into contact with the second polymer solution to coat the first region instead of the second region, thereby generating a second polymer film containing the therapeutic agent. Includes.

[0351] In certain embodiments, the step of bringing the internal portion into contact with a first polymer solution includes screen printing, web printing, jet printing, aerosol deposition, spray coating, immersion coating, drop casting, spin coating, or brush coating processes.

[0352] In certain embodiments, the step of bringing the internal portion into contact with the first polymer solution includes an immersion coating process.

[0353] In certain embodiments, the step of bringing a first region into contact with a second polymer solution includes screen printing, rotary printing, jet printing, aerosol deposition, spray coating, dipping coating, drop casting, spin coating, or brush coating processes.

[0354] In certain embodiments, the step of bringing a first region into contact with a second polymer solution includes an immersion coating process.

[0355] In certain embodiments, the step of bringing the internal portion into contact with the first polymer solution is performed before the step of bringing the first region into contact with the second polymer solution. In certain embodiments, the step of bringing the first region into contact with the second polymer solution is performed before the step of bringing the internal portion into contact with the first polymer solution.

[0356] In a particular embodiment, a method for manufacturing an analyte sensor containing a therapeutic agent is: (i) A step of providing an analyte sensor that is made to be located beneath the surface of the subject's skin and in contact with the subject's interstitial fluid, and includes an internal part having a second region containing an active area and a first region distal to the second region. (ii) A step of preparing a first polymer solution containing a first polymer, or providing a first polymer solution containing a first polymer. (iii) A step of preparing a second polymer solution comprising a second polymer and a therapeutic agent, or providing a second polymer solution comprising a second polymer and a therapeutic agent. (iv) A step of immersing the internal portion in the first polymer solution to coat the first region and the second region and to generate a first polymer film, and (v) A step of immersing the first region in a second polymer solution to coat the first region instead of the second region, thereby generating a second polymer film containing the therapeutic agent on top of the first polymer film. Includes.

[0357] In a particular embodiment, a method for manufacturing an analyte sensor containing a therapeutic agent is: (i) A step of providing an analyte sensor that is made to be located beneath the surface of the subject's skin and in contact with the subject's interstitial fluid, and includes an internal part having a second region containing an active area and a first region distal to the second region. (ii) A step of preparing a first polymer solution containing a first polymer, or providing a first polymer solution containing a first polymer. (iii) A step of preparing a second polymer solution comprising a second polymer and a therapeutic agent, or providing a second polymer solution comprising a second polymer and a therapeutic agent. (iv) A step of immersing the first region in a second polymer solution to coat the first region instead of the second region, thereby generating a second polymer film containing the therapeutic agent, and (v) A step of immersing the body portion in the first polymer solution to coat the first and second regions and to generate the first polymer film on top of the second polymer film, Includes.

[0358] As shown in Figure 8, according to one or more embodiments of the present disclosure, a method for covering an analyte sensor including a sensor tail (for example, an internal portion made to be located beneath the surface of the subject's skin and in contact with the subject's interstitial fluid) including a first region not containing any detection spots and a second region containing a plurality of detection spots, (i) A step of preparing a first polymer solution and a second polymer solution which differs from the first polymer solution and contains a therapeutic agent, (ii) A step of immersing the sensor tail in a first polymer solution to cover a first region and a second region including a plurality of detection spots, If necessary, the first polymer solution on the sensor tail is dried to form a first polymer film. (iii) The step of immersing the sensor tail in the second polymer solution such that the second polymer solution covers a first region of the sensor tail rather than a second region containing multiple detection spots, and If necessary, the second polymer solution on the sensor tail is dried to form a second polymer film. It may include.

[0359] In certain embodiments, the method of the present disclosure may further include the steps of immersing a sensor tail in a first polymer solution, and then, if necessary, drying the first polymer solution on the sensor tail to form a first polymer film, repeating this step until the first polymer film, e.g., the first polymer film (e.g., 510 in Figure 9 or 410 in Figure 10), reaches a first set or predetermined thickness (e.g., before immersing the sensor tail in a second polymer solution). In certain embodiments, the method of the present disclosure may further include the steps of immersing a sensor tail in a second polymer solution, and then, if necessary, drying the second polymer solution on the sensor tail to form a second polymer film, repeating this step until the second polymer film, e.g., the second polymer film (e.g., 512 in Figure 9 or 412 in Figure 10), reaches a second set or predetermined thickness (e.g., after the formation of the first polymer film).

