Temperature-insensitive membrane materials and analyte sensors containing the same

Abstract

To provide temperature-insensitive membrane materials and analyte sensors containing the same.SOLUTION: Membranes permeable to an analyte may overlay an active sensing region of a sensor to limit the analyte flux and improve the response linearity of the sensor. Temperature variation of the analyte permeability can be problematic in some instances. Polymeric membrane compositions having limited variation in analyte permeability as a function of temperature may comprise: a polymer backbone comprising one or more side chains that comprise a heterocycle; and an amine-free polyether arm appended, via an alkyl spacer or a hydroxy-functionalized alkyl spacer, to the heterocycle of at least a portion of the one or more side chains.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to temperature insensitive membrane materials and analyte sensors containing same. [Background technology]

[0002] Detection of various analytes in an individual's body can be essential for monitoring health conditions. Deviations from normal analyte levels can often be indicative of a number of physiological conditions. For example, glucose levels can be particularly important for detecting and monitoring individuals with diabetes. By monitoring blood glucose levels with sufficient regularity, a diabetic patient may be able to take corrective action (e.g., inject insulin to lower blood glucose levels or eat to raise blood glucose levels) before significant physiological harm occurs. Other analytes commonly subject to physiological dysregulation that may also be desirable to monitor include, but are not limited to, lactate, oxygen, pH, A1c, ketones, drug levels, etc.

[0003] Analyte monitoring of an individual may occur periodically or continuously over a period of time. Periodic analyte monitoring may be performed by taking samples of bodily fluids, such as blood, at set time intervals and analyzing them ex vivo (outside the body). Continuous analyte monitoring may be performed using one or more sensors that remain at least partially implanted within the individual's tissue, such as cutaneously, subcutaneously, or intravenously, so that analysis may be performed in vivo. The implanted sensors may collect analyte data continuously or sporadically, depending on the individual's particular health needs and / or previously measured analyte levels.

[0004] Periodic ex vivo analyte monitoring is sufficient to determine the physiological status of many individuals. However, ex vivo analyte monitoring can be inconvenient or painful for some individuals. Furthermore, if analyte measurements are not taken in a timely manner, there is no way to recover the lost data.

[0005] Continuous analyte monitoring using in vivo implanted sensors may be a more desirable approach for individuals with severe analyte dysregulation and / or rapidly fluctuating analyte levels, but may also be beneficial for other individuals. While continuous analyte monitoring with implanted sensors can be advantageous, there are challenges associated with these types of measurements. Intravenous analyte sensors have the advantage of providing analyte concentrations directly from the blood, but are invasive and can be painful for individuals to wear for extended periods of time. Subcutaneous and cutaneous analyte sensors are often less painful for individuals to wear and can often provide sufficient measurement accuracy.

[0006] While the entire sensor can be implanted (e.g., surgically) within an individual's body, it is often more desirable to implant primarily the working portion of the sensor internally (e.g., through a skin penetration), along with one or more additional sensors, with the additional sensor components remaining external to the individual's body. In certain instances, sensors suitable for measuring analyte levels in vivo can extend from a sensor housing designed to be worn "on the body," such as on the skin, for extended periods of time. Such on-body analyte sensors can be particularly desirable because they are often applied directly by the wearer, rather than relying on a medical professional to perform an invasive sensor implantation procedure.

[0007] The sensor may include a membrane disposed at least in the portion where the sensor is embedded. In one aspect, the membrane may improve the biocompatibility of the sensor in vivo. In another aspect, the membrane may be permeable or semi-permeable to the analyte of interest but limit the overall flow of analyte to the sensing portion of the sensor during operation. Limiting analyte access to the operating sensing portion of the sensor helps to avoid overloading (saturation) of the operating sensing component, thereby improving the performance and accuracy of the sensor. For example, in the case of sensors employing enzyme-based detection, limiting analyte access to the sensor allows the chemical reaction rate of the sensing process to be analyte-limited rather than enzyme-limited. Analyte-limited enzymatic reactions allow for easy calibration of analyte sensors as a function of sensor output. That is, if the enzymatic reaction is analyte-limited, the sensor output may be correlated in some way to the amount of analyte. In many cases, the sensor response may vary linearly as a function of analyte concentration in the biological fluid of interest when the enzymatic reaction is analyte-limited.

