Drug delivery compositions and methods for controlling drug delivery rates in subcutaneous sensors

Abstract

The present disclosure provides a drug delivery composition and a method for controlling the drug delivery rate of an analyte sensor. The drug delivery composition includes a copolymer including a plurality of copolymer chains, each of the plurality of copolymer chains including a backbone including a plurality of hydrophilic units and a plurality of hydrophobic units, a crosslinker, and a therapeutic agent, wherein the crosslinker crosslinks at least a portion of the hydrophilic units of each copolymer chain to form charges, and the hydrophobic units of the copolymer interact with the therapeutic agent through nonpolar intermolecular interactions. The drug delivery composition continuously releases the therapeutic agent at a set or predetermined drug delivery rate for a set or predetermined time.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Application No. 63 / 477,977, filed December 30, 2022, the entire contents of which are incorporated herein by reference in their entirety. The present disclosure relates to drug delivery compositions and methods for controlling drug delivery rates. For example, the present disclosure relates to analyte sensors comprising the drug delivery compositions and methods for controlling drug delivery rates for analyte sensors, e.g., subcutaneous sensors. The present disclosure further provides analyte sensors comprising such drug delivery compositions to reduce sensor signal inaccuracies or in vivo sensor failure, e.g., due to foreign body reaction (FBR). [Background technology]

[0002] Detection of one or more suitable analytes in an individual can sometimes be important for monitoring the health status of an individual, as deviations from normal analyte levels can be indicative of a physiological condition. For example, monitoring glucose levels can enable people with diabetes to take appropriate or suitable corrective measures, including administering medication or consuming certain food or beverage products to avoid significant physiological damage. Other analytes may be desirable for monitoring other physiological conditions. In certain cases, it may be desirable to monitor more than one analyte to monitor multiple physiological conditions, especially when a person suffers from coexisting conditions that result in simultaneous dysregulation of two or more analytes that are interrelated.

[0003] Analyte monitoring in an individual can be performed periodically or continuously over a period of time. Periodic analyte monitoring can be performed by withdrawing samples of bodily fluids, such as blood or urine, at set intervals and analyzing them ex vivo. Periodic ex vivo analyte monitoring can be sufficient for determining the physiological status of many individuals. However, ex vivo analyte monitoring can be inconvenient or painful in some cases. Furthermore, if analyte measurements are not obtained at the appropriate or convenient time, there is no way to recover the lost data. Continuous analyte monitoring can be performed using one or more sensors that remain at least partially implanted in the individual's tissue, for example, transdermally, subcutaneously, or intravenously, thereby allowing analysis to be performed in vivo. The implanted sensors can collect analyte data as needed, on a set schedule, or continuously, depending on the individual's particular health needs and / or previously measured analyte levels. Analyte monitoring with in vivo implanted sensors may be a more desirable approach for individuals with severe analyte dysregulation and / or rapidly fluctuating analyte levels, but it may also be beneficial for other individuals.

[0004] However, implantable sensors can suffer from a short lifespan when implanted in vivo. For example, the in vivo loss of sensor function observed in implantable sensors is believed to be primarily the result of certain responses, including immune responses, inflammation, fibrosis, and vascular degeneration, occurring in the tissue surrounding the implanted sensor (e.g., surrounding the sensor). These tissue responses may result from tissue damage caused by the insertion of the sensor into the skin and may result from the tissue reacting to the sensor as a foreign body. While the tissue responses at the sensor implant site are histopathologically similar to other forms of tissue inflammation, the ability to utilize anti-inflammatory agents (e.g., glucocorticoids and nonsteroidal anti-inflammatory agents) and / or other therapeutic agents to directly inhibit or reduce sensor-induced tissue damage, e.g., inhibit sensor-induced tissue damage and other physiological responses during the lifespan of the implanted sensor, has been limited. Thus, there is a need in the art to develop drug delivery compositions containing anti-inflammatory agents and / or other therapeutic agents, and methods for delivering such therapeutic compositions to the vicinity of an analyte sensor at desired or suitable delivery rates over a period of time. Summary of the Invention

[0005] The objects and aspects of the disclosed subject matter will be set forth in and obvious from the description which follows, and will be learned by the practice of the disclosed subject matter. Additional aspects of the disclosed subject matter will be realized and attained by the compositions, devices, and methods particularly pointed out in the written description and claims thereof, as well as the appended drawings. One or more aspects of the present disclosure are directed to a drug delivery composition. In certain embodiments, the drug delivery composition may include: (i) a copolymer comprising a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units, (ii) a crosslinking agent that crosslinks at least a portion of the hydrophilic units between each of the copolymer chains, and (iii) a therapeutic agent.

[0006] In certain embodiments, the hydrophilic units of the copolymer may include nitrogen-containing heterocyclic units such as pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, pyrazole units, etc. In certain embodiments, the hydrophobic units of the copolymer may include non-heteroatom-containing aromatic units (e.g., benzene (phenyl) units, naphthalene units, anthracene units, etc.), acyclic aliphatic units (e.g., linear or branched alkyl units, linear or branched alkenyl units, linear or branched alkynyl units, etc.), and / or cyclic aliphatic units (e.g., cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl units, etc.). In certain embodiments, the copolymer can be selected from the group consisting of polyvinylpyridine-based copolymers, polyvinylimidazole-based copolymers, polyacrylate-based copolymers, polyurethane-based copolymers, polyetherurethane-based copolymers, silicone-based copolymers, derivatives thereof, and combinations thereof. In certain embodiments, the copolymer may comprise a block polymer. In certain embodiments, the copolymer is a polyvinylpyridine-based copolymer. In certain embodiments, the polyvinylpyridine-based copolymer may be a copolymer of vinylpyridine and styrene or a derivative thereof.

[0007] In certain embodiments, the polyvinylpyridine-based copolymer can be a polyvinylpyridine-co-polystyrene polymer. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 30 mer% styrene units. In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD to 1,000 kD.

[0008] In certain embodiments, the crosslinker may be a diglycidyl- or triglycidyl-functional epoxy. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG(200-1000), glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG 200, diglycidyl-PEG 400, glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be diglycidyl-PEG 200. In certain embodiments, the cross-linking agent can be diglycidyl-PEG 400. In certain embodiments, the cross-linking agent can be glycerol triglycidyl ether.

[0009] In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 10 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 10 mol%. In certain embodiments, the therapeutic agent may include at least one selected from the group consisting of an antibiotic, an antiviral, an anti-inflammatory, an anti-cancer agent, an antiplatelet agent, an anticoagulant, a coagulant, an antiglycolytic agent, and combinations thereof.

[0010] In certain embodiments, the therapeutic agent may be an anti-inflammatory agent. 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 derivatives or salt forms thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt form thereof. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone acetate. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone sodium phosphate.

[0011] In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 50% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 200 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 10 μg of a therapeutic agent. In certain embodiments, the crosslinker binds to the hydrophilic units of the copolymer to form a charge. In certain embodiments, the therapeutic agent is not covalently attached to the copolymer. In certain embodiments, the therapeutic agent is covalently attached to the copolymer. In certain embodiments, the drug delivery composition can continuously release the therapeutic agent at a set or predetermined drug delivery rate for a set or predetermined number of days, such as at least 30 days.

[0012] One or more aspects of the present disclosure are directed to an analyte sensor. In certain embodiments, the analyte sensor may include: (i) a sensor tail including at least a first working electrode; (ii) an active area disposed on the surface of the first working electrode for detecting an analyte; (iii) a mass transport limiting membrane overcoating at least the active area and permeable to the analyte; (iv) a counter / reference electrode; and (v) a drug delivery composition including: (a) a copolymer including a plurality of copolymer chains, each of the plurality of copolymer chains including a backbone including a plurality of hydrophilic units and a plurality of hydrophobic units; (b) a crosslinker crosslinking at least a portion of the hydrophilic units between each of the copolymer chains; and (c) a therapeutic agent.

[0013] In certain embodiments, the analyte is glucose. In certain embodiments, the analyte sensor is a transcutaneous sensor. In certain embodiments, the analyte sensor is a subcutaneous sensor, such as a subcutaneously implantable sensor. In certain embodiments, the analyte sensor is an intravenous sensor, such as an intravenously implantable sensor. In certain embodiments, the hydrophilic units of the copolymer of the drug delivery composition present on the analyte sensor can include pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, pyrazole units, or other nitrogen-containing heterocyclic units. In certain embodiments, the hydrophilic units of the copolymer of the drug delivery composition present on the analyte sensor can include pyridine units.

[0014] In certain embodiments, the hydrophobic units of the copolymer of the drug delivery composition present on the analyte sensor can include non-heteroatom-containing aromatic units, such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units, such as linear or branched alkyl units, linear or branched alkenyl units, linear or branched alkynyl units, etc., and / or cyclic aliphatic units, such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl units, etc. In certain embodiments, the hydrophobic units of the copolymer of the drug delivery composition present on the analyte sensor can include non-heteroatom-containing aromatic units. In certain embodiments, the copolymer can be selected from the group consisting of polyvinylpyridine-based copolymers, polyvinylimidazole-based copolymers, polyacrylate-based copolymers, polyurethane-based copolymers, polyetherurethane-based copolymers, silicone-based copolymers, derivatives thereof, and combinations thereof. In certain embodiments, the copolymer may comprise a block polymer. In certain embodiments, the copolymer may be a polyvinylpyridine-based copolymer. In certain embodiments, the polyvinylpyridine-based copolymer may be a copolymer of vinylpyridine and styrene or derivatives thereof.

[0015] In certain embodiments, the polyvinylpyridine-based copolymer can be a polyvinylpyridine-co-polystyrene polymer. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 30 mer% styrene units. In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD to 1,000 kD.

[0016] In certain embodiments, the crosslinker may be a diglycidyl- or triglycidyl-functional epoxy. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG(200-1000), glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG 200, diglycidyl-PEG 400, glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be diglycidyl-PEG 200. In certain embodiments, the cross-linking agent can be diglycidyl-PEG 400. In certain embodiments, the cross-linking agent can be glycerol triglycidyl ether.

[0017] In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 10 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 10 mol%.

[0018] In certain embodiments, the therapeutic agent present in the drug delivery composition on the analyte sensor may include at least one selected from the group consisting of antibiotics, antivirals, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, clotting agents, antiglycolytic agents, and combinations thereof. In certain embodiments, the therapeutic agent may be an anti-inflammatory agent. 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 derivatives or salt forms thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt form thereof. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone acetate. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone sodium phosphate. In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 50% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 40% by weight based on the total weight of the copolymer.

[0019] In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 200 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 10 μg of a therapeutic agent. In certain embodiments, the crosslinker binds to the hydrophilic units of the copolymer to form a charge. In certain embodiments, the drug delivery composition can be disposed over an electrode of an analyte sensor. In certain embodiments, the drug delivery composition can be disposed over a working electrode of an analyte sensor. In certain embodiments, the drug delivery composition can be disposed over a counter / reference electrode of an analyte sensor. In certain embodiments, the drug delivery composition can be disposed over a counter electrode of an analyte sensor. In certain embodiments, the drug delivery composition can be disposed over a reference electrode of an analyte sensor.

[0020] In certain embodiments, the drug delivery composition can be disposed over a mass transport limiting membrane of an analyte sensor. In certain embodiments, the therapeutic agent is not covalently attached to the copolymer. In certain embodiments, the therapeutic agent is covalently attached to the copolymer. In certain embodiments, the drug delivery composition can continuously release the therapeutic agent at a set or predetermined drug delivery rate for a set or predetermined number of days, such as at least 30 days.

[0021] One or more aspects of the presently disclosed embodiments are directed to a method for controlling the drug delivery rate of an analyte sensor, e.g., a subcutaneous sensor, comprising a drug delivery composition. In certain embodiments, the present disclosure provides a method for delivering an analyte sensor of the present disclosure. In certain embodiments, the method may include the steps of preparing an analyte sensor disclosed herein, e.g., an analyte sensor comprising a drug delivery composition, and subcutaneously implanting the analyte sensor. Alternatively, or in addition, the drug delivery composition may be inserted into the subject's tissue proximate to the analyte sensor. In certain embodiments, a method for controlling a drug delivery rate of an analyte sensor and / or a method for delivering an analyte sensor, such as a subcutaneous sensor, may include the steps of (i) preparing a needle containing an analyte sensor and a drug delivery composition comprising (a) a copolymer including a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone including a plurality of hydrophilic units and a plurality of hydrophobic units, (b) a crosslinking agent that crosslinks at least a portion of the hydrophilic units between each of the copolymer chains, and (c) a therapeutic agent, (ii) penetrating a tissue of a subject with the needle, (iii) inserting the drug delivery compound and the analyte sensor into the tissue of the subject, and (iv) withdrawing the needle from the tissue of the subject. In certain embodiments, the analyte sensor is disposed within a channel of the needle, and the drug delivery composition is disposed within the channel of the needle distal to the analyte sensor.

[0022] In certain embodiments, a method for controlling a drug delivery rate of an analyte sensor and / or a method for delivering an analyte sensor, such as a subcutaneous sensor, may include the steps of: (i) preparing a needle-shaped object including an analyte sensor comprising a drug delivery composition including (a) a copolymer comprising a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units, (b) a crosslinking agent that crosslinks at least a portion of the hydrophilic units between each of the copolymer chains, and (c) a therapeutic agent; (ii) penetrating the needle-shaped object into tissue of a subject; (iii) inserting the analyte sensor into the tissue of a subject; and (iv) withdrawing the needle-shaped object from the tissue of a subject. In certain embodiments, the needle-shaped object may further include a second drug delivery composition, e.g., a second drug delivery composition disposed in a channel of the needle distal to the analyte sensor.

[0023] One or more aspects of the presently disclosed embodiments are directed to a needle, e.g., a preloaded needle, for delivering a drug delivery composition. In certain embodiments, the needle can include a drug delivery composition disclosed herein. In certain embodiments, the needle can include an analyte sensor and a drug delivery composition disclosed herein. For example, but not by way of limitation, the drug delivery composition can include (i) a copolymer including a plurality of copolymer chains, each of the plurality of copolymer chains including a backbone including a plurality of hydrophilic units and a plurality of hydrophobic units, (ii) a crosslinker that crosslinks at least a portion of the hydrophilic units between each of the copolymer chains, and (iii) a therapeutic agent. In certain embodiments, the analyte sensor is disposed within a channel of the needle, and the drug delivery composition is disposed within the channel of the needle distal to the analyte sensor.

[0024] In certain embodiments, the needle-shaped object can include an analyte sensor comprising a drug delivery composition disclosed herein. For example, but not by way of limitation, the drug delivery composition can include (i) a copolymer comprising a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units, (ii) a cross-linking agent that cross-links at least a portion of the hydrophilic units between each of the copolymer chains, and (iii) a therapeutic agent. In certain embodiments, the needle-shaped object can further include a second drug delivery composition, e.g., a second drug delivery composition disposed in the channel of the needle distal to the analyte sensor. In certain embodiments, the hydrophilic units of the copolymer can include nitrogen-containing heterocyclic units such as pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, pyrazole units, etc. In certain embodiments, the hydrophilic units of the copolymer can include pyridine units. In certain embodiments, the hydrophobic units of the copolymer can include non-heteroatom-containing aromatic units such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units such as linear or branched alkyl units, linear or branched alkenyl units, linear or branched alkynyl units, etc., and / or cyclic aliphatic units such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl units, etc. In certain embodiments, the hydrophobic units of the copolymer can include aromatic units.

[0025] In certain embodiments, the copolymer can be selected from the group consisting of polyvinylpyridine-based copolymers, polyvinylimidazole-based copolymers, polyacrylate-based copolymers, polyurethane-based copolymers, polyetherurethane-based copolymers, silicone-based copolymers, derivatives thereof, and combinations thereof. In certain embodiments, the copolymer may comprise a block polymer. In certain embodiments, the copolymer is a polyvinylimidazole-based copolymer. In certain embodiments, the polyvinylimidazole-based copolymer may be a copolymer of vinylimidazole and styrene or a derivative thereof. In certain embodiments, the polyvinylimidazole-based copolymer can be a polyvinylimidazole-co-polystyrene polymer, hi certain embodiments, the polyvinylimidazole-co-polystyrene polymer can be a poly(N-vinylimidazole)-co-polystyrene polymer, a poly(1-vinylimidazole)-co-polystyrene polymer, or a derivative thereof.

[0026] In certain embodiments, the copolymer is a polyvinylpyridine-based copolymer. In certain embodiments, the polyvinylpyridine-based copolymer may be a copolymer of vinylpyridine and styrene or a derivative thereof. In certain embodiments, the polyvinylpyridine-based copolymer can be a polyvinylpyridine-co-polystyrene polymer, hi certain embodiments, the polyvinylpyridine-co-polystyrene polymer can be a poly(4-vinylpyridine)-co-polystyrene polymer, a poly(2-vinylpyridine)-co-polystyrene polymer, or a derivative thereof. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 30 mer% styrene units. In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD to 1,000 kD.

[0027] In certain embodiments, the crosslinker may be a diglycidyl- or triglycidyl-functional epoxy. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG(200-1000), glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG 200, diglycidyl-PEG 400, glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be diglycidyl-PEG 200. In certain embodiments, the cross-linking agent can be diglycidyl-PEG 400. In certain embodiments, the cross-linking agent can be glycerol triglycidyl ether.

[0028] In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 10 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 10 mol%. In certain embodiments, the therapeutic agent may include at least one selected from the group consisting of an antibiotic, an antiviral, an anti-inflammatory, an anti-cancer agent, an antiplatelet agent, an anticoagulant, a coagulant, an antiglycolytic agent, and combinations thereof.

[0029] In certain embodiments, the therapeutic agent may be an anti-inflammatory agent. 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 derivatives or salts thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt thereof. In certain embodiments, the dexamethasone derivative is dexamethasone acetate. In certain embodiments, the dexamethasone derivative is dexamethasone sodium phosphate.

[0030] In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 50% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 200 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 10 μg of a therapeutic agent. In certain embodiments, the crosslinker binds to the hydrophilic units of the copolymer to form a charge. In certain embodiments, the therapeutic agent is not covalently attached to the copolymer. In certain embodiments, the therapeutic agent is covalently attached to the copolymer.

[0031] In certain embodiments, the drug delivery composition continuously releases the therapeutic agent at a set or predetermined drug delivery rate for a set or predetermined number of days, such as at least 30 days. In certain embodiments, the analyte sensor is configured to detect glucose. One or more aspects of the present disclosure are directed to a method for producing a drug delivery composition. In certain embodiments, the method may include the steps of: (a) providing a copolymer comprising a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units; (b) applying a crosslinker and a therapeutic agent to the copolymer; and (c) crosslinking at least a portion of the hydrophilic units between each of the copolymer chains with the crosslinker. The present disclosure further provides an analyte sensor as described herein for controlling a drug delivery rate of the analyte sensor, wherein the analyte sensor is implanted subcutaneously. In certain embodiments, the drug delivery composition of the present disclosure can be used to control the drug delivery rate of an analyte sensor, and the drug delivery composition and the analyte sensor are inserted into the tissue of a subject. In certain embodiments, the drug delivery composition and the analyte sensor are inserted into the tissue of a subject using a needle containing the drug delivery composition and the analyte sensor. In certain embodiments, the analyte sensor is disposed within a channel of the needle, and the drug delivery composition is disposed within the channel of the needle distal to the analyte sensor.

[0032] Additional aspects and embodiments will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the embodiments. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of the color drawing(s) of this patent or patent application publication will be provided by the Office upon request and payment of the necessary fee.

[0033] The following drawings are included to illustrate certain aspects of the present disclosure and should not be considered exclusive embodiments. The disclosed subject matter is capable of considerable modification, alteration, combination, and equivalents in form and function without departing from the scope of the present disclosure. [Brief explanation of the drawings]

[0034] [Figure 1] Exemplary drug delivery compositions according to certain embodiments of the present disclosure are described. [Figures 2A-2C] 1 provides a perspective view of an exemplary analyte sensor including two active areas on separate working electrodes. [Figure 3] 1 illustrates a cross-sectional view of an exemplary analyte sensor according to certain embodiments of the present disclosure. [Figure 4] 1 illustrates a cross-sectional view of an exemplary needle according to certain embodiments of the present disclosure. [Figure 5] 1 illustrates an exemplary test strip of a drug delivery composition on a biocompatible strip according to certain embodiments of the present disclosure. [Figure 6] 1 illustrates an exemplary sensor tail comprising a drug delivery composition according to certain embodiments of the present disclosure. [Figures 7A-7B] 1 illustrates an exemplary test sample of a drug delivery composition according to certain embodiments of the present disclosure. [Figure 8] An exemplary testing procedure for drug delivery compositions according to certain embodiments of the present disclosure is described. [Figure 9] HPLC of dexamethasone according to certain embodiments of the present disclosure is described. [Figure 10] 1 illustrates a calibration curve for dexamethasone according to certain embodiments of the present disclosure. [Figure 11] 1 illustrates the drug delivery profile of an exemplary drug delivery composition comprising 100% polyvinylpyridine, glycerol triglycidyl ether (Gly3), and dexamethasone, according to certain embodiments of the present disclosure. [Figure 12] 1 illustrates the drug delivery profile of an exemplary drug delivery composition comprising 100% polyvinylpyridine, diglycidyl-PEG 400 (PEG400), and dexamethasone, according to certain embodiments of the present disclosure. [Figure 13] Exemplary tested polymers and copolymers of drug delivery compositions according to certain embodiments of the present disclosure are described. [Figure 14] Exemplary crosslinkers for drug delivery compositions according to certain embodiments of the present disclosure are described. [Figure 15] Exemplary formulations of drug delivery compositions according to certain embodiments of the present disclosure are described. [Figure 16] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 17] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 18] Exemplary formulations of drug delivery compositions according to certain embodiments of the present disclosure are described. [Figure 19] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 20] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 21] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 22] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 23] 1 illustrates the concentration relationships between different cross-linking agents in exemplary drug delivery compositions according to certain embodiments of the present disclosure. [Figure 24] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 25] 10A-10C illustrate exemplary drug delivery composition formulations for analyte sensors according to certain embodiments of the present disclosure. [Figure 26] 1 illustrates a drug delivery profile of an exemplary drug delivery composition on an analyte sensor according to certain embodiments of the present disclosure. [Figure 27] 1 illustrates a per time point drug delivery profile of an exemplary drug delivery composition on an analyte sensor according to certain embodiments of the present disclosure. [Figure 28] 10A-10D illustrate factors influencing the drug delivery rate of exemplary drug delivery compositions according to certain embodiments of the present disclosure. [Figure 29] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 30] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 31] 1 illustrates a drug delivery profile for an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 32] 1 illustrates a drug delivery profile and per time point drug delivery profile of an exemplary drug delivery composition on an analyte sensor according to certain embodiments of the present disclosure. [Figure 33] 1 illustrates the solubility of Dex in a solution of polyvinylpyridine-ethanol:water (95:5 by volume) according to certain embodiments of the present disclosure. [Figure 34A] Exemplary formulations of drug delivery compositions according to certain embodiments of the present disclosure are described. [Figure 34B] Exemplary formulations of drug delivery compositions according to certain embodiments of the present disclosure are described. [Figure 35A] 1 illustrates a drug delivery profile and per time point drug delivery profile of an exemplary drug delivery composition on an analyte sensor according to certain embodiments of the present disclosure. [Figure 35B] 1 illustrates a drug delivery profile and per time point drug delivery profile of an exemplary drug delivery composition on an analyte sensor according to certain embodiments of the present disclosure. [Figure 35C] 1 illustrates exemplary drug delivery loads on analyte sensors and the effect of drug delivery loads on LSA according to certain embodiments of the present disclosure. [Figure 36] 1 is a flow chart illustrating a method of making an exemplary drug delivery composition according to certain embodiments of the present disclosure. [Figure 37]1 provides a diagram of an illustrative sensing system that can incorporate the analyte sensors of the present disclosure. [Figure 38A-38B] 1 provides a cross-sectional view of an exemplary analyte sensor including a single active area. [Figures 39A-39C] 1 provides a cross-sectional view of an exemplary analyte sensor including two active areas on separate working electrodes. [Figure 40] 1 provides a cross-sectional view of an exemplary analyte sensor including two active areas. DETAILED DESCRIPTION OF THE INVENTION

[0035] Detailed Description As described herein, the implantation of an analyte sensor can result in several physiological responses that can adversely affect the function of the sensor. For example, an inflammatory or immune response at the site of the analyte sensor and tissue damage induced by its implantation can result in loss of sensor functionality and sensitivity in vivo. To address the above needs, the present disclosure provides a drug delivery composition for treating tissue surrounding an implanted analyte sensor. For example, but not by way of limitation, the present disclosure provides an analyte sensor comprising a drug delivery composition including a therapeutic agent, such as a therapeutic agent described herein. In certain embodiments, the present disclosure provides a drug delivery composition that can be inserted near an analyte sensor implanted in a subject.

