Drug delivery composition and method of controlling drug delivery rate of subcutaneous sensor

Abstract

The present disclosure provides a drug delivery composition and a method of controlling a drug delivery rate of an analyte sensor. The drug delivery composition comprises: a copolymer comprising a plurality of copolymer chains, wherein each of the plurality of copolymer chains comprises a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units; a cross-linking agent; and a therapeutic agent wherein the crosslinking agent crosslinks at least a portion of the hydrophilic units of each copolymer chain to form an electrical charge and the hydrophobic units of the copolymer interact with the therapeutic agent through a non-polar intermolecular interaction. The drug delivery composition continuously releases the therapeutic agent at a set or predetermined drug delivery rate for a set or predetermined period of time.

Description

[0001] Citation of Related Applications

[0002] This application claims priority and the benefit of U.S. Provisional Application No. 63 / 477,977, filed on December 30, 2022, the entire content of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to drug delivery compositions and methods of controlling the rate of drug delivery. For example, the present disclosure relates to an analyte sensor comprising a drug delivery composition and a method of controlling the rate of drug delivery of an analyte sensor (e.g., a subcutaneous sensor). The present disclosure further provides an analyte sensor comprising such a drug delivery composition to reduce sensor signal inaccuracies or in vivo sensor failures (e.g., due to a foreign body response (FBR)). Background Art

[0004] Detecting one or more suitable analytes in an individual can sometimes be crucial for monitoring their health status, as deviations from normal analyte levels can indicate physiological conditions. For example, monitoring glucose levels can enable a diabetic patient to take appropriate or suitable corrective measures, including administering medications or consuming specific food or beverage products, to avoid serious physiological harm. Other analytes may be used to monitor other physiological conditions. In some cases, it may be necessary to monitor more than one analyte to monitor multiple physiological conditions, especially when a person has a comorbid condition that causes two or more analytes to be dysregulated in combination with each other.

[0005] Analyte monitoring of an individual can be performed periodically or can be continuous over a period of time. Periodic analyte monitoring can be performed by taking body fluid samples (e.g., blood or urine) at set time intervals and performing ex vivo analysis. Periodic ex vivo analyte monitoring is sufficient to determine the physiological status of many individuals. However, in some cases, ex vivo analyte monitoring may be inconvenient or painful. In addition, there is no way to recover lost data when an analyte measurement is not obtained at an appropriate or suitable time. Continuous analyte monitoring can be performed using one or more sensors that are at least partially implanted (e.g., dermally, subcutaneously, or intravenously) within an individual's tissue so that the analysis can be performed in vivo. The implanted sensors can collect analyte data on demand, according to a set schedule, or continuously, depending on an individual's specific health needs and / or previously measured analyte levels. Analyte monitoring using in vivo implanted sensors may be a more desirable method for individuals with severely dysregulated analytes and / or rapidly fluctuating analyte levels, although it may also be beneficial for other individuals.

[0006] However, implantable sensors may face the problem of short service life when implanted in the body. For example, the loss of in-vivo sensor function seen in implantable sensors is thought to be largely the result of certain responses (reactions) that occur in the tissue around the implanted sensor (e.g., surrounding the implanted sensor), including immune responses, inflammation, fibrosis, and vascular degeneration. These tissue responses can be the result of tissue trauma caused by the insertion of the sensor into the skin and can be the result of the tissue reacting to the sensor as a foreign body. Although the tissue responses at the sensor implantation site are histopathologically similar to other forms of tissue inflammation, the ability to directly inhibit or reduce tissue trauma caused by the sensor (e.g., inhibiting tissue trauma and other physiological responses caused by the sensor during the service life of the implanted sensor) using anti-inflammatory agents (e.g., glucocorticoids and non-steroidal anti-inflammatory agents) and / or other therapeutic agents is limited. Thus, there is a need in the art to develop a drug delivery composition comprising an anti-inflammatory agent and / or other therapeutic agents, and a method for delivering such a therapeutic composition near an analyte sensor at a desired or appropriate delivery rate over a period of time. Summary of the Invention

[0007] The objects and aspects of the disclosed subject matter will be set forth in and are apparent from the following description, and may be learned by practice of the disclosed subject matter. Additional aspects of the disclosed subject matter will be realized and attained by means of the compositions, devices, and methods particularly pointed out in the written description and the claims thereof, as well as the accompanying drawings.

[0008] One or more aspects of embodiments of the present disclosure relate to a drug delivery composition. In certain embodiments, the drug delivery composition may comprise (i) a copolymer comprising a plurality of copolymer chains, wherein each of the plurality of copolymer chains comprises a backbone containing 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 the respective copolymer chains, and (iii) a therapeutic agent.

[0009] In certain embodiments, the hydrophilic units of the copolymer may comprise 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 comprise aromatic units without heteroatoms (e.g., benzene (phenyl) units, naphthalene units, anthracene units, etc.), acyclic aliphatic units (e.g., straight-chain or branched-chain alkyl units), straight-chain or branched-chain alkenyl units, straight-chain or branched-chain alkynyl units, etc., and / or cyclic aliphatic units (e.g., cyclobutyl, cyclopentyl units, cyclohexyl units, cycloheptyl units, cyclooctyl units, cyclohexenyl units, etc.).

[0010] In certain embodiments, the copolymer may be selected from polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyetherurethane-based copolymers, silicone-based copolymers, their derivatives, and combinations thereof.

[0011] In certain embodiments, the copolymer may comprise a block polymer.

[0012] In certain embodiments, the copolymer is a polyvinylpyridine copolymer. In certain embodiments, the polyvinylpyridine copolymer may be a copolymer of vinylpyridine and styrene or a derivative thereof.

[0013] In certain embodiments, the polyvinylpyridine copolymer may be a polyvinylpyridine-co-polystyrene polymer.

[0014] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 1-50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 1-40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 1-30 mer% styrene units.

[0015] In certain embodiments, the copolymer has a weight average molecular weight in the range of about 5 kD - 1,000 kD.

[0016] In certain embodiments, the crosslinking agent may be a diglycidyl-functional epoxide (epoxy resin) or a triglycidyl-functional epoxide.

[0017] In certain embodiments, the crosslinking agent may be selected from diglycidyl-PEG (200 - 1000), glycerol triglycidyl ether, and combinations thereof.

[0018] In certain embodiments, the crosslinking agent may be selected from diglycidyl-PEG 200, diglycidyl-PEG 400, glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the crosslinking agent may be diglycidyl-PEG 200. In certain embodiments, the crosslinking agent may be diglycidyl-PEG 400. In certain embodiments, the crosslinking agent may be glycerol triglycidyl ether.

[0019] In certain embodiments, the mol% crosslinking of the copolymer can range from about 0.1 mol% to 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer can range from about 1 mol% to 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer can range from about 0.1 mol% to 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer can range from about 1 mol% to 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer can range from about 0.1 mol% to 10 mol%. In certain embodiments, the mol% crosslinking of the copolymer can range from about 1 mol% to 10 mol%.

[0020] In certain embodiments, the therapeutic agent can include at least one selected from the group consisting of antibiotic agents, antiviral agents, anti-inflammatory agents, anti-cancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof.

[0021] In certain embodiments, the therapeutic agent can be an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent can be one or more selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, ibuprofen, and their derivatives or salt forms. In certain embodiments, the anti-inflammatory agent is dexamethasone or its derivatives or salt forms. 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.

[0022] In certain embodiments, the pharmaceutical delivery composition can include a therapeutic agent in an amount ranging from 0.01 wt% to 50 wt% based on the total weight of the copolymer. In certain embodiments, the pharmaceutical delivery composition can include a therapeutic agent in an amount ranging from 0.01 wt% to 40 wt% based on the total weight of the copolymer.

[0023] In certain embodiments, the pharmaceutical delivery composition can include from about 0.1 μg to about 200 μg of the therapeutic agent. In certain embodiments, the pharmaceutical delivery composition can include from about 0.1 μg to about 20 μg of the therapeutic agent. In certain embodiments, the pharmaceutical delivery composition can include from about 0.1 μg to about 10 μg of the therapeutic agent.

[0024] In certain embodiments, the crosslinking agent binds (bonds) to the hydrophilic units of the copolymer to form charges.

[0025] In certain embodiments, the therapeutic agent is not covalently bound to the copolymer.

[0026] In certain embodiments, the therapeutic agent is covalently bound to the copolymer.

[0027] 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.

[0028] One or more aspects of the embodiments of the present disclosure relate to an analyte sensor. In certain embodiments, the analyte sensor can 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 permeable to the analyte, which at least covers the active area; (iv) a counter electrode / reference electrode; and (v) a drug delivery composition, the drug delivery composition including (a) a copolymer including a plurality of copolymer chains, wherein each of the plurality of copolymer chains includes a main chain including a plurality of hydrophilic units and a plurality of hydrophobic units, (b) a crosslinking agent that crosslinks at least a part of the hydrophilic units between the respective copolymer chains, and (c) a therapeutic agent.

[0029] In certain embodiments, the analyte is glucose. In certain embodiments, the analyte sensor is a dermal sensor. In certain embodiments, the analyte sensor is a subcutaneous sensor, such as a subcutaneously implanted sensor. In certain embodiments, the analyte sensor is an intravenous sensor, such as an intravenously implanted sensor.

[0030] In certain embodiments, the hydrophilic units of the copolymer of the drug delivery composition present on 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 hydrophilic units of the copolymer of the drug delivery composition present on the analyte sensor can include pyridine units.

[0031] In certain embodiments, the hydrophobic units of the copolymer of the drug delivery composition present on the analyte sensor can include aromatic units without heteroatoms, such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units, such as straight-chain or branched alkyl units, straight-chain or branched alkenyl units, straight-chain 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 aromatic units without heteroatoms.

[0032] In certain embodiments, the copolymer can be selected from polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyetherurethane copolymers, silicone copolymers, their derivatives, and combinations thereof.

[0033] In certain embodiments, the copolymer can include block polymers.

[0034] In certain embodiments, the copolymer can be a polyvinylpyridine copolymer. In certain embodiments, the polyvinylpyridine copolymer can be a copolymer of vinylpyridine and styrene or its derivatives.

[0035] In certain embodiments, the polyvinylpyridine copolymer can be a polyvinylpyridine-co-polystyrene polymer.

[0036] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can include about 1 - 50 mer% of styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can include about 1 - 40 mer% of styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer can include about 1 - 30 mer% of styrene units.

[0037] In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD - 1,000 kD.

[0038] In certain embodiments, the crosslinking agent can be a diglycidyl-functional epoxide or a triglycidyl-functional epoxide.

[0039] In certain embodiments, the crosslinking agent can be selected from diglycidyl-PEG(200 - 1000), glycerol triglycidyl ether, and combinations thereof.

[0040] In certain embodiments, the crosslinking agent can be selected from diglycidyl-PEG 200, diglycidyl-PEG 400, triglycidyl glycerol ether, and combinations thereof. In certain embodiments, the crosslinking agent can be diglycidyl-PEG 200. In certain embodiments, the crosslinking agent can be diglycidyl-PEG 400. In certain embodiments, the crosslinking agent can be triglycidyl glycerol ether.

[0041] In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 10 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 10 mol%.

[0042] In certain embodiments, the therapeutic agent present in the drug delivery composition on the analyte sensor can include at least one selected from the group consisting of antibiotic agents, antiviral agents, anti-inflammatory agents, anti-cancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof.

[0043] In certain embodiments, the therapeutic agent can be an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent can be one or more selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, ibuprofen, and their derivatives or salt forms. In certain embodiments, the anti-inflammatory agent is dexamethasone or its derivatives or salt forms. 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.

[0044] In certain embodiments, the drug delivery composition can include a therapeutic agent in an amount in the range of about 0.01 wt% - 50 wt% based on the total weight of the copolymer. In certain embodiments, the drug delivery composition can include a therapeutic agent in an amount in the range of about 0.01 wt% - 40 wt% based on the total weight of the copolymer.

[0045] In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 200 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 10 μg of a therapeutic agent.

[0046] In certain embodiments, the crosslinker binds to the hydrophilic units of the copolymer to form a charge.

[0047] In certain embodiments, the drug delivery composition can be disposed on the electrode of an analyte sensor. In certain embodiments, the drug delivery composition can be disposed on the working electrode of an analyte sensor. In certain embodiments, the drug delivery composition can be disposed on the counter / reference electrode of an analyte sensor. In certain embodiments, the drug delivery composition can be disposed on the counter electrode of an analyte sensor. In certain embodiments, the drug delivery composition can be disposed on the reference electrode of an analyte sensor.

[0048] In certain embodiments, the drug delivery composition can be disposed on the mass transport limiting membrane of an analyte sensor.

[0049] In certain embodiments, the therapeutic agent is not covalently bound to the copolymer.

[0050] In certain embodiments, the therapeutic agent is covalently bound to the copolymer.

[0051] 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.

[0052] One or more aspects of embodiments of the present disclosure relate to a method of controlling the drug delivery rate of an analyte sensor (such as a subcutaneous sensor) that comprises a drug delivery composition. In certain embodiments, the present disclosure provides a method of delivering the analyte sensors of the present disclosure. In certain embodiments, the method can comprise providing an analyte sensor as disclosed herein, such as an analyte sensor that comprises a drug delivery composition, and subcutaneously implanting the analyte sensor. Alternatively or additionally, the drug delivery composition can be inserted into the tissue of a subject in close proximity to the analyte sensor.

[0053] In certain embodiments, the method of controlling the drug delivery rate of an analyte sensor and / or the method of delivering an analyte sensor (e.g., a subcutaneous sensor) can include: (i) providing a sharp (tip) comprising an analyte sensor and a drug delivery composition, the drug delivery composition comprising: (a) a copolymer comprising a plurality of copolymer chains, wherein each of the plurality of copolymer chains comprises 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 the respective copolymer chains, and (c) a therapeutic agent; (ii) penetrating the tissue of a subject with the sharp; (iii) inserting the drug delivery composition and the analyte sensor into the tissue of the subject; and (iv) withdrawing the sharp from the tissue of the subject. In certain embodiments, the analyte sensor is located within the channel of the sharp and the drug delivery composition is located within the channel of the sharp distal to the analyte sensor.

[0054] In certain embodiments, the method of controlling the drug delivery rate of an analyte sensor and / or the method of delivering an analyte sensor (e.g., a subcutaneous sensor) can include: (i) providing a sharp comprising an analyte sensor that contains a drug delivery composition, the drug delivery composition comprising: (a) a copolymer comprising a plurality of copolymer chains, wherein each of the plurality of copolymer chains contains 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 the respective copolymer chains, and (c) a therapeutic agent; (ii) penetrating the tissue of a subject with the sharp; (iii) inserting the analyte sensor into the tissue of the subject; and (iv) withdrawing the sharp from the tissue of the subject. In certain embodiments, the sharp can further comprise a second drug delivery composition, e.g., a second drug delivery composition located within the channel of the sharp distal to the analyte sensor.

[0055] One or more aspects of embodiments of the present disclosure relate to a sharp object, such as a pre-loaded sharp object for delivering a drug delivery composition. In certain embodiments, the sharp object may comprise a drug delivery composition disclosed herein. In certain embodiments, the sharp object may comprise an analyte sensor and a drug delivery composition disclosed herein. By way of example, and not limitation, the drug delivery composition comprises: (i) a copolymer comprising a plurality of copolymer chains, wherein each of the plurality of copolymer chains comprises 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 the respective copolymer chains, and (iii) a therapeutic agent. In certain embodiments, the analyte sensor is located within a channel of the sharp object, and the drug delivery composition is located within the channel of the sharp object distal to the analyte sensor.

[0056] In certain embodiments, the sharp object may comprise an analyte sensor comprising a drug delivery composition disclosed herein. By way of example, and not limitation, the drug delivery composition comprises (i) a copolymer comprising a plurality of copolymer chains, wherein each of the plurality of copolymer chains comprises 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 the respective copolymer chains, and (iii) a therapeutic agent. In certain embodiments, the sharp object may further comprise a second drug delivery composition, such as a second drug delivery composition located within the channel of the sharp object distal to the analyte sensor.

[0057] In certain embodiments, the hydrophilic units of the copolymer may comprise nitrogen-containing heterocyclic units, such as pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, pyrazole units, and the like. In certain embodiments, the hydrophilic units of the copolymer may comprise pyridine units. In certain embodiments, the hydrophobic units of the copolymer may comprise aromatic units without heteroatoms, such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units, such as straight-chain or branched-chain alkyl units, straight-chain or branched-chain alkenyl units, straight-chain or branched-chain 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 may comprise aromatic units.

[0058] In certain embodiments, the copolymer may be selected from polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyetherurethane copolymers, silicone copolymers, their derivatives, and combinations thereof.

[0059] In certain embodiments, the copolymer may include a block polymer.

[0060] In certain embodiments, the copolymer is a polyvinylimidazole copolymer. In certain embodiments, the polyvinylimidazole copolymer can be a copolymer of vinylimidazole and styrene or a derivative thereof.

[0061] In certain embodiments, the polyvinylimidazole copolymer can be a polyvinylimidazole-co-polystyrene polymer. In 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.

[0062] In certain embodiments, the copolymer is a polyvinylpyridine copolymer. In certain embodiments, the polyvinylpyridine copolymer can be a copolymer of vinylpyridine and styrene or a derivative thereof.

[0063] In certain embodiments, the polyvinylpyridine 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.

[0064] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may include 1-50 mer% of styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may include 1-40 mer% of styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may include 1-30 mer% of styrene units.

[0065] In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD - 1,000 kD.

[0066] In certain embodiments, the crosslinking agent can be a diglycidyl-functional epoxide or a triglycidyl-functional epoxide.

[0067] In certain embodiments, the crosslinking agent can be selected from diglycidyl-PEG(200-1000), glycerol triglycidyl ether, and combinations thereof.

[0068] In certain embodiments, the crosslinking agent can be selected from diglycidyl-PEG 200, diglycidyl-PEG 400, triglycidyl glycerol ether, and combinations thereof. In certain embodiments, the crosslinking agent can be diglycidyl-PEG 200. In certain embodiments, the crosslinking agent can be diglycidyl-PEG 400. In certain embodiments, the crosslinking agent can be triglycidyl glycerol ether.

[0069] In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 10 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 10 mol%.

[0070] In certain embodiments, the therapeutic agent can include at least one selected from the group consisting of antibiotic agents, antiviral agents, anti-inflammatory agents, anti-cancer agents, antiplatelet agents, anticoagulants, coagulants, anti-glycolytic agents, and combinations thereof.

[0071] In certain embodiments, the therapeutic agent can be an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent can be one or more selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, ibuprofen, and their derivatives or salt forms. In certain embodiments, the anti-inflammatory agent is dexamethasone or its derivative or salt form. In certain embodiments, the derivative of dexamethasone is dexamethasone acetate. In certain embodiments, the derivative of dexamethasone is dexamethasone sodium phosphate.

[0072] In certain embodiments, the pharmaceutical delivery composition can include a therapeutic agent in an amount in the range of 0.01 wt% - 50 wt% based on the total weight of the copolymer. In certain embodiments, the pharmaceutical delivery composition can include a therapeutic agent in an amount in the range of 0.01 wt% - 40 wt% based on the total weight of the copolymer.

[0073] In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 200 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 10 μg of a therapeutic agent.

[0074] In certain embodiments, the crosslinker binds to the hydrophilic units of the copolymer to form a charge.

[0075] In certain embodiments, the therapeutic agent is not covalently bound to the copolymer.

[0076] In certain embodiments, the therapeutic agent is covalently bound to the copolymer.

[0077] 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.

[0078] In certain embodiments, the analyte sensor is configured to detect glucose.

[0079] One or more aspects of embodiments of the present disclosure relate to a method of manufacturing a drug delivery composition. In certain embodiments, the method can include: (a) providing a copolymer comprising a plurality of copolymer chains, wherein each of the plurality of copolymer chains comprises 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 the crosslinker to at least a portion of the hydrophilic units between the respective copolymer chains.

[0080] The present disclosure further provides an analyte sensor as described herein for controlling the drug delivery rate of an analyte sensor, wherein the analyte sensor is implanted subcutaneously.

[0081] In certain embodiments, the drug delivery composition of the present disclosure can be used to control the drug delivery rate of an analyte sensor, wherein the drug delivery composition and the analyte sensor are inserted into the tissue of a subject. In certain embodiments, a sharp object comprising the drug delivery composition and the analyte sensor is used to insert the drug delivery composition and the analyte sensor into the tissue of a subject. In certain embodiments, the analyte sensor is located within the channel of the sharp object, and the drug delivery composition is located within the channel of the sharp object distal to the analyte sensor.

[0082] 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 presented embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] This patent or application document contains at least one figure drawn in color. After a request and payment of the necessary fees, the Patent Office will provide a copy of this patent or published patent application with color drawings.

[0084] The following figures are included to illustrate certain aspects of the present disclosure and should not be considered exclusive embodiments. The disclosed subject matter may be subject to considerable modification, change, combination, and equivalents in form and function without departing from the scope of the present disclosure.

[0085] Figure 1 Shows an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0086] Figures 2A - 2C A perspective view of an exemplary analyte sensor is provided that includes two active regions located on separate working electrodes.

[0087] Figure 3 A cross-sectional view of an exemplary analyte sensor according to certain embodiments of the present disclosure is shown.

[0088] Figure 4 A cross-sectional view of an exemplary sharp object according to certain embodiments of the present disclosure is shown.

[0089] Figure 5 An exemplary coupon of a drug delivery composition on a biocompatible strip according to certain embodiments of the present disclosure is shown.

[0090] Figure 6 An exemplary sensor tail including a drug delivery composition according to certain embodiments of the present disclosure is shown.