[0008] The drawings are included to illustrate certain aspects of the disclosure and should not be construed as exclusive embodiments. The disclosed subject matter is capable of considerable modification, alteration, combination, and equivalents in form and function without departing from the scope of the present disclosure. Summary of the Invention [Problem to be solved by the invention]

[0009] One problem associated with incorporating membranes into analyte sensors is that the flux of analyte through the membrane can vary significantly as a function of temperature. While calibration coefficients or equations can be used to compensate for variability in analyte flux as a function of temperature, doing so can add significant complexity to the use of the sensor, especially if the analyte flux varies nonlinearly with temperature. Furthermore, the thermistors used to apply the calibration equations can be complex to operate, and their size can hinder efforts to miniaturize the sensor. A further challenge is that the calibration temperature measurement location may not necessarily be at the same temperature as the membrane covering the active portion of the sensor. Other components of the sensor may also vary in performance with temperature (e.g., enzyme reaction rate in the case of enzyme-based sensors), which can make isolating and applying the membrane's calibration coefficients or equations quite difficult. The increased complexity of the components and variability in their operating characteristics can increase costs and measurement errors. [Means for solving the problem]

[0010] The present disclosure generally describes analyte sensors suitable for in vivo use, and more particularly, membrane materials that exhibit limited analyte permeability variation as a function of temperature, and analyte sensors incorporating such membrane materials.

[0011] As described above, in vivo analyte sensors can incorporate membrane materials to improve biocompatibility and limit analyte access to the active sensing region of the sensor. Limiting analyte access to the sensing region can avoid sensor saturation and improve sensor performance and accuracy. For example, in the case of enzyme sensors, membrane materials can facilitate an analyte-limited detection process rather than an enzyme-limited detection process. Because the detection process is analyte-limited, easier sensor calibration can be achieved. In some cases, the sensor response can vary linearly as a function of analyte concentration in an analyte-limited detection process.

[0012] One problem associated with many membrane materials is that their analyte permeability can vary to a clinically significant degree as a function of temperature. Variations in analyte permeability as a function of temperature can create problems for sensor calibration, especially if the permeability variation is nonlinear with temperature. While certain membrane materials are known to have limited variability in analyte permeability as a function of temperature, their biocompatibility may leave room for improvement. Additionally, some membrane materials can be difficult to purify after synthesis.

[0013] The present disclosure provides polymer film compositions that, in certain embodiments, can provide a desirable combination of limited analyte permeability variation as a function of temperature and favorable biocompatibility properties. More specifically, the polymer film compositions disclosed herein comprise a polymer backbone having one or more side chains containing a heterocycle (also referred to herein as a heterocyclic polymer) and an amine-free polyether arm attached to at least a portion of the one or more side chains, particularly at least a portion of the heterocycle. The amine-free polyether arm can incorporate one or more polyethylene glycol moieties (blocks) and one or more polypropylene glycol moieties (blocks), which can be attached to the heterocycle via an alkyl spacer or a hydroxy-functionalized alkyl spacer. Other spacers, such as carbonyl, carboxylic acid ester, or carboxamide, may also be suitable in some embodiments. In some embodiments, a single polyethylene glycol moiety can be attached to a single polypropylene glycol moiety in a diblock configuration (e.g., an AB block pattern or a BA block pattern, where A is a polyethylene glycol block and B is a polypropylene glycol block) in the amine-free polyether arm. In other more specific embodiments, the one or more polyethylene glycol moieties and one or more polypropylene glycol moieties can be present in alternating blocks without intervening functional groups (e.g., when A is a polyethylene glycol block and B is a polypropylene glycol block, in some embodiments, in an ABA pattern, or according to other embodiments, in BAB). According to further embodiments of the present disclosure, the amine-free polyether arms can similarly comprise more than three alternating blocks. Both the block pattern and the number of ether units in each block can be varied in the polymer film compositions disclosed herein.In some embodiments, the terminal polyethylene glycol unit in the amine-free polyether arm can be attached to the heterocycle or other side chain of the heterocyclic polymer via an alkyl spacer or a hydroxyl-functionalized alkyl spacer, or alternative spacers such as carbonyl, carboxyl ester, or carboxamide. In other embodiments, the terminal polypropylene glycol unit in the amine-free polyether arm can be attached to the heterocycle or other side chain of the heterocyclic polymer via an alkyl spacer or a hydroxyl-functionalized alkyl spacer, or alternative spacers such as carbonyl, carboxyl ester, or carboxamide.