[0360] Alternatively, in a particular embodiment as shown in Figure 15, a method for covering an analyzer sensor including a sensor tail which includes a first region not containing any detection spots and a second region containing multiple detection spots is: (i) A step of preparing a first polymer solution and a second polymer solution which differs from the first polymer solution and contains a therapeutic agent, (ii) A step of immersing the sensor tail in the second polymer solution such that the second polymer solution covers a first region of the sensor tail, rather than a second region containing multiple detection spots, If necessary, the second polymer solution on the sensor tail is dried to form a second polymer film. (iii) A step of immersing the sensor tail in a first polymer solution to cover a first region (for example, covered with a second polymer film) and a second region including a plurality of detection spots. If necessary, the first polymer solution on the sensor tail is dried to form a first polymer film. It may include.

[0361] In a particular embodiment, the method may further include the steps of immersing the sensor tail in a second polymer solution and, if necessary, drying the second polymer solution on the sensor tail to form a second polymer film, repeating this until the second polymer film, for example, the second polymer film 512 in Figure 11, reaches a first set or predetermined thickness (for example, before immersing the sensor tail in the first polymer solution). In a particular embodiment, the method may further include the steps of immersing the sensor tail in a first polymer solution and, if necessary, drying the first polymer solution on the sensor tail to form a first polymer film, repeating this until the first polymer film, for example, the first polymer film 510 in Figure 11, reaches a first set or predetermined thickness (for example, after the formation of the second polymer film).

[0362] In certain embodiments, the first polymer film may have a thickness (e.g., dry film thickness) ranging from about 0.1 μm to about 1,000 μm, for example, from about 1 μm to about 500 μm, from about 10 μm to about 300 μm, or from about 10 μm to about 100 μm. In certain embodiments, the sensor tail may be immersed multiple times in the first polymer solution. For example, but not limited to, the sensor tail of the Disclosure may be immersed at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten times in the first polymer solution to obtain a first set or predetermined thickness. In certain embodiments, the sensor tail of the Disclosure may be immersed at least twice in the first polymer solution to obtain a first set or predetermined thickness. In certain embodiments, the sensor tail of the Disclosure may be immersed at least three times in the first polymer solution to obtain a first set or predetermined thickness. In certain embodiments, the sensor tail of the Disclosure may be immersed in a first polymer solution at least four times to obtain a first set or predetermined thickness. In certain embodiments, the sensor tail of the Disclosure may be immersed in the first polymer solution a number of times between about two and about five times to obtain a first set or predetermined thickness. In certain embodiments, the sensor tail of the Disclosure may be immersed in the first polymer solution for a period of about one second to about five seconds. In certain embodiments, there may be a period of about one to twenty minutes (e.g., a waiting period) between each immersion in the first polymer solution.

[0363] In certain embodiments, the second region of the sensor tail can be ablated and / or planed before immersion of the second region in the second polymer solution. For example, but not limited to, a portion of the substrate and / or a portion of the working electrode can be removed from the second region by ablation and / or planing.

[0364] In certain embodiments, the second polymer film containing the therapeutic agent may have a thickness (e.g., dry film thickness) ranging from about 0.1 μm to about 1,000 μm, for example, about 1 μm to about 500 μm, about 10 μm to about 500 μm, about 10 μm to about 400 μm, about 10 μm to about 300 μm, about 10 μm to about 200 μm, or about 10 μm to about 100 μm. In certain embodiments, the second polymer film containing the therapeutic agent may have a thickness ranging from about 1 μm to about 500 μm. In certain embodiments, the second polymer film containing the therapeutic agent may have a thickness rangin...

Claims

1. A method for manufacturing an analyte sensor containing a therapeutic agent, a) A step of providing an analyte sensor that is made to be located beneath the surface of the skin of a subject and is in contact with the interstitial fluid of the subject, and includes an internal part having a second region containing an active area and a first region distal to the second region. b) A step of preparing a first polymer solution containing the first polymer, c) A step of preparing a second polymer solution containing a second polymer and a therapeutic agent, d) A step of immersing the internal portion in the first polymer solution to coat the first region and the second region and to produce a first polymer film, and e) A step of immersing the first region in the second polymer solution to coat the first region instead of the second region, thereby generating a second polymer film containing the therapeutic agent on the first polymer film, A method that includes this.

2. A method for manufacturing an analyte sensor containing a therapeutic agent, a) A step of providing an analyte sensor that is made to be located beneath the surface of the skin of a subject and is in contact with the interstitial fluid of the subject, and includes an internal part having a second region containing an active area and a first region distal to the second region. b) A step of preparing a first polymer solution containing the first polymer, c) A step of preparing a second polymer solution containing a second polymer and a therapeutic agent, d) A step of immersing the first region in the second polymer solution to coat the first region instead of the second region, thereby generating a second polymer film containing the therapeutic agent, and e) A step of immersing the internal portion in the first polymer solution to cover the first region and the second region, and forming a first polymer film on the second polymer film, A method that includes this.

3. The method according to claim 1 or 2, wherein the therapeutic agent is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof.