[0036] In certain embodiments, the drug delivery compositions of the present disclosure provide sustained release of a therapeutic agent over an extended period of time, e.g., 14 days or longer, e.g., about 30 days or longer. In certain embodiments, sustained release of a therapeutic agent, e.g., an anti-inflammatory agent, in the vicinity of the analyte sensor can result in prevention and / or reduction of inflammation or an immune response in the tissue surrounding the implantation site. For example, but not by way of limitation, prevention and / or reduction of inflammation in the tissue surrounding the implantation site can extend the life of the implanted analyte sensor. In certain embodiments, prevention and / or reduction of an immune response to the analyte sensor can extend the life of the implanted analyte sensor. In certain embodiments, extending the life of the implanted analyte sensor means maintaining the accuracy of the analyte sensor towards the end of the sensor's life and / or minimizing, reducing, and / or eliminating inaccuracies in the analyte signal towards the end of the sensor's life.

[0037] In certain embodiments, the lifespan of an analyte sensor disclosed herein can be extended to greater than about 2 days, greater than about 3 days, greater than about 4 days, greater than about 5 days, greater than about 6 days, greater than about 7 days, greater than about 8 days, greater than about 9 days, greater than about 10 days, greater than about 11 days, greater than about 12 days, greater than about 13 days, greater than about 14 days, greater than about 15 days, greater than about 16 days, greater than about 17 days, greater than about 18 days, greater than about 19 days, or greater than about 20 days. In certain embodiments, an analyte sensor comprising a drug delivery composition of the present disclosure can have a lifespan of about 14 days or more, about 15 days or more, about 16 days or more, about 17 days or more, about 18 days or more, about 19 days or more, about 20 days or more, about 21 days or more, about 22 days or more, about 23 days or more, about 24 days or more, about 25 days or more, about 26 days or more, about 27 days or more, about 28 days or more, about 29 days or more, or about 30 days or more. In certain embodiments, the lifespan of the analyte sensors disclosed herein can be extended to provide analyte sensors having a lifespan of about 30 days or greater.

[0038] Hereinafter, specific embodiments will be described in more detail so that those skilled in the art can easily implement the specific embodiments. For example, embodiments of the present disclosure will be described in more detail with reference to the drawings. However, the present disclosure may be embodied in many different forms and should not be construed as being limited to the example embodiments described herein. For clarity, but not by way of limitation, the detailed description of the presently disclosed subject matter is divided into the following subsections. I. Definition, II. Therapeutic Agents III. Drug delivery compositions, IV. Analyte Sensors; V. Delivery Devices and Methods, and VI. Illustrative Embodiments

[0039] I. Definition The terms used in this disclosure generally have their ordinary meanings in the art, within the context of this disclosure and within the specific context that each term is used in. Certain terms are discussed or found elsewhere herein to provide further guidance to those of skill in the art regarding the description of the compositions and methods of the present disclosure and how to make and use them. The terminology used in this specification is used only to describe the embodiments and is not intended to limit the present disclosure. Unless otherwise clearly indicated by the context, singular expressions include plural expressions. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. Furthermore, the use of "may," when describing embodiments of the present disclosure, means "one or more embodiments of the present disclosure."

[0040] The terms "comprise(s), "include(s), "having," "have / has," "contain(s)," and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not exclude additional actions or structures. The present disclosure also contemplates other embodiments that "comprise," "consist of," and "consist essentially of" the embodiments or elements presented herein, whether or not explicitly described. As used herein, "or" should not be construed as exclusive. For example, "A or B" is construed to include A, B, A+B, etc. Furthermore, as used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. Terms such as "at least one of," "one of," and "selected from," when preceding a list of elements, modify the list of elements as a whole, and not individual elements of the list.

[0041] The term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within or more than three times the standard deviation per practice in the art. In certain embodiments, "about" can mean within 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. In certain embodiments, particularly with respect to biological systems or processes, the term can mean within one order of magnitude, preferably within 5 times, and more preferably within 2 times of a value.

[0042] Any numerical range recited herein is intended to include subranges of the same numerical precision within the recited range. For example, a range described as "1.0 to 10.0" or "between 1.0 and 10.0" is intended to include all subranges between (and including) the recited minimum of 1.0 and the recited maximum of 10.0, i.e., having minimum values ​​equal to or greater than 1.0 and maximum values ​​equal to or less than 10.0, e.g., 2.4 to 7.6. Similarly, a range described as "within 35% of 10" is intended to include all subranges between (and including) the recited minimum of 6.5 (i.e., (1 - 35 / 100) x 10) and the recited maximum of 13.5 (i.e., (1 + 35 / 100) x 10), i.e., having minimum values ​​equal to or greater than 6.5 and maximum values ​​equal to or less than 13.5, e.g., 7.4 to 10.6. Every maximum numerical limit mentioned herein is intended to include every lower numerical limit subsumed therein, and every minimum numerical limit mentioned herein is intended to include every higher numerical limit subsumed therein. As used herein, "analyte sensor" or "sensor" may refer to any device capable of receiving sensory information from a user, including, by way of illustration and not limitation, a temperature sensor, a blood pressure sensor, a pulse or heart rate sensor, a glucose level sensor, an analyte sensor, a physical activity sensor, a body movement sensor, or any other sensor for gathering physical or biological information. Analytes measured by an analyte sensor may include, by way of example and not limitation, glutamate, glucose, ketone, lactate, oxygen, hemoglobin A1C, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartate, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, and the like.

[0043] The term "biological fluid," as used herein, refers to any bodily fluid or bodily fluid derivative in which an analyte can be measured. Non-limiting examples of biological fluids include dermal fluid, interstitial fluid, plasma, blood, lymph, synovial fluid, cerebrospinal fluid, saliva, bronchoalveolar lavage fluid, amniotic fluid, sweat, tears, and the like. In certain embodiments, the biological fluid is dermal fluid or interstitial fluid. In certain embodiments, the biological fluid is interstitial fluid. The term "covalent bond," as used herein, means a chemical bond involving the sharing of electron pairs between atoms. Similarly, "covalently bonded" means the formation of a chemical bond in a manner involving the sharing of electron pairs between atoms. The term "non-covalent" or similar terms, as used herein, refers to chemical interactions that do not involve the sharing of electrons, but rather involve more diffuse variations in electromagnetic interactions between or within molecules.

[0044] As used herein, the term "polyvinylpyridine-based polymer" refers to a polymer (e.g., copolymer) that includes polyvinylpyridine (e.g., poly(2-vinylpyridine) or poly(4-vinylpyridine)) or a derivative thereof. As used herein, the term "multi-component membrane" means a membrane that includes two or more types of membrane polymers. As used herein, the term "single-component membrane" means a membrane that includes one type of membrane polymer. The term "reference electrode," as used herein, can refer to a reference electrode or an electrode that functions as both a reference electrode and a counter electrode. Similarly, the term "counter electrode," as used herein, refers to both a counter electrode and a counter electrode that also functions as a reference electrode. In certain embodiments, the term "counter / reference electrode," as used herein, refers to both a counter electrode and a counter electrode that also functions as a reference electrode. As used herein, the term "crosslinking mol %" can refer to the degree of crosslinking by a crosslinker in the copolymer matrix of the drug delivery composition. For example, in certain embodiments, the copolymer can be a polyvinylpyridine-co-polystyrene copolymer, and the "crosslinking mol %" of the crosslinker can be expressed as follows:

[0045]

number

[0046] II. Therapeutic Drugs The present disclosure provides compositions of therapeutic agents and analyte sensors comprising the therapeutic agents. In certain embodiments, a composition (e.g., a drug delivery composition) or analyte sensor of the present disclosure can include two or more therapeutic agents. In certain embodiments, a therapeutic agent to be delivered by the present disclosure may be a therapeutic agent effective in reducing, minimizing, preventing, and / or inhibiting a tissue's response to the implantation of an analyte. For example, but not by way of limitation, a therapeutic agent to be delivered by the present disclosure may be a therapeutic agent effective in reducing, minimizing, preventing, and / or inhibiting inflammation in a tissue. In certain embodiments, a therapeutic agent for use in the present disclosure may be an immunosuppressant. Non-limiting examples of immunosuppressants include anti-inflammatory agents, anti-cancer agents, anti-rejection agents, and combinations thereof. In certain embodiments, a therapeutic agent for use in the present disclosure may include at least one selected from the group consisting of an antibiotic, an antiviral, an anti-inflammatory, an anti-cancer agent, an antiplatelet agent, an anticoagulant, a coagulant, an antiglycolytic agent, and combinations thereof. In certain embodiments, the therapeutic agent is an antibiotic. In certain embodiments, the therapeutic agent is an antiviral. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the therapeutic agent is an anti-cancer 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.

[0047] In certain embodiments, the therapeutic agent is an antiviral agent, which may include, but is not limited to, Umifenovir, Baloxavir marboxil, Darunavir, Nitazoxanide, Peramivir, Tipranavir, and others. In certain embodiments, the therapeutic agent is an antibiotic, which may include, but is not limited to, Rifaximin, Ertapenem, Doripenem, Cefadroxil, Clindamycin, Amoxicillin, Penicillin, and others. In certain embodiments, the therapeutic agent is an anti-cancer agent, which may include, but is not limited to, Gilteritinib, Glasdegib, Ivosidenib, Enasidenib, Midostaurin, Venetoclax, Alpelisib, and others.

[0048] In certain embodiments, the therapeutic agent may be an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent is a non-steroidal 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 derivatives or salt forms thereof. Non-limiting salt forms include pharmaceutically acceptable salts, including acetate and phosphate salts. In certain embodiments, the anti-inflammatory agent is a salt of dexamethasone. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt form thereof. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone acetate. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone sodium phosphate.

[0049] III. Drug Delivery Compositions The present disclosure provides compositions, e.g., drug delivery compositions, comprising one or more therapeutic agents and a polymer. In certain embodiments, the drug delivery compositions of the present disclosure can be incorporated into an analyte sensor described herein, e.g., an implantable analyte sensor. In certain embodiments, the drug delivery compositions of the present disclosure can be placed proximate to an analyte sensor, e.g., an implantable analyte sensor. Incorporation of the drug delivery composition into the analyte sensor itself or delivery of the drug delivery composition proximate to the analyte sensor at its in vivo location allows for targeted delivery of the therapeutic agent contained in the drug delivery composition to the implantation site and tissue surrounding the analyte sensor.

[0050] In certain embodiments, targeted delivery of a therapeutic agent included in a drug delivery composition to the implantation site of an analyte sensor allows for a reduction in in vivo sensor failure due to FBR. In certain embodiments, targeted delivery of a therapeutic agent included in a drug delivery composition to the implantation site of an analyte sensor allows for a reduction in sensor signal inaccuracies due to FBR. In certain embodiments, targeted delivery of a therapeutic agent included in a drug delivery composition to the implantation site of an analyte sensor allows for a reduction in late sensor decay (LSA). For example, but not limited to, targeted delivery of a therapeutic agent included in a drug delivery composition to the implantation site of an analyte sensor allows for a reduction and / or elimination of analyte signal inaccuracies that may be observed following in vivo implantation.

[0051] In certain embodiments, a therapeutic agent can be incorporated into the drug delivery composition. For example, but not limited to, a therapeutic agent can be non-covalently mixed with the copolymer of the composition, or an investigational drug can be covalently bound to the copolymer of the composition. In certain embodiments, a therapeutic agent can be covalently bound to one or more polymer chains of the composition, either directly or via a linker. In certain embodiments, a therapeutic agent can be covalently bound to one or more polymer chains of the polymer matrix via a hydrolyzable bond to enable delayed release of the therapeutic agent after insertion of an analyte sensor in vivo.

[0052] In certain embodiments, the therapeutic agent is non-covalently admixed with the copolymer of the composition, for example as shown in FIG. FIG. 1 illustrates an exemplary drug delivery composition according to some embodiments of the present disclosure. As shown in FIG. 1, certain embodiments of the present disclosure provide a drug delivery composition, which may include a polymer and a therapeutic agent. In certain embodiments, the drug delivery composition may include a copolymer including multiple copolymer chains and a therapeutic agent. In certain embodiments, each of the multiple copolymer chains includes a backbone including multiple hydrophilic units and multiple hydrophobic units. In certain embodiments, the drug delivery composition of the present disclosure further includes a crosslinker, e.g., a crosslinker that crosslinks at least a portion of the hydrophilic units between each of the copolymer chains. For example, but not by way of limitation, the drug delivery composition may include (i) a copolymer including multiple copolymer chains, each of the multiple copolymer chains including a backbone including multiple hydrophilic units and multiple hydrophobic units, (ii) a crosslinker that crosslinks at least a portion of the hydrophilic units between each of the copolymer chains, and (iii) a therapeutic agent, as shown in FIG. 1.

[0053] In certain embodiments, the hydrophilic units of the copolymer chains may comprise nitrogen-containing heterocyclic units. Non-limiting examples of nitrogen-containing heterocyclic units include pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, pyrazole units, and the like. For example, in certain embodiments, the hydrophilic units of the copolymer may be pyridine units, as shown in Figure 1. Of course, embodiments of the present disclosure are not limited in this respect. In certain embodiments, the hydrophobic units of the copolymer can include non-heteroatom-containing aromatic units such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units such as linear or branched alkyl units, linear or branched alkenyl units, linear or branched alkynyl units, etc., and / or cyclic aliphatic units such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl units, etc. For example, in certain embodiments, the hydrophobic units of the copolymer can be benzene (phenyl) units, as shown in Figure 1. Of course, embodiments of the present disclosure are not limited in this respect.

[0054] In certain embodiments, the copolymer may be an alternating copolymer, a random copolymer, a block copolymer, or a graft copolymer. In certain embodiments, the copolymer may be a graft copolymer. In certain embodiments, the copolymer may be an alternating copolymer. In certain embodiments, the copolymer may be a random copolymer. In certain embodiments, the copolymer may be a block copolymer. In certain embodiments, the mer% of hydrophobic units, i.e., the ratio of x / (x+y) in the copolymer shown in Figure 1, is in the range of about 1% to 99%, about 1% to 90%, about 1% to 80%, about 1% to 70%, about 1% to 60%, about 1% to 50%, about 1% to 40%, about 1% to 30%, about 1% to 25%, about 1% to 20%, about 1% to 15%, about 1% to 10%, about 2% to 10%, about 3% to 10%, about 4% to 10%, about 5% to 10%, about 6% to 10%, about 7% to 10%, about 8% to 10%, or about 9% to 10%, or any range defined between any two of the above values, e.g., in the range of about 7% to 15%. In certain embodiments, the mer% of hydrophobic units in the copolymer is in the range of about 5% to 25%. In certain embodiments, the mer% of the hydrophobic units in the copolymer is in the range of about 5% to 20%. In certain embodiments, the mer% of the hydrophobic units in the copolymer is in the range of about 5% to 15%. In certain embodiments, the mer% of the hydrophobic units in the copolymer is in the range of about 5% to 10%.

[0055] In certain embodiments, the copolymer can be selected from the group consisting of polyvinylpyridine-based copolymers, polyvinylimidazole-based copolymers, polyacrylate-based copolymers, polyurethane-based copolymers, polyetherurethane-based copolymers, silicone-based copolymers, derivatives thereof, and combinations thereof. In certain embodiments, the copolymer may be a polyurethane-based copolymer. Non-limiting examples of polyurethane-based copolymers include ether-based polyurethanes or ester-based polyurethanes. In certain embodiments, the copolymer may be a polyvinylimidazole-based copolymer. In certain embodiments, the polyvinylimidazole-based copolymer may be a copolymer of vinylimidazole and styrene or a derivative thereof.

[0056] In certain embodiments, the polyvinylimidazole-based copolymer can be a polyvinylimidazole-co-polystyrene polymer, hi certain embodiments, the polyvinylimidazole-co-polystyrene polymer can be a poly(N-vinylimidazole)-co-polystyrene polymer, a poly(1-vinylimidazole)-co-polystyrene polymer, or a derivative thereof. In certain embodiments, the copolymer may be a polyvinylpyridine-based copolymer. In certain embodiments, the polyvinylpyridine-based copolymer may be a copolymer of vinylpyridine and styrene or a derivative thereof.

[0057] In certain embodiments, the polyvinylpyridine-based copolymer may be a polyvinylpyridine-co-polystyrene polymer. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer comprises poly(4-vinylpyridine) and styrene. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer comprises poly(2-vinylpyridine) and styrene. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may be a poly(4-vinylpyridine)-co-polystyrene polymer, a poly(2-vinylpyridine)-co-polystyrene polymer, or a derivative thereof.

[0058] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can contain about 1 to 50 mer% styrene units, about 1 to 40 mer% styrene units, about 1 to 30 mer% styrene units, about 1 to 20 mer% styrene units, or about 1 to 15 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can contain about 1 to 50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can contain about 1 to 40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can contain about 1 to 30 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can contain about 1 to 20 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can contain about 1 to 15 mer% styrene units.

[0059] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 5-25 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 5-20 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 5-15 mer% styrene units.

[0060] In certain embodiments, the weight average molecular weight of the copolymer is about 5 kD to 1,000 kD, about 5 kD to 900 kD, about 5 kD to 800 kD, about 5 kD to 700 kD, about 5 kD to 600 kD, about 5 kD to 500 kD, about 5 kD to 400 kD, about 5 kD to 300 kD, about 10 kD to 300 kD, about 20 kD to 300 kD, about 30 kD to 300 kD, or about The weight average molecular weight of the copolymer is within the range of 40 kD to 300 kD, about 50 kD to 300 kD, about 60 kD to 300 kD, about 70 kD to 300 kD, about 80 kD to 300 kD, about 90 kD to 300 kD, about 100 kD to 300 kD, or about 100 kD to 200 kD, or any range defined between any two of the above values, e.g., about 100 kD to 400 kD. In certain embodiments, the weight average molecular weight of the copolymer is within the range of about 100 kD to 250 kD. In certain embodiments, the weight average molecular weight of the copolymer can be determined by a suitable method, such as gel permeation chromatography.

[0061] In certain embodiments, the copolymers for use in the present disclosure can absorb about 5% to about 95% of their weight in water. For example, but not by way of limitation, the copolymers for use in the present disclosure can 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 copolymers can absorb at least 5% of their weight in water. In certain embodiments, the copolymers can absorb at least 10% of their weight in water. In certain embodiments, the copolymers can absorb at least 20% of their weight in water. In certain embodiments, the copolymers can absorb at least 30% of their weight in water. In certain embodiments, the copolymer can absorb at least 40% of its weight in water. In certain embodiments, the copolymer can absorb at least 50% of its weight in water. In certain embodiments, the copolymer can absorb at least 60% of its weight in water. In certain embodiments, the copolymer can absorb at least 70% of its weight in water. In certain embodiments, the copolymer can absorb at least 80% of its weight in water. In certain embodiments, the copolymer can absorb at least 90% of its weight in water. In certain embodiments, the copolymer can absorb at least 95% of its weight in water. In certain embodiments, the copolymer can absorb from about 5% to about 25% of its weight in water.