[0091] Figures 7A - 7B An exemplary test sample of a drug delivery composition according to certain embodiments of the present disclosure is shown.

[0092] Figure 8 An exemplary test procedure for a drug delivery composition according to certain embodiments of the present disclosure is shown.

[0093] Figure 9 The HPLC of dexamethasone according to certain embodiments of the present disclosure is shown.

[0094] Figure 10 A calibration curve of dexamethasone according to certain embodiments of the present disclosure is shown.

[0095] Figure 11Shows the drug delivery curve (drug delivery profile, drug delivery overview) of an exemplary drug delivery composition according to certain embodiments of the present disclosure, including 100% polyvinylpyridine, triglycidyl ether (Gly3), and dexamethasone.

[0096] Figure 12 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure, including 100% polyvinylpyridine, diglycidyl-PEG 400 (PEG400), and dexamethasone.

[0097] Figure 13 Shows exemplary test polymers and copolymers of a drug delivery composition according to certain embodiments of the present disclosure.

[0098] Figure 14 Shows exemplary crosslinking agents of a drug delivery composition according to certain embodiments of the present disclosure.

[0099] Figure 15 Shows an exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure.

[0100] Figure 16 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0101] Figure 17 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0102] Figure 18 Shows an exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure.

[0103] Figure 19 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0104] Figure 20 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0105] Figure 21 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0106] Figure 22 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0107] Figure 23 Shows the concentration relationship between different crosslinking agents in an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0108] Figure 24 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0109] Figure 25 Shows an exemplary formulation of an exemplary drug delivery composition for an analyte sensor according to certain embodiments of the present disclosure.

[0110] Figure 26 Shows the drug delivery curve of an exemplary drug delivery composition on an analyte sensor according to certain embodiments of the present disclosure.

[0111] Figure 27 Shows the drug delivery curve of an exemplary drug delivery composition on an analyte sensor at each time point according to certain embodiments of the present disclosure.

[0112] Figure 28 Shows the influencing factors on the drug delivery rate of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0113] Figure 29 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0114] Figure 30 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0115] Figure 31 Shows the drug delivery curve of an exemplary drug delivery composition according to certain embodiments of the present disclosure.

[0116] Figure 32 Shows the drug delivery curve of an exemplary drug delivery composition on an analyte sensor and the drug delivery curve at each time point according to certain embodiments of the present disclosure.

[0117] Figure 33 Shows the solubility of Dex in a polyvinylpyridine - ethanol:water (volume ratio 95:5) solution according to certain embodiments of the present disclosure.

[0118] Figure 34A Shows an exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure.

[0119] Figure 34B Shows an exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure.

[0120] Figure 35AShows the drug delivery curve of an exemplary drug delivery composition on an analyte sensor and the drug delivery curve at each time point, in accordance with certain embodiments of the present disclosure.

[0121] Figure 35B Shows the drug delivery curve of an exemplary drug delivery composition on an analyte sensor and the drug delivery curve at each time point, in accordance with certain embodiments of the present disclosure.

[0122] Figure 35C Shows exemplary drug delivery loading amounts on an analyte sensor and the effect of these amounts on the LSA, in accordance with certain embodiments of the present disclosure.

[0123] Figure 36 Is a flowchart showing a method of manufacturing an exemplary drug delivery composition, in accordance with certain embodiments of the present disclosure.

[0124] Figure 37 Provides a drawing of an illustrative sensing system that can be coupled to an analyte sensor of the present disclosure.

[0125] Figures 38A - 38B Provides a cross-sectional view of an exemplary analyte sensor including a single active region.

[0126] Figures 39A - 39C Provides a cross-sectional view of an exemplary analyte sensor including two active regions located on separate working electrodes.

[0127] Figure 40 Provides a cross-sectional view of an exemplary analyte sensor including two active regions. Detailed Description

[0128] As described herein, implantation of an analyte sensor can result in a variety of physiological responses that can have a negative impact on sensor function. For example, inflammation or immune responses at the tissue trauma site caused by the analyte sensor and its implantation may lead to loss of sensor function and sensitivity in vivo.

[0129] To address the above needs, the present disclosure provides drug delivery compositions for treating (treating) the tissue surrounding an implanted analyte sensor. For example, but not by way of limitation, the present disclosure provides analyte sensors including a therapeutic agent (e.g., a drug delivery composition containing a therapeutic agent as described herein). In certain embodiments, the present disclosure provides drug delivery compositions that can be inserted near an analyte sensor implanted in a subject.

[0130] In certain embodiments, the drug delivery compositions of the present disclosure provide for the sustained release of a therapeutic agent over an extended period of time, such as over a period of 14 days or longer, such as over a period of about 30 days. In certain embodiments, the sustained release of a therapeutic agent (such as an anti-inflammatory agent) in close proximity to the analyte sensor can prevent and / or reduce inflammation or an immune response in the tissue surrounding the implantation site. For example, but not by way of limitation, preventing and / or reducing inflammation in the tissue surrounding the implantation site can extend the useful life of the implanted analyte sensor. In certain embodiments, preventing and / or reducing an immune response to the analyte sensor can extend the useful life of the implanted analyte sensor. In certain embodiments, extending the useful life of the implanted analyte sensor means maintaining the accuracy of the analyte sensor near the end of its useful life and / or minimizing, reducing, and / or eliminating inaccuracies in the analyte signal near the end of the sensor's useful life.

[0131] In certain embodiments, the useful life of the analyte sensors disclosed herein can be increased by more than about 2 days, more than about 3 days, more than about 4 days, more than about 5 days, more than about 6 days, more than about 7 days, more than about 8 days, more than about 9 days, more than about 10 days, more than about 11 days, more than about 12 days, more than about 13 days, more than about 14 days, more than about 15 days, more than about 16 days, more than about 17 days, more than about 18 days, more than about 19 days, or more than about 20 days. In certain embodiments, an analyte sensor comprising the drug delivery compositions of the present disclosure can have a useful life of about 14 days or longer, about 15 days or longer, about 16 days or longer, about 17 days or longer, about 18 days or longer, about 19 days or longer, about 20 days or longer, about 21 days or longer, about 22 days or longer, about 23 days or longer, about 24 days or longer, about 25 days or longer, about 26 days or longer, about 27 days or longer, about 28 days or longer, about 29 days or longer, or about 30 days or longer. In certain embodiments, the useful life of the analyte sensors disclosed herein can be extended to obtain an analyte sensor having a useful life of about 30 days or longer.

[0132] In the following, specific embodiments will be described in more detail so that those of ordinary skill in the art can easily implement them. For example, embodiments of the present disclosure will be explained in more detail with reference to the accompanying drawings. However, the present disclosure can be embodied in many different forms and should not be construed as limited to the exemplary embodiments set forth herein.

[0133] For clarity, but not by way of limitation, the detailed description of the presently disclosed subject matter is divided into the following subsections:

[0134] I. Definitions;

[0135] II. Therapeutic Agents;

[0136] III. Pharmaceutical delivery compositions;

[0137] IV. Analyte sensors;

[0138] V. Delivery devices and delivery methods; and

[0139] VI. Exemplary embodiments.

[0140] I. Definitions

[0141] The terms used in this disclosure generally have their ordinary meanings in the art, in the context of this disclosure, and in the particular context in which each term is used. Certain terms are discussed (or elsewhere in this specification) to provide additional guidance to those skilled in the art for describing the compositions and methods of this disclosure and how to make and use them.

[0142] The terms used herein are for the purpose of describing embodiments only and are not intended to limit the disclosure. Unless the context clearly dictates otherwise, singular expressions include plural expressions.

[0143] As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Further, "may" as used in describing the embodiments of this disclosure refers to "one or more embodiments of this disclosure".

[0144] The terms "comprising", "including", "having", "has", "containing", and variations thereof used herein are intended as open transitional phrases, terms, or words that do not exclude additional act or structure. The disclosure also contemplates other embodiments that "comprise" the embodiments or elements presented herein, "consist of", and "consist essentially of" the embodiments or elements presented herein, whether or not explicitly set forth.

[0145] As used herein, "or" should not be construed in an exclusive sense; for example, "A or B" should be understood to include A, B, A + B, etc. Further, as used herein, the term "and / or" includes any and all combinations of one or more of the related listed items. Expressions such as "at least one", "one of", and "selected from", when preceding a list of elements, modify the entire list of elements rather than a single element in the list.

[0146] The terms "about" or "substantially" mean within an acceptable error range of a particular value as determined by a person of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measuring system. For example, in accordance with the practice in the art, "about" can mean within 3 or more standard deviations. In certain embodiments, "about" can mean a range up to 20% of a given value, preferably up to 10% of the range, more preferably up to 5% of the range, and still more preferably up to 1% of the range. In certain embodiments, particularly for biological systems or methods, the term can mean within an order of magnitude of a value, preferably within 5-fold, and more preferably within 2-fold.

[0147] Any numerical range recited herein is intended to include all sub-ranges subsumed within the same numerical precision of the recited range. For example, a range of "1.0 to 10.0" or "between 1.0 and 10.0" is intended to include all sub-ranges between the recited minimum value of 1.0 and the recited maximum value of 10.0 (including that value), i.e., the minimum value is equal to or greater than 1.0 and the maximum value is equal to or less than 10.0, such as 2.4 to 7.6. Similarly, a range described as "within 35% of 10" is intended to include all sub-ranges between the recited minimum value of 6.5 (i.e., (1 - 35 / 100) times 10) and the recited maximum value of 13.5 (i.e., (1 + 35 / 100) times 10) (and including that value), i.e., the minimum value is equal to or greater than 6.5 and the maximum value is equal to or less than 13.5, such as 7.4 to 10.6. Any maximum numerical limitation recited herein is intended to include all lower numerical limitations subsumed therein, and any minimum numerical limitation recited in this specification is intended to include all higher numerical limitations subsumed therein.

[0148] As used herein, an "analyte sensor" or "sensor" can refer to any device capable of receiving sensor information from a user, including by way of illustration and not limitation, a body 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 collecting physical or biological information. Analytes that can be measured by an analyte sensor can include (by way of example and not limitation) glutamate, glucose, ketones, lactate, oxygen, hemoglobin A1C, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartic acid, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, uric acid, and the like.

[0149] As used herein, the term "biological fluid" refers to any body fluid or body fluid derivative in which an analyte can be measured. Non-limiting examples of biological fluids include dermal fluid (skin fluid), interstitial fluid, plasma, blood, lymph, synovial fluid, cerebrospinal fluid, saliva, bronchoalveolar lavage, 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.

[0150] As used herein, the term "covalent bond" refers to a chemical bond involving the sharing of electron pairs between atoms. Similarly, "covalent binding" refers to chemical binding in a manner involving the sharing of electron pairs between atoms.

[0151] As used herein, the term "non-covalent" or similar terms refer to chemical interactions that do not involve electron sharing, but rather involve more dispersed changes in electromagnetic interactions between or within molecules.

[0152] As used herein, the term "polyvinylpyridine polymer" refers to a polymer (e.g., copolymer) that includes polyvinylpyridine (e.g., poly(2-vinylpyridine) or poly(4-vinylpyridine)) or a derivative thereof.

[0153] As used herein, the term "multicomponent membrane" refers to a membrane that contains two or more types of membrane polymers.

[0154] As used herein, the term "single-component membrane" refers to a membrane that contains one type of membrane polymer.

[0155] The term "reference electrode" as used herein can refer to a reference electrode or an electrode that serves simultaneously as 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 serves as a reference electrode. In certain embodiments, the term "counter electrode / reference electrode" as used herein refers to both a counter electrode and a counter electrode that also serves as a reference electrode.

[0156] As used herein, the term "mol% crosslinking" can refer to the degree of crosslinking of a crosslinking agent in the copolymer matrix of a drug delivery composition. For example, in certain embodiments, the copolymer can be a polyvinylpyridine-co-polystyrene copolymer, and the "mol% crosslinking" of the crosslinking agent can be calculated using the following formula:

[0157]

[0158] where the crosslinker functionality is the number of reactive crosslinking groups in a crosslinker molecule.

[0159] II. Therapeutic Agent

[0160] The present disclosure provides compositions of therapeutic agents and analyte sensors comprising therapeutic agents. In certain embodiments, the compositions (e.g., drug delivery compositions) or analyte sensors of the present disclosure may comprise two or more therapeutic agents.

[0161] In certain embodiments, the therapeutic agent delivered in accordance with the present disclosure may be a therapeutic agent effective to reduce, minimize, prevent, and / or inhibit the tissue response to the implantation of the analyte sensor. For example, but not by way of limitation, the therapeutic agent delivered in accordance with the present disclosure may be a therapeutic agent effective to reduce, minimize, prevent, and / or inhibit inflammation in the tissue.

[0162] In certain embodiments, the 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 drugs, and combinations thereof.

[0163] In certain embodiments, the therapeutic agent for use in the present disclosure may comprise at least one selected from the group consisting of antibiotic agents, antiviral agents, anti-inflammatory agents, anti-cancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof. In certain embodiments, the therapeutic agent is an antibiotic agent. In certain embodiments, the therapeutic agent is an antiviral agent. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the therapeutic agent is an 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.

[0164] In certain embodiments, the therapeutic agent is an antiviral agent. In certain embodiments, the antiviral agent may include, but is not limited to, Umifenovir, Baloxavir marboxil, Darunavir, Nitazoxanide, Peramivir, Tipranavir, and the like.

[0165] In certain embodiments, the therapeutic agent is an antibiotic agent. In certain embodiments, the antibiotic agent may include, but is not limited to, Rifaximin, Ertapenem, Doripenem, Cefadroxil, Clindamycin, Amoxicillin, Penicillin, and the like.

[0166] In certain embodiments, the therapeutic agent is an anti-cancer agent. In certain embodiments, the anti-cancer agent can include, but is not limited to, Gilteritinib, Glasdegib, Ivosidenib, Enasidenib, Midostaurin, Venetoclax, Alpelisib, etc.

[0167] In certain embodiments, the therapeutic agent can 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 can be one or more selected from triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, ibuprofen, and their derivatives or salt forms. Non-limiting salt forms include pharmaceutically acceptable salts, including acetates and phosphates. In certain embodiments, the anti-inflammatory agent is a salt of dexamethasone.

[0168] In certain embodiments, the anti-inflammatory agent is dexamethasone or its derivatives or salt forms. 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.

[0169] III. Drug Delivery Compositions

[0170] The present disclosure provides a composition comprising one or more therapeutic agents and a polymer, such as a drug delivery composition. In certain embodiments, the drug delivery composition of the present disclosure can be incorporated into an analyte sensor, such as the implantable analyte sensor described herein. In certain embodiments, the drug delivery composition of the present disclosure can be placed adjacent to an analyte sensor, such as an implantable analyte sensor. Incorporating the drug delivery composition within the analyte sensor itself or delivering the drug delivery composition to an in vivo location adjacent to the analyte sensor, thereby allowing the therapeutic agent contained in the drug delivery composition to be targeted to the implantation site and the tissue surrounding the analyte sensor.

[0171] In certain embodiments, targeting a therapeutic agent contained in a drug delivery composition to the analyte sensor implantation site allows for reducing in vivo sensor failure (malfunction) due to FBR. In certain embodiments, targeting a therapeutic agent contained in a drug delivery composition to the analyte sensor implantation site allows for reducing sensor signal inaccuracy due to FBR. In certain embodiments, targeting a therapeutic agent contained in a drug delivery composition to the analyte sensor implantation site allows for reducing late sensor attenuation (LSA). For example, but not by way of limitation, targeting a therapeutic agent to the analyte sensor implantation site contained in a drug delivery composition allows for reducing and / or eliminating analyte signal inaccuracies observable after in vivo implantation.

[0172] In certain embodiments, a therapeutic agent can be incorporated into a drug delivery composition. For example, but not by way of limitation, a therapeutic agent can be non-covalently mixed with the copolymer of the composition, or a therapeutic agent can be covalently attached to the copolymer of the composition. In certain embodiments, a therapeutic agent can be covalently attached directly or through a linker to one or more polymer chains of the composition. In certain embodiments, a therapeutic agent can be covalently attached through a hydrolyzable bond to one or more polymer chains of a polymer matrix to allow for delayed release of the therapeutic agent after insertion of an analyte sensor in vivo.

[0173] In certain embodiments, a therapeutic agent is non-covalently mixed with the copolymer of the composition, such as Figure 1 shown.

[0174] Figure 1 An exemplary drug delivery composition according to some embodiments of the present disclosure is shown. As Figure 1 shown, certain embodiments of the present invention provide a drug delivery composition, and the drug delivery composition can include a polymer and a therapeutic agent. In certain embodiments, the drug delivery composition can include a copolymer containing a plurality of copolymer chains and a therapeutic agent. In certain embodiments, each of the plurality of copolymer chains contains a backbone including a plurality of hydrophilic units and a plurality of hydrophobic units. In certain embodiments, the drug delivery composition of the present disclosure further contains a crosslinking agent, such as crosslinking at least a portion of the hydrophilic units between the respective copolymer chains. For example, but not by way of limitation, the drug delivery composition can include (i) a copolymer including a plurality of copolymer chains, wherein each of the plurality of copolymer chains contains a backbone containing 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 the respective copolymer chains, and (iii) a therapeutic agent, as Figure 1 shown.

[0175] In certain embodiments, the hydrophilic units of the copolymer may include 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, etc. For example, in certain embodiments, as Figure 1 shown, the hydrophilic unit of the copolymer may be a pyridine unit. Of course, the embodiments of the present disclosure are not limited thereto.

[0176] In certain embodiments, the hydrophobic units of the copolymer may include aromatic units without heteroatoms, such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units, such as straight-chain or branched alkyl units, straight-chain or branched alkenyl units, straight-chain 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, as Figure 1 shown, the hydrophobic unit of the copolymer may be a benzene (phenyl) unit. Of course, the embodiments of the present disclosure are not limited thereto.

[0177] 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.

[0178] In certain embodiments, the mer% of the hydrophobic units in the copolymer (i.e., Figure 1 the ratio of x / (x + y) shown therein) is in the range of about 1% - 99%, about 1% - 90%, about 1% - 80%, about 1% - 70%, about 1% - 60%, about 1% - 50%, about 1% - 40%, about 1% - 30%, about 1% - 25%, about 1% - 20%, about 1% - 15%, about 1% - 10%, about 2% - 10%, about 3% - 10%, about 4% - 10%, about 5% - 10%, about 6% - 10%, about 7% - 10%, about 8% - 10%, or about 9% - 10%, or in any range defined between any two of the foregoing values, such as in the range of about 7% - 15%. In certain embodiments, the mer% of the hydrophobic units in the copolymer is in the range of about 5% - 25%. In certain embodiments, the mer% of the hydrophobic units in the copolymer is in the range of about 5% - 20%. In certain embodiments, the mer% of the hydrophobic units in the copolymer is in the range of about 5% - 15%. In certain embodiments, the mer% of the hydrophobic units in the copolymer is in the range of about 5% - 10%.

[0179] In certain embodiments, the copolymer may be selected from polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyetherurethane copolymers, silicone copolymers, their derivatives, and combinations thereof.

[0180] In certain embodiments, the copolymer may be a polyurethane copolymer. Non-limiting examples of polyurethane copolymers include ether-based polyurethanes or ester-based polyurethanes.

[0181] In certain embodiments, the copolymer may be a polyvinylimidazole copolymer. In certain embodiments, the polyvinylimidazole copolymer may be a copolymer of vinylimidazole and styrene or a derivative thereof.

[0182] In certain embodiments, the polyvinylimidazole copolymer may be a polyvinylimidazole-co-polystyrene polymer. In certain embodiments, the polyvinylimidazole-co-polystyrene polymer may be a poly(N-vinylimidazole)-co-polystyrene polymer, a poly(1-vinylimidazole)-co-polystyrene polymer, or a derivative thereof.

[0183] In certain embodiments, the copolymer may be a polyvinylpyridine copolymer. In certain embodiments, the polyvinylpyridine copolymer may be a copolymer of vinylpyridine and styrene or a derivative thereof.

[0184] In certain embodiments, the polyvinylpyridine 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.

[0185] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 1-50 mer% styrene units, from about 1-40 mer% styrene units, from about 1-30 mer% styrene units, from about 1-20 mer% styrene units, or from about 1-15 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 1-50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 1-40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 1-30 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 1-20 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 1-15 mer% styrene units.

[0186] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 5-25 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 5-20 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise from about 5-15 mer% styrene units.

[0187] In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD - 1,000 kD, about 5 kD - 900 kD, about 5 kD - 800 kD, about 5 kD - 700 kD, about 5 kD - 600 kD, about 5 kD - 500 kD, about 5 kD - 400 kD, about 5 kD - 300 kD, about 10 kD - 300 kD, about 20 kD - 300 kD, about 30 kD - 300 kD, about 40 kD - 300 kD, about 50 kD - 300 kD, about 60 kD - 300 kD, about 70 kD - 300 kD, about 80 kD - 300 kD, about 90 kD - 300 kD, about 100 kD - 300 kD, or about 100 kD - 200 kD, or any range defined between any two of the foregoing values, such as in the range of about 100 kD - 400 kD. In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 100 kD - 250 kD. In certain embodiments, the molecular weight of the copolymer can be determined by a suitable method (such as gel permeation chromatography).