4. The method according to claim 3, wherein the therapeutic agent is an anti-inflammatory agent.

5. The method according to claim 4, wherein the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, derivatives thereof, salt forms thereof, and combinations thereof.

6. The method according to any one of claims 3 to 5, wherein the anti-inflammatory agent is dexamethasone, a derivative thereof, or a salt thereof.

7. The method according to any one of claims 1 to 6, wherein the second polymer solution comprises the polymer, the therapeutic agent, and the solvent.

8. The method according to claim 7, wherein the solvent comprises an alcohol, a buffer, or a combination thereof.

9. The method according to claim 8, wherein the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 2,2-dimethyl-1-propanol, 1-butanol, 2-butanol, isobutanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2-methyl-1-pentanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, triphenylmethanol, and combinations thereof.

10. The method according to any one of claims 1 to 9, wherein the second polymer solution further comprises a crosslinking agent.

11. The method according to any one of claims 1 to 10, wherein the therapeutic agent is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the second polymer solution.

12. The method according to any one of claims 1 to 11, wherein the polymer is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the second polymer solution.

13. The method according to any one of claims 1 to 12, wherein the crosslinking agent is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the second polymer solution.

14. The method according to any one of claims 1 to 13, wherein the second polymer solution has a viscosity of about 20 centipoise to about 250 centipoise.

15. The method according to any one of claims 1 to 14, wherein the second polymer solution has a viscosity of about 20 centipoise to about 80 centipoise.

16. The method according to any one of claims 1 to 15, wherein the second polymer in the second polymer solution is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyether urethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof.

17. The method according to claim 16, wherein the polyvinylpyridine polymer is a polyvinylpyridine copolymer.

18. The method according to claim 17, wherein the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer.

19. The method according to any one of claims 1 to 18, wherein the first region is immersed in the second polymer solution for a period of about 1 second to about 5 seconds.

20. The method according to any one of claims 1 to 19, further comprising the step of drying the second polymer solution for a period of about 1 to about 20 minutes after immersion.

21. The method according to any one of claims 1 to 20, wherein the first region of the analyte sensor is immersed in the second polymer solution one or more times to form a polymer film having a thickness of about 5 μm to about 40 μm.

22. The method according to any one of claims 1 to 21, wherein the first region of the analyte sensor is immersed in the second polymer solution at least three times.

23. The method according to any one of claims 1 to 22, wherein the first region is ablated or planed before the first region is immersed in the second polymer solution.

24. The method according to any one of claims 1 to 23, wherein the length of the second region is approximately 5 μm to approximately 50 μm.

25. The method according to any one of claims 1 to 24, wherein the length of the first region is approximately 5 μm to approximately 50 μm.

26. The method according to any one of claims 1 to 25, wherein the length of the first region is approximately 5 μm to approximately 20 μm.

27. The method according to any one of claims 1 to 26, wherein the active area includes a plurality of detection regions.

28. The method according to claim 27, wherein at least one of the plurality of detection areas is a spot.

29. The method according to any one of claims 1 to 28, wherein the first polymer in the first polymer solution is different from the second polymer.

30. The method according to any one of claims 1 to 29, wherein the first polymer in the first polymer solution is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyether urethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof.

31. The method according to claim 30, wherein the polyvinylpyridine polymer is a polyvinylpyridine copolymer.

32. The method according to claim 31, wherein the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer.

33. The method according to any one of claims 1 to 32, wherein the internal portion of the analyte sensor is immersed in the first polymer solution for a period of about 1 second to about 5 seconds.

34. The method according to any one of claims 1 to 33, further comprising the step of drying the first polymer solution for a period of about 1 to about 20 minutes after immersion.

35. The method according to any one of claims 1 to 34, wherein the internal portion of the analyte sensor is immersed in the first polymer solution one or more times to generate a first polymer film having a thickness of about 5 μm to about 40 μm.

36. The method according to any one of claims 1 to 35, wherein the internal portion of the analyte sensor is immersed in the first polymer solution at least five times.

37. The method according to any one of claims 1 to 36, wherein the ratio of the thinnest point to the thickest point of the second polymer film is less than about 0.

9.

38. A method for manufacturing an analyte sensor containing a therapeutic agent, a) A step of providing an analyte sensor that is made to be located beneath the surface of the skin of a subject and is in contact with the interstitial fluid of the subject, and includes an internal part having a second region containing an active area and a first region distal to the second region. b) A step of preparing a first polymer solution containing a first polymer, or providing a first polymer solution containing a first polymer. c) A step of preparing a second polymer solution containing a second polymer and a therapeutic agent, or providing a second polymer solution containing a second polymer and a therapeutic agent. d) A step of bringing the internal portion into contact with the first polymer solution to coat the first region and the second region and to generate a first polymer film, and e) A step of bringing the first region into contact with the second polymer solution to coat the first region instead of the second region, thereby generating a second polymer film containing the therapeutic agent. A method that includes this.