[0014] The polymer film compositions of the present disclosure can be synthesized by reacting a heterocyclic polymer with a polyether arm precursor having a terminal leaving group, particularly a reactive functional group such as an alkyl halide or a terminal epoxide. More specifically, a primary alkyl halide, such as a primary alkyl bromide, can terminate the amine-free polyether arm precursor, resulting in an alkyl spacer that attaches the amine-free polyether arm to the heterocycle. In contrast, epoxide termination of the amine-free polyether arm precursor results in the amine-free polyether arm being attached to the heterocycle via a hydroxy-functionalized alkyl group, specifically an alkyl group bearing a secondary hydroxyl functionality. The selection of a particular amine-free polyether arm precursor, including the selection of the reactive functional group, can be based on factors such as ease of synthesis and the in vivo properties of the resulting polymer. In a more detailed configuration, a primary alkyl halide or epoxide can be attached to the polyethylene glycol portion of the amine-free polyether arm precursor (i.e., via a terminal ether linkage and an intervening spacer group). In other particular configurations, a primary alkyl halide or epoxide can be attached to the polypropylene glycol portion of an amine-free polyether arm precursor (i.e., via a terminal ether bond and an intervening spacer group).

[0015] Advantageously, the amine-free polyether arm precursors described herein can be synthesized independently before reacting with the heterocyclic polymer. Independent synthesis of the amine-free polyether arm precursors can provide greater side chain compositional uniformity in the resulting polymer film composition compared to that achieved by stepwise growth of arms from a polymer backbone, which can produce different arm lengths. Furthermore, reacting the amine-free polyether arm precursors with the polymer backbone in a single step can provide improved yields, improved synthetic consistency, and increased throughput, making it easier to correlate changes in film properties with structural changes. A further advantage of the polymer film compositions disclosed herein is that they can often be synthesized with greater purity and compositional uniformity than comparable polymer compositions with amine functional groups in the polyether arms.

[0016] A further advantage of the present disclosure is that the ratio of polyethylene oxide to polypropylene oxide within the polymer film compositions of the present invention can be varied much more easily than in similar polymer compositions having amine functional groups in the polyether arms. More specifically, the distribution and ratio of polyethylene oxide to polypropylene oxide can be fixed within the amine-free polyether arm precursors before conjugation to the heterocyclic polymer occurs. Advantageously and surprisingly, this feature can allow the ratio of polyethylene glycol to polypropylene glycol to be tailored to promote a desired biological response in vivo, as discussed further herein.

[0017] At least some of the polymeric film compositions disclosed herein may exhibit low or non-existent cytotoxicity in vivo, as well as other favorable biocompatibility properties. In certain embodiments, the ratio of polyethylene oxide to polypropylene oxide can adjust the resulting biocompatibility properties, such that the polymeric film composition may be characterized as having a cytotoxicity score of 2 or less, as measured by the Minimum Essential Elution Media Test. In some or other specific embodiments, the polymeric film compositions described herein meet the biocompatibility requirements specified in International Organization for Standardization (ISO) 10993-1 when evaluated according to the regulatory-specified test protocol.