[0188] In certain embodiments, the copolymers for use in the present disclosure are capable of absorbing from about 5% to about 95% of their weight in water. By way of example, and not limitation, the copolymers for use in the present disclosure are capable of absorbing from about 5% to about 95%, from about 5% to about 90%, from about 5% to about 85%, from about 10% to about 95%, from about 15% to about 95%, from about 20% to about 95%, from about 25% to about 95%, from about 30% to about 95%, from about 5% to about 30%, from about 5% to about 35%, from about 5% to about 25%, or from about 5% to about 20% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 5% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 10% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 20% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 30% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 40% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 50% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 60% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 70% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 80% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 90% of their weight in water. In certain embodiments, the copolymers are capable of absorbing at least about 95% of their weight in water. In certain embodiments, the copolymers are capable of absorbing from about 5% to about 25% of their weight in water.

[0189] In certain embodiments, the copolymers for use in the present disclosure can have a Shore A hardness of from about 20 to about 100. For example, but not by way of limitation, the copolymers for use in the present disclosure can have a Shore A hardness of from about 20 to about 90, from about 20 to about 80, from about 20 to about 70, from about 20 to about 60, from about 20 to about 50, from about 20 to about 40, from about 20 to about 30, from about 30 to about 100, from about 40 to about 100, from about 50 to about 100, from about 60 to about 100, from about 70 to about 100, from about 80 to about 100, from about 90 to about 100, from about 70 to about 95, from about 70 to about 90, from about 70 to about 85, from about 70 to about 80, from about 75 to about 95, from about 80 to about 95, from about 85 to about 95, from about 80 to about 93, or from about 80 to about 90. In certain embodiments, the copolymers for use in the present disclosure can have a Shore A hardness of about 80. In certain embodiments, the copolymers for use in the present disclosure can have a Shore A hardness of about 90. In certain embodiments, the copolymers for use in the present disclosure can have a Shore A hardness of about 93. In certain embodiments, the copolymers for use in the present disclosure can have a Shore A hardness of from about 80 to about 100, such as before implantation into a subject or before being hydrated. In certain embodiments, the copolymers for use in the present disclosure can have a Shore A hardness of from about 20 to about 60, such as when implanted into a subject or when hydrated.

[0190] In certain embodiments, the linear expansion of the copolymer used in the present disclosure is from about 10% to about 200%. For example, but not by way of limitation, the linear expansion of the copolymer used in the present disclosure can 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%, from about 70% to about 100%, from about 75% to about 100%, from about 80% to about 100%, from about 85% to about 100%, from about 90% to about 100%, from about 95% to about 100%, from about 20% to about 95%, from about 20% to about 90%, from about 20% to about 85%, from about 20% to about 80%, from about 20% to about 75%, from about 20% to about 70%, from about 20% to about 65%, from about 20% to about 60%, from about 20% to about 55%, from about 20% to about 50%, from about 20% to about 45%, from about 20% to about 40%, from about 20% to about 30%, from about 30% to about 60%, from about 40% to about 50%, from about 40% to about 60%, from about 20% to about 30% or from about 50% to about 70%. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 25%. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 40%. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 45%. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 50%. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 60%. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 100%. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 110% or greater, about 100% or greater, about 90% or greater, about 80% or greater, about 70% or greater, about 60% or greater, about 50% or greater, about 40% or greater, about 30% or greater, about 20% or greater or about 10% or greater. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 110% or greater. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 100% or greater. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 90% or greater. In certain embodiments, the linear expansion of the copolymer used in the present disclosure is about 80% or greater.In certain embodiments, the linear expansion of the copolymer for use in the present disclosure is about 70% or greater. In certain embodiments, the linear expansion of the copolymer for use in the present disclosure is about 60% or greater. In certain embodiments, the linear expansion of the copolymer for use in the present disclosure is about 50% or greater. In certain embodiments, the linear expansion of the copolymer for use in the present disclosure is about 40% or greater. In certain embodiments, the linear expansion of the copolymer for use in the present disclosure is about 30% or greater. In certain embodiments, the linear expansion of the copolymer for use in the present disclosure is about 20% or greater. In certain embodiments, the linear expansion of the copolymer for use in the present disclosure is about 10% or greater.

[0191] In certain embodiments, the copolymer has a linear expansion of about 45% and is capable of absorbing about 70% of its weight in water. In certain embodiments, the copolymer has a linear expansion of about 25% and is capable of absorbing about 55% of its weight in water. In certain embodiments, the copolymer has a linear expansion of about 40% and is capable of absorbing about 60% of its weight in water. In certain embodiments, the copolymer has a linear expansion of about 50% and is capable of absorbing about 50% of its weight in water. In certain embodiments, the copolymer has a linear expansion of about 60% and is capable of absorbing about 80% of its weight in water. In certain embodiments, the copolymer has a linear expansion of about 100% and is capable of absorbing about 90% of its weight in water. In certain embodiments, the copolymer has a linear expansion of about 10% and is capable of absorbing about 30% of its weight in water. In certain embodiments, the copolymer has a linear expansion of about 180% and is capable of absorbing about 95% of its weight in water.

[0192] In certain embodiments, the pharmaceutical delivery composition of the present disclosure may further include a crosslinking agent. By way of example, and not limitation, the crosslinking agent crosslinks at least a portion of the hydrophilic units and / or hydrophobic units between the respective copolymer chains. In certain embodiments, the crosslinking agent crosslinks at least a portion of the hydrophilic units between the respective copolymer chains. In certain embodiments, the crosslinking agent crosslinks at least a portion of the nitrogen-containing heterocyclic units, such as pyridine units, between the respective copolymer chains. By way of example, and not limitation, the crosslinking agent crosslinks at least a portion of the pyridine units, such as Figure 1 shown.

[0193] In certain embodiments, the crosslinking agent may be a diglycidyl-functional epoxide or a triglycidyl-functional epoxide.

[0194] In certain embodiments, the crosslinking agent may be selected from diglycidyl-PEG(200 - 1000), glycerol triglycidyl ether, and combinations thereof. For example, in certain embodiments, as Figure 1As shown, the crosslinking agent is diglycidyl-PEG(200-1000) with a molecular weight of 200 g / mol - 1000 g / mol. The term "diglycidyl-PEG" used in the present disclosure may refer to polyethylene glycol diglycidyl ether.

[0195] In certain embodiments, the crosslinking agent may be selected from diglycidyl-PEG 200, diglycidyl-PEG 400, triglycidyl glycerol ether, and combinations thereof. In certain embodiments, the crosslinking agent may be diglycidyl-PEG 200. In certain embodiments, the crosslinking agent may be diglycidyl-PEG 400. In certain embodiments, the crosslinking agent may be triglycidyl glycerol ether.

[0196] In certain embodiments, the drug delivery composition comprises a crosslinking agent (e.g., including a certain amount of crosslinking agent), which provides a certain mol% crosslinking of the polymer (e.g., copolymer) present in the drug delivery composition. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 40 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 40 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.2 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 25 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 25 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 20 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 20 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 15 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 15 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.1 mol% - 10 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 0.5 mol% - 10 mol%. In certain embodiments, the mol% crosslinking of the copolymer can be in the range of about 1 mol% - 10 mol%.

[0197] In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 20 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 19 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 18 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 17 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 16 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 15 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 14 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 13 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 12 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 11 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 10 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 9 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 8 mol% crosslinking (such as crosslinking of a copolymer). In certain embodiments, the drug delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the drug delivery composition provides no more than about 7 mol% crosslinking (such as crosslinking of a copolymer).In certain embodiments, the pharmaceutical delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the pharmaceutical delivery composition provides no more than about 6 mol% crosslinking (such as crosslinking of the copolymer). In certain embodiments, the pharmaceutical delivery compositions of the present disclosure include a crosslinking agent, wherein the amount of the crosslinking agent in the pharmaceutical delivery composition provides no more than about 5 mol% crosslinking (such as crosslinking of the copolymer).

[0198] In certain embodiments, based on the total weight of the copolymer (e.g., in a drug delivery composition), the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 50 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 40 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of 0.01 wt% - 30 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 20 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 15 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 10 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 9 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 8 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 7 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 6 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 5 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 4 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 3 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 2 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 1 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 0.01 wt% - 5 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a crosslinking agent in an amount in the range of about 1 wt% - 40 wt%.In certain embodiments, based on the total weight of the copolymer, the drug delivery composition may comprise an amount of crosslinker in the range of about 1 wt% - 30 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition may comprise an amount of crosslinker in the range of about 1 wt% - 25 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition may comprise an amount of crosslinker in the range of about 1 wt% - 20 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition may comprise an amount of crosslinker in the range of about 1 wt% - 15 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition may comprise an amount of crosslinker in the range of about 1 wt% - 10 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition may comprise an amount of crosslinker in the range of about 1 wt% - 5 wt%.

[0199] As Figure 1 shown, the crosslinker crosslinks at least two polymer backbones of two or more copolymer chains by bonding (binding) to the hydrophilic units of two or more copolymer chains. In certain embodiments, the copolymer can be a polyvinylpyridine-co-polystyrene polymer, and the crosslinker can be diglycidyl-PEG. Diglycidyl-PEG can have two crosslinking glycidyl groups, and each glycidyl group can bond to the pyridine nitrogen atom of a different copolymer chain to crosslink the main chain of the copolymer chain and form a positive charge on the pyridine moiety, as Figure 1 shown. The charge formed can regulate the swellability of the drug delivery composition. Additionally, by using an appropriate amount of diglycidyl-PEG with a suitable molecular weight and / or triglycidyl ether of glycerol having three crosslinkable glycidyl groups, the degree of crosslinking of the copolymer can be finely adjusted as shown in the examples.

[0200] In certain embodiments, the drug delivery composition can include one or more therapeutic agents. Non-limiting examples of therapeutic agents are disclosed in Section II of this article. For example, but not by way of limitation, the therapeutic agent can include at least one selected from the group consisting of antibiotic agents, antiviral agents, anti-inflammatory agents, anti-cancer agents, antiplatelet agents, anticoagulants, coagulants, anti-glycolytic agents, and combinations thereof. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent can be one or more selected from the group consisting of triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, ibuprofen, 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.

[0201] As Figure 1 shown, in certain embodiments, the therapeutic agent is dexamethasone. Dexamethasone is present non-covalently in the cross-linked copolymer matrix and is trapped in the cross-linked copolymer matrix. Dexamethasone can interact with the hydrophilic and hydrophobic units of the cross-linked copolymer matrix through non-polar and polar interactions.

[0202] In certain embodiments, the therapeutic agent can be covalently bound to the copolymer.

[0203] In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 0.01 wt% to 50 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 0.01 wt% to 40 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 1 wt% to 40 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 5 wt% to 40 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutic agent in the range of from 10 wt% to 40 wt%, such as dexamethasone or a derivative thereof. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 20 wt% to 40 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 30 wt% to 40 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 5 wt% to 20 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 5 wt% to 10 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 1 wt% to 10 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 1 wt% to 20 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 1 wt% to 30 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of a therapeutic agent, such as dexamethasone or a derivative thereof, in the range of from about 10 wt% to 20 wt%.

[0204] In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 50 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 49 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 48 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 47 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 46 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 45 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 44 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 43 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 42 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 41 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 40 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 39 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 38 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 37 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 36 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 35 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise a therapeutically effective amount of a therapeutic agent, such as dexamethasone or a derivative thereof, not greater than about 34 wt%.In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically active agent, such as dexamethasone or a derivative thereof, in an amount not greater than about 33 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically active agent, such as dexamethasone or a derivative thereof, in an amount not greater than about 32 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically active agent, such as dexamethasone or a derivative thereof, in an amount not greater than about 31 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically active agent, such as dexamethasone or a derivative thereof, in an amount not greater than about 30 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically active agent, such as dexamethasone or a derivative thereof, in an amount not greater than about 25 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically active agent, such as dexamethasone or a derivative thereof, in an amount not greater than about 20 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically active agent, such as dexamethasone or a derivative thereof, in an amount not greater than about 15 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically active agent, such as dexamethasone or a derivative thereof, in an amount not greater than about 10 wt%.

[0205] In certain embodiments, the drug delivery composition can include from about 0.0005 mg to about 0.2 mg of a therapeutically active agent (such as dexamethasone), or any value therebetween. In certain embodiments, the drug delivery composition can include 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 therapeutically active agent, such as dexamethasone. In certain embodiments, the drug delivery composition can include from about 0.0005 mg to about 0.1 mg, from about 0.0005 mg to about 0.05 mg, from about 0.0005 mg to about 0.01 mg, from about 0.0005 mg to about 0.005 mg, or from about 0.0005 mg to about 0.001 mg of a therapeutically active agent, such as dexamethasone. In certain embodiments, the drug delivery composition can include from about 0.0005 mg to about 0.1 mg. In certain embodiments, the drug delivery composition can include from about 0.0005 mg to about 0.01 mg. In certain embodiments, the drug delivery composition can include from about 0.001 mg to about 0.1 mg. In certain embodiments, the drug delivery composition can include from about 0.001 mg to about 0.01 mg. In certain embodiments, the drug delivery composition can include from about 0.001 mg to about 0.005 mg. In certain embodiments, the drug delivery composition can include from about 0.001 mg to about 0.003 mg.

[0206] In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 200 μg of a therapeutic agent, such as 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, from about 20 μg to about 200 μg, from about 25 μg to about 200 μg, from about 30 μg to about 200 μg, from about 35 μg to about 200 μg, from about 40 μg to about 200 μg, from about 45 μg to about 200 μg, from about 50 μg to about 200 μg, from about 55 μg to about 200 μg, from about 60 μg to about 200 μg, from about 65 μg to about 200 μg, from about 70 μg to about 200 μg, from about 75 μg to about 200 μg, from about 80 μg to about 200 μg, from about 85 μg to about 200 μg, from about 90 μg to about 200 μg, from about 95 μg to about 200 μg, from about 100 μg to about 200 μg, from about 110 μg to about 200 μg, from about 120 μg to about 200 μg, from about 130 μg to about 200 μg, from about 140 μg to about 200 μg, from about 150 μg to about 200 μg, from about 160 μg to about 200 μg, from about 170 μg to about 200 μg, from about 180 μg to about 200 μg, from about 190 μg to about 200 μg, from about 0.1 μg to about 190 μg, from about 0.1 μg to about 180 μg, from about 0.1 μg to about 170 μg, from about 0.1 μg to about 160 μg, from about 0.1 μg to about 150 μg, from about 0.1 μg to about 140 μg, from about 0.1 μg to about 130 μg, from about 0.1 μg to about 120 μg, from about 0.1 μg to about 110 μg, from about 0.1 μg to about 100 μg, from about 1 μg to about 150 μg, from about 5 μg to about 150 μg, or from about 5 μg to about 120 μg.In certain embodiments, the drug delivery composition can comprise from about 1 μg to about 100 μg of a therapeutic agent, such as 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, from about 1 μg to about 20 μg, from about 1 μg to about 15 μg, from about 1 μg to about 14 μg, from about 1 μg to about 13 μg, from about 1 μg to about 12 μg, from about 1 μg to about 11 μg, from about 1 μg to about 10 μg, from about 1 μg to about 9 μg, from about 2 μg to about 100 μg, from about 3 μg to about 100 μg, from about 4 μg to about 100 μg, from about 5 μg to about 100 μg, from about 6 μg to about 100 μg, from about 7 μg to about 100 μg, from about 8 μg to about 100 μg, from about 9 μg to about 100 μg, from about 10 μg to about 100 μg, from about 11 μg to about 100 μg, from about 12 μg to about 100 μg, from about 13 μg to about 100 μg, from about 14 μg to about 100 μg, from about 15 μg to about 100 μg, from about 16 μg to about 100 μg, from about 17 μg to about 100 μg, from about 18 μg to about 100 μg, from about 19 μg to about 100 μg, from about 20 μg to about 100 μg, from about 25 μg to about 100 μg, from about 30 μg to about 100 μg, from about 35 μg to about 100 μg, from about 40 μg to about 100 μg, from about 45 μg to about 100 μg, from about 50 μg to about 100 μg, from about 55 μg to about 100 μg, from about 60 μg to about 100 μg, from about 65 μg to about 100 μg, from about 70 μg to about 100 μg, from about 75 μg to about 100 μg, from about 80 μg to about 100 μg, from about 85 μg to about 100 μg, from about 90 μg to about 100 μg, from about 95 μg to about 100 μg, from about 5 μg to about 50 μg, from about 5 μg to about 45 μg, from about 5 μg to about 40 μg, from about 5 μg to about 35 μg, from about 5 μg to about 30 μg, from about 5 μg to about 25 μg, or from about 5 μg to about 20 μg. In certain embodiments, the drug delivery composition can comprise from about 1 μg to about 5 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 1 μg to about 10 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 1 μg to about 15 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 1 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 5 μg to about 20 μg of a therapeutic agent.In certain embodiments, the drug delivery composition can comprise from about 1 μg to about 30 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 5 μg to about 10 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 5 μg to about 15 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 5 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 5 μg to about 25 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 5 μg to about 30 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 30 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 20 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 15 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 10 μg of a therapeutic agent. In certain embodiments, the drug delivery composition can comprise from about 0.1 μg to about 5 μg of a therapeutic agent.

[0207] In certain embodiments, the drug delivery composition can continuously release a therapeutic agent (e.g., dexamethasone) at a drug delivery rate (e.g., average drug delivery rate) of from about 0.01 μg / day to about 1 mg / day of the therapeutic agent or any value therebetween (e.g., when administered adjacent to the analyte sensor and / or when incorporated into the analyte sensor). In certain embodiments, the drug delivery composition can continuously release a therapeutic agent (e.g., dexamethasone) at a drug delivery rate (e.g., average drug delivery rate) of 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, 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 of the therapeutic agent or any value therebetween (e.g., when administered adjacent to the analyte sensor and / or when incorporated into the analyte sensor). 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 from about 0.2 μg / day to about 5 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 from 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 from 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 outcome, such as reducing, minimizing, decreasing, 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 outcome, such as minimizing signal inaccuracy near the end of the sensor's useful 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, for example, sensor signal inaccuracy or in vivo sensor failure due to FBR.In certain embodiments, the drug delivery composition can continuously release the therapeutic agent at a set or predetermined drug delivery rate to achieve a desired therapeutic outcome, such as minimizing and / or reducing LSA.

[0208] In certain embodiments, the drug delivery composition can continuously release the 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 (e.g., when administered adjacent to the analyte sensor and / or when incorporated into the analyte sensor). In certain embodiments, the drug delivery composition can continuously release the 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 the 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 the 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 the 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 the 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 the therapeutic agent (e.g., at a set or predetermined drug delivery rate) for at least 25 days. 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.

[0209] In certain embodiments, e.g., over a period of about 30 - 31 days (such as when administered adjacent to an analyte sensor and / or when incorporated into an analyte sensor), the delivery composition of the present disclosure releases from about 1% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 5% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 10% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 20% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 30% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 40% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 50% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 60% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 70% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 80% to about 100% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 30% to about 90% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery composition of the present disclosure releases from about 40% to about 90% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition).In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery compositions of the present disclosure release from about 50% to about 90% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery compositions of the present disclosure release from about 1% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery compositions of the present disclosure release from about 10% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery compositions of the present disclosure release from about 20% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery compositions of the present disclosure release from about 30% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). In certain embodiments, e.g., over a period of about 30 - 31 days, the delivery compositions of the present disclosure release from about 40% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition). By way of example, and not by way of limitation, e.g., over a period of about 30 - 31 days, the delivery compositions of the present disclosure release from about 45% to about 80% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition), release from about 50% to about 80% of the therapeutic agent, release from about 55% to about 80% of the therapeutic agent, release from about 60% to about 80% of the therapeutic agent, release from about 65% to about 80% of the therapeutic agent, release from about 70% to about 80% of the therapeutic agent, release from about 75% to about 80% of the therapeutic agent, release from about 40% to about 75% of the therapeutic agent, release from about 40% to about 70% of the therapeutic agent, release from about 40% to about 65% of the therapeutic agent, release from about 40% to about 60% of the therapeutic agent, release from about 40% to about 55% of the therapeutic agent, release from about 40% to about 50% of the therapeutic agent, release from about 40% to about 45% of the therapeutic agent, release from about 45% to about 75% of the therapeutic agent, release from about 50% to about 75% of the therapeutic agent, release from about 55% to about 80% of the therapeutic agent, or release from about 60% to about 75% of the therapeutic agent. In certain embodiments, the wearing time of the sensors described herein is about 30 - 31 days. In certain embodiments, the period of about 30 - 31 days is the useful life of the sensors described herein.

[0210] 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 the therapeutic agent loaded into the composition) can be released no earlier than about 7 days before the end of the sensor's useful life (e.g., the end of the wear time). 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 the therapeutic agent loaded into the composition) can be released no earlier than about 7 days before the end of the sensor's useful life (e.g., the end of the wear time). 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 the therapeutic agent loaded into the composition) can be released no earlier than about 7 days before the end of the sensor's useful life (e.g., the end of the wear time). 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 the therapeutic agent loaded into the composition) can be released no earlier than about 7 days before the end of the sensor's useful life (e.g., the end of the wear time). In certain embodiments, up to about 60% of the therapeutic agent present in the drug delivery composition on the analyte sensor (e.g., the total amount of the therapeutic agent loaded into the composition) can be released no earlier than about 7 days before the end of the sensor's useful life (e.g., the end of the wear time). In certain embodiments, up to about 50% of the therapeutic agent present in the drug delivery composition on the analyte sensor (e.g., the total amount of the therapeutic agent loaded into the composition) can be released no earlier than about 7 days before the end of the sensor's useful life (e.g., the end of the wear time). In certain embodiments, up to about 40% of the therapeutic agent present in the drug delivery composition on the analyte sensor (e.g., the total amount of the therapeutic agent loaded into the composition) can be released no earlier than about 7 days before the end of the sensor's useful life (e.g., the end of the wear time).