39. The method according to claim 38, wherein the step of bringing the internal portion into contact with a first polymer solution includes a screen printing, rotary printing, jet printing, aerosol deposition, spray coating, immersion coating, drop casting, spin coating, or brush coating process.

40. The method according to claim 39, wherein the step of bringing the first region into contact with the second polymer solution includes a screen printing, rotary printing, jet printing, aerosol deposition, spray coating, dipping coating, drop casting, spin coating, or brush coating process.

41. The method according to any one of claims 38 to 40, wherein the therapeutic agent is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof.

42. The method according to claim 41, wherein the therapeutic agent is an anti-inflammatory agent.

43. The method according to claim 42, wherein the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, derivatives thereof, salt forms thereof, and combinations thereof.

44. The method according to any one of claims 41 to 43, wherein the anti-inflammatory agent is dexamethasone, a derivative thereof, or a salt thereof.

45. The method according to any one of claims 38 to 44, wherein the second polymer solution comprises the polymer, the therapeutic agent, and the solvent.

46. The method according to claim 45, wherein the solvent comprises an alcohol, a buffer, or a combination thereof.

47. The method according to claim 46, wherein the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 2,2-dimethyl-1-propanol, 1-butanol, 2-butanol, isobutanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2-methyl-1-pentanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, triphenylmethanol, and combinations thereof.

48. The method according to any one of claims 38 to 47, wherein the second polymer solution further comprises a crosslinking agent.

49. The method according to any one of claims 38 to 48, wherein the therapeutic agent is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution.

50. The method according to any one of claims 38 to 49, wherein the polymer is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution.

51. The method according to any one of claims 40 to 50, wherein the crosslinking agent is present in the second polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution.

52. The method according to any one of claims 38 to 51, wherein the second polymer solution has a viscosity of about 20 centipoise to about 250 centipoise.

53. The method according to any one of claims 38 to 52, wherein the second polymer solution has a viscosity of about 20 centipoise to about 80 centipoise.

54. The method according to any one of claims 38 to 53, wherein the second polymer in the second polymer solution is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyetherurethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof.

55. The method according to claim 54, wherein the polyvinylpyridine polymer is a polyvinylpyridine copolymer.

56. The method according to claim 55, wherein the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer.

57. The method according to any one of claims 38 to 56, wherein the first region is in contact with the second polymer solution for a period of about 1 second to about 5 seconds.

58. The method according to any one of claims 38 to 57, further comprising the step of drying the second polymer solution for a period of about 1 to about 20 minutes after contact.

59. The method according to any one of claims 38 to 58, wherein a first region of the analyte sensor is contacted with the second polymer solution once or more times to form a second polymer film having a thickness of about 5 μm to about 40 μm.

60. The method according to any one of claims 38 to 59, wherein the first region of the analyte sensor is in contact with the second polymer solution at least three times.

61. The method according to any one of claims 38 to 60, wherein the first region is ablated or planed before the first region is brought into contact with the second polymer solution.

62. The method according to any one of claims 38 to 61, wherein the length of the second region is approximately 5 μm to approximately 50 μm.

63. The method according to any one of claims 38 to 62, wherein the length of the first region is approximately 5 μm to approximately 50 μm.

64. The method according to any one of claims 38 to 63, wherein the length of the first region is approximately 5 μm to approximately 20 μm.

65. The method according to any one of claims 38 to 64, wherein the active area includes a plurality of detection areas.

66. The method according to claim 65, wherein at least one of the plurality of detection areas is a spot.

67. The method according to any one of claims 38 to 66, wherein the step of bringing the internal portion into contact with the first polymer solution is performed before the step of bringing the first region into contact with the second polymer solution.

68. The method according to claim 67, wherein the second polymer film covers the first polymer film at least partially.

69. The method according to any one of claims 38 to 66, wherein the step of bringing the first region into contact with the second polymer solution is performed before the step of bringing the internal portion into contact with the first polymer solution.

70. The method according to claim 69, wherein the first polymer film covers the second polymer film at least partially.

71. The method according to any one of claims 38 to 70, wherein the ratio of the thinnest point to the thickest point of the second polymer film is less than about 0.

9.

72. The method according to any one of claims 1 to 71, wherein the total amount of therapeutic agent in the second polymer membrane is about 0.01 μg to about 500 μg.

73. The method according to any one of claims 1 to 71, wherein the total amount of therapeutic agent in the second polymer membrane is less than about 5 μg.