[0018] Thus, the polymer film compositions disclosed herein may be particularly advantageous for use in various in vivo analyte sensors, especially when the analyte sensors are intended for long-term wear. However, it should be understood that the polymer film compositions disclosed herein may also be utilized in ex vivo analyte sensors without departing from the scope of the present disclosure. In certain embodiments, the polymer film compositions described herein may be temperature-insensitive to glucose permeability. For example, other analytes, such as lactate, may also permeate the polymer film composition at a temperature-insensitive rate that may differ from the rate of glucose.

[0019] Thus, in some embodiments, the polymer film composition of the present disclosure can comprise a polymer backbone comprising one or more side chains comprising a heterocycle, and amine-free polyether arms attached to at least some of the heterocycles of the one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer. Such amine-free polyether arms are distinguished from crosslinkers (i.e., groups covalently linking two or more polymer backbones) by the characteristic that the amine-free polyether arms are attached to a single polymer backbone.

[0020] Polymers suitable for use in various embodiments of the present disclosure may include a polymer backbone that is branched or unbranched, homopolymeric, or heteropolymeric. Homopolymers can be formed by polymerization of a single type of monomer. Heteropolymers (also called copolymers) contain two or more different types of monomers linked together in a single polymer chain. Copolymers, according to various embodiments, can have a random, alternating, or block distribution of the different monomer units.

[0021] Heterocycles suitable for incorporation into the polymer film compositions of the present disclosure can include any cyclic moiety containing one or more carbon atoms along with any combination of N, P, O, S, or Si atoms, and the cyclic moiety can be aromatic or aliphatic. Suitable functional groups incorporating heteroatoms within an aliphatic or heteroaromatic cyclic moiety include, for example, -O-, -S-, -SS-, -OS-, -NR 1 R 2 , =N-, =NN=, -N=N-NR 1 R 2 , -PR 3 -, -P(O)2-, -P(O)R 3 -, -OP(O)2-, -SO-, -S(O)-, -S(O)2-, etc., where R 1 ~R 3 can independently be hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl. Where possible, any of R1-R3 can be linear or branched. Substituted variations of R1-R3 can include any of the above groups in which a carbon or hydrogen atom is replaced with a heteroatom such as F, Cl, Br, I, N, P, O, S, or Si. In exemplary, but non-limiting, embodiments, suitable substitutions can include, for example, halide groups, alcohol groups, ketone groups, ether groups, thioether groups, disulfide groups, and the like.

[0022] In more detailed embodiments, the polymer backbone can include heterocyclic or heteroaromatic nitrogen moieties in one or more side chains. In even more detailed embodiments, the polymer backbone can include heteroaromatic nitrogen moieties in one or more side chains. Suitable heteroaromatic nitrogen moieties can include, for example, acridine, carbazole, carboline, cinnoline, imidazole, indazole, indole, indoline, indolizine, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, triazole, derivatives thereof, and the like.

[0023] According to some embodiments, one or more comonomers may be present in combination with the monomer unit having a heteroaromatic nitrogen moiety. Suitable comonomers for incorporation into the polymer film composition of the present disclosure include, for example, styrene compounds that may have substitutions on the aromatic ring. Suitable substituted styrene compounds include, for example, alkyl-substituted styrene, halogen-substituted styrene, hydroxyl-substituted styrene, or any combination thereof.

[0024] In more detailed embodiments, the polymer film composition of the present disclosure can include polyvinylpyridine or polyvinylimidazole, and any copolymers thereof. In particular embodiments, the polymer film composition of the present disclosure can include polyvinylpyridine, particularly a copolymer of vinylpyridine (especially 4-vinylpyridine) and styrene, or polyvinylimidazole, particularly a copolymer of vinylimidazole (especially 2-vinylimidazole) and styrene. In some embodiments, substituted styrenes can be utilized.