[0211] In certain embodiments, for example, over a period of about 30 - 31 days (e.g., when administered adjacent to an analyte sensor and / or when incorporated into an analyte sensor), no more than about 90% of the therapeutic agent present in the drug delivery composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, for example, over a period of about 30 - 31 days, no more than about 95% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, for example, over a period of about 30 - 31 days, no more than about 80% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, for example, over a period of about 30 - 31 days, no more than about 75% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, for example, over a period of about 30 - 31 days, no more than about 70% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, for example, over a period of about 30 - 31 days, no more than about 65% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, for example, over a period of about 30 - 31 days, no more than about 60% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, for example, over a period of about 30 - 31 days, no more than about 55% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, for example, over a period of about 30 - 31 days, no more than about 50% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released.

[0212] In certain embodiments, within the first 5, 6, or 7 days after insertion of the composition (e.g., when administered adjacent to an analyte sensor and / or when incorporated into an analyte sensor), no more than about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of the therapeutic agent present in the drug delivery composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 30% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 30% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 7 days after insertion of the composition, no more than about 30% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 35% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 35% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 7 days after insertion of the composition, no more than about 35% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 40% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 40% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 7 days after insertion of the composition, no more than about 40% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 45% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 45% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 7 days after insertion of the composition, no more than about 45% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 50% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 50% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released.In certain embodiments, within the first 7 days after insertion of the composition, no more than about 50% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 55% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 55% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 7 days after insertion of the composition, no more than about 55% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 60% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 60% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 7 days after insertion of the composition, no more than about 60% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 65% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 65% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 7 days after insertion of the composition, no more than about 65% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 70% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 70% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 7 days after insertion of the composition, no more than about 70% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 5 days after insertion of the composition, no more than about 75% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 6 days after insertion of the composition, no more than about 75% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released. In certain embodiments, within the first 7 days after insertion of the composition, no more than about 75% of the therapeutic agent present in the composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released.

[0213] In certain embodiments, between about day 7 and about day 14 after insertion of the composition (e.g., when administered adjacent to an analyte sensor and / or when incorporated into an analyte sensor), no more than about 25% or 30% of the therapeutic agent present in the drug delivery composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released.

[0214] In certain embodiments, between about day 14 and about day 31 after insertion of the composition (e.g., when administered adjacent to an analyte sensor and / or when incorporated into an analyte sensor), no more than about 25% or 30% of the therapeutic agent present in the drug delivery composition (e.g., the total amount of the therapeutic agent loaded into the composition) is released.

[0215] In certain embodiments, when the exemplary drug delivery composition contacts the 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., the surrounding environment) to form a hydrogel. In certain embodiments, a diffusion-controlled or selective drug release mechanism of the drug delivery composition can be used. For example, in certain embodiments, the copolymer can be a polyvinylpyridine copolymer. In certain embodiments, the therapeutic agent can be dexamethasone. In certain embodiments, since dexamethasone is a small molecule drug, the size of dexamethasone is much smaller than the mesh size (mesh spacing) of the hydrogel formed after the drug delivery composition contacts the patient's tissue, and thus dexamethasone is released from the drug delivery composition through a diffusion process. For a hydrogel containing only polyvinylpyridine, even with very dense cross-linking (e.g., using the cross-linking agents of the present disclosure), the mesh size is almost always too large to restrict the diffusion of dexamethasone, resulting in uncontrolled drug release.

[0216] However, adding hydrophobic units / regions to the copolymer slows down the release of the therapeutic agent from the hydrogel. For example, but not by way of limitation, a polymer affinity-controlled drug release mechanism according to certain embodiments of the present disclosure can be used. In certain embodiments, the copolymer has a backbone comprising hydrophilic units and hydrophobic units, such as a polyvinylpyridine-co-polystyrene polymer. Hydrophobic therapeutic agents such as dexamethasone can interact with the hydrophobic units / regions of the copolymer matrix through non-polar intermolecular interactions, thereby slowing down the release of the therapeutic agent from the hydrogel. Thus, the higher the affinity of the polymer for the hydrophobic therapeutic agent, the slower the release rate of the drug from the drug delivery composition, and the slower the drug delivery rate of the drug delivery composition. As used herein, the term "polymer affinity" refers to the strength of the non-polar intermolecular interaction between the hydrophobic units of the copolymer and the therapeutic agent. In certain embodiments, the hydrophobic unit can be an aliphatic chain, such as methyl, ethyl, propyl, etc., or an aromatic ring, such as phenyl.

[0217] In certain embodiments, by modulating the polymer affinity and swellability of the copolymer, the drug delivery rate of the drug delivery composition can be even more finely tuned. For example, in certain embodiments, the water uptake can be controlled by the amount of crosslinker added to the drug delivery composition. In certain embodiments, the copolymer can be a polyvinylpyridine copolymer, such as a polyvinylpyridine-co-polystyrene polymer. When the crosslinker (e.g., diglycidyl-PEG or triglycidyl ether of glycerol) crosslinks the copolymer backbone by bonding to the nitrogen atom of the pyridine unit of the copolymer, positive charges are formed on the copolymer backbone. When the drug delivery composition contacts the tissue to form a hydrogel, the positive charges facilitate water uptake. When the amount of crosslinker in the drug delivery composition increases, the positive charges formed on the copolymer backbone increase, which increases the water permeability, thereby increasing the swellability of the drug delivery composition and the diffusion of the therapeutic drug. Thus, the drug delivery rate of the drug delivery composition is increased. As shown in Example 1, when the mer% of the hydrophobic units of the copolymer increases, the affinity of the polymer for the hydrophobic therapeutic agent increases, which is conducive to slowing down the release of the therapeutic agent from the hydrogel, thereby reducing the drug delivery rate of the drug delivery composition. Therefore, by balancing the hydrophobic interaction and the water uptake of the drug delivery composition, the drug delivery rate of the drug delivery composition can be finely regulated.

[0218] Additional information regarding polyvinylpyridine polymers is provided in U.S. Patent Publication No. 2003 / 0042137 (e.g., Formula 2b), the content of which (e.g., amounts) is incorporated herein by reference in its entirety. Additional information regarding polyvinylpyridine-co-styrene copolymers is provided in U.S. Patent No. 8,761,857, the content of which (e.g., amounts) is incorporated herein by reference in its entirety. Additional information regarding polyvinylpyridine polymers and polyvinylpyridine-co-styrene copolymers is provided in U.S. Patent Publication No. 2022 / 0202322 (e.g., in Schemes 3-1, 3-2, and 3-3), the content of which (e.g., amounts, e.g., in paragraphs

[0442] and

[0457] ) is incorporated herein by reference in its entirety.

[0219] The present disclosure further provides a method of manufacturing the drug delivery composition described herein. Referring Figure 36 , certain embodiments provide a method 1000 of manufacturing a drug delivery composition. In certain embodiments, method 1000 may include: a task 1002 of providing a copolymer described herein (e.g., the copolymer includes a plurality of copolymer chains, wherein each of the plurality of copolymer chains includes a backbone comprising a plurality of hydrophilic units and a plurality of hydrophobic units); a task 1004 of applying a crosslinker and a therapeutic agent to the copolymer; and a task 1006 of crosslinking the crosslinker between the respective copolymer chains to at least a portion of the hydrophilic units.

[0220] IV. Analyte Sensor

[0221] A. General Structure of an Analyte Sensor System

[0222] The present disclosure relates to incorporating a therapeutic agent into an analyte sensor, such as an in - vivo analyte sensor, and / or delivering a therapeutic composition adjacent to the analyte sensor.

[0223] However, before detailing these aspects of the embodiments, it is first necessary to describe examples of devices that may be present in, for example, an in - vivo analyte monitoring system, and examples of their operation, all of which may be used in conjunction with the embodiments described herein.

[0224] 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, for example, automatically according to a schedule. As another example, a “Flash analyte monitoring” system (or “Flash glucose monitoring” system or simply “Flash (Freestyle Libre)” system) can transmit data from a sensor control device in response to a scan or data request from the reader device, for example, using near - field communication (NFC) or radio - frequency identification (RFID) protocols. In - vivo analyte monitoring systems operate without finger - stick calibration.

[0225] In - vivo analyte monitoring systems can be distinguished from “in - vitro” systems that contact a biological sample outside the body (or “ex - vivo”) and typically include a metering device having a port for receiving an analyte test strip carrying the user's body fluid, and the body fluid can be analyzed to determine the user's blood analyte level.

[0226] An in - vivo monitoring system can include a sensor that, when placed in the body, contacts the user's body fluid and senses the level of the analyte contained therein. The sensor can be part of a sensor control device located on the user's body and contains electronics and a power source for implementing and controlling analyte sensing. The sensor control device and its variants can also be referred to as a “sensor control unit”, an “on - body electronics” device or unit, an “on - body” device or unit, or a “sensor data communication” device or unit, to name a few.

[0227] The in - body monitoring system may also include a device that receives the sensed analyte data from the sensor control device and processes and / or displays the sensed analyte data to the user in any number of forms. This device and its variations may be referred to as a “handheld reader device”, “reader device” (or simply “reader”), “handheld electronic device” (or simply “handheld”), “portable data processing” device or unit, “data receiver”, “receiver” device or unit (or simply “receiver”), or “remote” device or unit, to name a few. Other devices such as personal computers have also been used or incorporated into in - body and in - vitro monitoring systems.

[0228] Figure 37 Figures are provided that illustrate exemplary sensing systems (sensing systems) that may incorporate the analyte sensors of the present disclosure. As shown, the sensing system 100 includes a sensor control device 102 and a reader device 120, which are 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, encrypted or non - encrypted. According to certain embodiments, the reader device 120 may constitute an output medium for viewing analyte concentrations and alerts or notifications determined by the sensor 104 or an associated processor, as well as for allowing one or more user inputs. The reader device 120 may be a multi - purpose smartphone or a dedicated electronic reader instrument. Although only one reader device 120 is shown, in some cases there may be multiple reader devices 120. The reader device 120 may also communicate with a remote terminal 170 and / or a trusted computer system 180 via communication paths / links 141 and / or 142, respectively, which may also be wired or wireless, one - way or two - way, encrypted or non - encrypted. The reader device 120 may also or alternatively communicate with a network 150 (such as a mobile phone network, the Internet, or a cloud server) via a communication path / link 151. The network 150 may further be communicatively coupled to the remote terminal 170 via a communication path / link 152 and / or to the trusted computer system 180 via a communication path / link 153. Alternatively, the sensor 104 may communicate directly with the remote terminal 170 and / or the trusted computer system 180 without the presence of an intermediate reader device 120. For example, but not by way of limitation, according to certain embodiments, the sensor 104 may communicate with the remote terminal 170 and / or the trusted computer system 180 via a direct communication link to the network 150, as described in and incorporated herein by reference in its entirety in U.S. Patent Application Publication 2011 / 0213225. Any suitable electronic communication protocol may be used for each communication path or link, such as near - field communication (NFC), radio - frequency identification (RFID), or Low-power protocols, WiFi, etc. According to certain embodiments, the remote terminal 170 and / or the trusted computer system 180 may be accessed by an individual other than the primary user interested in the user's analyte level. The reader device 120 may include a display 122 and an optional input component 121. According to certain embodiments, the display 122 may include a touchscreen interface.

[0229] The sensor control device 102 includes a sensor housing 103 that may house circuitry and a power source for operating the sensor 104. Optionally, the power source and / or active circuitry may be omitted. A processor (not shown) may be communicatively coupled to the sensor 104, where the processor is physically located within the sensor housing 103 or the reader device 120. According to certain embodiments, the sensor 104 protrudes from the lower side of the sensor housing 103 and extends through an adhesive layer 105 that is adapted to adhere the sensor housing 103 to a tissue surface, such as the skin.

[0230] B. Analyte Sensor Tail

[0231] Figure 37 The sensor 104 is adapted to be at least partially inserted into a target tissue (tissue of interest), such as the dermal layer or the subcutaneous layer of the skin. The sensor 104 may include a sensor tail of sufficient length to insert to the desired depth in 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 region for detecting an analyte (e.g., on the working electrode). A counter electrode may be present in combination with at least one working electrode. Specific electrode configurations of the sensor tail are described in more detail below.

[0232] The active region may be configured to detect a specific analyte, as described in further detail below. For example, but not by way of limitation, the analyte may be glucose, ketones, lactate, alcohol, glutamate, creatinine, sarcosine, ascorbic acid, and combinations thereof. For example, but not by way of limitation, a glucose-responsive active region may include a glucose-responsive enzyme, a ketone-responsive active region may include a ketone-responsive enzyme, a lactate-responsive active region may include a lactate-responsive enzyme, an alcohol-responsive active region may include an alcohol-responsive enzyme, a glutamate-responsive active region may include a glutamate-responsive enzyme, a creatinine-responsive active region may include a creatinine-responsive enzyme system, a sarcosine-responsive active region may include a sarcosine-responsive enzyme system, and an ascorbic acid-responsive active region may include an ascorbic acid-responsive enzyme system.

[0233] The membrane can cover the active region, as described in further detail below. In certain embodiments, the membrane covering the analyte-responsive active region can be used as a mass transport limiting membrane and / or for improving biocompatibility. The mass transport limiting membrane can be used as a diffusion limiting barrier to reduce the mass transport rate of the analyte. For example, but not by way of limitation, using the mass transport limiting membrane to restrict the entry of the analyte into the analyte-responsive active region can help avoid sensor overload (saturation), thereby improving detection performance and accuracy. In certain embodiments, the membrane comprises the copolymer of the present disclosure.

[0234] In certain embodiments of the present disclosure, one or more analytes in any biological fluid of interest, such as dermal fluid, interstitial fluid, plasma, blood, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, bronchoalveolar lavage fluid, amniotic fluid, etc., can be monitored. In certain embodiments, the analyte sensor of the present disclosure can be adapted to assay dermal fluid or interstitial fluid to determine the concentration of one or more analytes in vivo. In certain embodiments, the biological fluid is interstitial fluid.

[0235] Still referring to Figure 37 , the sensor 104 can automatically forward (send) data to the reader device 120. For example, but not by way of limitation, the analyte concentration data can be automatically and periodically communicated, such as when the data is obtained or at a certain frequency after a certain period of time, where the data is stored in the memory until transmission (e.g., every minute, every five minutes, or other predetermined period). In certain embodiments, the sensor 104 can communicate with the reader device 120 in a non-automatic manner rather than according to a set schedule. For example, but not by way of limitation, when the sensor electronics (electronic components) enter the communication range of the reader device 120, RFID technology can be used to transmit (communicate) data from the sensor 104. The data can be stored in the memory of the sensor 104 until it is transmitted to the reader device 120. Thus, the user does not have to always stay in close proximity to the reader device 120, but can upload the data at a convenient time. In certain embodiments, a combination of automatic and non-automatic data transmission can be implemented. For example, and not by way of limitation, the data transmission can continue automatically until the reader device 120 is no longer within the communication range of the sensor 104.

[0236] An introducer may be present temporarily to facilitate entry of the sensor 104 into tissue. In some illustrative embodiments, the introducer may include a needle or similar sharp object. Those skilled in the art will readily recognize that other types of introducers may be present in alternative embodiments, such as a sheath or blade. More specifically, the needle or other introducer may reside temporarily near the sensor 104 prior to tissue insertion and then subsequently be retracted. When present, the needle or other introducer may assist in inserting the sensor 104 into tissue by opening the entry channel followed by the sensor 104. For example and without limitation, according to one or more embodiments, the needle may assist in penetrating the epidermis as a pathway into the dermis to allow implantation of the sensor 104. After opening the pathway, the needle or other introducer may be retracted so as not to pose a sharp object hazard. In some embodiments, a suitable needle may be solid or hollow, beveled or non-beveled, and / or have a circular or non-circular cross-section. In more specific embodiments, a suitable needle may be comparable in cross-sectional diameter and / or tip design to an acupuncture needle and may have a cross-sectional diameter of about 250 microns. However, a suitable needle may have a larger or smaller cross-sectional diameter if required for certain specific applications.

[0237] In some embodiments, the tip of the needle (when present) may be angled with respect to the end of the sensor 104 such that the needle first penetrates the tissue and opens a pathway for the sensor 104. In some embodiments, the sensor 104 may be located within the lumen or groove of the needle and the needle similarly opens a pathway for the sensor 104. In either case, after assisting with sensor insertion, the needle tip is subsequently retracted.

[0238] i. Electrode configuration

[0239] Sensor configurations featuring a single active region configured to detect a corresponding single analyte may employ a two-electrode or three-electrode detection motif as further described herein with reference to Figure 3 and 53A-53B. Sensor configurations featuring two different active regions for detecting the same or different (independent) analytes (the active regions being on different working electrodes or on the same working electrode) are subsequently described with reference to Figure 3 and 53A-55C, respectively. Sensor configurations having multiple working electrodes may be particularly advantageous for incorporating two different active regions within the same sensor tail as the signal contributions from each active region can be more readily determined.

[0240] When there is a single working electrode in an analyte sensor, a three - electrode sensor configuration can include a working electrode, a counter electrode, and a reference electrode. A related two - electrode sensor configuration can include a working electrode and a second electrode, where the second electrode can serve as both a counter electrode and a reference electrode (i.e., a counter / reference electrode) simultaneously. The respective electrodes can be at least partially stacked (laminated) on top of each other and / or laterally spaced apart from each other on the sensor tail. Suitable sensor configurations can be of a substantially flat shape, a substantially cylindrical shape, or any suitable shape. In any of the sensor configurations disclosed herein, the respective electrodes can be electrically isolated from each other by a dielectric material or a similar insulator.

[0241] An analyte sensor characterized by multiple working electrodes can similarly include at least one additional electrode. When there is one additional electrode, the one additional electrode can serve as a counter / reference electrode for each of the multiple working electrodes. When there are two additional electrodes, one of the additional electrodes can be used as a counter electrode for each of the multiple working electrodes, and the other of the additional electrodes can be used as a reference electrode for each of the multiple working electrodes.

[0242] Figure 3 A diagram showing an illustrative two - electrode analyte sensor configuration is compatible with the applications disclosed herein. As shown, the analyte sensor 200 includes a substrate 212 disposed between a working electrode 214 and a counter / reference electrode 216. Alternatively, 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 inserted therebetween (configuration not shown). An active region 218 is arranged as at least one layer on at least a portion of the working electrode 214. The active region 218 can include multiple points or a single point, configured to detect an analyte at a low working electrode potential, as further discussed herein. In certain embodiments, the active region 218 can contain an electron transfer agent described herein.

[0243] Still referring to Figure 3 , a membrane 220 covers at least the active region 218. In certain embodiments, the membrane 220 contains a copolymer of the present disclosure. By way of example, and not limitation, the membrane 220 contains a copolymer that includes a first monomer, such as styrene, and a second monomer that includes a heterocyclic - containing component, such as vinylpyridine, such as 4 - vinylpyridine.

[0244] In some embodiments, the membrane 220 may also cover 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 covered with the membrane 220. The membrane 220 may include one or more polymeric membrane materials having the ability to limit analyte flux to the active region 218 (i.e., the membrane 220 is a mass transport limiting membrane having a certain permeability to the analyte of interest). The composition and thickness of the membrane 220 may vary to facilitate the desired analyte flux to the active region 218, thereby providing the desired signal intensity and stability. The analyte sensor 200 is operable to determine an analyte by any of coulometric, amperometric, voltammetric, or potentiometric electrochemical detection techniques.

[0245] Figure 38A and 38B FIG. shows an illustrative three - electrode analyte sensor configuration, which is also compatible for use in the applications disclosed herein. The three - electrode analyte sensor configuration may be similar to the analyte sensor 200 shown in Figure 3 , except that additional electrodes 217 ( Figure 38A and 38B ) are included in the analyte sensors 201 and 202. Using the additional electrodes 217, the counter / reference electrode 216 can be used as a counter electrode or a reference electrode, and the additional electrodes 217 can perform other electrode functions not considered. The working electrode 214 continues to perform its original function. The additional electrodes 217 may be disposed on the working electrode 214 or the electrode 216, with an insulating layer of dielectric material therebetween. By way of example and not limitation, as Figure 38A shows, the dielectric layers 219a, 219b, and 219c separate the electrodes 214, 216, and 217 from each other and provide electrical isolation. Alternatively, at least one of the electrodes 214, 216, and 217 may be located on the opposite face of the substrate 212, as Figure 38B shows. Thus, in some embodiments, the electrode 214 (working electrode) and the electrode 216 (counter electrode) may be located on opposite faces of the substrate 212, and the electrode 217 (reference electrode) is located on one of the electrodes 214 or 216 and is spaced therefrom by a dielectric material. A reference material layer 230 (e.g., Ag / AgCl) may be present on the electrode 217, and the location of the reference material layer 230 is not limited to the locations shown in Figure 38A and 38B . As compared with Figure 3Similar to the sensor 200 shown, the active regions 218 in the analyte sensors 201 and 202 can include multiple points or a single point. In certain embodiments, the active region 218 can include a redox mediator disclosed herein. Additionally, the analyte sensors 201 and 202 are operable to determine an analyte by coulometric, amperometric, voltammetric, or potentiometric electrochemical detection techniques.