[0062] In certain embodiments, copolymers for use in the present disclosure may have a Shore A hardness of about 20 to about 100. For example, but not by way of limitation, copolymers for use in the present disclosure may have a Shore A hardness of about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 100, about 40 to about 100, about 50 to about 100, about 60 to about 100, or about 100 to about 100. The copolymers for use in the present disclosure may have a Shore A hardness of about 100, about 70 to about 100, about 80 to about 100, about 90 to about 100, about 70 to about 95, about 70 to about 90, about 70 to about 85, about 70 to about 80, about 75 to about 95, about 80 to about 95, about 85 to about 95, about 80 to about 93, or about 80 to about 90. In certain embodiments, the copolymers for use in the present disclosure may have a Shore A hardness of about 80. In certain embodiments, the copolymers for use in the present disclosure may have a Shore A hardness of about 90. In certain embodiments, the copolymers for use in the present disclosure may have a Shore A hardness of about 93. In certain embodiments, the copolymers for use in the present disclosure may have a Shore A hardness of about 80 to about 100, e.g., before implantation in a subject or before hydration. In certain embodiments, the copolymers for use in the present disclosure may have a Shore A hardness of about 20 to about 60, e.g., when implanted in a subject or when hydrated.

[0063] In certain embodiments, the copolymers for use in the present disclosure have a linear coefficient of thermal expansion of from about 10% to about 200%. For example, but not by way of limitation, the linear expansion coefficient of copolymers for use in the present disclosure may be from about 10% to about 190%, from about 10% to about 180%, from about 10% to about 170%, from about 10% to about 160%, from about 10% to about 150%, from about 10% to about 140%, from about 10% to about 130%, from about 10% to about 120%, from about 10% to about 110%, from about 10% to about 100%, from about 25% to about 100%, from about 30% to about 100%, from about 35% to about 100%, from about 40% to about 100%, from about 45% to about 100%, from about 50% to about 100%, from about 55% to about 100%, from about 60% to about 100%, from about 65% to about 100%, Approximately 70% to approximately 100%, approximately 75% to approximately 100%, approximately 80% to approximately 100%, approximately 85% to approximately 100%, approximately 90% to approximately 100%, approximately 95% to approximately 100%, approximately 20% to approximately 95%, approximately 20% to approximately 90%, approximately 20% to approximately 85%, approximately 20% to approximately 80%, approximately 20% to approximately 75%, approximately 20% to approximately 70%, approximately The coefficient of linear expansion of the copolymer for use in the present disclosure may be 20% to about 65%, about 20% to about 60%, about 20% to about 55%, about 20% to about 50%, about 20% to about 45%, about 20% to about 40%, about 20% to about 30%, about 30% to about 60%, about 40% to about 50%, about 40% to about 60%, about 20% to about 30%, or about 50% to about 70%. In certain embodiments, the coefficient of linear expansion of the copolymer for use in the present disclosure is about 25%. In certain embodiments, the coefficient of linear expansion of the copolymer for use in the present disclosure is about 40%. In certain embodiments, the coefficient of linear expansion of the copolymer for use in the present disclosure is about 45%. In certain embodiments, the coefficient of linear expansion of the copolymer for use in the present disclosure is about 50%. In certain embodiments, the coefficient of linear expansion of the copolymer for use in the present disclosure is about 60%. In certain embodiments, the linear coefficient of thermal expansion of the copolymers for use in the present disclosure is about 100%. In certain embodiments, the linear coefficient of thermal expansion of the copolymers for use in the present 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 coefficient of thermal expansion of the copolymers for use in the present disclosure is about 110% or more.In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 100% or greater. In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 90% or greater. In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 80% or greater. In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 70% or greater. In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 60% or greater. In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 50% or greater. In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 40% or greater. In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 30% or greater. In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 20% or greater. In certain embodiments, the coefficient of linear expansion of the copolymers for use in the present disclosure is about 10% or greater.

[0064] In certain embodiments, the copolymer has a linear coefficient of expansion of about 45% and can absorb about 70% of its mass in water. In certain embodiments, the copolymer has a linear coefficient of expansion of about 25% and can absorb about 55% of its mass in water. In certain embodiments, the copolymer has a linear coefficient of expansion of about 40% and can absorb about 60% of its mass in water. In certain embodiments, the copolymer has a linear coefficient of expansion of about 50% and can absorb about 50% of its mass in water. In certain embodiments, the copolymer has a linear coefficient of expansion of about 60% and can absorb about 80% of its mass in water. In certain embodiments, the copolymer has a linear coefficient of expansion of about 100% and can absorb about 90% of its mass in water. In certain embodiments, the copolymer has a linear coefficient of expansion of about 10% and can absorb about 30% of its mass in water. In one particular embodiment, the copolymer has a linear coefficient of expansion of about 180% and can absorb about 95% of its mass in water.

[0065] In certain embodiments, the drug delivery composition of the present disclosure may further comprise a crosslinker. For example, but not by way of limitation, the crosslinker crosslinks at least a portion of the hydrophilic and / or hydrophobic units between each copolymer chain. In certain embodiments, the crosslinker crosslinks at least a portion of the hydrophilic units between each copolymer chain. In certain embodiments, the crosslinker crosslinks at least a portion of the nitrogen-containing heterocyclic units, e.g., pyridine units, between each copolymer chain. For example, but not by way of limitation, the crosslinker crosslinks at least a portion of the pyridine units between each copolymer chain, as shown in FIG. 1. In certain embodiments, the crosslinker may be a diglycidyl- or triglycidyl-functional epoxy.

[0066] In certain embodiments, the crosslinker can be selected from the group consisting of diglycidyl-PEG (200-1000), glycerol triglycidyl ether, and combinations thereof. For example, in certain embodiments, the crosslinker is diglycidyl-PEG (200-1000) having a molecular weight of 200 g / mol to 1000 g / mol, as shown in Figure 1. The term "diglycidyl-PEG" as used in the present disclosure can refer to polyethylene glycol diglycidyl ether. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG200, diglycidyl-PEG400, glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be diglycidyl-PEG200. In certain embodiments, the cross-linking agent can be diglycidyl-PEG400. In certain embodiments, the cross-linking agent can be glycerol triglycidyl ether.

[0067] In certain embodiments, the drug delivery composition includes a cross-linking agent (e.g., includes a certain amount of cross-linking agent) that provides a certain mol % of cross-linking to a polymer, e.g., a copolymer, present in the drug delivery composition. In certain embodiments, the cross-linking mol % of the copolymer can be in the range of about 0.1 mol % to 50 mol %. In certain embodiments, the cross-linking mol % of the copolymer can be in the range of about 1 mol % to 50 mol %. In certain embodiments, the cross-linking mol % of the copolymer can be in the range of about 0.1 mol % to 40 mol %. In certain embodiments, the cross-linking mol % of the copolymer can be in the range of about 1 mol % to 40 mol %. In certain embodiments, the cross-linking mol % of the copolymer can be in the range of about 0.1 mol % to 30 mol %. In certain embodiments, the cross-linking mol % of the copolymer can be in the range of about 0.2 mol % to 30 mol %. In certain embodiments, the cross-linking mol % of the copolymer can be in the range of about 1 mol % to 30 mol %. In certain embodiments, the cross-linking mol % of the copolymer can be in the range of about 0.1 mol % to 25 mol %. In certain embodiments, the crosslinked mol% of the copolymer can range from about 1 mol% to 25 mol%. In certain embodiments, the crosslinked mol% of the copolymer can range from about 0.1 mol% to 20 mol%. In certain embodiments, the crosslinked mol% of the copolymer can range from about 1 mol% to 20 mol%. In certain embodiments, the crosslinked mol% of the copolymer can range from about 0.1 mol% to 15 mol%. In certain embodiments, the crosslinked mol% of the copolymer can range from about 1 mol% to 15 mol%. In certain embodiments, the crosslinked mol% of the copolymer can range from about 0.1 mol% to 10 mol%. In certain embodiments, the crosslinked mol% of the copolymer can range from about 0.5 mol% to 10 mol%. In certain embodiments, the crosslinked mol% of the copolymer can range from about 1 mol% to 10 mol%.

[0068] In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 20 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 19 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 18 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 17 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 16 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 15 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 14 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 13 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 12 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 11 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 10 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 9 mol% or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinker, and the amount of crosslinker in the drug delivery composition provides about 8 mol % or less crosslinking (eg, of a copolymer).In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 7 mol % or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 6 mol % or less crosslinking (e.g., of a copolymer). In certain embodiments, the drug delivery composition of the present disclosure includes a crosslinking agent, and the amount of crosslinking agent in the drug delivery composition provides about 5 mol % or less crosslinking (e.g., of a copolymer).

[0069] In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 50% by weight based on the total weight of the copolymer (e.g., in the drug delivery composition). In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 30% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 20% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 15% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 10% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 9% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 8% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 7% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 6% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 5% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 4% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 3% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 2% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker ranging from about 0.01% to 1% by weight based on the total weight of the copolymer.In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 0.01% to 5% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 1% to 40% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 1% to 30% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 1% to 25% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 1% to 20% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 1% to 15% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 1% to 10% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of crosslinker in the range of about 1% to 5% by weight, based on the total weight of the copolymer.

[0070] As shown in Figure 1, the crosslinker crosslinks at least two polymer backbones of two or more copolymer chains through bonds to the hydrophilic units of the two or more copolymer chains. In certain embodiments, the copolymer can be a polyvinylpyridine-co-polystyrene polymer, and the crosslinker can be diglycidyl-PEG. As shown in Figure 1, diglycidyl-PEG can have two crosslinkable glycidyl groups, each of which can be bonded to a nitrogen atom of a pyridine in a different copolymer chain to crosslink the backbones of the copolymer chains, forming a positive charge on the pyridine moiety. The formed charge can control the swelling property of the drug delivery composition. Furthermore, as shown in the examples, the degree of crosslinking of the copolymer can be precisely controlled by using an appropriate amount of diglycidyl-PEG with an appropriate molecular weight and / or glycerol triglycidyl ether with three crosslinkable glycidyl groups.

[0071] In certain embodiments, the drug delivery composition may include one or more therapeutic agents. Non-limiting examples of therapeutic agents are disclosed in Section II herein. For example, but not by way of limitation, the therapeutic agent may include at least one selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. 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 derivatives or salt forms thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt form thereof. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone acetate. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone sodium phosphate.

[0072] In certain embodiments, the therapeutic agent is dexamethasone, as shown in Figure 1. The dexamethasone is non-covalently present in the crosslinked copolymer matrix and is trapped within the crosslinked copolymer matrix. The dexamethasone can interact with the hydrophilic and hydrophobic units of the crosslinked copolymer matrix through non-polar and polar interactions. In certain embodiments, the therapeutic agent can be covalently attached to the copolymer.

[0073] In certain embodiments, the drug delivery composition may include a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from about 0.01% to 50% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from about 0.01% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from about 1% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from about 5% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from 10% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount ranging from about 20% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of about 30% to 40% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of about 5% to 20% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of about 5% to 10% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of about 1% to 10% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of about 1% to 20% by weight, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of about 1% to 30% by weight, based on the total weight of the copolymer.In certain embodiments, the drug delivery composition may include an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of about 10% to 20% by weight based on the total weight of the copolymer.

[0074] In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 50% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 49% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 48% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 47% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 46% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 45% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 44% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 43% by weight or less, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 42% by weight or less, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 41% by weight or less, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 40% by weight or less, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 39% by weight or less, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 38% by weight or less, based on the total weight of the copolymer.In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 37% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 36% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 35% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 34% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 33% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 32% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 31% by weight or less based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 30% by weight or less, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 25% by weight or less, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 20% by weight or less, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 15% by weight or less, based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may comprise a therapeutic agent, such as dexamethasone or a derivative thereof, in an amount of about 10% by weight or less, based on the total weight of the copolymer.

[0075] In certain embodiments, the drug delivery composition can contain about 0.0005 mg to about 0.2 mg of a therapeutic agent, such as dexamethasone, or any value therebetween. In certain embodiments, the drug delivery composition can contain 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 of a therapeutic agent, such as dexamethasone. In certain embodiments, the drug delivery composition can contain 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 of a therapeutic agent, such as dexamethasone. In certain embodiments, the drug delivery composition can contain about 0.0005 mg to about 0.1 mg. In certain embodiments, the drug delivery composition may comprise from about 0.0005 mg to about 0.01 mg. In certain embodiments, the drug delivery composition may comprise from about 0.001 mg to about 0.1 mg. In certain embodiments, the drug delivery composition may comprise from about 0.001 mg to about 0.01 mg. In certain embodiments, the drug delivery composition may comprise from about 0.001 mg to about 0.005 mg. In certain embodiments, the drug delivery composition may comprise from about 0.001 mg to about 0.003 mg.

[0076] In certain embodiments, the drug delivery composition contains from about 0.1 μg to about 200 μg, for example, from about 0.5 μg to about 200 μg, from about 1 μg to about 200 μg, from about 1.5 μg to about 200 μg, from about 2.0 μg to about 200 μg, from about 2.5 μg to about 200 μg, from about 3 μg to about 200 μg, from about 4 μg to about 200 μg, from about 5 μg to about 200 μg, from about 10 μg to about 200 μg, from about 15 μg to about 200 μg, or from about 20 μg to about 200 μg. 200μg, about 25μg to about 200μg, about 30μg to about 200μg, about 35μg to about 200μg, about 40μg to about 200μg, about 45μg to about 200μg, about 50μg to about 200μg, about 55μg g ~ approx. 200 μg, approx. 60 μg ~ approx. 200 μg, approx. 65 μg ~ approx. 200 μg, approx. 70 μg ~ approx. 200 μg, approx. 90μg to about 200μg, about 95μg to about 200μg, about 100μg to about 200μg, about 110μg to about 200μg, about 120μg to about 200μg, about 130μg to about 200μg, about 140μg ~Approx. 200μg, approx. 150μg ~ approx. 200μg, approx. 160μg ~ approx. 200μg, approx. 170μg ~ approx. 200μg, approx. 180μg ~ approx. 200μg, approx. 190μg ~ approx. 200μg, approx. 0.1μg ~ approx. 19 The therapeutic agent may comprise 0 μg, about 0.1 μg to about 180 μg, about 0.1 μg to about 170 μg, about 0.1 μg to about 160 μg, about 0.1 μg to about 150 μg, about 0.1 μg to about 140 μg, about 0.1 μg to about 130 μg, about 0.1 μg to about 120 μg, about 0.1 μg to about 110 μg, about 0.1 μg to about 100 μg, about 1 μg to about 150 μg, about 5 μg to about 150 μg, or about 5 μg to about 120 μg.In certain embodiments, the drug delivery composition contains from about 1 μg to about 100 μg, e.g., from about 1 μg to about 95 μg, from about 1 μg to about 90 μg, from about 1 μg to about 85 μg, from about 1 μg to about 80 μg, from about 1 μg to about 75 μg, from about 1 μg to about 70 μg, from about 1 μg to about 65 μg, from about 1 μg to about 60 μg, from about 1 μg to about 55 μg, from about 1 μg to about 50 μg, from about 1 μg to about 45 μg, from about 1 μg to about 40 μg, from about 1 μg to about 35 μg, from about 1 μg to about 30 μg, from about 1 μg to about 25 μg, or from about 1μg to about 20μg, about 1μg to about 15μg, about 1μg to about 14μg, about 1μg to about 13μg, about 1μg to about 12μg, about 1μg to about 11μg, about 1μg to about 10μg, about 1μg to about 9μg, about 2μg to about 100μg, about 3μg g ~ approx. 100 μg, approx. 4 μg ~ approx. 100 μg, approx. 5 μg ~ approx. 100 μg, approx. 6 μg ~ approx. 100 μg, approx. 7 μg ~ approx. 00μg, about 12μg to about 100μg, about 13μg to about 100μg, about 14μg to about 100μg, about 15μg to about 100μg, about 16μg to about 100μg, about 17μg to about 100μg, about 18μg to about 100μg, about 19μg ~approx. 100μg, approx. 20μg ~ approx. 100μg, approx. 25μg ~ approx. 100μg, approx. 30μg ~ approx. 100μg, approx. 35μg ~ approx. 100μg, approx. 40μg ~ approx. 100μg, approx. 45μg ~ approx. The drug delivery composition may contain 5 μg to about 100 μg, about 60 μg to about 100 μg, about 65 μg to about 100 μg, about 70 μg to about 100 μg, about 75 μg to about 100 μg, about 80 μg to about 100 μg, about 85 μg to about 100 μg, about 90 μg to about 100 μg, about 95 μg to about 100 μg, about 5 μg to about 50 μg, about 5 μg to about 45 μg, about 5 μg to about 40 μg, about 5 μg to about 35 μg, about 5 μg to about 30 μg, about 5 μg to about 25 μg, or about 5 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may contain about 1 μg to about 5 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may contain about 1 μg to about 10 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 1 μg to about 15 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 1 μg to about 20 μg of a therapeutic agent.In certain embodiments, the drug delivery composition may comprise about 5 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may comprise about 1 μg to about 30 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may comprise about 5 μg to about 10 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may comprise about 5 μg to about 15 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may comprise about 5 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may comprise about 5 μg to about 25 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may comprise about 5 μg to about 30 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may comprise about 0.1 μg to about 30 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may comprise about 0.1 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition may comprise about 0.1 μg to about 15 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 10 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 5 μg of a therapeutic agent.

[0077] In certain embodiments, the drug delivery composition (e.g., when administered proximate to and / or incorporated into an analyte sensor) can continuously release a therapeutic agent at a drug delivery rate (e.g., average drug delivery rate) of about 0.01 μg / day to about 1 mg / day of the therapeutic agent, e.g., dexamethasone, or any value therebetween. In certain embodiments, the drug delivery composition (e.g., when administered proximate to and / or incorporated into the analyte sensor) provides about 0.1 μg / day, about 0.2 μg / day, about 0.3 μg / day, about 0.4 μg / day, about 0.5 μg / day, about 0.6 μg / day, about 0.7 μg / day, about 0.8 μg / day, about 0.9 μg / day, about 1 μg / day, about 2 μg / day, about 3 μg / day, about 4 μg / day, about 5 μg / day, about 6 μg / day, about 7 μg / day, about 8 μg / day, about 9 μg / day, or about 10 μg / day , about 20 μg / day, about 30 μg / day, about 40 μg / day, about 50 μg / day, about 60 μg / day, about 70 μg / day, about 80 μg / day, about 90 μg / day, about 100 μg / day, about 200 μg / day, about 300 μg / day, about 400 μg / day, about 500 μg / day, about 600 μg / day, about 700 μg / day, about 800 μg / day, about 900 μg / day, or about 1 mg / day, or any value therebetween. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent at a drug delivery rate (e.g., average drug delivery rate) of about 0.2 μg / day to about 5 μg / day of a therapeutic agent, e.g., dexamethasone. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent at a drug delivery rate (e.g., average drug delivery rate) of about 0.2 μg / day to about 2 μg / day of the therapeutic agent, e.g., dexamethasone. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent at a drug delivery rate (e.g., average drug delivery rate) of about 0.2 μg / day to about 1 μg / day of the therapeutic agent, e.g., dexamethasone. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent at a set or predetermined drug delivery rate to achieve a desired therapeutic effect, such as reducing, minimizing, reducing, preventing, and / or inhibiting inflammation.In certain embodiments, the drug delivery composition can continuously release a therapeutic agent at a set or predetermined drug delivery rate to achieve a desired therapeutic effect, such as minimizing signal inaccuracies toward the end of the sensor's life. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent at a set or predetermined drug delivery rate to reduce and / or minimize sensor signal inaccuracies or in vivo sensor failure due to, for example, FBR. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent at a set or predetermined drug delivery rate to achieve a desired therapeutic effect, such as minimizing and / or reducing LSA.

[0078] In certain embodiments, the drug delivery composition (e.g., when administered proximate to and / or incorporated into an analyte sensor) can continuously release a therapeutic agent at a set or predetermined drug delivery 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 certain embodiments, the drug delivery composition can continuously release a therapeutic agent (e.g., at a set or predetermined drug delivery rate) for at least 5 days. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent (e.g., at a set or predetermined drug delivery rate) for at least 10 days. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent (e.g., at a set or predetermined drug delivery rate) for at least 15 days. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent (e.g., at a set or predetermined drug delivery rate) for at least 20 days. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent (e.g., at a set or predetermined drug delivery rate) for at least 21 days. In certain embodiments, the drug delivery composition can continuously release a therapeutic agent (e.g., at a set or predetermined drug delivery rate) for at least 25 days. In certain embodiments, the drug delivery composition may continuously release a therapeutic agent at a set or predetermined drug delivery rate for a set or predetermined number of days, such as at least 30 days.

[0079] In certain embodiments, a delivery composition of the present disclosure (e.g., when administered proximate to an analyte sensor and / or incorporated into an analyte sensor) releases about 1% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) within, for example, about 30-31 days. In certain embodiments, a delivery composition of the present disclosure releases about 5% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) within, for example, about 30-31 days. In certain embodiments, a delivery composition of the present disclosure releases about 10% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) within, for example, about 30-31 days. In certain embodiments, a delivery composition of the present disclosure releases about 20% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) within, for example, about 30-31 days. In certain embodiments, a delivery composition of the present disclosure releases about 30% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, a delivery composition of the present disclosure releases about 40% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, a delivery composition of the present disclosure releases about 50% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, a delivery composition of the present disclosure releases about 60% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, the delivery compositions of the present disclosure release about 70% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, the delivery compositions of the present disclosure release about 80% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days.In certain embodiments, the delivery compositions of the present disclosure release about 30% to about 90% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, the delivery compositions of the present disclosure release about 40% to about 90% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, the delivery compositions of the present disclosure release about 50% to about 90% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, the delivery compositions of the present disclosure release about 1% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, the delivery compositions of the present disclosure release about 10% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30 to 31 days. In certain embodiments, a delivery composition of the present disclosure releases about 20% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30-31 days. In certain embodiments, a delivery composition of the present disclosure releases about 30% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30-31 days. In certain embodiments, a delivery composition of the present disclosure releases about 40% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), for example, within a period of about 30-31 days.For example, but not by way of limitation, a delivery composition of the present disclosure may release about 45% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition), release about 50% to about 80% of the therapeutic agent, release about 55% to about 80% of the therapeutic agent, release about 60% to about 80% of the therapeutic agent, release about 65% to about 80% of the therapeutic agent, release about 70% to about 80% of the therapeutic agent, release about 75% to about 80% of the therapeutic agent, or release a therapeutic agent within a period of, for example, about 30 to 31 days. Release of about 40% to about 75% of the therapeutic agent, release of about 40% to about 70% of the therapeutic agent, release of about 40% to about 65% of the therapeutic agent, release of about 40% to about 60% of the therapeutic agent, release of about 40% to about 55% of the therapeutic agent, release of about 40% to about 50% of the therapeutic agent, release of about 40% to about 45% of the therapeutic agent, release of about 45% to about 75% of the therapeutic agent, release of about 50% to about 75% of the therapeutic agent, release of about 55% to about 80% of the therapeutic agent, or release of about 60% to about 75% of the therapeutic agent. In certain embodiments, a period of about 30 to 31 days is the useful life of the sensors described herein. In certain embodiments, a period of about 30 to 31 days is the lifespan of the sensors described herein.