74. A method for manufacturing an analyte sensor containing a therapeutic agent, a) A step of providing an analyte sensor including (i) a working electrode, (ii) a pair and / or reference electrode, and (iii) an active region. b) A step of preparing a first polymer solution containing a first polymer, or providing a first polymer solution containing a first polymer. c) A step of preparing a second polymer solution containing a second polymer and a therapeutic agent, or providing a second polymer solution containing a second polymer and a therapeutic agent. d) A step of depositing the second polymer solution onto at least a portion of the pair and / or reference electrodes to produce a therapeutic agent-containing polymer composition, and e) A step of depositing the first polymer solution onto the body portion to form a first polymer film on at least a portion of the therapeutic agent-containing polymer composition. A method that includes this.

75. The method according to claim 74, wherein the step of depositing a second polymer solution on at least a portion of the pair and / or reference electrodes includes a screen printing, rotary printing, jet printing, aerosol deposition, spray coating, immersion coating, drop casting, spin coating, or brush coating process.

76. The method according to claim 74 or 75, wherein the step of depositing a first polymer solution on the internal portion includes a screen printing, rotary printing, jet printing, aerosol deposition, spray coating, immersion coating, drop casting, spin coating, or brush coating process.

77. The method according to any one of claims 74 to 76, wherein the step of depositing a second polymer solution on at least a portion of the pair and / or reference electrodes includes the step of depositing the second polymer solution on the pair and / or reference electrodes as two or more spots of the therapeutic agent-containing polymer composition.

78. The method according to claim 77, wherein at least one of the spots is circular, elliptical, a regular polygon, or an irregular polygon.

79. The method according to claim 77 or 78, wherein at least two of the two or more spots contain the same amount of the therapeutic agent.

80. The method according to claim 77 or 78, wherein at least two of the two or more spots contain different amounts of the therapeutic agent.

81. The method according to claim 80, wherein the difference in the amount of the therapeutic agent between at least two of the two or more spots is about 10% or more.

82. The method according to any one of claims 77 to 81, wherein at least two of the two or more spots have the same thickness.

83. The method according to any one of claims 77 to 81, wherein at least two of the two or more spots have different thicknesses.

84. The method according to claim 83, wherein the difference in thickness between the two spots is approximately 10% or more.

85. In a method for manufacturing an analyte containing a therapeutic agent, a) A step of forming a pattern of multiple first conductive layers on a substrate to generate multiple working electrodes, b) A step of forming a pattern of a plurality of second conductive layers on the substrate to generate a plurality of pairs and / or reference electrodes, c) A step of forming one or more spots of a therapeutic agent-containing polymer composition comprising a polymer and a therapeutic agent on each of the plurality of pairs and / or reference electrodes and / or reference electrodes, and d) A step of separating individual analyte sensors from the substrate, wherein each individual analyte sensor includes at least one working electrode and at least one pair and / or reference electrode. A method that includes this.

86. The method according to claim 85, wherein one or more of the spots are circular, elliptical, regular polygonal, or irregular polygonal.

87. The method according to claim 85 or 86, wherein two or more spots are formed on the pair and / or reference electrodes, and at least two of the two or more spots contain the same amount of the therapeutic agent.

88. The method according to claim 85 or 86, wherein two or more spots are formed on the pair and / or reference electrodes, and at least two of the two or more spots contain different amounts of the therapeutic agent.

89. The method according to claim 88, wherein the difference in the amount of the therapeutic agent between the two or more spots is about 10% or more.

90. The method according to any one of claims 85 to 89, wherein two or more spots are formed on the pair and / or reference electrodes, and at least two of the two or more spots have the same thickness.

91. The method according to any one of claims 85 to 89, wherein two or more spots are formed on the pair and / or reference electrodes, and at least two of the two or more spots have different thicknesses.

92. The method according to claim 91, wherein the difference in thickness between two or more individual regions is approximately 10% or more.

93. The method according to any one of claims 74 to 92, wherein the step of forming one or more spots of the therapeutic agent-containing polymer composition on each of the plurality of pairs and / or reference electrodes includes the step of distributing two or more layers of a polymer solution containing the therapeutic agent.

94. The method according to claim 93, wherein at least one of the two or more spots of the therapeutic agent-containing polymer composition is formed by distributing two layers of the polymer composition, and a second spot of the two or more spots of the therapeutic agent-containing polymer composition is formed by distributing three layers of the polymer solution.

95. The method according to any one of claims 74 to 94, wherein the therapeutic agent is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof.

96. The method according to claim 95, wherein the therapeutic agent is an anti-inflammatory agent.

97. The method according to claim 96, wherein the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, derivatives thereof, salt forms thereof, and combinations thereof.

98. The method according to any one of claims 95 to 97, wherein the anti-inflammatory agent is dexamethasone, a derivative thereof, or a salt thereof.

99. The method according to any one of claims 74 to 84 and 93 to 98, wherein the second polymer solution or the polymer solution comprises the polymer, the therapeutic agent, and the solvent.