[0246] Similar to the analyte sensor 200, a membrane 220 can also cover the active region 218 in the analyte sensors 201 and 202 as well as other sensor components, thus acting as a mass transport limiting membrane. In certain embodiments, the additional electrode 217 can be covered with the membrane 220. Although Figure 38A and 38B the electrodes 214, 216, and 217 have been depicted as being covered with the membrane 220, it should be appreciated that in certain embodiments, only the working electrode 214 is covered. Additionally, the thickness of the membrane 220 at each of the electrodes 214, 216, and 217 can be the same or different. Similar to the two-electrode analyte sensor configuration ( Figure 3 ) and in the sensor configurations of Figure 38A and 38B , one or both sides of the analyte sensors 201 and 202 can be covered with the membrane 220, or the entire analyte sensors 201 and 202 can be covered. Thus, Figure 38A and 38B the three-electrode sensor configuration shown in

[0247] Figure 39A should be understood not to limit the embodiments disclosed herein, and alternative electrode and / or layer configurations are still within the scope of the present disclosure. Figure 39A With Figure 3 similarity, except that there are two active regions on the working electrode 214: a first active region 218a and a second active region 218b, which are responsive to the same or different analytes and are laterally spaced apart from each other on the surface of the working electrode 214. The active regions 218a and 218b can include multiple points or a single point, configured to detect each analyte. The composition of the membrane 220 can be different or the same at the active regions 218a and 218b. The first active region 218a and the second active region 218b can be configured to detect their respective analytes at different working electrode potentials, as further discussed below.

[0248] Figure 39B and 39CCross-sectional views of illustrative three-electrode sensor configurations of sensors 204 and 205 are shown, each sensor feature being a single working electrode having a first active region 218a and a second active region 218b disposed thereon. Figure 39B and 39C otherwise similar to Figure 39B and 39C and is better understood by reference. Similar to Figure 39A the composition of the membrane 220 can be different or the same in the active regions 218a and 218b. In certain embodiments, either of the active regions 218a and 218b can include a redox mediator described herein. In certain embodiments, only one of the active regions 218a and 218b can include a redox mediator described herein. For example, but not by way of limitation, only the active region 218a includes a redox mediator described herein. In certain embodiments, only the active region 218b includes a redox mediator described herein. In certain embodiments, both of the active regions 218a and 218b include a redox mediator described herein. In certain embodiments, the electron transfer agent present in the active region 218a is different from the redox mediator present in 218b. Alternatively, the electron transfer agent present in the active region 218a is the same as the redox mediator present in 218b.

[0249] Reference Figures 2A - 2C and Figure 40 further describes in detail an illustrative sensor configuration having multiple working electrodes (specifically two working electrodes). Although the following description primarily relates to a sensor configuration having two working electrodes, it should be understood that by extending the disclosure herein, more than two working electrodes can be incorporated. Additional working electrodes can be used to endow the analyte sensor with additional sensing capabilities for analytes other than the first analyte and the second analyte.

[0250] Figure 40A cross-sectional view of an illustrative analyte sensor configuration having two working electrodes, a reference electrode, and a counter electrode is shown, which is compatible for use in the applications disclosed herein. As shown, the analyte sensor 300 includes working electrodes 304 and 306 disposed on opposite faces of a substrate 302. A first active region 310a is disposed on the surface of the working electrode 304, and a second active region 310b is disposed on the surface of the working electrode 306. The counter electrode 320 is electrically isolated from the working electrode 304 by a dielectric layer 322, and the reference electrode 321 is electrically isolated from the working electrode 306 by a dielectric layer 323. Outer dielectric layers 330 and 332 are disposed on the reference electrode 321 and the counter electrode 320, respectively. According to various embodiments, the membrane 340 may cover at least the active regions 310a and 310b, as well as other components of the analyte sensor 300 or the entire analyte sensor 300. In certain embodiments, the membrane 340 comprises the copolymer disclosed herein. For example, but not by way of limitation, the membrane 340 comprises a copolymer that comprises a first monomer (e.g., styrene) and a second monomer that comprises a heterocyclic component (e.g., vinylpyridine, such as 4-vinylpyridine).

[0251] In certain embodiments, the membrane 340 may be continuous but compositionally different over the active region 310a and / or the active region 310b to provide different permeability values and thereby differentially regulate the analyte flux at each location. For example, but not by way of limitation, the one or more electrodes may be covered by a first membrane portion 340a and / or a second membrane portion 340b. In certain embodiments, different membrane formulations may be sprayed and / or printed onto opposite faces of the analyte sensor 300. Dip coating techniques may also be suitable, particularly for depositing at least a portion of a bilayer membrane onto one of the active regions 310a and 310b. In certain embodiments, the membrane 340 may be compositionally the same or different over the active regions 310a and 310b. For example, but not by way of limitation, the membrane 340 may include a bilayer covering the active region 310a and be a homogeneous membrane covering the active region 310b, or the membrane 340 may include a bilayer covering the active region 310b and be a homogeneous membrane covering the active region 310a. In certain embodiments, according to a particular embodiment of the present disclosure, one of the first membrane portion and the second membrane portion may comprise a bilayer membrane, and the other of the first membrane portion and the second membrane portion may comprise a single membrane polymer. In certain embodiments, the analyte sensor may include more than one membrane 340, such as two or more membranes. For example, but not by way of limitation, the analyte sensor may include a membrane covering the one or more active regions (e.g., 310a and 310b), as well as an additional membrane covering the entire sensor, such as Figure 40As shown. In such configurations, a bilayer film can be formed over the one or more active regions (such as 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 the copolymer of the present disclosure, and the second film can include a different polymer. In certain embodiments, either of the active regions 310a and 310b can include an electron transfer agent described herein. In certain embodiments, only one of the active regions 310a and 310b can include a redox mediator described herein. For example, but not by way of limitation, only the active region 310a includes the redox mediator described herein. In certain embodiments, only the active region 310b includes the redox mediator described herein. In certain embodiments, both of the active regions 310a and 310b include the redox mediator described herein. In certain embodiments, the redox mediator present in the active region 310a is different from the electron transfer agent present in 310b. Alternatively, the redox mediator present in the active region 310a is the same as the electron transfer agent present in 310b.

[0252] having multiple working electrodes and different from Figure 40 An alternative sensor configuration to the configuration shown, the features of which can be a counter / reference electrode instead of separate counter and reference electrodes 320, 321, and / or the features can be a layer and / or film arrangement different from the explicitly depicted arrangement. For example, but not by way of limitation, the positioning of the counter electrode 320 and the reference electrode 321 can be opposite to Figure 40 the positioning depicted in. Further, the working electrodes 304 and 306 do not necessarily need to be located on opposite faces of the substrate 302 in the manner Figure 40 shown.

[0253] Although suitable sensor configurations can have electrodes characterized as being substantially planar, it should be understood that sensor configurations having non-planar electrode features can be advantageous and are particularly suitable for the applications disclosed herein. In particular, substantially cylindrical electrodes concentrically arranged with each other can facilitate the deposition of mass transport limiting films, as described below. For example, but not by way of limitation, concentric working electrodes spaced apart along the length of the sensor tail can promote film deposition by sequential dip coating operations in a manner similar to that described above for the substantially planar sensor configuration. Figures 2A - 2C A perspective view of an analyte sensor is shown, the features of which are two working electrodes arranged concentrically with respect to each other. It should be understood that in the present disclosure, sensor configurations having a concentric electrode arrangement but lacking a second working electrode are also possible.

[0254] Figure 2AA perspective view showing an illustrative sensor configuration is presented, where multiple electrodes are substantially cylindrical and arranged concentrically with each other around a central substrate. As shown, the analyte sensor 400 includes a central substrate 402, around which all the electrodes and dielectric layers are concentrically arranged with each other. In particular, the working electrode 410 is disposed on the surface of the central substrate 402, and the dielectric layer 412 is disposed on the portion of the working electrode 410 that is distal to the sensor tip 404. The working electrode 420 is disposed on the dielectric layer 412, and the dielectric layer 422 is disposed on the portion of the working electrode 420 that is distal to the sensor tip 404. The counter electrode 430 is disposed on the dielectric layer 422, and the dielectric layer 432 is disposed on the portion of the counter electrode 430 that is distal to the sensor tip 404. The reference electrode 440 is disposed on the dielectric layer 432, and the dielectric layer 442 is disposed on the portion of the reference electrode 440 that is distal to the sensor tip 404. Thus, the exposed surfaces of the working electrode 410, the working electrode 420, the counter electrode 430, and the reference electrode 440 are spaced apart from each other along the longitudinal axis B of the analyte sensor 400.

[0255] Still referring to Figure 2A , a first active region 414a and a second active region 414b that are responsive to different analytes are respectively disposed on the exposed surfaces of the working electrodes 410 and 420, thereby allowing contact with a fluid for sensing. Although in Figure 2A the active regions 414a and 414b are depicted as three discrete points, it should be understood that there may be fewer or more than three points in alternative sensor configurations, including a continuous active region layer. In certain embodiments, either of the active regions 414a and 414b may include an electron transfer agent as described herein. In certain embodiments, only one of the active regions 414a and 414b may include a redox mediator as described herein. For example, but not by way of limitation, only the active region 414a includes a redox mediator as described herein. In certain embodiments, only the active region 414b includes a redox mediator as described herein. In certain embodiments, both of the active regions 414a and 414b include a redox mediator as described herein. In certain embodiments, the redox mediator present in the active region 414a is different from the electron transfer agent present in 414b. Alternatively, the redox mediator present in the active region 414a is the same as the electron transfer agent present in 414b.

[0256] In Figure 2A , the sensor 400 is partially covered with a membrane 450 on the working electrodes 410 and 420 and the active regions 414a and 414b disposed thereon. Figure 2BAn alternative sensor configuration is shown, in which substantially the entire sensor 401 is covered with a membrane 450. The membrane 450 can be compositionally the same or different at the active regions 414a and 414b. For example, the membrane 450 can include a bilayer covering the active region 414a and be a homogeneous membrane covering the active region 414b. In certain embodiments, the membrane 450 comprises a copolymer of the present disclosure. For example, but not by way of limitation, the membrane 450 comprises a copolymer that includes a first monomer (such as styrene) and a second monomer that includes a heterocyclic component, such as vinylpyridine, such as 4-vinylpyridine.

[0257] It should also be understood that Figure 2A and 2B the positioning of the respective electrodes in Figure 2A and 2B can be different from that clearly depicted. For example, the positions of the counter electrode 430 and the reference electrode 440 can be opposite to the configuration shown in Figure 2A and 2B Similarly, the positions of the working electrodes 410 and 420 are not limited to the positions clearly shown in Figure 2C is shown Figure 2B an alternative configuration of the sensor configuration shown in Figure 2C in which the sensor 405 contains a counter electrode 430 and a reference electrode 440 located closer to the sensor tip 404 and working electrodes 410 and 420 located farther from the sensor tip 404. A sensor configuration in which the working electrodes 410 and 420 are located farther from the sensor tip 404 can be advantageous because it provides a larger surface area for depositing the active regions 414a and 414b (the five discrete sensing points illustratively shown in

[0258] In certain embodiments, one or more electrodes of the analyte sensors described herein are wire electrodes, such as permeable wire electrodes. In certain embodiments, the sensor tail includes a working electrode and a reference electrode that helically winds 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 one or more enzymes to react with an analyte on the electrode. In certain embodiments, each electrode is formed from a fine wire having a diameter of from about 0.001 inches or less to about 0.010 inches or greater. In certain embodiments, the working electrode has a diameter of from about 0.001 inches or less to about 0.010 inches or greater, such as, from about 0.002 inches to about 0.008 inches or from about 0.004 inches to about 0.005 inches. In certain embodiments, the electrodes are formed from a plated insulator, a plated wire, or a bulk conductive material. In certain embodiments, the working electrode includes a wire formed from a conductive material such as platinum, platinum-iridium, palladium, graphite, gold, carbon, a conductive polymer, an alloy, and the like. In certain embodiments, the conductive material is a permeable conductive material. In certain embodiments, the electrodes can be formed by a variety of manufacturing techniques such as bulk metal processing, depositing a metal onto a substrate, etc., and the electrodes can be formed from a plated wire (such as platinum plated on a steel wire) or a bulk metal (such as a platinum wire). In certain embodiments, the electrodes are formed from tantalum wire, such as tantalum wire coated with platinum.

[0259] In certain embodiments, the reference electrode (which can be used as a separate reference electrode or as a dual reference and counter electrode) is formed from silver, silver / silver chloride, and the like. In certain embodiments, the reference electrode is juxtaposed with the working electrode and / or twisted with or wound around the working electrode. In certain embodiments, the reference electrode helically winds around the working electrode. In certain embodiments, the wire assembly can be covered with or adhered to an insulating material to provide an insulating attachment.

[0260] In certain embodiments, additional electrodes may be included in the sensor tail. By way of example, and not limitation, the analyte sensors of the present disclosure may include a three - electrode system (working electrode, reference electrode, and counter electrode) and / or additional working electrodes (e.g., an electrode for detecting a second analyte). In certain embodiments in which the sensor includes two working electrodes, the two working electrodes may be juxtaposed and the reference electrode is disposed around the working electrodes (e.g., helically wound around the two or more working electrodes). In certain embodiments, the two or more working electrodes may extend parallel to each other. In certain embodiments, the reference electrode is coiled around the working electrodes and extends to the distal end (i.e., the in - vivo end) of the sensor tail. In certain embodiments, the reference electrode extends (e.g., helically) to the exposed area of the working electrodes.

[0261] In certain embodiments, one or more working electrodes are helically wound around the reference electrode. In certain embodiments in which two or more working electrodes are provided, the working electrodes may be formed in a double - helix, triple - helix, quadruple - helix, or more - helix configuration along the length of the sensor tail (e.g., around the reference electrode, an insulating rod, or other support structure). In certain embodiments, the electrodes (e.g., two or more working electrodes) are formed coaxially. By way of example, and not limitation, all electrodes share the same central axis.

[0262] In certain embodiments, the working electrode comprises a tube in which the reference electrode is disposed or coiled, and an insulator is included therebetween. Alternatively, the reference electrode comprises a tube in which the working electrode is disposed or coiled, and an insulator is included therebetween. In certain embodiments, a polymer (e.g., insulating) rod is provided, on which the one or more electrodes (e.g., one or more electrode layers) are disposed (e.g., by electroplating). In certain embodiments, a metal (e.g., steel or tantalum) rod or wire is provided, coated (coated) with an insulating material (described herein), on which the one or more working electrodes and reference electrodes are disposed. By way of example, and not limitation, the present disclosure provides a sensor, e.g., a sensor tail, comprising one or more tantalum wires, on a portion of which a conductive material is disposed to serve as a working electrode. In certain embodiments, a platinum - coated tantalum wire is covered with an insulating material, on which the insulating material is partially covered with a silver / silver chloride composition to serve as a reference electrode and / or a counter electrode.

[0263] 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 peeled off or otherwise removed to expose the electroactive surface of the working electrode. For example, but not by way of limitation, a portion of the insulator can be removed by manual means, excimer laser, chemical etching, laser ablation, grit-blasting, etc. Alternatively, a portion of the electrode can be masked prior to depositing the insulator to maintain an exposed electroactive surface area. In certain embodiments, the length of the portion of the insulator that is peeled and / or removed can be from about 0.1 mm or less to about 2 mm or greater, such as a length of about 0.5 mm to about 0.75 mm. 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, the insulator layer can also use glass or ceramic materials. In certain embodiments, the insulator comprises parylene. In certain embodiments, the insulator comprises polyurethane. In certain embodiments, the insulator comprises polyurethane and polyvinylpyrrolidone.

[0264] ii. Sensing chemistry

[0265] The analyte sensors of the present disclosure can include one or more enzymes for detecting one or more analytes. In certain embodiments, the active region (e.g., disposed on the working electrode) of the analyte sensors of the present disclosure can be configured to detect one or more analytes. In certain embodiments, the active region contains one or more enzymes for detecting analytes. In certain embodiments, the analyte sensors of the present disclosure can include more than one active region, where each active region is configured to detect the same analyte or different analytes. In certain embodiments, the sensor does not include an enzyme, and the analyte is directly oxidized at the working electrode.

[0266] In certain embodiments, the active region of the sensors of the present disclosure can include one or more enzymes for detecting analytes, including but not limited to glucose, lactate (lactic acid), ketones (e.g., ketone bodies), glutamine, alcohols, aspartic acid, asparagine, glutamic acid, creatinine, hematocrit, acetoacetate (acetoacetic acid), fructosamine, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase (e.g., CK-MB), creatine, DNA, RNA, growth factors, growth hormones, hormones (e.g., thyroid stimulating hormone), steroids, vitamins (e.g., ascorbic acid), uric acid, neurochemicals (e.g., acetylcholine, norepinephrine, and dopamine), oxygen, albumin, hemoglobin A1C, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, blood urea nitrogen, sarcosine, prostate specific antigen, prothrombin, thrombin, troponin, pyruvate, acetaldehyde, ascorbate, galactose, L-xylonic acid-1,4-lactone, glutathione disulfide, hydrogen peroxide, linoleate (linoleic acid), 1,3-bisphosphoglycerate, 6-phospho-D-gluconic acid-1,5-lactone, hemoglobin, drugs (e.g., antibiotics (e.g., gentamicin, vancomycin, etc.), digitoxin, digoxin, theophylline, insulin, and warfarin), abused drugs (e.g., painkillers, sedatives, 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 region of the sensors of the present disclosure can be used to detect glutamate, glucose, ketones, lactate, oxygen, hemoglobin A1C, albumin, alcohol, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, hematocrit, aspartate, asparagine, magnesium, oxygen, pH, phosphorus, potassium, sodium, total protein, and uric acid.

[0267] In certain embodiments, the one or more enzymes can include multiple enzymes, such as an enzyme system, that together respond to the analyte.

[0268] In certain embodiments, the enzyme can be an oxidoreductase. In certain embodiments, the oxidoreductase can be an enzyme belonging to Enzyme Class 1. By way of example, and not limitation, the enzyme can belong to Enzyme Class 1.1 (such as 1.1.1 or 1.1.3), Enzyme Class 1.4 (such as 1.4.3), or Enzyme Class 1.5. In certain embodiments, the enzyme can be a NAD(P)+-dependent dehydrogenase. In certain embodiments, the enzyme can be a flavin adenine dinucleotide (FAD)-dependent oxidoreductase. In certain embodiments, the enzyme can be a hydrolase. In certain embodiments, the hydrolase can be an enzyme belonging to Enzyme Class 3. By way of example, and not limitation, the enzyme can belong to Enzyme Class 3.5, such as 3.5.2 or 3.5.3.

[0269] In certain embodiments, the active region of the sensor of the present disclosure can include one or more enzymes that can be used to detect glucose. By way of example, and not limitation, the analyte sensor of the present disclosure can include one or more enzymes for detecting glucose. In certain embodiments, the analyte sensor can include glucose oxidase and / or glucose dehydrogenase for detecting glucose. In certain embodiments, the analyte sensor can include glucose oxidase. In certain embodiments, the glucose dehydrogenase can be 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 region can further include diaphorase. In certain embodiments, the enzyme for detecting glucose is FAD-dependent glucose oxidase.

[0270] In certain embodiments, the active region of the sensor of the present disclosure can include one or more enzymes that can be used to detect ketones. By way of example, and not limitation, the analyte sensor of the present disclosure can include one or more enzymes for detecting ketones, such as an enzyme system. In certain embodiments, the ketone-responsive active region can include an enzyme system that includes multiple enzymes capable of acting in concert to facilitate the detection of ketones, as described in U.S. Patent Publication No. 2020 / 0237275 (the content of which is incorporated herein by reference in its entirety). In certain embodiments, the analyte sensor includes β-hydroxybutyrate dehydrogenase. In certain embodiments, the active region can further include diaphorase. In certain embodiments, the analyte sensor can include β-hydroxybutyrate dehydrogenase and diaphorase for detecting ketones.

[0271] In some embodiments, the active region of the sensors of the present disclosure can include one or more enzymes that can be used to detect lactate. For example, but not by way of limitation, the analyte sensors of the present disclosure can include one or more enzymes for detecting lactate, such as an enzyme system. In some embodiments, the lactate-responsive active region can include an enzyme system that contains multiple enzymes that can act in concert to facilitate lactate detection, as described in U.S. Publication No. 2019 / 0320947 (the content of which is incorporated herein by reference in its entirety). In some embodiments, the analyte sensor can include lactate dehydrogenase. In some embodiments, the analyte sensor can include lactate oxidase. In some embodiments, the active region can further include diaphorase. In some embodiments, the analyte sensor can include lactate oxidase and diaphorase.

[0272] In some embodiments, the active region of the sensors of the present disclosure can include one or more enzymes that can be used to detect alcohol. For example, but not by way of limitation, the analyte sensors of the present disclosure can include one or more enzymes for detecting alcohol, such as an enzyme system. In some embodiments, the ethanol-responsive active region can include an enzyme system that contains multiple enzymes that can act in concert to facilitate ethanol detection, as described in U.S. Patent Publication No. 2020 / 0237277 (the content of which is incorporated herein by reference in its entirety). In some embodiments, the analyte sensor can include alcohol dehydrogenase or ketoreductase.

[0273] In some embodiments, the active region of the sensors of the present disclosure can include one or more enzymes that can be used to detect creatinine. For example, but not by way of limitation, the analyte sensors of the present disclosure can include one or more enzymes for detecting creatinine, such as an enzyme system. In some embodiments, the creatinine-responsive active region can include an enzyme system that contains multiple enzymes that can act in concert to facilitate creatinine detection, such as that described in U.S. Patent Publication No. 2020 / 0241015 (the content of which is incorporated herein by reference in its entirety). In some embodiments, the analyte sensor can include amidohydrolase, creatinase, and / or sarcosine oxidase.

[0274] In some embodiments, the active region of the sensors of the present disclosure may include one or more enzymes that can be used to detect glutamate. For example, but not by way of limitation, the analyte sensors of the present disclosure may include one or more enzymes for detecting glutamate, such as an enzyme system. In some embodiments, the analyte sensor may include glutamate dehydrogenase or glutamate oxidase.