[0080] In certain embodiments, up to about 100% of the therapeutic agent present in the drug delivery composition on the analyte sensor (e.g., the total amount of therapeutic agent loaded in the composition) is released no earlier than about 7 days before the end of the sensor's life (e.g., the end of its useful life). In certain embodiments, up to about 90% of the therapeutic agent present in the drug delivery composition on the analyte sensor (e.g., the total amount of therapeutic agent loaded in the composition) is released no earlier than about 7 days before the end of the sensor's life (e.g., the end of its useful life). In certain embodiments, up to about 80% of the therapeutic agent present in the drug delivery composition on the analyte sensor (e.g., the total amount of therapeutic agent loaded in the composition) is released no earlier than about 7 days before the end of the sensor's life (e.g., the end of its useful life). In certain embodiments, up to about 70% of the therapeutic agent present in the drug delivery composition on the analyte sensor (e.g., the total amount of therapeutic agent loaded in the composition) is released no earlier than about 7 days before the end of the sensor's life (e.g., the end of its useful life). In certain embodiments, up to about 60% of the therapeutic agents present in the drug delivery composition on the analyte sensor (e.g., the total amount of therapeutic agents loaded in the composition) are released no earlier than about 7 days before the end of the sensor's life (e.g., the end of its useful life). In certain embodiments, up to about 50% of the therapeutic agents present in the drug delivery composition on the analyte sensor (e.g., the total amount of therapeutic agents loaded in the composition) are released no earlier than about 7 days before the end of the sensor's life (e.g., the end of its useful life). In certain embodiments, up to about 40% of the therapeutic agents present in the drug delivery composition on the analyte sensor (e.g., the total amount of therapeutic agents loaded in the composition) are released no earlier than about 7 days before the end of the sensor's life (e.g., the end of its useful life).

[0081] In certain embodiments, about 90% or less of the therapeutic agent present in the drug delivery composition (e.g., the total amount of therapeutic agent loaded in the composition) is released (e.g., when administered proximate to and / or incorporated into an analyte sensor) within a period of, for example, about 30-31 days. In certain embodiments, about 95% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within a period of, for example, about 30-31 days. In certain embodiments, about 80% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within a period of, for example, about 30-31 days. In certain embodiments, about 75% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within a period of, for example, about 30-31 days. In certain embodiments, about 70% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within a period of, for example, about 30-31 days. In certain embodiments, about 65% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released, for example, within a period of about 30-31 days. In certain embodiments, about 60% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released, for example, within a period of about 30-31 days. In certain embodiments, about 55% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released, for example, within a period of about 30-31 days. In certain embodiments, about 50% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released, for example, within a period of about 30-31 days.

[0082] In certain embodiments, about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% or less of the therapeutic agent present in the drug delivery composition (e.g., the total amount of therapeutic agent loaded in the composition) is released (e.g., when administered proximate to and / or incorporated into the analyte sensor) within the first 5, 6, or 7 days after insertion of the composition. In certain embodiments, about 30% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition. In certain embodiments, about 30% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition. In certain embodiments, about 30% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 7 days after insertion of the composition. In certain embodiments, about 35% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition. In certain embodiments, about 35% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition. In certain embodiments, about 35% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 7 days after insertion of the composition. In certain embodiments, about 40% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition. In certain embodiments, about 40% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition. In certain embodiments, about 40% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 7 days after insertion of the composition. In certain embodiments, about 45% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition, hi certain embodiments, about 45% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition.In certain embodiments, about 45% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 7 days after insertion of the composition. In certain embodiments, about 50% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition. In certain embodiments, about 50% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition. In certain embodiments, about 50% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 7 days after insertion of the composition. In certain embodiments, about 55% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition. In certain embodiments, about 55% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition. In certain embodiments, about 55% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 7 days after insertion of the composition. In certain embodiments, about 60% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition. In certain embodiments, about 60% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition. In certain embodiments, about 60% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 7 days after insertion of the composition. In certain embodiments, about 65% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition. In certain embodiments, about 65% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition. In certain embodiments, about 65% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released during the first 7 days after insertion of the composition.In certain embodiments, about 70% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition. In certain embodiments, about 70% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition. In certain embodiments, about 70% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 7 days after insertion of the composition. In certain embodiments, about 75% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 5 days after insertion of the composition. In certain embodiments, about 75% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 6 days after insertion of the composition. In certain embodiments, about 75% or less of the therapeutic agent present in the composition (e.g., the total amount of therapeutic agent loaded in the composition) is released within the first 7 days after insertion of the composition.

[0083] In certain embodiments, no more than about 25% or 30% of the therapeutic agent present in the drug delivery composition (e.g., the total amount of therapeutic agent loaded in the composition) (e.g., when administered proximate to and / or incorporated into the analyte sensor) is released between about 7 days and about 14 days after insertion of the composition.

[0084] In certain embodiments, no more than about 25% or 30% of the therapeutic agent present in the drug delivery composition (e.g., the total amount of therapeutic agent loaded in the composition) (e.g., when administered proximate to and / or incorporated into the analyte sensor) is released between about 14 days and about 31 days after insertion of the composition.

[0085] In certain embodiments, when an exemplary drug delivery composition contacts a tissue or fluid (e.g., interstitial fluid) of a subject in need thereof, the drug delivery composition will adsorb water from the physiological surroundings (e.g., surrounding tissue) to form a hydrogel. In certain embodiments, a diffusion-controlled or selected drug release mechanism for the drug delivery composition can be used. For example, in certain embodiments, the copolymer can be a polyvinylpyridine-based copolymer. In certain embodiments, the therapeutic agent can be dexamethasone. In certain embodiments, because dexamethasone is a small molecule drug and its size is significantly smaller than the mesh size of the hydrogel formed after the drug delivery composition contacts the patient's tissue, dexamethasone is released from the drug delivery composition through a diffusion process. For polyvinylpyridine-only hydrogels, even with very dense crosslinking, such as those utilizing the crosslinkers disclosed herein, the mesh size is always too large to limit the diffusion of dexamethasone, resulting in an uncontrolled drug release.

[0086] However, the addition of hydrophobic units / regions to the copolymer may delay the release of the therapeutic agent from the hydrogel. For example, but not by way of limitation, a polymer affinity-controlled drug release mechanism can be employed according to certain embodiments of the present disclosure. In certain embodiments, a copolymer, such as a polyvinylpyridine-co-polystyrene polymer, has a backbone comprising hydrophilic and hydrophobic units. A hydrophobic therapeutic agent, such as dexamethasone, can interact with the hydrophobic units / regions of the copolymer matrix through nonpolar intermolecular interactions, thereby delaying the release of the therapeutic agent from the hydrogel. Therefore, a high affinity of the polymer for a hydrophobic therapeutic agent slows the release rate of the drug from the drug delivery composition, thereby slowing the drug delivery rate of the drug delivery composition. As used herein, the term "polymer affinity" refers to the strength of the nonpolar intermolecular interactions between the hydrophobic units of the copolymer and the therapeutic agent. In certain embodiments, the hydrophobic units can be aliphatic chains, such as methyl, ethyl, or propyl, or aromatic rings, such as phenyl.

[0087] In certain embodiments, the drug delivery rate of a drug delivery composition can be more precisely tuned by adjusting the polymer affinity and the copolymer's swelling property. For example, in certain embodiments, the water absorption rate can be controlled by the amount of crosslinker added to the drug delivery composition. In certain embodiments, the copolymer can be a polyvinylpyridine-based copolymer, such as a polyvinylpyridine-co-polystyrene polymer. When a crosslinker, such as diglycidyl-PEG or glycerol triglycidyl ether, crosslinks the copolymer backbone through bonding to the nitrogen atoms of the pyridine units of the copolymer, a positive charge is formed on the copolymer backbone. When the drug delivery composition contacts tissue to form a hydrogel, the positive charge facilitates water absorption. Increasing the amount of crosslinker in the drug delivery composition increases the positive charge formed on the copolymer backbone, which increases the water permeability, thereby increasing the swelling property of the drug delivery composition and the diffusion of the therapeutic agent. As a result, the drug delivery rate of the drug delivery composition increases. As shown in Example 1, increasing the mer% of hydrophobic units in the copolymer increases the affinity of the polymer for hydrophobic therapeutic agents, which facilitates slowing the release of the therapeutic agents from the hydrogel, thereby decreasing the drug delivery rate of the drug delivery composition. Therefore, by balancing the hydrophobic interactions with the water absorption of the drug delivery composition, the drug delivery rate of the drug delivery composition can be precisely tuned.

[0088] Further information regarding polyvinylpyridine-based polymers is provided in U.S. Patent Publication No. 2003 / 0042137 (e.g., Formula 2b), the contents (e.g., amounts) of which are incorporated herein by reference in their entirety. Further information regarding polyvinylpyridine-co-styrene copolymers is provided in U.S. Patent No. 8,761,857, the contents (e.g., amounts) of which are incorporated herein by reference in their entirety. Further information regarding polyvinylpyridine-based polymers and polyvinylpyridine-co-styrene copolymers is provided in U.S. Patent Publication No. 2022 / 0202322 (e.g., Schemes 3-1, 3-2, and 3-3), the contents (e.g., amounts, e.g., paragraphs

[0442] and

[0457] ) of which are incorporated herein by reference in their entirety.

[0089] The present disclosure further provides methods of manufacturing the drug delivery compositions described herein. Referring to Figure 36, certain embodiments provide a method 1000 of manufacturing a drug delivery composition. In certain embodiments, the method 1000 can include a task 1002 of preparing a copolymer described herein (e.g., the copolymer includes multiple copolymer chains, each of which includes a backbone including multiple hydrophilic units and multiple hydrophobic units), a task 1004 of applying a crosslinker and a therapeutic agent to the copolymer, and a task 1006 of crosslinking the crosslinker across at least a portion of the hydrophilic units between each copolymer chain.

[0090] IV. Analyte Sensors A. General Structure of an Analyte Sensor System The present disclosure relates to the incorporation of therapeutic agents into analyte sensors, for example, in vivo analyte sensors, and / or the delivery of therapeutic compositions in the vicinity of the analyte sensor. However, before describing aspects of these embodiments in detail, it is first desirable to describe examples of devices that may be present, for example, in an in vivo analyte monitoring system, as well as examples of their operation, all of which may be used with the embodiments described herein. 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 device to a reader device without prompting, e.g., automatically according to a schedule. As another example, a "flash analyte monitoring" system (or "flash glucose monitoring" system or simply "flash" system) can transfer data from a sensor control device in response to a scan or data request by a reader device equipped with a protocol such as near-field communication (NFC) or radio frequency identification (RFID). In vivo analyte monitoring systems can also operate without the need for fingerstick calibration.

[0091] In vivo analyte monitoring systems can be distinguished from "in vitro" systems, which include a measurement device having a port for receiving an analyte test strip that contacts a biological sample outside the body (i.e., "ex vivo") and typically carries a user's bodily fluid that can be analyzed to determine the analyte level in the user's blood. In-vivo monitoring systems may include sensors that contact a user's bodily fluids while deployed in vivo and sense the level of analytes contained therein. The sensors may be part of a sensor control device that resides on the user's body and includes electronic circuitry and a power source that enable and control the sensing of the analyte. Sensor control devices and variations thereof may also be referred to as "sensor control units," "on-body electronics" devices or units, "on-body" devices or units, or "sensor data communication" devices or units, to name a few. An in-vivo monitoring system may also include a device that accepts sensed analyte data from the sensor control device, processes the sensed analyte data, and / or presents it to a user in any number of forms. This device and variations thereof may be referred to as a "handheld reader device," a "reader device" (or simply "reader"), a "handheld electronic circuit" (or simply "handheld"), a "portable data processing" device or unit, a "data receiver," a "receiver" device or unit (or simply "receiver"), or a "remote" device or unit, to name a few. Other devices, such as personal computers, have also been utilized in conjunction with or incorporated into in-vivo and in-vitro monitoring systems.

[0092] FIG. 37 provides a schematic diagram of an illustrative sensing system that can incorporate the analyte sensors of the present disclosure. As shown, sensing system 100 includes a sensor control device 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, one-way or two-way, and encrypted or unencrypted. According to certain embodiments, reader device 120 may provide an output medium for reviewing analyte concentrations and alerts or notifications determined by sensor 104 or its associated processor, as well as allowing one or more inputs from a user. Reader device 120 may be a general-purpose smartphone or a dedicated electronic reader device. While only one reader device 120 is shown, multiple reader devices 120 may be present in certain cases. Reader device 120 can communicate with remote terminal 170 and / or trusted computer system 180 via communication path / link 141 and / or 142, each of which may also be wired or wireless, unidirectional or bidirectional, and encrypted or unencrypted. Reader device 120 can also or alternately communicate with network 150 (e.g., a mobile telephone network, the Internet, or a cloud server) via communication path / link 151. Network 150 can further be communicatively coupled to remote terminal 170 via communication path / link 152 and / or to trusted computer system 180 via communication path / link 153. Alternately, sensor 104 can communicate directly with remote terminal 170 and / or trusted computer system 180 without the presence of an intervening reader device 120. For example, but not by way of limitation, in certain embodiments, the sensor 104 may communicate with a remote terminal 170 and / or a trusted computer system 180 via a direct communication link to the network 150, as described in U.S. Patent Application Publication No. 2011 / 0213225, which is incorporated herein by reference in its entirety.Any suitable electronic communication protocol may be used for each communication path or link, such as near field communication (NFC), radio frequency identification (RFID), BLUETOOTH® or BLUETOOTH® low energy protocol, WiFi, or other. According to certain embodiments, the remote terminal 170 and / or trusted computer system may be accessible by individuals other than the primary user who are interested in the user's analyte levels. The reader device 120 may include a display 122 and optional input component 121. According to certain embodiments, the display 122 may include a touchscreen interface.

[0093] The sensor control device 102 includes a sensor housing 103 that can house circuitry and a power source for operating the sensor 104. The power source and / or active circuitry can optionally be omitted. A processor (not shown) can be communicatively coupled to the sensor 104, the processor being physically located within the sensor housing 103 or the reader device 120. According to certain embodiments, the sensor 104 protrudes from an underside of the sensor housing 103 and extends through an adhesive layer 105 adapted to adhere the sensor housing 103 to a tissue surface, such as skin.

[0094] B. Analyte Sensor Tail The sensor 104 of FIG. 37 is adapted to be at least partially inserted into a tissue of interest, such as the skin or the subcutaneous layer of the skin. The sensor 104 may include a sensor tail of sufficient length to insert to a desired depth into a given tissue. The sensor tail may include at least one working electrode. In certain embodiments, the sensor tail may include two working electrodes. In certain configurations, the sensor tail may include an active area for detecting an analyte, for example, on the working electrode. There may be a counter electrode in combination with the at least one working electrode. Specific electrode configurations on the sensor tail are described in more detail below.

[0095] As described in more detail below, active areas can be configured to detect specific analytes. For example, but not by way of limitation, the analytes can be glucose, ketones, lactate, alcohol, glutamate, creatinine, sarcosine, ascorbate, and combinations thereof. For example, but not by way of limitation, a glucose-responsive active area can include a glucose-responsive enzyme, a ketone-responsive active area can include a ketone-responsive enzyme, a lactate-responsive active area can include a lactate-responsive enzyme, an alcohol-responsive active area can include an alcohol-responsive enzyme, a glutamate-responsive active area can include a glutamate-responsive enzyme, a creatine-responsive active area can include a creatine-responsive enzyme system, a sarcosine-responsive active area can include a sarcosine-responsive enzyme system, and an ascorbate-responsive active area can include an ascorbate-responsive enzyme system.

[0096] As also described in more detail below, the active area can be overcoated with a membrane. In certain embodiments, the membrane overcoating the analyte-responsive active area can function as a mass transport limiting membrane and / or to improve biocompatibility. The mass transport limiting membrane can act as a diffusion-limiting barrier to reduce the rate of mass transport of the analyte. For example, but not by way of limitation, limiting the access of the analyte to the analyte-responsive active area with a mass transport limiting membrane helps avoid overloading (saturation) of the sensor, thereby improving detection performance and accuracy. In certain embodiments, the membrane comprises a copolymer of the present disclosure. In certain embodiments of the present disclosure, one or more analytes 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, amniotic fluid, etc. In certain embodiments, the analyte sensors of the present disclosure are adapted to assay skin fluid or interstitial fluid, and the concentration of one or more analytes can be determined in vivo. In certain embodiments, the biological fluid is interstitial fluid.

[0097] Still referring to FIG. 37 , the sensor 104 can automatically transmit data to the reader device 120. For example, but not by way of limitation, analyte concentration data can be automatically and periodically transmitted at a certain frequency, such as when the data is acquired or after a certain period of time has elapsed, with the data stored in memory until transmission (e.g., every minute, every five minutes, or some other predetermined time). In certain embodiments, the sensor 104 can communicate with the reader device 120 in a non-automated manner and not on a set schedule. For example, but not by way of limitation, data can be transmitted from the sensor 104 using RFID technology when the sensor's electronics come within range of the reader device 120. The data can remain stored in the sensor's 104 memory until transmitted to the reader device 120. That is, a user need not constantly maintain close proximity to the reader device 120, but can instead upload data at their convenience. In certain embodiments, a combination of automated and non-automated data transfer can be performed. For example, but not by way of limitation, data transfer may continue on an automated basis until the reader device 120 is no longer within range of the sensor 104 .

[0098] An introducer may be transiently present to facilitate the introduction of the sensor 104 into the tissue. In certain illustrative embodiments, the introducer may include a needle or similar needle-like object. As those skilled in the art will readily recognize, in alternative embodiments, other types of introducers may be present, such as a sheath or blade. More specifically, the needle or other introducer may be transiently present near the sensor 104 prior to insertion into the tissue and then removed. While present, the needle or other introducer may facilitate the insertion of the sensor 104 into the tissue by opening an access path through which the sensor 104 travels. For example, without limitation, according to one or more embodiments, the needle may facilitate penetration of the epidermis as an access path to the dermis, allowing implantation of the sensor 104 to occur. After opening the access path, the needle or other introducer may be removed so as not to present a needle-like hazard. In certain embodiments, suitable needles may be solid or hollow, beveled or unbeveled, and / or circular or non-circular in cross section. In more particular embodiments, suitable needles may have a cross-sectional diameter and / or tip shape similar to an acupuncture needle having a cross-sectional diameter of about 250 μm, although suitable needles may have a larger or smaller cross-sectional diameter if needed for a particular application.

[0099] In certain embodiments, the tip of the needle (while present) is angled beyond the end of the sensor 104, allowing the needle to penetrate the tissue first and open an access path for the sensor 104. In certain embodiments, the sensor 104 resides within a lumen or channel of the needle, which likewise allows the needle to open an access path for the sensor 104. In either case, the needle is removed after facilitating insertion of the sensor. i. Electrode configuration

[0100] Sensor configurations featuring a single active area configured to detect a corresponding single analyte can employ two-electrode or three-electrode detection motifs, as further described herein with reference to Figures 3 and 53A-53B. Sensor configurations featuring two different active areas for detecting the same or different analytes on separate working electrodes or on the same working electrode are described separately thereafter with reference to Figures 3 and 53A-53C. Sensor configurations with multiple working electrodes can be particularly advantageous for incorporating two different active areas within the same sensor tail, as the signal contribution from each active area can be more easily determined. Where a single working electrode is present in an analyte sensor, a three-electrode sensor configuration may include a working electrode, a counter electrode, and a reference electrode. A related two-electrode sensor configuration includes a working electrode and a second electrode, in which the second electrode may function as both the counter electrode and the reference electrode (i.e., the counter / reference electrode). The various electrodes may be at least partially stacked (layered) on top of each other and / or spaced apart laterally on the sensor tail. Suitable sensor configurations may be substantially planar in shape, substantially cylindrical in shape, 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.

[0101] Analyte sensors featuring multiple working electrodes can also include at least one additional electrode. If one additional electrode is present, it can function as a counter / reference electrode for each of the multiple working electrodes. If two additional electrodes are present, one of the additional electrodes can function as a counter electrode for each of the multiple working electrodes, and the other of the additional electrodes can function as a reference electrode for each of the multiple working electrodes. FIG. 3 shows a schematic diagram of an illustrative two-electrode analyte sensor configuration suitable for use in the present disclosure. As shown, the analyte sensor 200 includes a substrate 212 disposed between a working electrode 214 and a counter / reference electrode 216. Alternately, the working electrode 214 and the counter / reference electrode 216 can be located on the same side of the substrate 212 with a dielectric material interposed therebetween (configuration not shown). An active area 218 is disposed as at least one layer on at least a portion of the working electrode 214. The active area 218 can include multiple spots or a single spot configured to detect analytes at low potentials of the working electrode, as discussed further herein. In certain embodiments, the active area 218 can include an electron transfer agent as described herein.

[0102] 3, film 220 overcoats at least active area 218. In certain embodiments, film 220 comprises a copolymer of the present disclosure. For example, but not by way of limitation, film 220 comprises a copolymer including a first monomer, such as styrene, and a second monomer including a heterocycle-containing component, such as vinylpyridine, e.g., 4-vinylpyridine.

[0103] In certain embodiments, the membrane 220 may overcoat part or all of the working electrode 214 and / or the counter / reference electrode 216, or the entire analyte sensor 200. One or both sides of the analyte sensor 200 may be overcoated with the membrane 220. The membrane 220 may comprise one or more polymeric membrane materials capable of limiting the flux of analyte to the active area 218 (i.e., the membrane 220 is a mass transport limiting membrane with some permeability to the analyte of interest). The composition and thickness of the membrane 220 may be varied to facilitate the flux of the desired analyte to the active area 218, thereby providing the desired signal strength and stability. The analyte sensor 200 may be operable to assay the analyte by any of the following electrochemical detection techniques: coulometric, amperometric, voltammetric, or potentiometric.