100. The method according to claim 99, wherein the solvent comprises an alcohol, a buffer, or a combination thereof.

101. The method according to claim 100, wherein the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 2,2-dimethyl-1-propanol, 1-butanol, 2-butanol, isobutanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2-methyl-1-pentanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, triphenylmethanol, and combinations thereof.

102. The method according to any one of claims 74 to 84 and 93 to 101, wherein the second polymer solution or the polymer solution further comprises a crosslinking agent.

103. The method according to any one of claims 74 to 84 and 93 to 102, wherein the therapeutic agent is present in the second polymer solution or in the polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass, based on the total mass of the polymer solution.

104. The method according to any one of claims 74 to 84 and 93 to 103, wherein the polymer is present in the second polymer solution or in the polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass based on the total mass of the polymer solution.

105. The method according to any one of claims 74 to 84 and 93 to 104, wherein the crosslinking agent is present in the second polymer solution or in the polymer solution in an amount ranging from about 0.01% by mass to about 50% by mass based on the total mass of the polymer solution.

106. The method according to any one of claims 74 to 84 and 93 to 105, wherein the second polymer solution or the polymer solution has a viscosity of about 20 centipoise to about 250 centipoise.

107. The method according to any one of claims 74 to 84 and 93 to 106, wherein the second polymer solution or the polymer solution has a viscosity of about 20 centipoise to about 80 centipoise.

108. The method according to any one of claims 74 to 84 and 93 to 107, wherein the second polymer solution or the polymer in the polymer solution is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyether urethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof.

109. The method according to claim 108, wherein the polyvinylpyridine polymer is a polyvinylpyridine copolymer.

110. The method according to claim 109, wherein the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer.

111. The method according to any one of claims 85 to 110, further comprising the step of forming an active region in each of the plurality of working electrodes.

112. The method according to any one of claims 74 to 83 and 111, wherein the active area includes a plurality of detection regions.

113. The method according to claim 112, wherein at least one of the plurality of detection areas is a detection spot.

114. The method according to any one of claims 93 to 113, further comprising the step of forming a film that covers at least a portion of the therapeutic agent-containing polymer composition of each individual analyte sensor.

115. The method according to claim 114, wherein the film is made from a polymer selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane polymers, polyetherurethane polymers, silicone polymers, copolymers thereof, derivatives thereof, and combinations thereof.

116. It is an analyte sensor, Sensor tail section including non-detection area and activity detection area including multiple detection spots, Equipped with, The non-detection region is located around the activity detection region and constitutes a drug loading structure filled with a therapeutic agent-containing polymer composition, comprising an analyte sensor.

117. The analyte sensor according to claim 116, wherein the drug loading structure includes at least one selected from slots, holes, pores, grooves, and recesses.

118. The analyte sensor according to claim 117, wherein the drug loading structure includes two slots symmetrically arranged along the plurality of detection spots.

119. The analyte sensor according to claim 117, wherein the drug loading structure includes a plurality of holes symmetrically arranged around the plurality of detection spots.

120. The analyte sensor according to claim 117, wherein the slot is elliptical, polygonal, or irregularly shaped.

121. The analyte sensor according to claim 117, wherein the hole is circular, regular polygonal, or irregular polygonal.

122. The analyte sensor according to claim 116, wherein the therapeutic agent-containing polymer composition comprises a polymer matrix and a therapeutic agent.

123. The analyte sensor according to claim 122, wherein the polymer matrix is ​​made from a copolymer selected from the group consisting of polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyetherurethane copolymers, silicone copolymers, derivatives thereof, and combinations thereof.

124. The analyte sensor according to claim 123, wherein the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer or a derivative thereof.

125. The analyte sensor according to claim 124, wherein the polyvinylpyridine / polystyrene copolymer may contain 1 to 50 monomer% styrene units.

126. The analyte sensor according to claim 122, wherein the therapeutic agent is at least one selected from the group consisting of anti-inflammatory agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, antibiotics, antiviral agents, and combinations thereof.

127. The analyte sensor according to claim 126, wherein the therapeutic agent is an anti-inflammatory agent.

128. The analyte sensor according to claim 127, wherein the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, derivatives thereof, salt forms thereof, and combinations thereof.

129. The analyte sensor according to claim 128, wherein the anti-inflammatory agent is dexamethasone, a derivative thereof, or a salt thereof.

130. The analyte sensor according to claim 122, wherein the therapeutic agent is in the range of 0.01% by mass to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition.

131. The analyte sensor according to claim 116, wherein the analyte sensor is a subcutaneous sensor.

132. The analyte sensor according to claim 131, wherein the analyte sensor is configured to detect glucose.

133. (i) A step of providing a sensor tail including a non-detection area and an activity detection area including multiple detection spots, (ii) A step of cutting off at least a portion of the non-detection area of ​​the sensor tail to form a drug loading structure, and (iii) A step of loading the drug loading structure with a polymer composition containing a therapeutic agent, A method for preparing an analyte sensor, including [the specified element].