[0275] In some embodiments, the active region of the present disclosure may include one or more sensing points (such as shown by 218a and 218b in Figure 39A ), where each sensing point may include one or more enzymes for detecting an analyte.

[0276] In some embodiments, the active region may further include a stabilizer, such as for stabilizing the 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 some embodiments, the stabilizer may be human serum albumin. In some embodiments, the stabilizer may be bovine serum albumin.

[0277] In some embodiments, the active region may further include a cofactor or coenzyme for the one or more enzymes present in the active region. In some embodiments, the cofactor may be nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP). In some embodiments, the coenzyme may be NAD.

[0278] In some embodiments, the sensors of the present disclosure do not include an analyte-responsive active region containing an enzyme. In some embodiments, the sensors of the present disclosure include a working electrode on which no enzyme is disposed, or include an inactive enzyme disposed on the working electrode, such as an enzyme lacking enzyme activity (e.g., for the analyte of interest). In some 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, the sensors of the present disclosure for detecting ascorbic acid do not include an enzyme on the working electrode. In some embodiments, ascorbic acid is directly oxidized at the working electrode, generating a signal related to the level of ascorbic acid in the biological fluid contacting the sensor.

[0279] In certain embodiments, a working electrode that does not include an enzyme or includes an inactive enzyme can be used to detect a background signal. In certain embodiments, the background signal includes signals caused by chemical species present in the sample other than the analyte of interest, 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, levodopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, triglyceride, 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 present on the same analyte sensor that is configured to detect the analyte. In certain embodiments, the signal from the working electrode that does not have an enzyme (or has an inactive enzyme) can be subtracted from the signal obtained from the working electrode configured to detect the analyte to determine the signal contribution from the analyte.

[0280] In certain embodiments, the analyte sensors disclosed herein can include an electron transfer agent. For example, but not by way of limitation, the active region can include an electron transfer agent. In certain embodiments, the presence of the electron transfer agent in the active region can depend on the enzyme or enzyme system used to detect the analyte and / or the composition of the working electrode.

[0281] An electron transfer agent suitable for use in the presently disclosed analyte sensors can facilitate the transport of electrons to an adjacent working electrode after the analyte undergoes an enzymatic oxidation-reduction reaction within the active region, thereby generating a current indicative of the presence of that particular analyte. The amount of current generated is proportional to the amount of analyte present.

[0282] In certain embodiments, suitable electron transfer agents can include electroreducible and electrooxidizable ions, complexes, or molecules (such as quinones) whose oxidation-reduction potential is several hundred millivolts higher or lower than that of the standard calomel electrode. In certain embodiments, redox mediators can include osmium complexes and other transition metal complexes, such as those described in U.S. Patent Nos. 6,134,461 and 6,605,200, which are incorporated herein by reference in their entirety. Additional examples of suitable redox mediators can include those described in U.S. Patent 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 entirety. Other examples of suitable redox mediators can include metal compounds or complexes of ruthenium, osmium, iron (such as polyvinylferrocene or hexacyanoferrate), or cobalt, such as including their metallocene compounds. Ligands suitable for metal complexes can include, for example, bidentate or higher denticity 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 denticity ligands can be present in the metal complex (such as an osmium complex) to achieve a full 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.

[0283] In certain embodiments, the electron transfer agents disclosed herein can include suitable functionality to facilitate covalent bonding with a polymer (also referred to herein as the polymer backbone) within the active region, as further discussed below. For example, but not by way of limitation, electron transfer agents for use in this 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 entirety. In certain embodiments, the electron transfer agent is a bidentate osmium complex bound to a polymer as described herein (e.g., the polymer backbone described in Section 4 below). In certain embodiments, the electron transfer agent is a tridentate osmium complex bound to a polymer as described herein (e.g., the polymer backbone described in Section 4 below). In certain embodiments, the polymer-bound electron transfer agent (referred to as "X7") shown in Figure 3 of U.S. Patent No. 8,444,834 can be used in the sensors of this disclosure.

[0284] In certain embodiments, one or more working electrodes of the analyte sensors of this disclosure do not have a redox mediator disposed on the working electrode. In certain embodiments, one or more working electrodes of the analyte sensors of this disclosure do not have a redox mediator or an enzyme disposed on the working electrode. In certain embodiments, such working electrodes can be used to detect analytes that can be directly oxidized at the working electrode.

[0285] iii. Mass-limiting membrane

[0286] In certain embodiments, the analyte sensors of this disclosure further include 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 mass-limiting membrane and / or improve biocompatibility. In certain embodiments, the membrane (e.g., Figure 3 220 in) can cover at least a portion of the active region.

[0287] When the sensor is in use, the mass-limiting membrane can act as a diffusion-limiting barrier to reduce the mass transfer rate of analytes (such as glucose, alcohol, ketone, or lactate). For example, but not by way of limitation, using a mass-limiting membrane to restrict the entry of analytes (such as glucose) into the sensing point can help avoid sensor overload (saturation), thereby improving detection performance and accuracy. In certain embodiments, the mass-limiting layer can restrict the flux of analytes to the working electrode in the electrochemical sensor such that the sensor exhibits a linear response over a wide range of analyte concentrations.

[0288] In some embodiments, the mass limiting membrane can be homogeneous and can be single-component (containing a single membrane polymer). In some embodiments, the mass limiting membrane can be multi-component (containing two or more different membrane polymers). In some embodiments, the multi-component membrane can exist as a bilayer membrane or a homogeneous mixture of two or more membrane polymers. A uniform mixture can be deposited by combining two or more membrane polymers in solution and then depositing the solution on the working electrode (e.g., by dip coating).

[0289] In some embodiments, the mass limiting membrane can include two or more layers, such as a bilayer or trilayer membrane. In some embodiments, each layer can include a different polymer or the same polymer at different concentrations or thicknesses.

[0290] In some embodiments, the mass limiting membrane can include a polymer containing a heterocyclic nitrogen group. In some embodiments, the mass limiting membrane can include polyvinylpyridine polymers. Non-limiting examples of polyvinylpyridine polymers are disclosed in U.S. Patent Publication No. 2003 / 0042137, the content of which is incorporated herein by reference in its entirety. In some embodiments, the polyvinylpyridine polymer has a molecular weight of from about 50 kD to about 500 kD, such as from about 50 kD to about 200 kD.

[0291] In some embodiments, the mass limiting membrane can include polyvinylpyridine (e.g., poly(2-vinylpyridine) or poly(4-vinylpyridine)), polyvinylimidazole, polyvinylpyridine copolymers (e.g., copolymers of vinylpyridine and styrene), polyacrylates, polyurethanes, polyether polyurethanes (polyether urethanes), silicones, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene copolymers, polyolefins, polyesters, polycarbonates, biostable polytetrafluoroethylene, homopolymers, copolymers or terpolymers of polyurethanes, polypropylenes, polyvinyl chlorides, polyvinylidene fluorides, polybutylene terephthalates, polymethyl methacrylates, polyetheretherketones, cellulose polymers, polysulfones and their block copolymers (including, for example, diblock, triblock, alternating, random and graft copolymers or chemically related materials, etc.).

[0292] In certain embodiments, the mass limiting membrane can comprise polyvinylpyridine (e.g., poly(4-vinylpyridine) and / or poly(2-vinylpyridine)). In certain embodiments, the mass limiting membrane can comprise poly(4-vinylpyridine). In certain embodiments, the mass limiting membrane can comprise a copolymer of vinylpyridine and styrene. In certain embodiments, the mass limiting membrane can comprise a polyvinylpyridine-co-styrene copolymer. By way of example, and not by way of limitation, the polyvinylpyridine-co-styrene copolymer can comprise a polyvinylpyridine-co-styrene copolymer in which a portion of the pyridine nitrogen atoms are functionalized with non-crosslinked polyethylene glycol tails and a portion of the pyridine nitrogen atoms are functionalized with alkylsulfonic acid groups (e.g., propylsulfonic acid). In certain embodiments, the derivatized polyvinylpyridine-co-styrene copolymer used as the membrane polymer can be the 10Q5 polymer as described in U.S. Patent No. 8,761,857, the content of which is incorporated herein by reference in its entirety.

[0293] Suitable copolymers of vinylpyridine and styrene can have a styrene content in the range of from about 0.01% to about 50% mole percent (mol %), 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, the copolymer of vinylpyridine and styrene can comprise a styrene content of from about 2% to about 25% mol %. Substituted styrenes can be used similarly and in similar amounts.

[0294] Suitable copolymers of vinylpyridine and styrene can have a weight average molecular weight of 5 kD or greater, or about 10 kD or greater, or about 15 kD or greater, or about 20 kD or greater, or about 25 kD or greater, or about 30 kD or greater, or about 40 kD or greater, or about 50 kD or greater, or about 75 kD or greater, or about 90 kD or greater, about 100 kD or greater, or about 110 kD or greater. In non-limiting examples, suitable copolymers of vinylpyridine and styrene can have a weight average molecular weight in the range of 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 in the range of from about 10 kD to about 125 kD.

[0295] In certain embodiments, the quality limiting membrane may further comprise a silicone polymer such as polydimethylsiloxane (PDMS). By way of example, and not limitation, the quality limiting membrane may comprise a polyvinylpyridine-co-styrene copolymer (e.g., a derivatized polyvinylpyridine-co-styrene copolymer) and a silicone polymer (e.g., polydimethylsiloxane (PDMS)).

[0296] iv. Interference domain

[0297] In certain embodiments, the analyte sensor of the present disclosure may further comprise an interference domain. By way of example, and not limitation, the sensor tail 100 or 200 of the analyte sensor may further comprise an interference domain. In certain embodiments, the interference domain may comprise a polymer domain that restricts the flow of one or more interferents (e.g., towards the surface of the working electrode). In certain embodiments, the interference domain may act as a molecular sieve, allowing analytes and other substances to be measured by the working electrode to pass through while blocking other substances such as interferents. In certain embodiments, 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, levodopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, triglyceride, urea, and uric acid.

[0298] In certain embodiments, the interference domain is located between the working electrode and the active region. In certain embodiments, non-limiting examples of polymers that may be used for the interference domain may include polyurethanes, polymers having pendant ionic groups, and polymers having a controlled pore size. In certain embodiments, the interference domain may be formed from one or more cellulose derivatives.

[0299] Non-limiting examples of cellulose derivatives include polymers such as cellulose acetate, cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate trimellitate, etc.

[0300] In certain embodiments, the interference domain is part of the quality limiting membrane rather than a separate membrane. In certain embodiments, the interference domain is located between one or more sensing points and the quality limiting membrane.

[0301] In certain embodiments, the interference domain can include a thin hydrophobic membrane that does not swell and restricts the diffusion of high molecular weight species. For example, but not by way of limitation, the interference domain can be permeable to relatively low molecular weight substances such as hydrogen peroxide while restricting the passage of higher molecular weight substances (such as ketones, glucose, acetaminophen, and / or ascorbic acid).

[0302] C. Incorporation of Drug Delivery Compositions

[0303] The present disclosure further provides an analyte sensor comprising a drug delivery composition described herein (e.g., one or more of the drug delivery compositions disclosed herein). The present disclosure provides an analyte sensor of the present disclosure, comprising a sensor tail (e.g., Figure 3 200 in), the sensor tail 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 non-limiting examples of therapeutic agents that can be included in the drug delivery compositions are described in Section II.

[0304] Incorporating a therapeutic agent within the analyte sensor itself allows for targeted delivery of the therapeutic agent to the implantation site and the tissue surrounding the analyte sensor, and allows for release of the therapeutic agent in vivo in close proximity to the analyte sensor. In certain embodiments, the therapeutic agent delivered according to the present disclosure can be a therapeutic agent effective to reduce, minimize, prevent, and / or inhibit the tissue response to analyte sensor implantation and / or tissue infection, thereby preventing and / or reducing analyte signal inaccuracies towards the end of the sensor lifespan. In certain embodiments, the therapeutic agent to be delivered according to the present disclosure can be a therapeutic agent effective to reduce, minimize, prevent, and / or inhibit the tissue response to analyte sensor implantation and / or tissue infection, thereby preventing and / or reducing LSA.

[0305] The present disclosure provides an analyte sensor of the present disclosure, such as a sensor tail, which further comprises a drug delivery composition. FIGS. 2-3 and 38-40C show cross-sectional views of exemplary analyte sensors according to certain embodiments of the present disclosure. As Figure 3As shown, the analyte sensor can include: (i) a sensor tail 200 including at least a first working electrode 214 on a substrate 212; (ii) an active region 218 disposed on the surface of the first working electrode for detecting an analyte; (iii) a mass transport limiting membrane 220 permeable to the analyte, covering at least the active region; (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, wherein each of the plurality of copolymer chains includes 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 the respective copolymer chains, and (c) a therapeutic agent (e.g., wherein the therapeutic agent is not covalently bound to the copolymer).

[0306] In certain embodiments, the analyte sensor including the drug delivery composition is configured to detect glucose. In certain embodiments, the analyte sensor including the drug delivery composition is configured to detect, for example, glucose and ketones on a first working electrode and a second working electrode, respectively. In certain embodiments, the analyte sensor including the drug delivery composition is configured to detect lactate. In certain embodiments, the analyte sensor including the drug delivery composition is configured to detect creatinine. In certain embodiments, the analyte sensor including the drug delivery composition is configured to detect ketones. In certain embodiments, the analyte sensor including the drug delivery composition is configured to detect alcohol.

[0307] In certain embodiments, the analyte sensor including the drug delivery composition is a dermal sensor.

[0308] In certain embodiments, the analyte sensor including the drug delivery composition is a subcutaneous sensor, such as a subcutaneously implanted sensor. In certain embodiments, the analyte sensor including the drug delivery composition is an analyte sensor that detects an analyte in the interstitial fluid of a subject.

[0309] In certain embodiments, the analyte sensor including the drug delivery composition is a venous sensor, such as a vein-implanted sensor.

[0310] In some embodiments, the drug delivery composition may be disposed on the structure or components of an analyte sensor. In some embodiments, the drug delivery composition may be incorporated into the analyte sensors of the present disclosure. For example, but not by way of limitation, the drug delivery compositions of the present disclosure may be disposed on or incorporated into components of an analyte sensor (e.g., components of the sensor tail of an analyte sensor). In some embodiments, the drug delivery composition may be disposed on the structure or components of an analyte sensor. For example, but not by way of limitation, the drug delivery composition may be disposed on an electrode (e.g., a counter / reference electrode (e.g., Figure 38A 216) and / or a working electrode (e.g., Figure 38A 214)), an insulating material (e.g., a dielectric material (e.g., Figure 38A 219a-c)), a substrate (e.g., Figure 38A 212) and / or a mass transport limiting membrane (e.g., Figure 38A 220) on the surface.

[0311] In some embodiments, the drug delivery composition may be disposed on the working electrode. In some embodiments, the drug delivery composition may be disposed on the counter / reference electrode. In some embodiments in which the analyte sensor includes a counter electrode and a reference electrode, the composition (e.g., the drug delivery composition) may be disposed on the counter / reference electrode. In some embodiments, the drug composition (e.g., the drug delivery composition) may be disposed on the counter electrode. In some embodiments, the composition (e.g., the drug delivery composition) may be disposed on the reference electrode. In some embodiments in which the analyte sensor includes a counter electrode and a reference electrode, the composition (e.g., the drug delivery composition) may be disposed on the counter electrode. In some embodiments in which the analyte sensor includes a counter electrode and a reference electrode, the composition (e.g., the drug delivery composition) may be disposed on the reference electrode.

[0312] In some embodiments, the drug delivery composition may be disposed on the mass transport limiting membrane 220.

[0313] In certain embodiments, the hydrophilic units of the copolymer of the drug delivery composition disposed on the analyte sensor may include nitrogen-containing heterocyclic units such as pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, pyrazole units, and the like. In certain embodiments, the hydrophobic units of the copolymer of the drug delivery composition disposed on the analyte sensor may include aromatic units without heteroatoms such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units such as straight-chain or branched alkyl units, straight-chain or branched alkenyl units, straight-chain or branched alkynyl units, etc., and / or cyclic aliphatic units such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl units, and the like.

[0314] In certain embodiments, the copolymer of the drug delivery composition disposed on the analyte sensor may be selected from polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyetherurethane copolymers, silicone copolymers, their derivatives, and combinations thereof.

[0315] In certain embodiments, the copolymer of the drug delivery composition disposed on the analyte sensor may include block polymers.

[0316] In certain embodiments, the copolymer of the drug delivery composition disposed on the analyte sensor is a polyvinylimidazole copolymer. In certain embodiments, the polyvinylimidazole copolymer may be a copolymer of vinylimidazole and styrene or its derivatives.

[0317] In certain embodiments, the polyvinylimidazole copolymer may be a polyvinylimidazole-co-polystyrene polymer. In certain embodiments, the polyvinylimidazole-co-polystyrene polymer may be a poly(N-vinylimidazole)-co-polystyrene polymer, a poly(1-vinylimidazole)-co-polystyrene polymer, or its derivatives.

[0318] In certain embodiments, the copolymer of the drug delivery composition disposed on the analyte sensor is a polyvinylpyridine copolymer. In certain embodiments, the polyvinylpyridine copolymer may be a copolymer of vinylpyridine and styrene or its derivatives.

[0319] In certain embodiments, the polyvinylpyridine copolymer may be a polyvinylpyridine-co-polystyrene polymer. 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 its derivatives. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer is a poly(4-vinylpyridine)-co-polystyrene polymer.

[0320] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise 1-50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise 1-40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise 1-30 mer% styrene units.

[0321] In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD - 1,000 kD.

[0322] In certain embodiments, the crosslinking agent may be a diglycidyl-functional epoxide or a triglycidyl-functional epoxide.

[0323] In certain embodiments, the crosslinking agent may be selected from diglycidyl-PEG(200 - 1000), triglycidyl glycerol ether, and combinations thereof.

[0324] In certain embodiments, the crosslinking agent may be selected from diglycidyl-PEG 200, diglycidyl-PEG400, triglycidyl glycerol ether, and combinations thereof. In certain embodiments, the crosslinking agent may be diglycidyl-PEG200. In certain embodiments, the crosslinking agent may be diglycidyl-PEG 400. In certain embodiments, the crosslinking agent may be triglycidyl glycerol ether.

[0325] In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 0.1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 0.1 mol% - 40 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 1 mol% - 40 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 0.1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 0.1 mol% - 10 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 1 mol% - 10 mol%.

[0326] In certain embodiments, the therapeutic agent may include at least one selected from the group consisting of antibiotic agents, antiviral agents, anti-inflammatory agents, anti-cancer agents, antiplatelet agents, anticoagulants, coagulants, anti-glycolytic agents, and combinations thereof.

[0327] In certain embodiments, the therapeutic agent can be an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent can be selected from triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, ibuprofen, and their derivatives or salt forms. In certain embodiments, the anti-inflammatory agent is dexamethasone or its derivatives or salt forms. 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.

[0328] In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of the therapeutic agent in the range of 0.01 wt% - 50 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can comprise an amount of the therapeutic agent in the range of 0.01 wt% - 40 wt%.

[0329] In certain embodiments, the crosslinking agent binds to the hydrophilic units of the copolymer to form a charge.

[0330] In certain embodiments, the therapeutic agent is not covalently bound to the copolymer.

[0331] In certain embodiments, the therapeutic agent is covalently bound to the copolymer.

[0332] 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.

[0333] In certain embodiments, the mass transfer limiting membrane disposed on the analyte sensor can include polyvinylpyridine (such as poly(4-vinylpyridine) or poly(α-vinylpyridine)), polyvinylimidazole, polyvinylpyridine copolymer (such as a copolymer of vinylpyridine and styrene), polyacrylate, polyurethane, polyetherurethane (polyether-polyurethane), silicone, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene, homopolymers, copolymers or terpolymers of polyurethane, polypropylene, polyvinyl chloride, polyvinylidene fluoride, polybutylene terephthalate, polymethyl methacrylate, polyetheretherketone, cellulose polymer, polysulfone and their block copolymers (including for example diblock, triblock, alternating, random and graft copolymers) or chemically related materials and / or similar materials.

[0334] For a more detailed description of the drug delivery compositions that may be included in an analyte sensor and the characteristics of such drug delivery compositions, reference may be made to the relevant portions of the drug delivery compositions disclosed above, such as Section III above. For a more detailed description of the analyte sensor, reference may be made to the relevant portions of the analyte sensor disclosed above.

[0335] V. Delivery Devices and Delivery Methods

[0336] The present disclosure further provides devices for delivering the drug delivery compositions disclosed herein, devices for delivering the analyte sensors disclosed herein, and devices 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, methods for delivering the analyte sensors disclosed herein, and methods 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 (e.g., a subcutaneous sensor).

[0337] In certain embodiments, the methods of the present disclosure may include providing a drug delivery composition disclosed herein and implanting (e.g., subcutaneously) the drug delivery composition into a subject. In certain embodiments, the methods of the present disclosure may include providing an analyte sensor disclosed herein (e.g., an analyte sensor including a drug delivery composition) and implanting (e.g., subcutaneously) the analyte sensor into a subject. For example, but not by way of limitation, the analyte sensor and / or the drug delivery composition may be implanted into a subject by using a sharp object.

[0338] In certain embodiments, the present disclosure provides a sharp object including the analyte sensor and / or the drug delivery composition described herein. For example, but not by way of limitation, certain embodiments of the present disclosure relate to a sharp object, such as a pre-loaded sharp object for delivering a drug delivery composition. Figure 4 A cross-sectional view of an exemplary sharp object according to certain embodiments of the present disclosure is shown. As Figure 4 shown, in certain embodiments, the sharp object 401' may include an analyte sensor 403' and a drug delivery composition 402' (e.g., wherein the drug delivery composition includes (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 crosslinking agent that crosslinks at least a portion of the hydrophilic units between the respective copolymer chains, and (iii) a therapeutic agent). In certain embodiments, the sharp object may further include an analyte sensor, wherein the analyte sensor is located within a sharp object channel 404', and the drug delivery composition is located within the sharp object channel 404' distal to the analyte sensor.