[0104] 38A and 38B show schematic diagrams of illustrative three-electrode analyte sensor configurations, also suitable for use in the present disclosure. The three-electrode analyte sensor configuration may be similar to that shown for analyte sensor 200 of FIG. 3 (FIGS. 38A and 38B), except that analyte sensors 201 and 202 include an additional electrode 217. With the additional electrode 217, counter / reference electrode 216 can function as a counter electrode or a reference electrode, and the additional electrode 217 fulfills the function of the other electrode not otherwise fulfilled. Working electrode 214 continues to fulfill its original function. The additional electrode 217 can be disposed on working electrode 214 or electrode 216 with a separating layer of dielectric material therebetween. For example, but not by way of limitation, as shown in FIG. 38A, dielectric layers 219a, 219b, and 219c separate electrodes 214, 216, and 217 from one another and provide electrical insulation. Alternatively, as shown in FIG. 38B , at least one of electrodes 214, 216, and 217 may be located on opposite sides of substrate 212. That is, in certain embodiments, electrode 214 (working electrode) and electrode 216 (counter electrode) are located on opposite sides of substrate 212, and electrode 217 (reference electrode) may be located on one of electrodes 214 or 216 and separated therefrom by a dielectric material. A reference material layer 230 (e.g., Ag / AgCl) may be present on electrode 217, and the location of reference material layer 230 is not limited to that shown in FIGS. 38A and 38B . Similar to sensor 200 shown in FIG. 3 , active area 218 in analyte sensors 201 and 202 may include multiple spots or a single spot. In certain embodiments, active area 218 may include a redox mediator disclosed herein. Additionally, analyte sensors 201 and 202 may be operable to assay analytes by any of the following electrochemical detection techniques: coulometric, amperometric, voltammetric, or potentiometric.

[0105] Similar to analyte sensor 200, membrane 220 may overcoat active area 218 and other sensor components in analyte sensors 201 and 202, thereby acting as a mass transport limiting membrane. In certain embodiments, additional electrode 217 may be overcoated with membrane 220. While FIGS. 38A and 38B depict electrodes 214, 216, and 217 as being overcoated with membrane 220, it should be appreciated that in certain embodiments, only working electrode 214 is overcoated. Furthermore, the thickness of membrane 220 may be the same or different for each of electrodes 214, 216, and 217. Similar to the two-electrode analyte sensor configuration (FIG. 3), in the sensor configuration of FIGS. 38A and 38B, one or both sides of analyte sensors 201 and 202 may be overcoated with membrane 220, or the entire analyte sensors 201 and 202 may be overcoated. Therefore, it should be understood that the three-electrode sensor configuration shown in Figures 38A and 38B is a non-limiting example of the embodiments disclosed herein, and that alternative electrode and / or layer configurations remain within the scope of the present disclosure.

[0106] FIG. 39A shows an illustrative configuration of a sensor 203 having a single working electrode with two distinct active areas disposed therein. FIG. 39A is similar to FIG. 3 except that there are two active areas on the working electrode 214: a first active area 218a and a second active area 218b. These active areas are associated with the same or different analytes and are laterally separated from one another on the surface of the working electrode 214. The active areas 218a and 218b may include multiple spots or a single spot configured to detect each analyte. The composition of the membrane 220 may vary or be compositionally identical in the active areas 218a and 218b. The first active area 218a and the second active area 218b may be configured to detect their corresponding analytes at different working electrode potentials, as discussed further below.

[0107] 39B and 39C show cross-sectional schematic views of illustrative three-electrode sensor configurations for sensors 204 and 205, respectively, each featuring a single working electrode with a first active area 218a and a second active area 218b disposed thereon. FIGS. 39B and 39C are otherwise similar to FIGS. 39B and 39C and can be better understood by reference thereto. As in FIG. 39A, the composition of membrane 220 may vary or be compositionally identical in active areas 218a and 218b. In certain embodiments, both active areas 218a and 218b may include a redox mediator described herein. In certain embodiments, only one of active areas 218a and 218b may include a redox mediator described herein. For example, but not by way of limitation, only active area 218a includes a redox mediator described herein. In certain embodiments, only active area 218b includes a redox mediator described herein. In certain embodiments, both active areas 218a and 218b include a redox mediator as described herein. In certain embodiments, the electron transfer agent present in active area 218a is different from the redox mediator present in 218b. Alternatively, the electron transfer agent present in active area 218a is the same redox mediator present in 218b.

[0108] Illustrative sensor configurations having multiple working electrodes, specifically two working electrodes, are described in more detail with reference to Figures 2A-2C and 40. While the following description is primarily directed to sensor configurations having two working electrodes, it should be recognized that extensions of the disclosure herein can incorporate three or more working electrodes. The use of working electrodes can provide additional sensing capabilities to the analyte sensor beyond just the first analyte and second analyte.

[0109] 40 shows a cross-sectional schematic diagram of an illustrative analyte sensor configuration suitable for use in the present disclosure, having two working electrodes, a reference electrode, and a counter electrode. As shown, analyte sensor 300 includes working electrodes 304 and 306 disposed on opposite sides of substrate 302. A first active area 310a is disposed on the surface of working electrode 304, and a second active area 310b is disposed on the surface of working electrode 306. Counter electrode 320 is electrically insulated from working electrode 304 by dielectric layer 322, and reference electrode 321 is electrically insulated from working electrode 306 by dielectric layer 323. Outer dielectric layers 330 and 332 are disposed on reference electrode 321 and counter electrode 320, respectively. According to various embodiments, a membrane 340 can overcoat at least active areas 310a and 310b, along with other components of analyte sensor 300 or the entire analyte sensor 300. In certain embodiments, the membrane 340 comprises a copolymer of the present disclosure. For example, but not by way of limitation, the membrane 340 comprises a copolymer including a first monomer, such as styrene, and a second monomer including a heterocycle-containing component, such as vinylpyridine, e.g., 4-vinylpyridine.

[0110] In certain embodiments, the membrane 340 may be continuous but may vary in composition over the active area 310a and / or the active area 310b to provide different permeability values ​​at each location and differentially control analyte flux. For example, but not by way of limitation, one or more electrodes may be overcoated with a first membrane portion 340a and / or a second membrane portion 340b. In certain embodiments, different membrane formulations may be sprayed and / or printed on opposing sides of the analyte sensor 300. Dip-coating techniques may also be suitable, particularly for depositing at least a portion of a bilayer membrane over one of the active areas 310a and 310b. In certain embodiments, the membrane 340 may be identical or may vary in composition over the active areas 310a and 310b. For example, but not by way of limitation, the membrane 340 may include a bilayer overcoating the active area 310a and may be a homogeneous membrane overcoating the active area 310b, or the membrane 340 may include a bilayer overcoating the active area 310b and may be a homogeneous membrane overcoating the active area 310a. In certain embodiments, one of the first membrane portion and the second membrane portion may include a bilayer membrane, while the other of the first membrane portion and the second membrane portion may include a single membrane polymer, according to certain embodiments of the present disclosure. In certain embodiments, the analyte sensor may include more than one membrane 340, e.g., two or more membranes. For example, but not by way of limitation, the analyte sensor may include a membrane overcoating one or more active areas, e.g., 310a and 310b, and an additional membrane overcoating the entire sensor, as shown in FIG. 40 . In such a configuration, a bilayer membrane may be formed on one or more active areas, e.g., 310a and 310b. In certain embodiments, the two films can have different polymer compositions. For example, but not by way of limitation, the first film can include a copolymer of the present disclosure, and the second film can include a different polymer. In certain embodiments, either active area 310a or 310b can include an electron transfer agent described herein. In certain embodiments, only one of active areas 310a or 310b can include a redox mediator described herein.For example, but not by way of limitation, only active area 310a includes a redox mediator described herein. In certain embodiments, only active area 310b includes a redox mediator described herein. In certain embodiments, both active areas 310a and 310b include a redox mediator described herein. In certain embodiments, the redox mediator present in active area 310a is different from the electron transfer agent present in 310b. Alternatively, the redox mediator present in active area 310a is the same electron transfer agent present in 310b.

[0111] Alternative sensor configurations having multiple working electrodes and differing from the configuration shown in Figure 40 may feature counter / reference electrodes instead of separate counter and reference electrodes 320 and 321, and / or may feature layer and / or film arrangements that differ from those explicitly illustrated. For example, without limitation, the arrangement of counter and reference electrodes 320 and 321 may be reversed from that shown in Figure 40. Additionally, working electrodes 304 and 306 need not necessarily be on opposite sides of substrate 302 in the manner shown in Figure 40.

[0112] While preferred sensor configurations may feature electrodes of a substantially planar nature, it should be recognized that sensor configurations featuring non-planar electrodes may be advantageous and particularly suitable for use in the present disclosure. In particular, substantially cylindrical electrodes arranged coaxially with one another may facilitate deposition of a mass transport limiting membrane, as described herein below. For example, but not by way of limitation, coaxial working electrodes spaced apart along the length of the sensor tail may facilitate deposition of the membrane by sequential dip-coating operations in the same manner as described above for substantially planar sensor configurations. Figures 2A-2C show perspective views of analyte sensors featuring two working electrodes arranged coaxially with one another. It should be recognized that sensor configurations having a coaxial electrode arrangement but lacking a second working electrode are also possible in the present disclosure.

[0113] 2A shows a perspective view of an illustrative sensor configuration in which multiple electrodes are substantially cylindrical and coaxially arranged relative to a central substrate. As shown, the analyte sensor 400 includes a central substrate 402 around which all of the electrodes and dielectric layers are coaxially arranged relative to one another. In particular, a working electrode 410 is disposed on the surface of the central substrate 402, and a dielectric layer 412 is disposed over a portion of the working electrode 410 distal to the sensor tip 404. A working electrode 420 is disposed over the dielectric layer 412, and a dielectric layer 422 is disposed over a portion of the working electrode 420 distal to the sensor tip 404. A counter electrode 430 is disposed over the dielectric layer 422, and a dielectric layer 432 is disposed over a portion of the counter electrode 430 distal to the sensor tip 404. A reference electrode 440 is disposed over the dielectric layer 432, and a dielectric layer 442 is disposed over a portion of the reference electrode 440 distal to the sensor tip 404. Thus, the exposed surfaces of working electrode 410 , working electrode 420 , counter electrode 430 , and reference electrode 440 are spaced apart from one another along the longitudinal axis B of analyte sensor 400 .

[0114] Still referring to FIG. 2A , first and second active areas 414a and 414b associated with different analytes are disposed on the exposed surfaces of working electrodes 410 and 420, respectively, allowing contact with the fluid for sensing. While active areas 414a and 414b are depicted as three discrete spots in FIG. 2A , it should be appreciated that there may be fewer or more than three spots, including a continuous layer of active areas, in alternative sensor configurations. In certain embodiments, either one of active areas 414a and 414b may include an electron transfer agent described herein. In certain embodiments, only one of active areas 414a and 414b may include a redox mediator described herein. For example, but not by way of limitation, only active area 414a includes a redox mediator described herein. In certain embodiments, only active area 414b includes a redox mediator described herein. In certain embodiments, both active areas 414a and 414b include a redox mediator described herein. In certain embodiments, the redox mediator present in active area 414a is different from the electron transfer agent present in 414b, or alternatively, the redox mediator present in active area 414a is the same electron transfer agent present in 414b.

[0115] In FIG. 2A, the sensor 400 is partially coated with a film 450 over the working electrodes 410 and 420 and the active areas 414a and 414b disposed thereon. FIG. 2B illustrates an alternative sensor configuration in which substantially the entire sensor 401 is overcoated with the film 450. The film 450 may be the same as or compositionally different from the active areas 414a and 414b. For example, the film 450 may include a bilayer overcoating the active area 414a or may be a homogeneous film overcoating the active area 414b. In certain embodiments, the film 450 comprises a copolymer of the present disclosure. For example, but not by way of limitation, the film 450 may comprise a copolymer including a first monomer, such as styrene, and a second monomer including a heterocycle-containing moiety, such as vinylpyridine, e.g., 4-vinylpyridine.

[0116] It should be further recognized that the arrangement of the various electrodes in FIGS. 2A and 2B may differ from that explicitly depicted. For example, the locations of the counter electrode 430 and reference electrode 440 may be reversed from the configurations depicted in FIGS. 2A and 2B. Similarly, the locations of the working electrodes 410 and 420 are not limited to those explicitly depicted in FIGS. 2A and 2B. FIG. 2C illustrates an alternative sensor configuration to that shown in FIG. 2B, in which a sensor 405 includes a counter electrode 430 and a reference electrode 440 located proximal to the sensor tip 404, and working electrodes 410 and 420 located distal to the sensor tip 404. A sensor configuration in which the working electrodes 410 and 420 are located distal to the sensor tip 404 may be advantageous by providing a larger surface area for deposition of active areas 414a and 414b (five discrete sensing spots illustratively shown in FIG. 2C), thereby facilitating increased signal strength in some instances. Similarly, the central substrate 402 can be omitted in any of the coaxial sensor configurations disclosed herein and can instead support a layer onto which the innermost electrodes are subsequently deposited.

[0117] In certain embodiments, one or more electrodes of the analyte sensors described herein are wire electrodes, e.g., permeable wire electrodes. In certain embodiments, the sensor tail includes a working electrode and a reference electrode spirally wound around the working electrode. In certain embodiments, an insulator is disposed between the working electrode and the reference electrode. In certain embodiments, a portion of the electrode is exposed to allow reaction of one or more enzymes with the analyte on the electrode. In certain embodiments, each electrode is formed from a fine wire having a diameter of about 0.001 inch or less to about 0.010 inch or more. In certain embodiments, the working electrode has a diameter of about 0.001 inch or less to about 0.010 inch or more, e.g., about 0.002 inch to about 0.008 inch, or about 0.004 inch to about 0.005 inch. In certain embodiments, the electrodes are formed from plated insulators, plated wire, or bulk conductive material. In certain embodiments, the working electrode comprises a wire formed from platinum, platinum-iridium, palladium, graphite, gold, carbon, a conductive polymer, an alloy, or other conductive material. In certain embodiments, the conductive material is a transparent conductive material. In certain embodiments, the electrode can be formed by various manufacturing techniques (e.g., bulk metal processing, deposition of metal on a substrate, etc.). The electrode can be formed from a plated wire (e.g., platinum or steel wire) or a bulk metal (e.g., platinum wire). In certain embodiments, the electrode can be formed from, for example, a platinum-coated tantalum wire.

[0118] In certain embodiments, the reference electrode, which can function as a reference electrode alone or as a dual electrode countered by a reference, is formed from silver, silver / silver chloride, or the like. In certain embodiments, the reference electrode is juxtaposed to and / or intertwined with or surrounding the working electrode. In certain embodiments, the reference electrode is spirally wound around the working electrode. In certain embodiments, the wire assembly may be coated with or glued together with an insulating material to provide an insulating bond.

[0119] In certain embodiments, additional electrodes can be included in the sensor tail. For example, but not by way of limitation, the analyte sensors of the present disclosure can include a three-electrode system (working electrode, reference electrode, and counter electrode) and / or an additional working electrode (e.g., an electrode for detecting a second analyte). In certain embodiments in which the sensor includes two working electrodes, the two working electrodes can be juxtaposed, with the reference electrode disposed therearound (e.g., spirally wound around the two or more working electrodes). In certain embodiments, the two or more working electrodes can extend parallel to one another. In certain embodiments, the reference electrode is wrapped around the working electrode and extends toward the distal end (i.e., the in vivo end) of the sensor tail. In certain embodiments, the reference electrode extends (e.g., spirally) into the exposed region of the working electrode.

[0120] In certain embodiments, one or more working electrodes are spirally wound around the 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 spiral configuration along the length of the sensor tail (e.g., surrounding the reference electrode, insulating rod, or other support structure). In certain embodiments, the electrodes, e.g., two or more working electrodes, are formed coaxially. For example, but not by way of limitation, the electrodes all share the same central axis.

[0121] In certain embodiments, the working electrode comprises a tube within which a reference electrode, including an insulator, is disposed or wound. Alternatively, the reference electrode comprises a tube within which a working electrode, including an insulator, is disposed or wound. In certain embodiments, a polymeric (e.g., insulating) rod is provided, and one or more electrodes (e.g., one or more electrode layers) are disposed thereon (e.g., by electroplating). In certain embodiments, a metal (e.g., steel or tantalum) rod or wire is provided that is coated with an insulating material (as described herein) and has one or more working and reference electrodes disposed thereon. For example, but not by way of limitation, the present disclosure provides sensors, e.g., sensor tails, comprised of one or more tantalum wires, with a conductive material disposed over a portion of the one or more tantalum wires to function as the working electrode. In certain embodiments, a platinum-clad tantalum wire is coated with an insulating material, which is partially coated with a silver / silver chloride composition to function as the reference and / or counter electrode.

[0122] In certain embodiments where an insulator is disposed on a working electrode (e.g., on the platinum surface of the electrode), a portion of the insulator can be stripped or otherwise removed to expose the electrically active surface of the working electrode. For example, but not limited to, the portion of the insulator can be removed manually, by excimer laser, chemical etching, laser ablation, grit blasting, or other methods. Alternatively, to maintain an exposed electrically active surface area, a portion of the electrode can be masked before depositing the insulator. In certain embodiments, the portion of the insulator that is stripped and / or removed can be about 0.1 mm or less to about 2 mm or more in length, e.g., about 0.5 mm to about 0.75 mm in length. In certain embodiments, the insulator is a non-conductive polymer. In certain embodiments, the insulator includes parylene, fluorinated polymers, polyethylene terephthalate, polyvinylpyrrolidone, polyurethane, polyimide, and other non-conductive polymers. In certain embodiments, glass or ceramic materials can also be used in the insulating layer. In certain embodiments, the insulator includes parylene. In certain embodiments, the insulator includes polyurethane. In one particular embodiment, the insulator comprises polyurethane and polyvinylpyrrolidone.

[0123] ii. Sensing chemistry The analyte sensors of the present disclosure may include one or more enzymes for detecting one or more analytes. In certain embodiments, the active area of ​​the analyte sensors of the present disclosure, for example, disposed on the working electrode, can be configured for detecting one or more analytes. In certain embodiments, the active area includes one or more enzymes for detecting the analytes. In certain embodiments, the analyte sensors of the present disclosure may include two or more active areas, each configured to detect the same or different analytes. In certain embodiments, the sensor does not include an enzyme, and the analyte is oxidized directly at the working electrode.

[0124] In certain embodiments, the active area of ​​a sensor of the present disclosure may be a sensor that detects, but is not limited to, glucose, lactate, ketones (e.g., ketone bodies), glutamine, alcohol, aspartate, asparagine, glutamate, creatinine, hematocrit, acetoacetate, fructosamine, amylase, bilirubin, cholesterol, chorionic gonadotropin, 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, monkey The assay may include one or more enzymes for detecting analytes including cocine, prostate-specific antigen, prothrombin, thrombin, troponin, pyruvate, acetaldehyde, ascorbate, galactose, L-xylono-1,4-lactone, glutathione disulfide, hydrogen peroxide, linoleate, 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), drugs of abuse (e.g., analgesics, depressants, stimulants, and hallucinogens), metal ions (e.g., potassium, sodium, calcium, magnesium, manganese, iron, cobalt, molybdenum, zinc, and chloride), pH, carbonate, phosphate, sulfate, fatty acids, and antibodies. In certain embodiments, the analyte is glucose, glutamate, creatinine, sarcosine, and / or ascorbate. In certain embodiments, the analyte is glucose. In certain embodiments, the analyte is glutamate.In certain embodiments, one or more enzymes in the active area of ​​the sensors of the present disclosure can be used in the detection of glutamate, glucose, ketone, lactate, oxygen, hemoglobin A1C, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartate, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, and uric acid.

[0125] In certain embodiments, the one or more enzymes can include multiple enzymes, eg, an enzyme system, that are collectively responsive to the analyte. In certain embodiments, the enzyme may be an oxidoreductase. In certain embodiments, the oxidoreductase may be an enzyme belonging to enzyme class 1. For example, but not by way of limitation, the enzyme may belong to enzyme class 1.1 (e.g., 1.1.1 or 1.1.3), enzyme class 1.4 (e.g., 1.4.3), or enzyme class 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 class 3. For example, but not by way of limitation, the enzyme may belong to enzyme class 3.5, e.g., 3.5.2 or 3.5.3.

[0126] In certain embodiments, the active area of ​​a sensor of the present disclosure may include one or more enzymes that can be utilized to detect glucose. For example, but not by way of limitation, an analyte sensor of the present disclosure may include one or more enzymes for detecting glucose. In certain embodiments, the analyte sensor may include glucose oxidase and / or glucose dehydrogenase for detecting glucose. In certain embodiments, the analyte sensor may include glucose oxidase. In certain embodiments, the glucose dehydrogenase may be a pyrroloquinoline quinone (PQQ) or cofactor-dependent glucose dehydrogenase, such as flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenase or nicotinamide adenine dinucleotide (NAD)-dependent glucose dehydrogenase. In certain embodiments, the active area may further include diaphorase. In certain embodiments, the enzyme for detecting glucose is FAD-dependent glucose oxidase.

[0127] In certain embodiments, the active area of ​​a sensor of the present disclosure may include one or more enzymes that can be utilized to detect ketones. For example, but not by way of limitation, an analyte sensor of the present disclosure may include one or more enzymes, such as an enzyme system, for detecting ketones. In certain embodiments, a ketone-responsive active area may include an enzyme system comprising multiple enzymes that can act in concert to facilitate the detection of ketones, such as those described in U.S. Patent Publication No. 2020 / 0237275 (the contents of which are incorporated herein by reference in their entirety). In certain embodiments, the analyte sensor may include β-hydroxybutyrate dehydrogenase. In certain embodiments, the active area may further include diaphorase. In certain embodiments, the analyte sensor may include β-hydroxybutyrate dehydrogenase and diaphorase to detect ketones.