134. The method according to claim 133, wherein the drug loading structure includes at least one selected from slots, holes, pores, grooves, and recesses.

135. The method according to claim 134, wherein the drug loading structure includes two slots symmetrically arranged along the plurality of detection spots.

136. The method according to claim 134, wherein the drug loading structure includes a plurality of holes symmetrically arranged around the plurality of detection spots.

137. The method according to claim 134, wherein the slot is elliptical, polygonal, or irregularly shaped.

138. The method according to claim 134, wherein the hole is circular, regular polygonal, or irregular polygonal.

139. The method according to claim 133, wherein the therapeutic agent-containing polymer composition comprises a polymer matrix and a therapeutic agent.

140. The method according to claim 139, wherein the polymer matrix is ​​made from a copolymer selected from the group consisting of polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyetherurethane copolymers, silicone copolymers, derivatives thereof, and combinations thereof.

141. The method according to claim 140, wherein the polyvinylpyridine copolymer is a polyvinylpyridine / polystyrene copolymer or a derivative thereof.

142. The method according to claim 141, wherein the polyvinylpyridine / polystyrene copolymer may contain 1 to 50 monomer% of styrene units.

143. The method according to claim 139, wherein the therapeutic agent is at least one selected from the group consisting of anti-inflammatory agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, antibiotics, antiviral agents, and combinations thereof.

144. The method according to claim 143, wherein the therapeutic agent is an anti-inflammatory agent.

145. The method according to claim 144, wherein the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, derivatives thereof, salt forms thereof, and combinations thereof.

146. The method according to claim 145, wherein the anti-inflammatory agent is dexamethasone, a derivative thereof, or a salt thereof.

147. The method according to claim 139, wherein the therapeutic agent is in the range of 0.01% by mass to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition.

148. In the charging device, a) An insertion tip configured to penetrate the skin and coated with a therapeutic agent-containing polymer composition containing a therapeutic agent and a polymer, and b) Analytical sensor, i. Working electrode and, ii. An active region located on the working electrode, iii. A film that coats at least the active area, Analytical sensor including Equipped with a charging device.

149. The insertion device according to claim 148, wherein the insertion tip is retractable.

150. The insertion device according to claim 148 or 149, wherein the therapeutic agent-containing polymer composition for coating the insertion tip is detachably attached to the insertion tip.

151. The insertion device according to claim 148 or 149, wherein the therapeutic agent-containing polymer composition is designed to remain in the subject's tissue when the insertion tip is retracted.

152. The charging device according to any one of claims 148 to 151, wherein the therapeutic agent-containing polymer composition is made to release the therapeutic agent into the area surrounding the insertion site of the analyte sensor.

153. The charging device according to any one of claims 148 to 152, wherein the therapeutic agent is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, antiglycolytic agents, and combinations thereof.

154. The charging device according to any one of claims 148 to 153, wherein the therapeutic agent is an anti-inflammatory agent.

155. The charging device according to claim 154, wherein the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, and combinations thereof.

156. The charging device according to claim 154 or 155, wherein the anti-inflammatory agent is dexamethasone.

157. The charging device according to any one of claims 148 to 156, wherein the polymer in the therapeutic agent-containing polymer composition is a bioabsorbable polymer.

158. The charging device according to any one of claims 148 to 156, wherein the polymer is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane copolymers, polyether urethane polymers, silicone polymers, polycaprolactone polymers, polylactide polymers, polyglycolide polymers, polyethylene glycol polymers, derivatives thereof, and combinations thereof.

159. The charging device according to any one of claims 148 to 158, wherein the therapeutic agent is covalently bonded to the polymer.

160. The charging device according to any one of claims 148 to 158, wherein the therapeutic agent is not bound to the polymer.

161. The charging device according to any one of claims 148 to 160, wherein the aforementioned membrane is composed of poly(4-vinylpyridine).

162. The charging apparatus according to any one of claims 148 to 161, wherein the active region comprises one or more enzymes configured to detect an analyte.

163. The charging device according to claim 162, wherein the analyte is selected from the group consisting of glutamic acid, glucose, ketone, lactic acid, oxygen, glycated hemoglobin (HbA1c), albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartic acid, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, and combinations thereof.

164. The charging device according to any one of claims 148 to 163, wherein the active region further comprises an electron transfer agent.

165. The charging apparatus according to claim 164, wherein the electron transfer agent comprises a transition metal complex.

166. The charging apparatus according to any one of claims 148 to 165, wherein the analyte sensor further comprises albumin and, optionally, a pH buffer.

167. The loading apparatus according to any one of claims 148 to 166, wherein the analyzer sensor further comprises a reference electrode, a counter electrode, or both a reference electrode and a counter electrode.