[0339] In certain embodiments, the drug delivery composition has a shape and / or size that fits within the dimensions of a sharp (i.e., an insertion needle) for delivering the drug delivery composition (e.g., adjacent to the analyte sensor). For example, but not by way of limitation, the drug delivery composition has a shape corresponding to the lumen, channel, or groove of the sharp. In certain embodiments, the drug delivery composition has a shape that enables it to fit securely within the lumen, channel, or groove of a delivery device (e.g., a sharp) during transportation and also allows the drug delivery composition to be released from the delivery device into the tissue. In certain embodiments, the drug delivery composition has a cubic shape, a rectangular shape, a cylindrical shape, a spherical shape, a rhombic shape, or an irregular shape. As Figure 4 shown, the drug delivery composition 402’ can have a shape that fits the U-shaped channel 404’ of the exemplary sharp 401’. Alternatively, the drug delivery composition can have a spherical or cylindrical shape to fit the cylindrical channel of the sharp. In certain embodiments, the drug delivery composition unit can split into more than one fragment upon contact with the tissue.

[0340] In certain embodiments, the sharp for delivering the drug delivery composition can be the sharp for transdermally delivering an analyte sensor under the skin of a user. For example, but not by way of limitation, the drug delivery composition can be deployed in the tissue of the user simultaneously with the analyte sensor. As Figure 4 shown, the drug delivery composition 402’ can be placed in the lumen, channel, or groove at the distal tip of the sharp 401’, in front of the analyte sensor 403’. During the insertion of the analyte sensor, the analyte sensor 403’ moves out of the distal tip of the sharp 401’, and the drug delivery composition 402’ can be pushed out of the sharp 401’ and into the tissue of the user adjacent to the analyte sensor.

[0341] In certain embodiments, the sharp is part of the introducer disclosed herein. In certain embodiments, the sharp is part of a sharp module and / or a sensor applicator, for example, as disclosed in International Publication Nos. 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 sharp can be part of a sensor applicator, such as the Figure 32 B (e.g., the sharp labeled 3216), Figure 34B (e.g., the sharp labeled 3216), Figure 40as shown in B (e.g., the sharp object is labeled 3908) and FIG. 113 (e.g., the sharp object is labeled 11308). In certain embodiments, the sharp object can be part of a sensor module, such as that of WO 2019 / 236876 Figure 13 as shown (e.g., the sharp object (1318) is incorporated into the sensor module (labeled 1314) for insertion into the sensor (1316)).

[0342] Further details of non-limiting examples of applicators, their components, and their variations are described in U.S. Patent Publications No. 2013 / 0150691, 2016 / 0331283, and 2018 / 0235520, all of which are hereby incorporated by reference in their entirety and for all purposes. In certain embodiments, the sharp object is part of a sensor applicator, such as that of U.S. 2013 / 0150691 Figure 11 as shown in A (e.g., the sharp object is shown as 1030 and the sensor supported within the sharp object is labeled 1102). Further details of non-limiting embodiments of sharp object modules, sharp objects, their components, and their variations are described in U.S. Patent Publication No. 2014 / 0171771, which is hereby incorporated by reference in its entirety and for all purposes.

[0343] The present disclosure further provides a sharp object comprising the drug delivery composition. In certain embodiments, the sharp object can comprise a channel in which the drug delivery composition is retained. In certain embodiments, the drug delivery composition is located in the channel at the distal tip of the sharp object. In certain embodiments, the sharp object can further comprise an analyte sensor retained in the channel. In certain embodiments, both the drug delivery composition and the analyte sensor are retained in the channel of the sharp object, wherein the drug delivery composition is located distally of the analyte sensor in the channel of the sharp object, as Figure 4 shown.

[0344] In certain embodiments, a pre-loaded sharp object can be used in a method for delivering a drug delivery composition in vivo near an analyte sensor. For example, but not by way of limitation, the method can comprise providing a sharp object comprising (a) an analyte sensor and (b) a drug delivery composition, wherein the analyte sensor is located in the channel of the sharp object and wherein the drug delivery composition is located distally of the analyte sensor in the channel of the sharp object. In certain embodiments, the method can further comprise penetrating the tissue of a subject with the sharp object and inserting the drug delivery composition and the analyte sensor into the tissue of the subject. In certain embodiments, the method comprises withdrawing the sharp object from the tissue of the subject to retain the drug delivery composition and the analyte sensor in the tissue of the subject.

[0345] In certain embodiments, the present disclosure further provides methods for controlling the rate of drug delivery of an analyte sensor comprising a therapeutic agent. In certain embodiments, the method of controlling the rate of drug delivery of an analyte sensor (e.g., a subcutaneous sensor) can include: (i) providing a sharp, the sharp comprising an analyte sensor comprising a drug delivery composition according to certain embodiments of the present disclosure, (ii) piercing (penetrating) the tissue of a subject with the sharp, (iii) inserting the analyte sensor into the tissue of the subject, and (iv) withdrawing the sharp from the tissue of the subject. In certain embodiments, the sharp can include a second drug delivery composition located within a sharp channel distal to the analyte sensor.

[0346] In certain embodiments, the analyte sensor provided in the sharp and delivered by the disclosed methods can be any analyte sensor disclosed herein, such as an analyte sensor comprising a therapeutic agent. In certain embodiments, the therapeutic agent provided in the drug delivery composition can be different from the therapeutic agent incorporated in the analyte sensor. Alternatively, the therapeutic agent provided in the drug delivery composition can be the same as the therapeutic agent incorporated in 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 in the analyte sensor can both be dexamethasone.

[0347] Non-limiting examples of analyte sensors that can be delivered by a sharp are disclosed in Section IV. In certain embodiments, the analyte sensor is a subcutaneous sensor, such as a subcutaneously implanted sensor. In certain embodiments, the analyte sensor is a dermal sensor. In certain embodiments, the analyte sensor is a venous sensor, such as a vein-implanted 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.

[0348] Non-limiting examples of drug delivery compositions that can be delivered and / or incorporated into an analyte sensor by a sharp object are disclosed in Section III. For example, but not by way of limitation, the hydrophilic units of the copolymer present in the drug delivery composition 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 present in the drug delivery composition can include aromatic units without heteroatoms such as benzene (phenyl) units, naphthalene units, anthracene units, etc., acyclic aliphatic units such as straight-chain or branched alkyl units, straight-chain or branched alkenyl units, straight-chain or branched alkynyl units, etc., and / or cyclic aliphatic units such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl units, etc.

[0349] In certain embodiments, the copolymer can be selected from polyvinylpyridine copolymers, polyvinylimidazole copolymers, polyacrylate copolymers, polyurethane copolymers, polyetherurethane copolymers, silicone copolymers, derivatives thereof, and combinations thereof.

[0350] In certain embodiments, the copolymer can include a block polymer.

[0351] In certain embodiments, the polyvinylimidazole copolymer can be a copolymer of vinylimidazole and styrene or a derivative thereof.

[0352] In certain embodiments, the polyvinylimidazole copolymer can be a polyvinylimidazole-co-polystyrene polymer. In 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.

[0353] In certain embodiments, the polyvinylpyridine copolymer can be a copolymer of vinylpyridine and styrene or a derivative thereof.

[0354] In certain embodiments, the polyvinylpyridine 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.

[0355] In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise 1-50 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise 1-40 mer% styrene units. In certain embodiments, the polyvinylpyridine-co-polystyrene polymer may comprise 1-30 mer% styrene units.

[0356] In certain embodiments, the weight average molecular weight of the copolymer is in the range of about 5 kD - 1,000 kD.

[0357] In certain embodiments, the crosslinking agent may be a diglycidyl-functionalized epoxide or a triglycidyl-functionalized epoxide.

[0358] In certain embodiments, the crosslinking agent may be selected from diglycidyl-PEG(200 - 1000), glycerol triglycidyl ether, and combinations thereof.

[0359] In certain embodiments, the crosslinking agent may be selected from diglycidyl-PEG 200, diglycidyl-PEG400, glycerol triglycidyl ether, and combinations thereof. In certain embodiments, the crosslinking agent may be diglycidyl-PEG200. In certain embodiments, the crosslinking agent may be diglycidyl-PEG 400. In certain embodiments, the crosslinking agent may be glycerol triglycidyl ether.

[0360] In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 0.1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 1 mol% - 50 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 0.1 mol% - 40 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 1 mol% - 40 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 0.1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 1 mol% - 30 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 0.1 mol% - 10 mol%. In certain embodiments, the mol% crosslinking of the copolymer may be in the range of about 1 mol% - 10 mol%.

[0361] In certain embodiments, the therapeutic agent may comprise at least one selected from the group consisting of antibiotic agents, antiviral agents, anti-inflammatory agents, anti-cancer agents, antiplatelet agents, anticoagulants, coagulants, anti-glycolytic agents, and combinations thereof.

[0362] In certain embodiments, the therapeutic agent can be an anti-inflammatory agent. In certain embodiments, the anti-inflammatory agent can be one or more selected from triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, ibuprofen, and their derivatives or salt forms. In certain embodiments, the anti-inflammatory agent is dexamethasone or its derivative or salt form. In certain embodiments, the derivative of dexamethasone is dexamethasone acetate. In certain embodiments, the derivative of dexamethasone is dexamethasone sodium phosphate.

[0363] In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically effective amount of the therapeutic agent in the range of 0.01 wt% - 50 wt%. In certain embodiments, based on the total weight of the copolymer, the drug delivery composition can include a therapeutically effective amount of the therapeutic agent in the range of 0.01 wt% - 40 wt%.

[0364] In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 200 μg of the therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 20 μg of the therapeutic agent. In certain embodiments, the drug delivery composition can include from about 0.1 μg to about 10 μg of the therapeutic agent.

[0365] In certain embodiments, the crosslinking agent binds to the hydrophilic units of the copolymer to form charges.

[0366] In certain embodiments, the therapeutic agent is not covalently bound to the copolymer.

[0367] In certain embodiments, the therapeutic agent is covalently bound to the copolymer.

[0368] 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.

[0369] In certain embodiments, the analyte sensor is configured to detect glucose.

[0370] For a more detailed description of the drug delivery composition, reference can be made to the relevant part of the drug delivery composition disclosed above, such as Section III above. For a more detailed description of the analyte sensor, reference can be made to the relevant part of the analyte sensor disclosed above, such as Section IV above.

[0371] VI. Exemplary Embodiments

[0372] A. In certain non-limiting embodiments, the subject matter of the present disclosure provides a drug delivery composition comprising:

[0373] (i) A copolymer comprising a plurality of copolymer chains, wherein each of the plurality of copolymer chains comprises a main chain containing a plurality of hydrophilic units and a plurality of hydrophobic units;

[0374] (ii) A crosslinking agent that crosslinks at least a portion of the hydrophilic units between the respective copolymer chains; and

[0375] (iii) A therapeutic agent.

[0376] A1.A The pharmaceutical delivery composition according to A, wherein (i) the hydrophilic units are selected from pyridine units, pyridazine units, pyrimidine units, pyrazine units, triazine units, imidazole units, and pyrazole units, and / or (ii) the hydrophobic units are selected from aromatic units without heteroatoms, acyclic aliphatic units, and cyclic aliphatic units.

[0377] A1-1.A1 The pharmaceutical delivery composition according to A1, wherein the hydrophilic unit is a pyridine unit.

[0378] A1-2.A1 The pharmaceutical delivery composition according to A1, wherein the hydrophobic unit is an aromatic unit.

[0379] A2.A-A1-2 The pharmaceutical delivery composition according to A1-2, wherein the copolymer is selected from polyvinylpyridine copolymers, polyvinylimidazole copolymers, and combinations thereof.

[0380] A2-1.A2 The pharmaceutical delivery composition according to A2, wherein the copolymer is a polyvinylpyridine copolymer.

[0381] A3.A2 or A2-1 The pharmaceutical delivery composition according to A2 or A2-1, wherein the polyvinylpyridine copolymer is a polyvinylpyridine-co-polystyrene polymer.

[0382] A4.A3 The pharmaceutical delivery composition according to A3, wherein the polyvinylpyridine-co-polystyrene polymer contains about 1-50 mer% of styrene units.

[0383] A5.A3 or A4 The pharmaceutical delivery composition according to A3 or A4, wherein the polyvinylpyridine-co-polystyrene polymer contains about 1-30 mer% of styrene units.

[0384] A6.A-A5 The pharmaceutical delivery composition according to A-A5, wherein the weight average molecular weight of the copolymer is in the range of about 5 kD to about 1000 kD.

[0385] A7.A-A6 The pharmaceutical delivery composition according to A-A6, wherein the crosslinking agent is a diglycidyl-functional epoxide or a triglycidyl-functional epoxide.

[0386] The pharmaceutical delivery composition according to A8.A7, wherein the crosslinking agent is selected from diglycidyl-PEG(200-1000), triglycidyl glycerol ether, and combinations thereof.

[0387] The pharmaceutical delivery composition according to A9.A8, wherein the crosslinking agent is selected from diglycidyl-PEG 200, diglycidyl-PEG 400, triglycidyl glycerol ether, and combinations thereof.

[0388] The pharmaceutical delivery composition according to A10.A-A9, wherein the mol% crosslinking of the copolymer is in the range of about 0.1 mol% to about 50 mol%.

[0389] The pharmaceutical delivery composition according to A10-1.A10, wherein the mol% crosslinking of the copolymer is in the range of about 1 mol% to about 50 mol%.

[0390] The pharmaceutical delivery composition according to A11.A-A10, wherein the mol% crosslinking of the copolymer is in the range of about 0.2 mol% to about 30 mol%.

[0391] The pharmaceutical delivery composition according to A11-1.A-A10, wherein the mol% crosslinking of the copolymer is in the range of about 1 mol% to about 30 mol%.

[0392] The pharmaceutical delivery composition according to A12.A-A11-1, wherein the therapeutic agent is at least one selected from the group consisting of antibiotic agents, antiviral agents, anti-inflammatory agents, anti-cancer agents, antiplatelet agents, anticoagulants, coagulants, antiglycolytic agents, and combinations thereof.

[0393] The pharmaceutical delivery composition according to A13.A-A12, wherein the mol% crosslinking of the copolymer is in the range of about 0.5 mol% to about 10 mol%.

[0394] The pharmaceutical delivery composition according to A13-1.A-A12, wherein the mol% crosslinking of the copolymer is not greater than about 20 mol%.

[0395] The pharmaceutical delivery composition according to A14.A-A13-1, wherein the therapeutic agent is an anti-inflammatory agent.

[0396] The pharmaceutical delivery composition according to A15.A14, wherein the anti-inflammatory agent is selected from triamcinolone, betamethasone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, prednisone, methylprednisolone, fludrocortisone, acetylsalicylic acid, ibuprofen, derivatives thereof, salt forms thereof, and combinations thereof.

[0397] The pharmaceutical delivery composition according to A16.A - A15, wherein the anti - inflammatory agent is dexamethasone, its derivatives, or its salt form.

[0398] The pharmaceutical delivery composition according to A17.A - A16, wherein, based on the weight of the copolymer, the pharmaceutical delivery composition comprises a therapeutic agent in the range of about 0.01 wt% - about 40 wt%.

[0399] The pharmaceutical delivery composition according to A18.A - A17, wherein the cross - linker binds to the hydrophilic units of the copolymer to form a charge.

[0400] The pharmaceutical delivery composition according to A19.A - A18, wherein the pharmaceutical delivery composition comprises from about 0.1 μg to about 200 μg of the therapeutic agent.

[0401] The pharmaceutical delivery composition according to A20.A - A19, wherein the pharmaceutical delivery composition comprises from about 0.1 μg to about 20 μg of the therapeutic agent.

[0402] The pharmaceutical delivery composition according to A21.A - A20, wherein the pharmaceutical delivery composition comprises from about 0.1 μg to about 10 μg of the therapeutic agent.

[0403] The pharmaceutical delivery composition according to A22.A - A21, wherein the pharmaceutical delivery composition comprises from about 0.1 μg to about 5 μg of the therapeutic agent.

[0404] The pharmaceutical delivery composition according to A23.A - A22, wherein the therapeutic agent is not covalently bound to the copolymer.

[0405] B. In certain non - limiting embodiments, the subject matter of the present disclosure provides an analyte sensor, comprising:

[0406] (i) A sensor tail including at least a first working electrode;

[0407] (ii) An active region located on the surface of the first working electrode for detecting an analyte;

[0408] (iii) A mass - transfer - limiting membrane permeable to the analyte, the mass - transfer - limiting membrane covering at least the active region;

[0409] (iv) A counter / reference electrode; and

[0410] (v) The pharmaceutical delivery composition according to any one of A - A23.

[0411] The analyte sensor described in B1.B, wherein the drug delivery composition is disposed on the counter / reference electrode, working electrode, or mass transport limiting membrane.

[0412] The analyte sensor described in B2.B or B1, wherein the drug delivery composition is disposed on the counter electrode / reference electrode.

[0413] The analyte sensor described in B3.B or B1, wherein the drug delivery composition is disposed on the working electrode.

[0414] The analyte sensor described in B4.B or B1, wherein the drug delivery composition is disposed on the mass transport limiting membrane.

[0415] C. In certain non-limiting embodiments, the subject matter of the present disclosure provides a method for controlling the drug delivery rate of an analyte sensor and / or implanting the analyte sensor into a subject, the method comprising:

[0416] (i) providing an analyte sensor of any one of B - B4; and

[0417] (ii) subcutaneously implanting the analyte sensor.

[0418] D. In certain non-limiting embodiments, the subject matter of the present disclosure provides a method for controlling the drug delivery rate of an analyte sensor and / or implanting the analyte sensor into a subject, the method comprising:

[0419] (i) providing a sharp object comprising an analyte sensor and a drug delivery composition of any one of A - A23;

[0420] (ii) penetrating the tissue of the subject with the sharp object;

[0421] (iii) inserting the drug delivery composition and the analyte sensor into the tissue of the subject; and

[0422] (iv) withdrawing the sharp object from the tissue of the subject.

[0423] E. In certain non-limiting embodiments, the subject matter of the present disclosure provides a sharp object comprising a drug delivery composition of any one of A - A23.

[0424] The sharp object described in E1.E, further comprising an analyte sensor, wherein the analyte sensor is located within the sharp object channel and the drug delivery composition is located distally of the analyte sensor within the sharp object channel.

[0425] The sharp object described in E2.E or E1, wherein the analyte sensor may comprise a drug delivery composition of any one of A - A23.

[0426] F. In certain non-limiting embodiments, the subject matter of the present disclosure provides a method of manufacturing a drug delivery composition, the method comprising:

[0427] (i) providing a copolymer comprising a plurality of copolymer chains, wherein each of the plurality of copolymer chains comprises a backbone containing a plurality of hydrophilic units and a plurality of hydrophobic units;

[0428] (ii) applying a crosslinking agent and a therapeutic agent to the copolymer; and

[0429] (iii) crosslinking the crosslinking agent between the respective copolymer chains to at least a portion of the hydrophilic units.

[0430] Embodiment

[0431] Example 1: Incorporating a drug delivery composition into an analyte sensor

[0432] This example provides an analysis of a polymer-based drug delivery composition. In an exemplary embodiment of the present disclosure, polyvinylpyridine (PVP) or polyvinylpyridine-co-polystyrene (PVP-PS) copolymer is used as a representative copolymer of the drug delivery composition; dexamethasone (Dex) is used as a representative therapeutic agent of the drug delivery composition; diglycidyl-PEG 400 (hereinafter referred to as PEG 400), diglycidyl-PEG 200 (hereinafter referred to as PEG 200), or glycerol triglycidyl ether (hereinafter referred to as Gly3) is used as a representative crosslinking agent of the drug delivery composition.

[0433] A. Sample preparation

[0434] Figure 5 An exemplary coupon of a drug delivery composition on a biocompatible strip (which serves as a surrogate for the sensor tail) according to certain embodiments of the present disclosure is shown. As Figure 5 shown, in order to rapidly screen formulations of the drug delivery composition, coupons were utilized. For each tested drug delivery composition formulation, 5 μL of the drug delivery composition formulation solution was manually dispensed onto the sensor tail surrogate to produce test coupons. Multiple coupons were used for testing.

[0435] Figure 6Shows an example sensor tail including 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 is dip-coated with a drug delivery composition. In certain embodiments, sub-microliter-sized droplets containing the drug delivery composition are added to the sensor tail of the analyte sensor using an automated precision liquid dispensing device (e.g., BioDot). Generally, the drug delivery composition containing Dex is deposited onto the sensor tail, or the outer membrane of the analyte sensor, in a manner that does not interfere with the glucose oxidase (GOx) sensing chemistry.

[0436] B. Method for Measuring Dexamethasone (Dex)

[0437] Figures 7A - 7B Shows an example test sample of a drug delivery composition according to certain embodiments of the present disclosure. Figure 8 Shows an example test procedure for a drug delivery composition according to certain embodiments of the present disclosure.

[0438] In vitro Dex release of the drug delivery composition is carried out at 37 °C in a pH 7.4 phosphate buffered saline (PBS) solution under stirring (which is similar to physiological conditions).