[0128] In certain embodiments, the active area of ​​a sensor of the present disclosure may include one or more enzymes that can be utilized to detect lactate. For example, but not by way of limitation, an analyte sensor of the present disclosure may include one or more enzymes, such as an enzyme system, for detecting lactate. In certain embodiments, a lactate-responsive active area may include an enzyme system comprising multiple enzymes that can act in concert to facilitate the detection of lactate, as described in U.S. Publication No. 2019 / 0320947 (the contents of which are incorporated herein by reference in their entirety). In certain embodiments, the analyte sensor may include lactate dehydrogenase. In certain embodiments, the analyte sensor may include lactate oxidase. In certain embodiments, the active area may further include diaphorase. In certain embodiments, the analyte sensor may include lactate oxidase and diaphorase.

[0129] In certain embodiments, the active area of ​​the sensor of the present disclosure may include one or more enzymes that can be utilized to detect alcohol. For example, but not by way of limitation, the analyte sensor of the present disclosure may include one or more enzymes, such as an enzyme system, for detecting alcohol. In certain embodiments, the ethanol-responsive active area may include an enzyme system including multiple enzymes that can act in concert to facilitate the detection of ethanol, as in U.S. Patent Publication No. 2020 / 0237277 (the contents of which are incorporated herein by reference in their entirety). In certain embodiments, the analyte sensor may include alcohol dehydrogenase or ketoreductase.

[0130] In certain embodiments, the active area of ​​a sensor of the present disclosure may include one or more enzymes that can be utilized to detect creatinine. For example, but not by way of limitation, an analyte sensor of the present disclosure may include one or more enzymes, such as an enzyme system, for detecting creatinine. In certain embodiments, a creatinine-responsive active area may include an enzyme system including multiple enzymes that can act in concert to facilitate the detection of creatinine, as described in U.S. Patent Publication No. 2020 / 0241015 (the contents of which are incorporated herein by reference in their entirety). In certain embodiments, the analyte sensor may include amidohydrolase, creatine amidinohydrolase, and / or sarcosine oxidase. In certain embodiments, the active area of ​​a sensor of the present disclosure can include one or more enzymes that can be utilized to detect glutamate. For example, but not by way of limitation, an analyte sensor of the present disclosure can include one or more enzymes, e.g., an enzyme system, for detecting glutamate. In certain embodiments, the analyte sensor can include glutamate dehydrogenase or glucose oxidase.

[0131] In certain embodiments, the active area of ​​the present disclosure may include one or more sensing spots (e.g., as shown at 218a and 218b in Figure 39A), each of which may include one or more enzymes for detecting an analyte. In certain embodiments, the active area may further comprise a stabilizer, for example, to stabilize one or more enzymes. For example, but not by way of limitation, the stabilizer may be albumin, such as serum albumin. Non-limiting examples of serum albumin may 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. In certain embodiments, the active area may further comprise a cofactor or coenzyme for one or more enzymes present in the active area. 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.

[0132] In certain embodiments, the sensors of the present disclosure do not include an analyte-responsive active area that includes an enzyme. In certain embodiments, the sensors of the present disclosure include a working electrode that does not have an enzyme disposed thereon or that includes an inactive enzyme disposed thereon, e.g., an enzyme that lacks enzymatic activity (e.g., toward the analyte of interest). In certain embodiments, such sensors can be used to detect analytes that can be directly oxidized at the working electrode. For example, but not by way of limitation, a sensor of the present disclosure for detecting ascorbate does not include an enzyme on the working electrode. In certain embodiments, ascorbate is directly oxidized at the working electrode, resulting in a signal that correlates with the level of ascorbate in a biological fluid in contact with the sensor.

[0133] In certain embodiments, a working electrode containing no enzyme or an inactive enzyme can be used to detect background signals. In certain embodiments, the background signal includes signals caused by chemical species other than the analyte of interest present in the sample, such as signals caused by interferents. In certain embodiments, the background signal is a signal caused by one or more interferents. Non-limiting examples of interferents include acetaminophen, ascorbate, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, urea, and uric acid. In certain embodiments, the background signal can be used to calibrate, filter, and / or normalize signals obtained from a second working electrode (configured to detect the analyte) present on the same analyte sensor. In certain embodiments, the signal from a working electrode without an enzyme (or with an inactive enzyme) can be subtracted from the signal obtained from a working electrode configured to detect an analyte to determine the signal contribution from the analyte.

[0134] In certain embodiments, the analyte sensors disclosed herein can include an electron transfer agent. For example, but not by way of limitation, the active area can include an electron transfer agent. In certain embodiments, the presence of the electron transfer agent in the active area can depend on the enzyme or enzyme system used to detect the analyte and / or the composition of the working electrode. Electron transfer agents suitable for use in the presently disclosed analyte sensors can facilitate the transport of electrons to a nearby working electrode after the analyte undergoes an enzymatic redox reaction in the active area, thereby generating a current that is indicative of the presence of that particular analyte, the amount of current produced being proportional to the amount of analyte present.

[0135] In certain embodiments, suitable electron transfer agents may include electroreducible and electrooxidizable ions, complexes, or molecules (e.g., quinones) with redox potentials that are several hundred millivolts above or below 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. Pat. Nos. 6,134,461 and 6,605,200, the disclosures of which are incorporated herein by reference in their entireties. Further examples of suitable redox mediators may include those described in U.S. Pat. Nos. 6,736,957, 7,501,053, and 7,754,093, the disclosures of each of which are also incorporated herein by reference in their entireties. Other examples of suitable redox mediators may include metal compounds or complexes of ruthenium, osmium, iron (e.g., polyvinylferrocene or hexacyanoferrate), or cobalt, including, for example, metallocene compounds thereof. Suitable ligands for metal complexes can include, for example, bidentate or higher dentate ligands, such as bipyridine, biimidazole, phenanthroline, or pyridyl (imidazole). Other suitable bidentate ligands can include, for example, amino acids, oxalic acid, acetylacetone, diaminoalkanes, or o-diaminoarenes. Any combination of monodentate, bidentate, tridentate, tetradentate, or higher dentate ligands can be present in a metal complex, such as an osmium complex, to achieve 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.

[0136] In certain embodiments, the electron transfer agents disclosed herein can include suitable functionality to facilitate covalent attachment to a polymer (also referred to herein as the polymer backbone) in the active area, as discussed further below. For example, but not by way of limitation, electron transfer agents for use in the present disclosure can 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. Patent Nos. 8,444,834, 8,268,143, and 6,605,201, and U.S. Patent Publication No. 2022 / 0202326, the disclosures of which are incorporated herein by reference in their entireties. In certain embodiments, the electron transfer agent is a bidentate osmium complex attached to a polymer described herein, such as a polymer backbone described in Section 4 below. In certain embodiments, the electron transfer agent is a tridentate osmium complex attached to a polymer described herein, such as a polymer backbone described in Section 4 below. In certain embodiments, the polymer-bound electron transfer agent shown in Figure 3 of US Patent No. 8,444,834 (designated "X7") can be used in the sensors of the present disclosure.

[0137] In certain embodiments, one or more working electrodes of an analyte sensor of the present disclosure do not have a redox mediator disposed thereon. In certain embodiments, one or more working electrodes of an analyte sensor of the present disclosure do not have a redox mediator or enzyme disposed thereon. In certain embodiments, such working electrodes can be used to detect analytes that can be directly oxidized at the working electrode.

[0138] iii. Substance limiting membrane In certain embodiments, the analyte sensor of the present disclosure further comprises a membrane covering at least a portion of the sensing layer. For example, but not by way of limitation, the membrane can function as a substance-limiting membrane and / or to improve biocompatibility. In certain embodiments, the membrane (e.g., 220 in FIG. 3) can overcoat at least a portion of the active area.

[0139] The substance limiting membrane can act as a diffusion-limiting barrier to reduce the rate of mass transport of an analyte, such as glucose, alcohol, ketone, or lactate, when the sensor is in use. For example, but not by way of limitation, limiting the access of an analyte, such as glucose, to the sensing spot with the substance limiting membrane helps to avoid sensor overload (saturation), thereby improving detection performance and accuracy. In certain embodiments, the substance limiting layer can limit the flux of analyte to the working electrode in an electrochemical sensor, thereby enabling the sensor to have a linear response over a wide range of analyte concentrations.

[0140] In certain embodiments, the substance limiting membrane may be homogeneous and single-component (comprising a single membrane polymer). In certain embodiments, the substance limiting membrane may be multi-component (comprising two or more different membrane polymers). In certain embodiments, the multi-component membrane may exist as a bilayer membrane or as a homogeneous mixture of two or more membrane polymers. A homogeneous mixture may be deposited by combining two or more membrane polymers in solution and then depositing the solution onto the working electrode, for example, by dip coating. In certain embodiments, the substance restriction membrane may comprise two or more layers, such as a bilayer or trilayer membrane, in which each layer may comprise a different polymer or different concentrations or thicknesses of the same polymer. In certain embodiments, the substance restriction membrane may comprise a polymer containing a heterocyclic nitrogen group. In certain embodiments, the substance restriction membrane may comprise a polyvinylpyridine-based polymer. Non-limiting examples of polyvinylpyridine-based polymers are disclosed in U.S. Patent Publication No. 2003 / 0042137, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the polyvinylpyridine-based polymer has a molecular weight of about 50 kD to about 500 kD, for example, about 50 kD to about 200 kD.

[0141] In certain embodiments, the substance restriction membrane may comprise polyvinylpyridine (e.g., poly(2-vinylpyridine) or poly(4-vinylpyridine)), polyvinylimidazole, polyvinylpyridine copolymers (e.g., copolymers of vinylpyridine and styrene), polyacrylate, polyurethane, polyetherurethane, silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, polyurethane homopolymers, copolymers, or terpolymers, polypropylene, polyvinyl chloride, polyvinylidene difluoride, polybutylene terephthalate, polymethyl methacrylate, polyether ether ketone, cellulose polymers, polysulfone, and block copolymers thereof, including, for example, diblock, triblock, alternating, random, and graft copolymers, or chemically related materials.

[0142] In certain embodiments, the substance restriction membrane can comprise polyvinylpyridine (e.g., poly(4-vinylpyridine) and / or poly(2-vinylpyridine)). In certain embodiments, the substance restriction membrane can comprise poly(4-vinylpyridine). In certain embodiments, the substance restriction membrane can comprise a copolymer of vinylpyridine and styrene. In certain embodiments, the substance restriction membrane can comprise a polyvinylpyridine-co-styrene copolymer. For example, but not by way of limitation, the polyvinylpyridine-co-styrene copolymer can include a portion in which a portion of the pyridine nitrogen atoms are functionalized with a non-crosslinked polyethylene glycol tail and a portion of the pyridine nitrogen atoms are functionalized with an alkylsulfonic acid group, e.g., propylsulfonic acid. In certain embodiments, a derivatized polyvinylpyridine-co-styrene copolymer for use as a membrane polymer can be the 10Q5 polymer described in U.S. Pat. No. 8,761,857, the contents of which are incorporated herein by reference in their entirety.

[0143] Suitable copolymers of vinylpyridine and styrene may have a styrene content ranging from about 0.01% to about 50 mol% (mer%), or from about 0.05% to about 45 mol%, or from about 0.1% to about 40 mol%, or from about 0.5% to about 35 mol%, or from about 1% to about 30 mol%, or from about 2% to about 25 mol%, or from about 5% to about 20 mol%. In certain embodiments, copolymers of vinylpyridine and styrene may contain a styrene content ranging from about 2% to about 25 mol%. Substituted styrenes may also be utilized in similar amounts.

[0144] Suitable copolymers of vinylpyridine and styrene can 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. In a non-limiting example, suitable copolymers of vinylpyridine and styrene can have a weight average molecular weight ranging from about 5 kD to about 150 kD, or from about 10 kD to about 125 kD, or from about 15 kD to about 100 kD, or from about 20 kD to about 80 kD, or from about 25 kD to about 75 kD, or from about 30 kD to about 60 kD. In certain embodiments, the copolymer of vinylpyridine and styrene can have a weight average molecular weight ranging from about 10 kD to about 125 kD.

[0145] In certain embodiments, the substance limiting membrane can further comprise a silicone polymer, such as polydimethylsiloxane (PDMS). For example, but not by way of limitation, the substance limiting membrane can comprise a polyvinylpyridine-co-styrene copolymer (e.g., a derivatized polyvinylpyridine-co-styrene copolymer) and a silicone polymer (e.g., polydimethylsiloxane (PDMS)). iv. Interference Domain In certain embodiments, the analyte sensor of the present disclosure may further include an interference domain. For example, but not by way of limitation, the sensor tail 100 or 200 of the analyte sensor may further include an interference domain. In certain embodiments, the interference domain may include a polymer domain that restricts the flow of one or more interferents, for example, to the surface of the working electrode. In certain embodiments, the interference domain may function as a molecular sieve, allowing the passage of the analyte and other substances to be measured by the working electrode while preventing the passage of other substances, such as interferents. In certain embodiments, the interferents may affect the signal obtained at the working electrode. Non-limiting examples of interferents may include acetaminophen, ascorbate, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, urea, and uric acid.

[0146] In certain embodiments, the interference domain is located between the working electrode and the active area. In certain embodiments, non-limiting examples of polymers that can be used in the interference domain include polyurethanes, polymers with pendant ionic groups, and polymers with controlled pore sizes. In certain embodiments, the interference domain can be formed from one or more cellulose derivatives. Non-limiting examples of cellulose derivatives include cellulose acetate, cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate trimellitate, and other polymers. In certain embodiments, the interference domain is part of the substance restriction membrane and is not a separate membrane, hi certain embodiments, the interference domain is located between one or more sensing spots and the substance restriction membrane.

[0147] In certain embodiments, the interference domain may comprise a thin, hydrophobic membrane that is non-swelling and restricts the diffusion of high molecular weight species. For example, but not by way of limitation, the interference domain 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.

[0148] C. Incorporation of Drug Delivery Compositions The present disclosure further provides analyte sensors comprising a drug delivery composition described herein (e.g., one or more drug delivery compositions disclosed herein). The present disclosure provides analyte sensors of the present disclosure comprising a sensor tail (e.g., 200 in FIG. 3) further comprising a drug delivery composition. Non-limiting examples of drug delivery compositions that can be included in the analyte sensors disclosed herein are described in Section III, and therapeutic agents that can be included in the drug delivery compositions are described in Section II. Incorporation of a therapeutic agent into the analyte sensor itself allows for targeted delivery of the therapeutic agent to the implantation site and tissue surrounding the analyte sensor, allowing for release of the therapeutic agent in the immediate vicinity of the analyte sensor in vivo. In certain embodiments, a therapeutic agent to be delivered in accordance with the present disclosure may be a therapeutic agent that reduces, minimizes, prevents, and / or inhibits tissue response to analyte sensor implantation and / or tissue infection, thereby effective in preventing and / or reducing analyte signal inaccuracies toward the end of the sensor's life. In certain embodiments, a therapeutic agent to be delivered in accordance with the present disclosure may be a therapeutic agent that reduces, minimizes, prevents, and / or inhibits tissue response to analyte sensor implantation and / or tissue infection, thereby effective in preventing and / or reducing LSA.

[0149] The present disclosure provides an analyte sensor, e.g., a sensor tail, of the present disclosure, further comprising a drug delivery composition. Figures 2-3 and 38-40C show cross-sectional schematic views of an exemplary analyte sensor according to certain embodiments of the present disclosure. As shown in Figure 3, the analyte sensor may include: (i) a sensor tail 200 including at least a first working electrode 214 on a substrate 212; (ii) an active area 218 disposed on the surface of the first working electrode for detecting an analyte; (iii) an analyte-permeable mass transport limiting membrane 220 overcoating at least the active area; (iv) a counter / reference electrode 216 on the substrate 212; and (v) a drug delivery composition including: (a) a copolymer including a plurality of copolymer chains, each of the plurality of copolymer chains including a backbone including a plurality of hydrophilic units and a plurality of hydrophobic units; (b) a cross-linker that cross-links at least a portion of the hydrophilic units between each of the copolymer chains; and (c) a therapeutic agent (e.g., the therapeutic agent is not covalently attached to the copolymer).

[0150] In certain embodiments, an analyte sensor comprising the drug delivery composition is configured to detect glucose. In certain embodiments, an analyte sensor comprising the drug delivery composition is configured to detect glucose and ketones, e.g., on a first working electrode and a second working electrode, respectively. In certain embodiments, an analyte sensor comprising the drug delivery composition is configured to detect lactate. In certain embodiments, an analyte sensor comprising the drug delivery composition is configured to detect creatinine. In certain embodiments, an analyte sensor comprising the drug delivery composition is configured to detect ketones. In certain embodiments, an analyte sensor comprising the drug delivery composition is configured to detect alcohol.

[0151] In certain embodiments, the analyte sensor comprising the drug delivery composition is a transdermal sensor. In certain embodiments, the analyte sensor comprising the drug delivery composition is a subcutaneous sensor, such as a subcutaneously implantable sensor, hi certain embodiments, the analyte sensor comprising the drug delivery composition is an analyte sensor that detects an analyte in the interstitial fluid of a subject. In certain embodiments, the analyte sensor comprising the drug delivery composition is an intravenous sensor, such as an intravenously implantable sensor. In certain embodiments, the drug delivery composition may be disposed on a structure or component of an analyte sensor. In certain embodiments, the drug delivery composition may be incorporated into an analyte sensor of the present disclosure. For example, but not by way of limitation, the drug delivery composition of the present disclosure may be disposed on or incorporated into a component of an analyte sensor, such as a component of the sensor tail of an analyte sensor. In certain embodiments, the drug delivery composition may be disposed on a structure or component of an analyte sensor. For example, but not by way of limitation, the drug delivery composition may be disposed on the surface of an electrode (e.g., a counter / reference electrode (e.g., 216 in FIG. 38A) and / or a working electrode (e.g., 214 in FIG. 38A)), an insulator (e.g., a dielectric material (e.g., 219a-219c in FIG. 38A)), a substrate (e.g., 212 in FIG. 38A), and / or a mass transport limiting membrane (e.g., 220 in FIG. 38A).

[0152] In certain embodiments, the drug delivery composition can be disposed on the working electrode. In certain embodiments, the drug delivery composition can be disposed on the counter / reference electrode. In certain embodiments where the analyte sensor includes a counter electrode and a reference electrode, the composition (e.g., the drug delivery composition) can be disposed on the counter / reference electrode. In certain embodiments, the drug composition (e.g., the drug delivery composition) can be disposed on the counter electrode. In certain embodiments, the composition (e.g., the drug delivery composition) can be disposed on the reference electrode. In certain embodiments where the analyte sensor includes a counter electrode and a reference electrode, the composition (e.g., the drug delivery composition) can be disposed on the counter electrode. In certain embodiments where the analyte sensor includes a counter electrode and a reference electrode, the composition (e.g., the drug delivery composition) can be disposed on the reference electrode. In certain embodiments, the drug delivery composition can be disposed on the mass transport limiting membrane 220 .

[0153] In certain embodiments, the hydrophilic units of the copolymer of the drug delivery composition disposed over the analyte sensor can include nitrogen-containing heterocyclic units such as pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, pyrazole units, etc. In certain embodiments, the hydrophobic units of the copolymer of the drug delivery composition disposed over the analyte sensor can include non-heteroatom-containing aromatic units such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units such as linear or branched alkyl units, linear or branched alkenyl units, linear or branched alkynyl units, etc., and / or cyclic aliphatic units such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl units, etc.

[0154] In certain embodiments, the copolymer of the drug delivery composition disposed over the analyte sensor can be selected from the group consisting of polyvinylpyridine-based copolymers, polyvinylimidazole-based copolymers, polyacrylate-based copolymers, polyurethane-based copolymers, polyetherurethane-based copolymers, silicone-based copolymers, derivatives thereof, and combinations thereof. In certain embodiments, the copolymer of the drug delivery composition disposed over the analyte sensor can include a block copolymer. In certain embodiments, the copolymer of the drug delivery composition disposed over the analyte sensor is a polyvinylimidazole-based copolymer, which may be a copolymer of vinylimidazole and styrene or a derivative thereof. In certain embodiments, the polyvinylimidazole-based copolymer can be a polyvinylimidazole-co-polystyrene polymer, hi certain embodiments, the polyvinylimidazole-co-polystyrene polymer can be a poly(N-vinylimidazole)-co-polystyrene polymer, a poly(1-vinylimidazole)-co-polystyrene polymer, or a derivative thereof.

[0155] In certain embodiments, the copolymer of the drug delivery composition disposed over the analyte sensor is a polyvinylpyridine-based copolymer, which may be a copolymer of vinylpyridine and styrene or a derivative thereof.

[0156] In certain embodiments, the polyvinylpyridine-based copolymer can be a polyvinylpyridine-co-polystyrene polymer. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can be a poly(4-vinylpyridine)-co-polystyrene polymer, a poly(2-vinylpyridine)-co-polystyrene polymer, or a derivative thereof. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer is a poly(4-vinylpyridine)-co-polystyrene polymer. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain 1 to 50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain 1 to 40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain 1 to 30 mer% styrene units.

[0157] In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD to 1,000 kD. In certain embodiments, the crosslinker may be a diglycidyl- or triglycidyl-functional epoxy. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG(200-1000), glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG200, diglycidyl-PEG400, glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be diglycidyl-PEG200. In certain embodiments, the cross-linking agent can be diglycidyl-PEG400. In certain embodiments, the cross-linking agent can be glycerol triglycidyl ether.

[0158] In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 40 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 40 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 10 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 10 mol%.

[0159] In certain embodiments, the therapeutic agent may include at least one selected from the group consisting of an antibiotic, an antiviral, an anti-inflammatory, an anti-cancer agent, an antiplatelet agent, an anticoagulant, a coagulant, an antiglycolytic agent, and combinations thereof. In certain embodiments, the therapeutic agent may be an anti-inflammatory agent. 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 derivatives or salt forms thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt form thereof. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone acetate. In certain embodiments, the derivative and / or salt form of dexamethasone is dexamethasone sodium phosphate.

[0160] In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 50% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the crosslinker binds to the hydrophilic units of the copolymer to form a charge. In certain embodiments, the therapeutic agent is not covalently attached to the copolymer. In certain embodiments, the therapeutic agent is covalently attached to the copolymer. In certain embodiments, the drug delivery composition can continuously release the therapeutic agent at a set or predetermined drug delivery rate for a set or predetermined number of days, such as at least 30 days.