168. The charging device according to any one of claims 148 to 167, wherein the analyte sensor further includes a second active area that reacts with a second analyte.

169. The charging apparatus according to claim 168, wherein the second analyte is glucose, lactic acid, or ketone.

170. The charging device according to any one of claims 148 to 169, wherein the therapeutic agent-containing polymer composition is configured to release the therapeutic agent at a predetermined release rate.

171. The charging device according to any one of claims 148 to 170, wherein the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug delivery rate of about 0.01 μg / day to about 1 mg / day.

172. The charging device according to any one of claims 148 to 171, wherein the therapeutic agent is in the range of 0.01% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition, and / or the therapeutic agent-containing polymer composition contains about 0.01 μg to about 100 μg of the therapeutic agent.

173. The charging device according to any one of claims 148 to 172, wherein the therapeutic agent-containing polymer composition further comprises a crosslinking agent.

174. In a method for suppressing the immune response at the insertion site of a sharp instrument, a) A step of introducing an analyte sensor, comprising a therapeutic agent-containing polymer composition containing an effective amount of therapeutic agent and polymer suitable for suppressing the immune response at the insertion site, into the tissue at the insertion site using a sharp instrument, wherein the therapeutic agent-containing polymer composition covers the insertion tip, and b) A step of maintaining the therapeutic agent-containing polymer composition within the tissue after storing the sharp instrument, A method that includes this.

175. The method according to claim 174, wherein the therapeutic agent-containing polymer composition for coating the insertion tip of the sharp instrument is detachably attached to the insertion tip.

176. The method according to claim 174 or 175, wherein the therapeutic agent is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, antiglycolytic agents, and combinations thereof.

177. The method according to any one of claims 174 to 176, wherein the therapeutic agent is an anti-inflammatory agent.

178. The method according to claim 177, wherein the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, and combinations thereof.

179. The method according to claim 177 or 178, wherein the anti-inflammatory agent is dexamethasone.

180. The method according to any one of claims 174 to 179, wherein the polymer in the therapeutic agent-containing polymer composition is a bioabsorbable polymer.

181. The method according to claim 180, wherein the polymer is selected from the group consisting of polyvinylpyridine polymers, polyvinylimidazole polymers, polyacrylate polymers, polyurethane copolymers, polyether urethane polymers, silicone polymers, polycaprolactone polymers, polylactide polymers, polyglycolide polymers, polyethylene glycol polymers, derivatives thereof, and combinations thereof.

182. The method according to any one of claims 174 to 181, wherein the therapeutic agent is covalently bonded to the polymer composition.

183. The method according to any one of claims 174 to 181, wherein the therapeutic agent is not bonded to the polymer composition.

184. The method according to any one of claims 174 to 183, wherein the therapeutic agent-containing polymer composition is configured to release the therapeutic agent at a predetermined release rate.

185. The method according to any one of claims 174 to 184, wherein the analyte sensor comprises a working electrode, an active area disposed on the working electrode, and a film coating at least the active area, and the analyte sensor is separated from the therapeutic agent.

186. The method according to claim 185, wherein the film is composed of poly(4-vinylpyridine).

187. The method according to claim 185 or 186, wherein the active region comprises one or more enzymes configured to detect an analyte.

188. The method according to claim 187, wherein the analyte is selected from the group consisting of glutamic acid, glucose, ketone, lactic acid, oxygen, glycated hemoglobin (HbA1c), albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartic acid, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, and combinations thereof.

189. The method according to claim 187 or 188, wherein the analyte is glucose, lactic acid, or a ketone.

190. The method according to any one of claims 185 to 189, wherein the active region further comprises an electron transfer agent.

191. The method according to claim 190, wherein the electron transfer agent comprises a transition metal complex.

192. The method according to any one of claims 185 to 191, wherein the active region further comprises albumin and, optionally, a pH buffer.

193. The method according to any one of claims 174 to 192, wherein the analyte sensor further comprises a reference electrode, a counter electrode, or both a reference electrode and a counter electrode.

194. The method according to any one of claims 174 to 193, wherein the therapeutic agent-containing polymer composition is configured to release the active therapeutic agent into the area surrounding the insertion site of the sensor.

195. The method according to any one of claims 174 to 194, wherein the therapeutic agent-containing polymer composition can continuously release the therapeutic agent at a drug delivery rate of about 0.01 μg / day to about 1 mg / day.

196. The method according to any one of claims 174 to 195, wherein the therapeutic agent is in the range of 0.01% to 50% by mass based on the total mass of the therapeutic agent-containing polymer composition, and / or the therapeutic agent-containing polymer composition comprises about 0.01 μg to about 100 μg of the therapeutic agent.

197. The method according to any one of claims 174 to 196, wherein the therapeutic agent-containing polymer composition further comprises a crosslinking agent.

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