[0439] As Figure 7A shown, test samples 604 are cut from a sensor tail substitute 600 assigned with the drug delivery composition. As Figure 7B shown, sensor tails 700 including test samples 704 are cut from the drug-loading portion 702 of the sensor tail 700 of the analyte sensor. Then, as Figure 8 shown, multiple test samples (e.g., 6 sensor tails) are immersed in a pH 7.4 PBS solution in a vial and incubated with stirring in an oscillating incubator at 37 °C. At each time point (e.g., daily), the supernatant is collected for HPLC analysis, fresh PBS solution is added to the vial, and the vial is returned to the oscillating incubator until the next time point. These steps are repeated for up to 31 days.

[0440] For total Dex loading measurement, the test samples are extracted with 100% methanol under stirring at 37 °C for 24 hours to remove all Dex.

[0441] The concentration of Dex in the supernatant or methanol extract is measured by using high performance liquid chromatography (HPLC).

[0442] Figure 9 Shows the HPLC of dexamethasone according to certain embodiments of the present disclosure. Figure 10 Shows the calibration curve of dexamethasone according to certain embodiments of the present disclosure. Figure 9The area under the curve (AUC) of the Dex peak shown was measured from a suitable Dex concentration to create Figure 10 the calibration curve shown, which was used to measure the unknown Dex concentration.

[0443] C. 100% PVP matrix

[0444] Figure 11 The drug delivery curves of drug delivery compositions comprising 100% polyvinylpyridine, triglycidyl ether, and dexamethasone according to certain embodiments of the present disclosure are shown. Figure 12 The drug delivery curves of drug delivery compositions comprising 100% polyvinylpyridine, diglycidyl-PEG 400, and dexamethasone according to certain embodiments of the present disclosure are shown.

[0445] As Figure 11 and Figure 12 shown, even without a crosslinking agent or at a low crosslinking agent concentration, the 100% PVP polymer (i.e., no styrene units in the polymer backbone) does not retain Dex, and Dex diffuses rapidly out of the polymer matrix. Dex is completely released in less than 7 days ( Figure 11 and Figure 12 ). When the crosslinking agent concentration increases, the drug delivery rate increases due to the positive charge formed by crosslinking, which increases the swelling of the polymer matrix.

[0446] D. Studying the concentration effect of polystyrene in polyvinylpyridine-co-polystyrene copolymers and the concentration and type or species effect of crosslinking agents

[0447] Polyvinylpyridine polymers and various polyvinylpyridine-co-polystyrene copolymers were studied as copolymer components of drug delivery compositions. Figure 13 Exemplary test polymers and copolymers of drug delivery compositions according to certain embodiments of the present disclosure are shown. The weight-average molecular weight of the polymers and copolymers studied was approximately 175 kD, measured by suitable methods such as gel permeation chromatography. The mer% of styrene units in the copolymer (i.e., mer% polystyrene) was measured by nuclear magnetic resonance (NMR) spectroscopy.

[0448] Figure 14 Exemplary crosslinking agents for drug delivery compositions according to certain embodiments of the present disclosure are shown. In certain embodiments, diglycidyl-PEG 200 (PEG 200), diglycidyl-PEG 400 (PEG 400), or triglycidyl ether (Gly 3) were studied as crosslinking agents to crosslink the copolymer at different mol% degrees of crosslinking in the drug delivery composition. The mol% crosslinking of the copolymer was calculated based on the weight of the crosslinking agent relative to the total weight of the copolymer by the following formula:

[0449]

[0450] Among them, the crosslinker functionality is the number of reactive crosslinking groups in a crosslinker molecule. For example, the crosslinker functionality of diglycidyl-PEG 200 is 2, the crosslinker functionality of diglycidyl-PEG 400 is 2, and the crosslinker functionality of triglycidyl glycerol ether is 3.

[0451] Figure 15 An exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure is shown. As Figure 15 shown, in certain embodiments, a 93% PVP - 7% PS copolymer was studied as the copolymer in the drug delivery composition. PEG 200 and Gly3 were studied as crosslinkers in the drug delivery composition. The mol% crosslinking of the copolymer was 0%, 1 mol%, or 10 mol%. The loading percentage of Dex in the copolymer matrix was 30 wt%. Generally, an appropriate amount of Dex, crosslinker, and copolymer were mixed in a solvent (such as ethanol and water with a volume ratio of 95:5), and then 5 μL of the solution was manually dispensed onto the sensor tail substitute to make a test specimen.

[0452] Figure 16 A drug delivery curve of a drug delivery composition according to certain embodiments of the present disclosure is shown. As Figure 16 shown, 100% PVP is too hydrophilic, and Dex is released from the polymer matrix very quickly and is almost completely released in less than 7 days. In contrast, the release of Dex from the 20% PS copolymer without a crosslinker (referred to as "XL") is too slow. By adjusting the mer% of styrene units in the copolymer, the Dex release rate (i.e., the 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 that includes a Dex composition in which Dex is conjugated (bound) to the polymer within the composition.

[0453] Figure 17 A drug delivery curve of a drug delivery composition according to certain embodiments of the present disclosure is shown. As Figure 17 shown, when the mer% of styrene units in the copolymer increases and the mol% crosslinking of the copolymer remains constant, the release rate of Dex decreases; when the mer% of styrene units in the copolymer remains constant and the mol% crosslinking of the copolymer increases, the release rate of Dex increases.

[0454] Figure 18 An exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure is shown. As Figure 18As shown, in certain embodiments, an 87% PVP - 13% PS copolymer was studied as the polymer in the drug delivery composition. PEG 400 and Gly3 were studied as cross - linkers in the drug delivery composition. In the case of Gly3 as the cross - linker, the mol% cross - linking of the copolymer was 2 mol%, 5 mol% or 7 mol%. In the case of PEG 400 as the cross - linker, the mol% cross - linking of the copolymer was 1 mol%, 2 mol%, 5 mol%, 7 mol% or 10 mol%. The loading percentage of Dex in the copolymer matrix was 30 wt%. Generally, an appropriate amount of Dex, cross - linker and copolymer were mixed in a solvent (such as ethanol and water with a volume ratio of 95:5), and then 5 μL of the solution was manually dispensed onto the sensor tail substitute to make a test specimen.

[0455] Figure 19 The drug delivery curves of the drug delivery composition according to certain embodiments of the present disclosure are shown. As Figure 19 shown, for the copolymer containing 13% PS copolymer and cross - linker PEG 400, when the mol% cross - linking of the copolymer increases, the release rate of Dex from the copolymer matrix increases.

[0456] Figure 20 The drug delivery curves of the drug delivery composition according to certain embodiments of the present disclosure are shown. As Figure 20 shown, the copolymer is a 13% PS copolymer and the cross - linker is Gly3. When the mol% cross - linking of the copolymer matrix increases, the release rate of Dex from the copolymer matrix increases.

[0457] Figure 21 The drug delivery curves of the drug delivery composition according to certain embodiments of the present disclosure are shown. As Figure 21 shown, the copolymer is a 20% PS copolymer and the cross - linker is PEG 400. When the mol% cross - linking of the copolymer matrix increases, the release rate of Dex from the copolymer matrix increases.

[0458] Figure 22 The drug delivery curves of the drug delivery composition according to certain embodiments of the present disclosure are shown. As Figure 22 shown, the copolymer is a 20% PS copolymer and the cross - linker is Gly3. When the mol% cross - linking of the copolymer matrix increases, the release rate of Dex from the copolymer matrix increases. However, due to the high mer% of styrene units in the copolymer matrix, a higher amount of cross - linker is required to match the similar rate exhibited by copolymers containing a lower mer% of styrene.

[0459] Figure 23 The concentration relationship between different cross - linkers in the drug delivery composition according to certain embodiments of the present disclosure is shown.Figure 24 shows the drug delivery profile of a drug delivery composition according to certain embodiments of the present disclosure.

[0460] As Figure 23 and Figure 24 shown, in preparing the drug delivery composition, in order to control the mol% crosslinking of the copolymer, for different crosslinking agents, the functionality of the crosslinking agent, i.e., the number of reactive crosslinking groups in the crosslinking agent, must be considered, and the different weight concentrations of the crosslinking agent in the drug delivery composition must be adjusted. After considering the functionality of the crosslinking agent, PEG 400 and Gly3 exhibit similar crosslinking effects on the Dex release rate of the drug delivery composition.

[0461] Figure 25 shows an exemplary formulation of a drug delivery composition for an analyte sensor according to certain embodiments of the present disclosure. The formulation is applied to a sensor format. As Figure 25 shown, in certain embodiments, a 90% PVP - 10% PS copolymer was studied as the copolymer in the drug delivery composition on the analyte sensor. PEG400 and Gly3 were studied as crosslinking agents in the drug delivery composition. In the case of Gly3 as the crosslinking agent, the mol% crosslinking of the copolymer was 1 mol% or 5 mol%. In the case of PEG 400 as the crosslinking agent, the mol% crosslinking of the copolymer was 1 mol% or 5 mol%. The loading percentage of Dex in the copolymer matrix was 30 wt%. Generally, an appropriate amount of Dex, crosslinking agent, and copolymer were mixed in a solvent (e.g., ethanol and water in a volume ratio of 95:5), and then 5 μL of the solution was manually dispensed onto a biocompatible strip to make a test specimen, or the sensor tail of the analyte sensor was dip - coated with the drug delivery composition solution.

[0462] Figure 26 shows 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 shows the drug delivery profile of a drug delivery composition comprising a 90% PVP - 10% PS copolymer on an analyte sensor at each time point according to certain embodiments of the present disclosure. As Figure 26 shown, for the tested analyte sensors and specimens, when the crosslinking agent is the same and the mol% crosslinking of the copolymer is the same, the Dex release rates are similar. In addition, when the mol% crosslinking of the copolymer increases, the release rate of Dex increases ( Figure 26 ). As Figure 27As shown, for sensors containing 10% PS and 1% PEG400, 1% Gly3, or 5% Gly3, the amount of Dex released by each sensor at each time point is in the range of 0.2 μg to 1.5 μg, and Dex can be continuously released for at least 31 days.

[0463] Figure 28 Factors affecting the drug delivery rate of a drug delivery composition according to certain embodiments of the present disclosure are shown. When the PS content (e.g., amount) of the hydrophobic copolymer increases, i.e., the mer% of styrene units in the copolymer increases, the Dex release rate decreases due to the increased affinity of the polymer for Dex. When the amount of crosslinker in the drug delivery composition increases, i.e., the mol% crosslinking of the copolymer increases, the release rate of Dex increases due to the increased swelling and hydrophilicity of the copolymer matrix. When the same molar amount of PEG 400 and Gly3 is used in the drug delivery composition, the Dex release rate in the drug delivery composition using Gly3 as the crosslinker increases due to the higher functionality of Gly3 and thus higher mol% crosslinking. When dexamethasone acetate (DexA) is used instead of dexamethasone as the therapeutic agent, the release rate of DexA decreases. This is because DexA is less polar than Dex and has a stronger non-polar interaction with the styrene units of the copolymer, thereby slowing down the release of DexA from the copolymer matrix. The Dex release rate of the drug delivery composition on the analyte sensor is similar to the Dex release rate of the drug delivery composition when used alone. Baking out (i.e., extending the polymer curing time) does not affect the Dex release rate.

[0464] Figure 29 Drug delivery curves of a drug delivery composition according to certain embodiments of the present disclosure are shown. As Figure 29 shown, by adjusting the mer% of hydrophobic units (e.g., styrene units) in the copolymer and / or by adjusting the mol% crosslinking of the copolymer with a crosslinker (e.g., by adjusting the amount and / or type or kind of crosslinker used), the Dex release rate can be finely tuned.

[0465] Figure 30 Drug delivery curves of a drug delivery composition according to certain embodiments of the present disclosure are shown. As Figure 30 shown, when the mol% crosslinking of the copolymer is 10 mol%, by adjusting the mer% of styrene units in the copolymer, the release rate of Dex can be slowed down by using a higher mer% of styrene (13%, 20% PS) or by using a less hydrophilic crosslinker (Gly3), thereby achieving a sustained delivery of Dex in a continuous amount over 31 days.

[0466] Figure 31shows the drug delivery curve of a drug delivery composition according to certain embodiments of the present disclosure. As Figure 31 shown, when the mol% crosslinking of the copolymer is 1%, by adjusting the mer% of styrene units in the copolymer, the mer% of styrene (7 - 20%) can be adjusted within a wide range, thereby adjusting the Dex release rate of the drug delivery composition to continuously deliver Dex within 31 days. Therefore, 1 mol% crosslinking of the copolymer provides a wide range for adjusting the drug delivery rate of the drug delivery composition.

[0467] Figure 32 shows the drug delivery curve of the drug delivery composition on an analyte sensor and the drug delivery curve at each time point according to certain embodiments of the present disclosure. As Figure 32 shown, for the analyte sensor using a drug delivery composition comprising a 90% PVP - 10% PS copolymer tested, when the crosslinking agent is the same and the mol% crosslinking of the copolymer increases, the release rate of Dex increases. When using PEG 400 as the crosslinking agent, 5 mol% crosslinking of the copolymer releases a higher amount of dex at an earlier time point and stops releasing Dex after about 23 days. Therefore, by adjusting the mol% crosslinking within a given copolymer, the desired drug release rate can be achieved.

[0468] Figure 33 shows the solubility of Dex in a polyvinylpyridine - ethanol: water (volume ratio 95:5) solution according to certain embodiments of the present disclosure. The solubility of Dex in a PVP - ethanol: aqueous solution was measured. For solutions containing 0 wt% - 30 wt% Dex relative to the weight of the PVP polymer, the solution became clear after vortexing / sonicating the solution for 15 minutes. For solutions containing 40 wt% Dex relative to the weight of the PVP polymer, the solution became clear after mixing overnight on a nutator. The solution containing 50 wt% Dex relative to the weight of the PVP polymer did not become clear after mixing overnight on a nutator. Therefore, the drug delivery composition can include up to 40 wt% Dex relative to the amount of the copolymer to form a clear drug delivery composition.

[0469] Figure 34A shows an exemplary formulation of a drug delivery composition according to certain embodiments of the present disclosure. As Figure 34A shown, the effect of Dex loading in the drug delivery composition on the Dex release rate was studied. The copolymer was a 93% PVP - 7% PS copolymer. The mol% crosslinking of the copolymer was 1 mol%, crosslinked by Gly3. The loading of Dex in the drug delivery composition was 30 wt%, 15 wt% or 5 wt% relative to the weight of the copolymer.

[0470] Figure 34B Exemplary formulations of drug delivery compositions comprising different percentages of dexamethasone are shown. Figure 34B Table 1 of shows drug delivery compositions comprising 40 wt% Dex loading relative to the copolymer weight. Figure 34B Table 2 of shows drug delivery compositions comprising 26 wt% Dex loading relative to the copolymer weight. Figure 34B Table 3 of shows drug delivery compositions comprising 15 wt% Dex loading relative to the copolymer weight.

[0471] Figure 35A Drug delivery curves of the drug delivery compositions on an analyte sensor and the drug delivery curves at each time point according to certain embodiments of the present disclosure are shown. As Figure 35A shown, Dex can be continuously released for at least 31 days. For 5 wt% Dex loading, 70% of Dex is released within 31 days. For 30 wt% Dex loading, approximately 50% of Dex is released within 31 days. At each time point, the amount of Dex released daily by the drug delivery composition containing 30 wt% Dex is 2 times the amount of Dex released daily by the drug delivery composition containing 15 wt% Dex, and is 6 times the amount of Dex released daily by the drug delivery composition containing 5 wt% Dex. After normalization using Dex loading, as Figure 35A shown in the inset of the right figure, the Dex release rates of all three drug delivery compositions are similar. Thus, within the complete solubility range, the Dex loading in the drug delivery composition does not affect the Dex release rate.

[0472] Figure 35B Drug delivery curves of the drug delivery compositions on an analyte sensor and the drug delivery curves at each time point according to certain embodiments of the present disclosure are shown. The drug delivery composition according to Figure 34B (10% PS copolymer with 1 mol% Gly3) is deposited on the counter electrode at the tail of the sensor. As Figure 35B shown, Dex can be continuously released for at least 31 days, and approximately 60 - 75% of the loaded Dex is released at the end of 31 days. For 6.79 μg and 4.67 μg Dex loading, approximately 70% of Dex is released within 31 days. For 2.26 μg Dex loading, approximately 75% of Dex is released within 31 days. For 6.58 μg Dex loading, approximately 60% of Dex is released within 31 days. For 3.99 μg Dex loading, approximately 65% of Dex is released within 31 days. For 2.1 μg Dex loading, approximately 70% of Dex is released within 31 days. For each composition, approximately 50% of Dex is released between days 13 - 16.

[0473] Figure 35CIt is shown that incorporating as little as 2.1 μg of Dex into the analyte sensor can significantly reduce LSA. As Figure 35C shown, the LSA reduction is similar between an analyte sensor comprising 6.6 μg and an analyte sensor comprising 2.1 μg. LSA is determined by calculating the average and median sensitivity within a rolling 12-hour window, if there are >= 3 points within the window, and if both the average and median sensitivity are below 80% of the stable sensitivity (defined as the median sensitivity within 10 - 120 hours), then it is an LSA instance. If there are >= 5 LSA instances within a 24-hour window, and the first instance is more than 24 hours before the end of the sensor's useful life, then the LSA start time is defined as the time of the first LSA instance. In-LSA index = area below 1 / (T_end of useful life - T_LSA start). The higher the index, the more severe the LSA.

[0474] ****

[0475] The analyte sensor and / or any other related devices or components according to the embodiments of the present invention described herein can be implemented using any suitable hardware, firmware (such as an application specific integrated circuit), software, or a combination of software, firmware, and hardware. For example, the various components of the sensor can be formed on a single integrated circuit (IC) chip, or on separate IC chips. Further, the various components of the sensor can be implemented on a flexible printed circuit film, tape carrier package (TCP), printed circuit board (PCB), or formed on a substrate. Further, the various components of the sensor can be processes or threads running on one or more processors in 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, which can be implemented in a computing device using standard memory devices (such as random access memory (RAM)). The computer program instructions can also be stored in other non-transitory computer-readable media, such as a CD-ROM, flash drive, etc. In addition, those skilled in the art should recognize that the functions of various computing devices can be combined or integrated into a single computing device, or the functions of a particular computing device can be distributed over one or more other computing devices, without departing from the scope of the exemplary embodiments of the present invention.

[0476] Although embodiments of the present disclosure have been described, it should be understood that the present disclosure should not be limited to these embodiments, but that one or more suitable changes and modifications can be made by those of ordinary skill in the art within the spirit and scope of the present disclosure as claimed below and its equivalents.

Claims

1. A drug delivery composition comprising: (i) a copolymer comprising a plurality of copolymer chains, wherein Each of the plurality of copolymer chains comprises 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 individual copolymer chains; and (iii) Therapeutic agents.

2. The drug delivery composition according to claim 1, wherein (a) the hydrophilic unit is selected from a pyridine unit, a pyridazine unit, a pyrimidine unit, a pyrazine unit, a triazine unit, an imidazole unit and a pyrazole unit, and / or (b) the hydrophobic unit is selected from an aromatic unit containing no heteroatoms, a non-cyclic aliphatic unit and a cyclic aliphatic unit.

3. The drug delivery composition according to claim 1 or 2, wherein The copolymer is selected from polyvinyl pyridine copolymers, polyvinyl imidazole copolymers, and combinations thereof.

4. The drug delivery composition according to claim 3, wherein The polyvinyl pyridine copolymer is a polyvinyl pyridine-co-polystyrene polymer.

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

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

7. The drug delivery composition according to any one of claims 1 to 6, wherein The weight average molecular weight of the copolymer is in the range of about 5 kD to about 1000 kD.

8. The drug delivery composition according to any one of claims 1 to 7, wherein The crosslinking agent is a diglycidyl functional epoxide or a triglycidyl functional epoxide.

9. The drug delivery composition according to claim 8, wherein The cross-linking agent is selected from diglycidyl-PEG (200-1000), glyceryl triglycidyl ether, and combinations thereof.

10. The drug delivery composition according to claim 9, wherein The cross-linking agent is selected from diglycidyl-PEG200, diglycidyl-PEG 400, glycerol triglycidyl ether, and combinations thereof.

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

12. The drug delivery composition according to claim 11, wherein The mol % crosslinking 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, antivirals, anti-inflammatory agents, anticancer agents, antiplatelet agents, anticoagulants, blood coagulants, antiglycolytic agents, and combinations thereof.

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

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

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

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

18. The drug delivery composition according to any one of claims 1 to 17, wherein The cross-linking agent is combined with the hydrophilic unit of the copolymer to form charges.

19. An analyte sensor comprising: (i) a sensor tail comprising 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 covering at least the active area; (iv) counter electrode / reference electrode; and (v) The drug delivery composition according to any one of claims 1 to 18.

20. A method of controlling a drug delivery rate of an analyte sensor, the method comprising: (i) providing the analyte sensor of claim 19; as well as (ii) implanting the analyte sensor subcutaneously.

21. A method of controlling a drug delivery rate of an analyte sensor, the method comprising: (i) providing a sharp object, the sharp object comprising an analyte sensor and a drug delivery composition according to any one of claims 1 to 18; (ii) penetrating tissue of a subject with the sharp object; (iii) inserting the drug delivery composition and the analyte sensor into a tissue of the subject; as well as (iv) retracting the sharp object from the tissue of the subject.

22. A sharp object comprising an analyte sensor and the drug delivery composition of any one of claims 1 to 18, wherein: The analyte sensor is located within the channel of the sharp object, and the drug delivery composition is located within the channel of the sharp object distal to the analyte sensor.

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

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

25. The drug delivery composition according to 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 tissue of a subject.

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

27. The drug delivery composition for use according to claim 26, wherein The analyte sensor is located within the channel of the sharp object, and the drug delivery composition is located within the channel of the sharp object distal to the analyte sensor.

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