[0161] In certain embodiments, the mass transport limiting membrane disposed over the analyte sensor can include polyvinylpyridine (e.g., poly(4-vinylpyridine) or poly(α-vinylpyridine)), polyvinylimidazole, polyvinylpyridine copolymers (e.g., copolymers of vinylpyridine and styrene), polyacrylate, polyurethane, polyetherurethane, silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, polyurethane homopolymers, copolymers, or terpolymers, polypropylene, polyvinyl chloride, polyvinylidene difluoride, polybutylene terephthalate, polymethyl methacrylate, polyether ether ketone, cellulose polymers, polysulfone, and block copolymers thereof, including, for example, diblock, triblock, alternating, random, and graft copolymers, or other chemically related materials. For a more detailed description of drug delivery compositions that may be included in analyte sensors and characteristics of such drug delivery compositions, reference may be made, for example, to the relevant portions of the drug delivery compositions disclosed in Section III above. For a more detailed description of analyte sensors, reference may be made to the relevant portions of the analyte sensors disclosed above.

[0162] V. Delivery Devices and Methods The present disclosure further provides devices for delivering the drug delivery compositions disclosed herein, for delivering the analyte sensors disclosed herein, and for simultaneously delivering the drug delivery compositions and analyte sensors disclosed herein. The present disclosure further provides methods for delivering the drug delivery compositions disclosed herein, for delivering the analyte sensors disclosed herein, and for simultaneously delivering the drug delivery compositions and analyte sensors disclosed herein. The present disclosure further provides methods for controlling the drug delivery rate of an analyte sensor, such as a subcutaneous sensor.

[0163] In certain embodiments, the disclosed methods can include preparing a drug delivery composition disclosed herein and implanting the drug delivery composition (e.g., subcutaneously) in a subject. In certain embodiments, the disclosed methods can include preparing an analyte sensor disclosed herein (e.g., including a drug delivery composition) and implanting the analyte sensor (e.g., subcutaneously) in a subject. For example, but not by way of limitation, the analyte sensor and / or drug delivery composition can be implanted in a subject using a needle.

[0164] In certain embodiments, the present disclosure provides a needle comprising an analyte sensor and / or a drug delivery composition described herein. For example, but not by way of limitation, certain embodiments of the present disclosure are directed to a needle, e.g., a preloaded needle, for delivering a drug delivery composition. FIG. 4 shows a cross-sectional schematic view of an exemplary needle according to certain embodiments of the present disclosure. As shown in FIG. 4 , in certain embodiments, a needle 401′ can comprise an analyte sensor 403′ and a drug delivery composition 402′ (e.g., the drug delivery composition comprises: (i) a copolymer comprising a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units; (ii) a cross-linking agent that cross-links at least a portion of the hydrophilic units between each of the copolymer chains; and (iii) a therapeutic agent). In certain embodiments, the needle can further comprise an analyte sensor, wherein the analyte sensor is disposed within a channel 404′ of the needle, and the drug delivery composition is disposed within the channel 404′ of the needle distal to the analyte sensor.

[0165] In certain embodiments, the drug delivery composition has a shape and / or size that fits within the dimensions of a needle (i.e., insertion needle) used to deliver the drug delivery composition (e.g., in the vicinity of the analyte sensor). For example, but not by way of limitation, the drug delivery composition has a shape that corresponds to the lumen, channel, or groove of the needle. In certain embodiments, the drug delivery composition has a shape that allows it to fit securely within the lumen, channel, or groove of a delivery device, e.g., a needle, during transport, but also allows for release of the drug delivery composition from the delivery device into tissue. In certain embodiments, the drug delivery composition has a cubic, rectangular, cylindrical, spherical, diamond, or irregular shape. As shown in FIG. 4 , the drug delivery composition 402′ can have a shape that fits within the U-shaped channel 404′ of the exemplary needle 401′. Alternatively, the drug delivery composition can have a spherical or cylindrical shape that fits within the cylindrical shape of the needle. In certain embodiments, the drug delivery composition unit can split into two or more pieces upon contact with tissue.

[0166] In certain embodiments, the needle used to deliver the drug delivery composition may be a needle used to transdermally deliver an analyte sensor under a user's skin. For example, but not by way of limitation, the drug delivery composition can be placed in the user's tissue simultaneously with the analyte sensor. As shown in FIG. 4 , the drug delivery composition 402′ can be disposed in a lumen, channel, or groove in the distal tip of the needle 401′ in front of the analyte sensor 403′. During the analyte sensor insertion process, movement of the analyte sensor 403′ out of the distal tip of the needle 401′ can force the drug delivery composition 402′ from the needle 401′ to the user's tissue nearest the analyte sensor in vivo.

[0167] In certain embodiments, the needle is part of an introducer disclosed herein. In certain embodiments, the needle is part of a sharp module and / or sensor applicator, for example, as disclosed in International Publications WO 2018 / 136898, WO 2019 / 236859, and WO 2019 / 236876, and U.S. Patent Publication No. 2020 / 0196919, each of which is incorporated herein by reference in its entirety. For example, but not by way of limitation, the needle may be part of the sensor applicator shown in FIG. 32B (e.g., the needle is annotated as 3216), FIG. 34B (e.g., the needle is annotated as 3216), FIG. 40B (e.g., the needle is annotated as 3908), and FIG. 113 (e.g., the needle is annotated as 11308) of WO 2019 / 236859. In certain embodiments, the needle may be part of the sensor module shown in FIG. 13 of WO 2019 / 236876 (e.g., needle (1318) is incorporated into the sensor module (annotated as 1314) for insertion of sensor (1316)). Further details regarding non-limiting embodiments of the applicator, its components, and variations thereof are described in U.S. Patent Publication Nos. 2013 / 0150691, 2016 / 0331283, and 2018 / 0235520, all of which are incorporated herein by reference in their entirety for all purposes. In certain embodiments, the needle is part of the sensor applicator shown in FIG. 11A of U.S. Patent Publication No. 2013 / 0150691 (e.g., the needle is shown as 1030 and the sensor supported within the needle is annotated as 1102). Further details regarding non-limiting embodiments of the sharp module, the needle, its components, and variations thereof are described in U.S. Patent Publication No. 2014 / 0171771, which is incorporated herein by reference in its entirety for all purposes.

[0168] The present disclosure further provides a needle-shaped object comprising a drug delivery composition. In certain embodiments, the needle-shaped object may include a channel comprising the drug delivery composition held within the channel. In certain embodiments, the drug delivery composition is located within the channel at the distal tip of the needle. In certain embodiments, the needle-shaped object may further include an analyte sensor held within the channel. In certain embodiments, as shown in FIG. 4, both the drug delivery composition and the analyte sensor are held within the channel of the needle, and the drug delivery composition is located within the channel of the needle distal to the analyte sensor. In certain embodiments, a preloaded needle can be used in a method for delivering a drug delivery composition near an analyte sensor in vivo. For example, but not by way of limitation, the method can include preparing a needle containing (a) an analyte sensor and (b) a drug delivery composition, wherein the analyte sensor is disposed in a channel of the needle and the drug delivery composition is disposed in the channel of the needle distal to the analyte sensor. In certain embodiments, the method can further include penetrating the needle into a tissue of a subject and inserting the drug delivery composition and the analyte sensor into the tissue of the subject. In certain embodiments, the method can include withdrawing the needle from the tissue of the subject, retaining the drug delivery composition and the analyte sensor in the tissue of the subject.

[0169] In certain embodiments, the present disclosure further provides a method for controlling the drug delivery rate of an analyte sensor including a therapeutic agent. In certain embodiments, the method for controlling the drug delivery rate of an analyte sensor, such as a subcutaneous sensor, may include the steps of (i) preparing a needle-shaped object including an analyte sensor including a drug delivery composition according to certain embodiments of the present disclosure, (ii) penetrating a tissue of a subject with the needle, (iii) inserting the analyte sensor into the tissue of the subject, and (iv) withdrawing the needle from the tissue of the subject. In certain embodiments, the needle may include a second drug delivery composition disposed distal to the analyte sensor in a channel of the needle. In certain embodiments, the analyte sensor provided in the needle and delivered by the disclosed methods can be any analyte sensor disclosed herein, for example, an analyte sensor including a therapeutic agent. In certain embodiments, the therapeutic agent provided in the drug delivery composition can be different from the therapeutic agent incorporated into the analyte sensor. Alternatively, the therapeutic agent provided in the drug delivery composition can be the same as the therapeutic agent incorporated into the analyte sensor. For example, but not by way of limitation, the therapeutic agent provided in the drug delivery composition and the therapeutic agent incorporated into the analyte sensor can both be dexamethasone.

[0170] Non-limiting examples of analyte sensors that can be delivered by needles are disclosed in Section IV. In certain embodiments, the analyte sensor is a subcutaneous sensor, such as a subcutaneously implantable sensor. In certain embodiments, the analyte sensor is a transcutaneous sensor. In certain embodiments, the analyte sensor is an intravenous sensor, such as an intravenously 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.

[0171] Non-limiting examples of drug delivery compositions that can be delivered by needles and / or incorporated into analyte sensors are disclosed in Section III. For example, but not by way of limitation, the hydrophilic units of the copolymers present in the drug delivery compositions can include nitrogen-containing heterocyclic units, such as pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, pyrazole units, etc. In certain embodiments, the hydrophobic units of the copolymers present in the drug delivery compositions can include non-heteroatom-containing aromatic units, such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units, such as linear or branched alkyl units, linear or branched alkenyl units, linear or branched alkynyl units, etc., and / or cyclic aliphatic units, such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl units, etc.

[0172] In certain embodiments, the copolymer can be selected from the group consisting of polyvinylpyridine-based copolymers, polyvinylimidazole-based copolymers, polyacrylate-based copolymers, polyurethane-based copolymers, polyetherurethane-based copolymers, silicone-based copolymers, derivatives thereof, and combinations thereof. In certain embodiments, the copolymer may comprise a block polymer. In certain embodiments, the polyvinylimidazole-based copolymer may be a copolymer of vinylimidazole and styrene or a derivative thereof. In certain embodiments, the polyvinylimidazole-based copolymer can be a polyvinylimidazole-co-polystyrene polymer, hi certain embodiments, the polyvinylimidazole-co-polystyrene polymer can be a poly(N-vinylimidazole)-co-polystyrene polymer, a poly(1-vinylimidazole)-co-polystyrene polymer, or a derivative thereof. In certain embodiments, the polyvinylpyridine-based copolymer may be a copolymer of vinylpyridine and styrene or a derivative thereof. In certain embodiments, the polyvinylpyridine-based copolymer can be a polyvinylpyridine-co-polystyrene polymer, hi certain embodiments, the polyvinylpyridine-co-polystyrene polymer can be a poly(4-vinylpyridine)-co-polystyrene polymer, a poly(2-vinylpyridine)-co-polystyrene polymer, or a derivative thereof.

[0173] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may contain about 1 to 30 mer% styrene units. In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD to 1,000 kD. In certain embodiments, the crosslinker may be a diglycidyl- or triglycidyl-functional epoxy. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG(200-1000), glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be selected from the group consisting of diglycidyl-PEG 200, diglycidyl-PEG 400, glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the cross-linking agent can be diglycidyl-PEG 200. In certain embodiments, the cross-linking agent can be diglycidyl-PEG 400. In certain embodiments, the cross-linking agent can be glycerol triglycidyl ether.

[0174] In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 50 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 40 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 40 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 30 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 0.1 mol% to 10 mol%. In certain embodiments, the crosslinked mol% of the copolymer can be in the range of about 1 mol% to 10 mol%.

[0175] In certain embodiments, the therapeutic agent may include at least one selected from the group consisting of an antibiotic, an antiviral, an anti-inflammatory, an anti-cancer agent, an antiplatelet agent, an anticoagulant, a coagulant, an antiglycolytic agent, and combinations thereof. In certain embodiments, the therapeutic agent may be an anti-inflammatory agent. 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 derivatives or salts thereof. In certain embodiments, the anti-inflammatory agent is dexamethasone or a derivative or salt thereof. In certain embodiments, the dexamethasone derivative is dexamethasone acetate. In certain embodiments, the dexamethasone derivative is dexamethasone sodium phosphate.

[0176] In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 50% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition may include an amount of the therapeutic agent ranging from 0.01% to 40% by weight based on the total weight of the copolymer. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 200 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 10 μg of a therapeutic agent. In certain embodiments, the crosslinker binds to the hydrophilic units of the copolymer to form a charge. In certain embodiments, the therapeutic agent is not covalently attached to the copolymer. In certain embodiments, the therapeutic agent is covalently attached to the copolymer.

[0177] In certain embodiments, the drug delivery composition continuously releases the therapeutic agent at a set or predetermined drug delivery rate for a set or predetermined number of days, such as at least 30 days. In certain embodiments, the analyte sensor is configured to detect glucose. For a more detailed description of the drug delivery composition, please refer to, for example, the relevant portion of the drug delivery composition disclosed in Section III above. For a more detailed description of the analyte sensor, please refer to, for example, the relevant portion of the analyte sensor disclosed in Section IV above.

[0178] VI. Illustrative Embodiments A. In certain non-limiting embodiments, the presently disclosed subject matter comprises: (i) a copolymer comprising a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units; (ii) a cross-linking agent that cross-links at least a portion of the hydrophilic units between each copolymer chain; and (iii) therapeutic drug The present invention provides a drug delivery composition comprising:

[0179] A1. The drug delivery composition described in A, wherein (i) the hydrophilic units are selected from among pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, and pyrazole units, and / or (ii) the hydrophobic units are selected from among non-heteroatom-containing aromatic units, acyclic aliphatic units, and cyclic aliphatic units. A1-1. The drug delivery composition according to A1, wherein the hydrophilic unit is a pyridine unit. A1-2. The drug delivery composition according to A1, wherein the hydrophobic unit is an aromatic unit. A2. The drug delivery composition described in A-A1-2, wherein the copolymer is selected from the group consisting of polyvinylpyridine-based copolymers, polyvinylimidazole-based copolymers, and combinations thereof. A2-1. The drug delivery composition according to A2, wherein the copolymer is a polyvinylpyridine-based copolymer. A3. The drug delivery composition according to A2 or A2-1, wherein the polyvinylpyridine-based copolymer is a polyvinylpyridine-co-polystyrene polymer. A4. The drug delivery composition of A3, wherein the polyvinylpyridine-co-polystyrene polymer comprises about 1-50 mer% styrene units.

[0180] A5. The drug delivery composition of A3 or A4, wherein the polyvinylpyridine-co-polystyrene polymer comprises about 1-30 mer% styrene units. A6. A drug delivery composition according to A to A5, wherein the mass average molecular weight of the copolymer is within the range of about 5 kD to about 1,000 kD. A7. The drug delivery composition according to A-A6, wherein the crosslinker is a diglycidyl- or triglycidyl-functional epoxy. A8. The drug delivery composition according to A7, wherein the crosslinking agent is selected from the group consisting of diglycidyl-PEG (200-1000), glycerol triglycidyl ether, and combinations thereof. A9. The drug delivery composition according to A8, wherein the cross-linking agent is selected from the group consisting of diglycidyl-PEG 200, diglycidyl-PEG 400, glycerol triglycidyl ether, and combinations thereof.

[0181] A10. The drug delivery composition according to A-A9, wherein the crosslinking mol% of the copolymer is in the range of about 0.1 mol% to about 50 mol%. A10-1. The drug delivery composition according to A10, wherein the crosslinking mol% of the copolymer is in the range of about 1 mol% to about 50 mol%. A11. The drug delivery composition according to A-A10, wherein the crosslinking mol% of the copolymer is in the range of about 0.2 mol% to about 30 mol%. A11-1. The drug delivery composition according to A to A10, wherein the crosslinking mol% of the copolymer is within the range of about 1 mol% to about 30 mol%. A12. A drug delivery composition described in A to A11-1, wherein the therapeutic agent is at least one selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof. A13. The drug delivery composition according to A-A12, wherein the crosslinking mol% of the copolymer is in the range of about 0.5 mol% to about 10 mol%. A13-1. A drug delivery composition according to A to A12, wherein the crosslinking mol% of the copolymer is about 20 mol% or less. A14. The drug delivery composition according to A to A13-1, wherein the therapeutic agent is an anti-inflammatory agent.

[0182] A15. The drug delivery composition according to A14, wherein the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, derivatives thereof, salt forms thereof, and combinations thereof. A16. A drug delivery composition according to A to A15, wherein the anti-inflammatory agent is in the form of dexamethasone, a derivative thereof, or a salt thereof. A17. The drug delivery composition according to A-A16, comprising a therapeutic agent in the range of about 0.01% to about 40% by weight based on the weight of the copolymer. A18. The drug delivery composition according to A-A17, wherein the crosslinker binds to the hydrophilic units of the copolymer to form a charge. A19. A drug delivery composition according to A-A18, comprising about 0.1 μg to about 200 μg of a therapeutic agent.

[0183] A20. A drug delivery composition according to A-A19, comprising about 0.1 μg to about 20 μg of a therapeutic agent. A21. A drug delivery composition according to A-A20, comprising about 0.1 μg to about 10 μg of a therapeutic agent. A22. A drug delivery composition according to A-A21, comprising about 0.1 μg to about 5 μg of a therapeutic agent. A23. The drug delivery composition of A-A22, wherein the therapeutic agent is not covalently attached to the copolymer.

[0184] B. In certain non-limiting embodiments, the presently disclosed subject matter comprises: (i) a sensor tail including at least a first working electrode; (ii) an active area on the surface of the first working electrode for detecting the analyte; (iii) a mass transport limiting membrane permeable to the analyte, overcoating at least the active area; (iv) a counter / reference electrode, and (v) The drug delivery composition according to any one of A to A23 The present invention provides an analyte sensor comprising: B1. The analyte sensor of B, wherein the drug delivery composition is disposed on a counter / reference electrode, a working electrode, or a mass transport limiting membrane. B2. The analyte sensor of B or B1, wherein the drug delivery composition is disposed over a counter / reference electrode. B3. The analyte sensor of B or B1, wherein the drug delivery composition is disposed on the working electrode. B4. The analyte sensor of B or B1, wherein the drug delivery composition is disposed on a mass transport limiting membrane.

[0185] C. In certain non-limiting embodiments, the presently disclosed subject matter provides a method for controlling a drug delivery rate of an analyte sensor and / or a method for implanting an analyte sensor in a subject, the method comprising: (i) providing an analyte sensor according to any one of B to B4; and (ii) subcutaneously implanting the analyte sensor Includes.

[0186] D. In certain non-limiting embodiments, the presently disclosed subject matter provides a method for controlling a drug delivery rate of an analyte sensor and / or a method for implanting an analyte sensor in a subject, the method comprising: (i) providing a needle-shaped object comprising an analyte sensor and a drug delivery composition according to any one of A-A23; (ii) penetrating the target tissue with a needle-shaped object; (iii) inserting the drug delivery composition and the analyte sensor into the tissue of the subject; and (iv) Removing the needle-shaped object from the target tissue Includes.

[0187] E. In certain non-limiting embodiments, the presently disclosed subject matter provides a needle comprising the drug delivery composition of any one of A-A23. E1. The needle of E, further comprising an analyte sensor, wherein the analyte sensor is disposed within a channel of the needle, and wherein the drug delivery composition is disposed within the channel of the needle distal to the analyte sensor. E2. The needle-shaped object of E or E1, wherein the analyte sensor may comprise a drug delivery composition according to any one of A-A23. F. In certain non-limiting embodiments, the presently disclosed subject matter provides a method of making a drug delivery composition, the method comprising: (i) providing a copolymer comprising a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units; (ii) applying a crosslinker and a therapeutic agent to the copolymer; and (iii) crosslinking at least a portion of the hydrophilic units between each copolymer chain with a crosslinker. Includes. [Example]

[0188] Example 1 Incorporation of drug delivery compositions into analyte sensors This example provides an analysis of polymer-based drug delivery compositions. In example embodiments of the present disclosure, polyvinylpyridine (PVP) or polyvinylpyridine-co-polystyrene (PVP-PS) copolymer was utilized as a representative copolymer for the drug delivery composition. Dexamethasone (Dex) was utilized as a representative therapeutic agent for the drug delivery composition. Diglycidyl-PEG 400 (hereinafter, PEG 400), diglycidyl-PEG 200 (hereinafter, PEG 200), or glycerol triglycidyl ether (hereinafter, Gly3) was utilized as a representative crosslinker for the drug delivery composition.

[0189] A. Sample Preparation 5 illustrates an exemplary test strip of a drug delivery composition on a biocompatible strip (which serves as a surrogate for a sensor tail) according to certain embodiments of the present disclosure. As shown in FIG. 5, the test strip was utilized to rapidly screen drug delivery composition formulations. For each tested formulation of the drug delivery composition, a test strip was prepared by manually dispensing 5 μL of the drug delivery composition formulation solution onto the surrogate for the sensor tail. Multiple test strips were utilized for testing.

[0190] 6 illustrates an exemplary sensor tail containing a drug delivery composition according to certain embodiments of the present disclosure. For analyte sensor testing, in certain embodiments, the sensor tail of the analyte sensor was dip-coated with the drug delivery composition. In certain embodiments, an automated precision liquid dispensing device (e.g., BioDot) was used to apply submicroliter droplets containing the drug delivery composition onto the sensor tail of the analyte sensor. Generally, the Dex-containing drug delivery composition was deposited on the sensor tail or on the outer membrane of the analyte sensor in a manner that did not interfere with the glucose oxidase (GOx) sensing chemistry.

[0191] B. Dexamethasone (Dex) Measurement Method 7A-7B illustrate exemplary test samples of drug delivery compositions according to certain embodiments of the present disclosure. FIG. 8 illustrates an exemplary testing procedure for drug delivery compositions according to certain embodiments of the present disclosure. In vitro Dex release of the drug delivery composition was carried out under stirring at 37°C in phosphate buffered saline (PBS) at pH 7.4, which is similar to physiological conditions. As shown in FIG. 7A, a test sample 604 was excised from a sensor tail substitute 600 onto which a drug delivery composition had been dispensed. As shown in FIG. 7B, a sensor tail 700 containing a test sample 704 was excised from a drug-loaded section 702 of a sensor tail 700 of an analyte sensor. As shown in FIG. 8, several test samples, e.g., six sensor tails, were then immersed in a PBS solution at pH 7.4 in a vial and incubated under agitation in a shaking incubator at 37°C. At each time point, e.g., every day, the supernatant was collected for HPLC analysis, fresh PBS solution was added to the vial, and the vial was returned to the shaking incubator until the next time point. This step was repeated for up to 31 days.

[0192] For total Dex loading measurements, test samples were extracted with 100% methanol at 37°C under stirring for 24 hours to remove all Dex. The concentration of Dex in the supernatant or methanol extract was measured using high performance liquid chromatography (HPLC). Figure 9 illustrates HPLC of dexamethasone according to certain embodiments of the present disclosure. Figure 10 illustrates a calibration curve for dexamethasone according to certain embodiments of the present disclosure. The area under the curve (AUC) of the Dex peak shown in Figure 9 was measured from suitable Dex concentrations to generate the calibration curve shown in Figure 10, which was used to measure unknown Dex concentrations.

[0193] C. 100% PVP matrix Figure 11 illustrates the drug delivery profile of a drug delivery composition comprising 100% polyvinylpyridine, glycerol triglycidyl ether, and dexamethasone according to certain embodiments of the present disclosure. Figure 12 illustrates the drug delivery profile of a drug delivery composition comprising 100% polyvinylpyridine, diglycidyl-PEG 400, and dexamethasone according to certain embodiments of the present disclosure. As shown in Figures 11 and 12, even without crosslinker or with a low concentration of crosslinker, 100% PVP polymer (i.e., no styrene units in the polymer backbone) does not retain Dex, and Dex rapidly diffuses out of the polymer matrix. Dex is completely released in less than 7 days (Figures 11 and 12). Increasing the concentration of crosslinker increases the drug delivery rate due to the positive charges formed by crosslinking, which improves the swelling properties of the polymer matrix.

[0194] D. Examination of the Effects of Polystyrene Concentration and the Effects of Crosslinker Concentration and Type or Species in Polyvinylpyridine-co-Polystyrene Copolymers Polyvinylpyridine polymers and several polyvinylpyridine-co-polystyrene copolymers were investigated as copolymer components of drug delivery compositions. Figure 13 illustrates exemplary tested polymers and copolymers of drug delivery compositions according to certain embodiments of the present disclosure. The investigated polymers and copolymers have a weight average molecular weight of about 175 kD, as determined by a suitable method, such as gel permeation chromatography. The mer% of styrene units in the copolymers (i.e., the mer% of polystyrene) was determined by nuclear magnetic resonance (NMR) spectroscopy. 14 illustrates exemplary crosslinkers for drug delivery compositions according to certain embodiments of the present disclosure. In certain embodiments, diglycidyl-PEG 200 (PEG 200), diglycidyl-PEG 400 (PEG 400), or glycerol triglycidyl ether (Gly3) were investigated as crosslinkers to crosslink copolymers in the drug delivery compositions at various crosslinking mol %. The crosslinking mol % of the copolymers was determined according to the following formula:

[0195]

number

[0196] FIG. 15 illustrates an exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure. As shown in FIG. 15, in certain embodiments, a copolymer of 93% PVP and 7% PS was investigated as the copolymer in the drug delivery composition. PEG 200 and Gly3 were investigated as crosslinkers in the drug delivery composition. The crosslinking mol% of the copolymer was 0%, 1 mol%, or 10 mol%. The loading percentage of Dex relative to the copolymer matrix was 30% by mass. Generally, appropriate amounts of Dex, crosslinker, and copolymer were mixed in a solvent, such as 95:5 ethanol and water by volume, and then 5 μL of the solution was manually dispensed onto the sensor tail surrogate to fabricate the test strip. Figure 16 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 16, 100% PVP is too hydrophilic, and Dex is released from the polymer matrix too quickly, with nearly complete release in less than 7 days. In contrast, Dex release from a 20% PS copolymer (designated "XL") without a crosslinker is too slow. By adjusting the mer% of styrene units in the copolymer, the Dex release rate (i.e., drug delivery rate) can be adjusted, and Dex can be continuously released for at least 31 days. The Dex V3 sensor is a representative sensor containing a Dex composition, in which Dex is conjugated to a polymer in the composition.

[0197] Figure 17 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 17, if the mer% of styrene units in the copolymer increases and the crosslinking mol% of the copolymer remains constant, the release rate of Dex decreases. If the mer% of styrene units in the copolymer remains constant and the crosslinking mol% of the copolymer increases, the release rate of Dex increases. FIG. 18 illustrates an exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure. As shown in FIG. 18, in certain embodiments, 87% PVP-13% PS copolymer was considered as the polymer in the drug delivery composition. PEG 400 and Gly3 were considered as crosslinkers in the drug delivery composition. When Gly3 was used as the crosslinker, the crosslinking mol% of the copolymer was 2 mol%, 5 mol%, or 7 mol%. When PEG 400 was used as the crosslinker, the crosslinking mol% of the copolymer was 2 mol%, 5 mol%, 7 mol%, or 10 mol%. The loading percentage of Dex in the copolymer matrix was 30% by mass. Generally, appropriate amounts of Dex, crosslinker, and copolymer were mixed in a solvent, such as 95:5 ethanol and water by volume, and then 5 μL of the solution was manually dispensed onto the sensor tail surrogate to prepare the test strip.

[0198] Figure 19 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 19, for a copolymer comprising 13% PS copolymer and crosslinker PEG 400, the release rate of Dex from the copolymer matrix increases as the crosslinking mol% of the copolymer increases. Figure 20 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 20, the copolymer is a 13% PS copolymer and the crosslinker is Gly3. As the crosslinking mol% of the copolymer matrix increases, the release rate of Dex from the copolymer matrix increases. Figure 21 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 21, the copolymer is 20% PS copolymer and the crosslinker is PEG 400. As the crosslinking mol% of the copolymer matrix increases, the release rate of Dex from the copolymer matrix increases.

[0199] Figure 22 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 22, the copolymer is a 20% PS copolymer and the crosslinker is Gly3. As the crosslinking mol% of the copolymer matrix increases, the release rate of Dex from the copolymer matrix increases. However, due to the higher mer% of styrene units in the copolymer matrix, a higher amount of crosslinker is required to match the similar rate demonstrated with copolymers containing a lower mer% of styrene. Figure 23 illustrates the concentration relationships between different crosslinkers in a drug delivery composition according to certain embodiments of the present disclosure. Figure 24 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figures 23 and 24, when preparing drug delivery compositions, the functionality of the crosslinker, i.e., the number of reactive crosslinkable groups in the crosslinker, must be considered, and various mass concentrations of the crosslinker in the drug delivery compositions must be adjusted to control the crosslinking mol% of the copolymer for different crosslinkers. After considering the functionality of the crosslinker, PEG 400 and Gly3 show similar crosslinking effects on the Dex release rate of the drug delivery compositions.

[0200] FIG. 25 illustrates an exemplary formulation of a drug delivery composition for an analyte sensor according to certain embodiments of the present disclosure. This formulation was applied to a sensor format. As shown in FIG. 25, in certain embodiments, a 90% PVP-10% PS copolymer was considered as the copolymer in the drug delivery composition on the analyte sensor. PEG 400 and Gly3 were considered as crosslinkers in the drug delivery composition. When Gly3 was used as the crosslinker, the crosslinking mol% of the copolymer was 1 mol% or 5 mol%. When PEG 400 was used as the crosslinker, the crosslinking mol% of the copolymer was 1 mol% or 5 mol%. The loading percentage of Dex in the copolymer matrix was 30% by mass. Generally, appropriate amounts of Dex, crosslinker, and copolymer were mixed in a solvent, such as 95:5 ethanol and water by volume, and then 5 μL of the solution was manually dispensed onto a biocompatible strip to prepare a test strip, or the sensor tail of the analyte sensor was dip-coated with the drug delivery composition solution.

[0201] Figure 26 illustrates the drug delivery profile of a drug delivery composition comprising a 90% PVP-10% PS copolymer on an analyte sensor according to certain embodiments of the present disclosure. Figure 27 illustrates the drug delivery profile per time point of a drug delivery composition comprising a 90% PVP-10% PS copolymer on an analyte sensor according to certain embodiments of the present disclosure. As shown in Figure 26, for the analyte sensors and test strips tested, when the crosslinker and crosslinking mol% of the copolymer were the same, the Dex release rate was similar. Furthermore, as the crosslinking mol% of the copolymer increased, the Dex release rate increased (Figure 26). As shown in Figure 27, the amount of Dex released per sensor per time point was in the range of 0.2 μg to 1.5 μg for sensors containing 10% PS and 1% PEG400, 1% Gly3, or 5% Gly3, and Dex could be continuously released for at least 31 days.

[0202] Figure 28 illustrates factors affecting the drug delivery rate of a drug delivery composition according to certain embodiments of the present disclosure. Increasing the PS content (e.g., amount) of the hydrophobic copolymer, i.e., increasing the mer% of styrene units in the copolymer, increases the affinity of the polymer for Dex, thereby decreasing the release rate of Dex. Increasing the amount of crosslinker in the drug delivery composition, i.e., increasing the crosslinking mol% of the copolymer, improves the swellability and hydrophilicity of the copolymer matrix, thereby increasing the release rate of Dex. When the same molar amounts of PEG 400 and Gly3 are used in the drug delivery composition, the release rate of Dex increases in the drug delivery composition employing Gly3 as the crosslinker due to the high functionality of Gly3, i.e., the high crosslinking mol%. When dexamethasone is replaced with dexamethasone acetate (DexA) as the therapeutic agent, the release rate of DexA decreases. This is because DexA is less polar than Dex and has stronger nonpolar interactions with the styrene units in the copolymer, which delays the release of DexA from the copolymer matrix. The Dex release rate of the drug delivery composition on the analyte sensor is similar to that of the drug delivery composition when used alone. Bakeout (i.e., extending the polymer curing time) does not affect the Dex release rate.

[0203] Figure 29 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 29, the release rate of Dex can be precisely tuned by adjusting the mer% of hydrophobic units (e.g., styrene units) in the copolymer and / or adjusting the crosslinking mol% of the copolymer with a crosslinker, for example, by adjusting the amount of crosslinker used and / or the type or type of crosslinker used. Figure 30 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 30, when the crosslinking mol% of the copolymer is 10 mol% by adjusting the mer% of the styrene units in the copolymer, the release rate of Dex can be slowed down to deliver a constant amount of Dex over 31 days by using a higher mer% of styrene (13%, 20% PS) or by using a less hydrophilic crosslinker (Gly3).

[0204] Figure 31 illustrates the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 31, when the crosslinking mol% of the copolymer is 1%, by adjusting the mer% of styrene units in the copolymer, the Dex release rate of the drug delivery composition can be adjusted to continuously deliver Dex over 31 days by adjusting the mer% of styrene over a wide range (7-20%). Thus, crosslinking 1 mol% of the copolymer provides a wide range for adjusting the drug delivery rate of the drug delivery composition.

[0205] Figure 32 illustrates the drug delivery profile and time-point drug delivery profile of a drug delivery composition on an analyte sensor according to certain embodiments of the present disclosure. As shown in Figure 32, for an analyte sensor tested employing a drug delivery composition containing a 90% PVP-10% PS copolymer, the Dex release rate increases as the crosslinking mol% of the copolymer increases, even when the crosslinking agent remains the same. When PEG 400 is used as the crosslinker, a copolymer with 5 mol% crosslinking releases a large amount of Dex at the early time point, with release ceasing after approximately 23 days. Thus, a desired drug release rate can be achieved by adjusting the crosslinking mol% within a given copolymer.

[0206] Figure 33 illustrates the solubility of Dex in a polyvinylpyridine-ethanol:water (95:5 by volume) solution according to certain embodiments of the present disclosure. The solubility of Dex in a PVP-ethanol:water solution was measured. For solutions containing 0% to 30% Dex by weight relative to the weight of the PVP polymer, the solution became clear within 15 minutes after vortexing / sonicating the solution. For a solution containing 40% Dex by weight relative to the weight of the PVP polymer, the solution became clear after mixing overnight on a nutator. A solution containing 50% Dex by weight relative to the weight of the PVP polymer did not become clear after mixing overnight on a nutator. Therefore, to produce a clear drug delivery composition, the drug delivery composition can contain up to 40% Dex by weight relative to the amount of copolymer.

[0207] Figure 34A illustrates an exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure. As shown in Figure 34A, the effect of Dex loading in the drug delivery composition on the release rate of Dex was investigated. The copolymer was 93% PVP-7% PS copolymer. The crosslinking mol% of the copolymer was 1 mol% by Gly3. The loading of Dex in the drug delivery composition was 30 wt%, 15 wt%, or 5 wt% relative to the mass of the copolymer. Figure 34B illustrates exemplary formulations of drug delivery compositions containing various percentages of dexamethasone. Table 1 in Figure 34B shows drug delivery compositions containing 40% Dex loading by weight relative to the weight of the copolymer. Table 2 in Figure 34B shows drug delivery compositions containing 26% Dex loading by weight relative to the weight of the copolymer. Table 3 in Figure 34B shows drug delivery compositions containing 15% Dex loading by weight relative to the weight of the copolymer.

[0208] FIG. 35A illustrates the drug delivery profile and time-point drug delivery profile of a drug delivery composition on an analyte sensor according to certain embodiments of the present disclosure. As shown in FIG. 35A, Dex can be continuously released for at least 31 days. For a 5% by weight Dex loading, 70% of the Dex is released over 31 days. For a 30% by weight Dex loading, approximately 50% of the Dex is released over 31 days. At each time point, the amount of Dex released daily by the drug delivery composition containing 30% by weight Dex is twice the amount of Dex released daily by the drug delivery composition containing 15% by weight Dex and six times the amount of Dex released daily by the drug delivery composition containing 5% by weight Dex. After normalizing for Dex loading, the Dex release rates are similar for all three drug delivery compositions, as shown in the inset panel on the right side of FIG. 35A. Therefore, at full solubility, the Dex loading in the drug delivery composition does not affect the Dex release rate.

[0209] Figure 35B illustrates the drug delivery profile and per-time point drug delivery profile of a drug delivery composition on an analyte sensor according to certain embodiments of the present disclosure. A drug delivery composition (10% PS copolymer and 1 mol% Gly3) according to Figure 34B was deposited on the counter electrode of the sensor tail. As shown in Figure 35B, Dex is released continuously for at least 31 days, with approximately 60-75% of the loaded Dex being released by the end of the 31-day period. For Dex loadings of 6.79 μg and 4.67 μg, approximately 70% of Dex is released over 31 days. For Dex loadings of 2.26 μg, approximately 75% of Dex is released over 31 days. For Dex loadings of 6.58 μg, approximately 60% of Dex is released by 31 days. For Dex loadings of 3.99 μg, approximately 65% ​​of Dex is released over 31 days. For a loading of 2.1 μg of Dex, approximately 70% of the Dex is released over 31 days. For each of the compositions, approximately 50% of the Dex was released between 13 and 16 days.

[0210] Figure 35C shows that incorporating as little as 2.1 μg of Dex into the analyte sensor significantly reduces LSA. As shown in Figure 35C, the reduction in LSA is similar between the analyte sensors containing 6.6 μg and 2.1 μg. LSA was determined by calculating the mean and median sensitivity over a 12-hour rolling window when there were three or more points within the window. An LSA case was defined as one in which both the mean and median sensitivity were less than 80% of the stable sensitivity (defined as the median sensitivity within 10 to 120 hours). If there were five or more LSA cases within a 24-hour window, and the first case occurred more than 24 hours before the end of the sensor's lifetime, the onset time of LSA was defined as the time of the first LSA case. The In-LSA index = area under 1 / (end of lifetime time - onset time of LSA). A higher index indicates more severe LSA.

[0211] Analyte sensors and / or any other related devices or components according to embodiments of the invention described herein can be implemented by utilizing any suitable hardware, firmware (e.g., application-specific integrated circuits), software, or a combination of software, firmware, and hardware. For example, various components of the sensor can be formed on a single integrated circuit (IC) chip or on separate IC chips. Furthermore, various components of the sensor can be implemented on a flexible printed circuit film, a tape carrier package (TCP), a printed circuit board (PCB), or formed on a single substrate. Furthermore, various components of the sensor can be processes or threads running on one or more processors within one or more computing devices, executing computer program instructions and interacting with other system components to perform the various functions described herein. The computer program instructions are stored in a memory that can be executed within the computing device using standard memory devices, such as random access memory (RAM). The computer program instructions may also be stored on other non-transitory computer-readable media, such as CD-ROMs, flash drives, etc. Additionally, those skilled in the art will recognize that the functionality of various computing devices may be combined or integrated into a single computing device, or the functionality of a particular computing device may be distributed across one or more computing devices, without departing from the scope of the exemplary embodiments of the present invention.

[0212] Although embodiments of the present disclosure have been described, it will be understood that the disclosure is not limited to these embodiments, and that one or more suitable changes and modifications may be made by those skilled in the art within the spirit and scope of the present disclosure and equivalents thereof as claimed herein.

Claims

1. (i) a copolymer comprising a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units; (ii) a cross-linking agent that cross-links at least a portion of the hydrophilic units between each copolymer chain; and (iii) therapeutic drug A drug delivery composition comprising:

2. 2. The drug delivery composition of claim 1, wherein (a) the hydrophilic units are selected from the group consisting of pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, and pyrazole units, and / or (b) the hydrophobic units are selected from the group consisting of non-heteroatom-containing aromatic units, acyclic aliphatic units, and cyclic aliphatic units.

3. The drug delivery composition of claim 1 or 2, wherein the copolymer is selected from the group consisting of polyvinylpyridine-based copolymers, polyvinylimidazole-based copolymers, and combinations thereof.

4. The drug delivery composition of claim 3, wherein the polyvinylpyridine-based copolymer is a polyvinylpyridine-co-polystyrene polymer.

5. The drug delivery composition of claim 4, wherein the polyvinylpyridine-co-polystyrene polymer contains about 1-50 mer% styrene units.

6. The drug delivery composition of claim 5, wherein the polyvinylpyridine-co-polystyrene polymer contains about 1-30 mer% styrene units.

7. The drug delivery composition of any one of claims 1 to 6, wherein the copolymer has a mass average molecular weight in the range of about 5 kD to about 1,000 kD.

8. The drug delivery composition of any one of claims 1 to 7, wherein the crosslinker is a diglycidyl- or triglycidyl-functional epoxy.

9. 9. The drug delivery composition of claim 8, wherein the cross-linking agent is selected from the group consisting of diglycidyl-PEG (200-1000), glycerol triglycidyl ether, and combinations thereof.

10. 10. The drug delivery composition of claim 9, wherein the cross-linking agent is selected from the group consisting of diglycidyl-PEG 200, diglycidyl-PEG 400, glycerol triglycidyl ether, and combinations thereof.

11. The drug delivery composition of any one of claims 1 to 10, wherein the crosslinking mol % of the copolymer is in the range of about 0.1 mol % to about 50 mol %.

12. The drug delivery composition of claim 11, wherein the crosslinking mol % of the copolymer is in the range of about 0.1 mol % to about 30 mol %.

13. The drug delivery composition according to any one of claims 1 to 12, wherein the therapeutic agent is at least one selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof.

14. The drug delivery composition of claim 13 , wherein the therapeutic agent is an anti-inflammatory agent.

15. 15. The drug delivery composition of claim 14, wherein the anti-inflammatory agent is selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, isobutylphenylpropanoic acid, derivatives thereof, salt forms thereof, and combinations thereof.

16. 16. The drug delivery composition of claim 15, wherein the anti-inflammatory agent is in the form of dexamethasone, a derivative thereof, or a salt thereof.

17. The drug delivery composition of any one of claims 1 to 16, comprising a therapeutic agent in the range of about 0.01% to about 40% by weight based on the weight of the copolymer.

18. The drug delivery composition of any one of claims 1 to 17, wherein the crosslinker binds to the hydrophilic units of the copolymer to form a charge.

19. (i) a sensor tail including at least a first working electrode; (ii) an active area on the surface of the first working electrode for detecting an analyte; (iii) a mass transport limiting membrane permeable to the analyte overcoating at least the active area; (iv) a counter / reference electrode, and (v) The drug delivery composition according to any one of claims 1 to 18.

12. An analyte sensor comprising:

20. (i) providing an analyte sensor according to claim 19; and (ii) subcutaneously implanting the analyte sensor.

10. A method for controlling a drug delivery rate of an analyte sensor, comprising:

21. (i) providing a needle comprising an analyte sensor and a drug delivery composition according to any one of claims 1 to 18; (ii) penetrating the target tissue with the needle-shaped object; (iii) inserting the drug delivery composition and the analyte sensor into tissue of the subject; and (iv) removing the needle-shaped object from the target tissue; 10. A method for controlling a drug delivery rate of an analyte sensor, comprising:

22. 19. A needle-shaped object comprising an analyte sensor and the drug delivery composition of any one of claims 1 to 18, wherein the analyte sensor is disposed in a channel of the needle, and the drug delivery composition is disposed in the channel of the needle distal to the analyte sensor.

23. (i) providing a copolymer comprising a plurality of copolymer chains, each of the plurality of copolymer chains comprising a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units; (ii) applying a crosslinker and a therapeutic agent to the copolymer; and (iii) cross-linking said cross-linking agent to at least a portion of the hydrophilic units between each copolymer chain. A method for producing a drug delivery composition, comprising:

24. 20. The analyte sensor of claim 19 for use in controlling a drug delivery rate of an analyte sensor, wherein the analyte sensor is implanted subcutaneously.

25. 19. The drug delivery composition of any one of claims 1 to 18 for use in controlling the drug delivery rate of an analyte sensor, wherein the drug delivery composition and analyte sensor are inserted into the tissue of the subject.

26. 26. The drug delivery composition for use according to claim 25, wherein the drug delivery composition and the analyte sensor are inserted into the tissue of the subject using a needle containing the drug delivery composition and the analyte sensor.

27. 27. The drug delivery composition for use according to claim 26, wherein the analyte sensor is disposed within a channel of the needle and the drug delivery composition is disposed within the channel of the needle distal to the analyte sensor.

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