[0025] According to certain embodiments, suitable copolymers of 4-vinylpyridine and styrene may comprise repeating units of Formula 1, where the variables a and b are both positive integers and Q is any functional group.

[0026] [ka]

[0027] In some embodiments, the variables a and b can independently range from about 2 to about 950, or from about 5 to about 900, or from about 10 to about 850, or from about 15 to about 800, or from about 20 to about 750, or from about 25 to about 700, or from about 30 to about 650, or from about 35 to about 600, or from about 40 to about 550, or from about 50 to about 500, or from 1 to about 10, or from about 1 to about 1000. In some embodiments, a can be greater than b. In other embodiments, a can be less than b. Depending on the desired film properties, the ratio of a to b may be from about 1:1 to about 1:100, or from about 1:1 to about 1:95, or from 1:1 to about 1:80, or from 1:1 to about 1:75, or from about 1:1 to about 1:50, or from about 1:1 to about 1:25, or from about 1:1 to about 1:10, or from about 1:1 to about 1:5, or from about 1:1 to about 1:3, or from about 1:1 to about 1 :2, or from about 1:1 to about 100:1, or from about 1:1 to about 95:1, or from about 1:1 to about 80:1, or from about 1:1 to about 75:1, or from about 1:1 to about 50:1, or from about 1:1 to about 25:1, or from about 1:1 to about 10:1, or from about 1:1 to about 5:1, or from about 1:1 to about 3:1, or from about 1:1 to about 2:1.

[0028] In some or other embodiments, suitable copolymers of 4-vinylpyridine and styrene may have a styrene content ranging from about 0.01% to about 50% mole percent, or from about 0.05% to about 45% mole percent, or from about 0.1% to about 40% mole percent, or from about 0.5% to about 35% mole percent, or from about 1% to about 30% mole percent, or from about 2% to about 25% mole percent, or from about 5% to about 20% mole percent. Substituted styrenes can also be used in similar amounts.

[0029] According to some or other various embodiments, suitable copolymers of 4-vinylpyridine and styrene may have a molecular weight of 5 kDa or more, or about 10 kDa or more, or about 15 kDa or more, or about 20 kDa or more, or about 25 kDa or more, or about 30 kDa or more, or about 40 kDa or more, or about 50 kDa or more, or about 75 kDa or more, or about 90 kDa or more, or about 100 kDa or more. In more specific embodiments, suitable copolymers of 4-vinylpyridine and styrene may have a molecular weight ranging from about 5 kDa to about 150 kDa, or from about 10 kDa to about 125 kDa, or from about 15 kDa to about 100 kDa, or from about 20 kDa to about 80 kDa, or from about 25 kDa to about 75 kDa, or from about 30 kDa to about 60 kDa. Other polymers suitable for use in the polymeric film compositions of the present disclosure may have molecular weight values ​​within similar ranges.

[0030] In the polymer film composition of the present disclosure, the amine-free polyether arms can be attached to at least some of the heterocycles in the side chains of the heterocyclic polymer. For example, in the case of polyvinylpyridine, the amine-free polyether arms can be covalently attached to the pyridine ring, particularly via the pyridine nitrogen atom.The proportion of side chains in the polymer film composition to which the amine-free polyether arms are attached is greater than or equal to about 0.1% of the available heterocycles in the heterocyclic polymer, or greater than or equal to about 0.2% of the available heterocycles in the heterocyclic polymer, or greater than or equal to about 0.3% of the available heterocycles in the heterocyclic polymer, or greater than or equal to about 0.4% of the available heterocycles in the heterocyclic polymer, or greater than or equal to about 0.5% of the available heterocycles in the heterocyclic polymer, or greater than or equal to about 0.6% of the available heterocycles in the heterocyclic polymer, or greater than or equal to about 0.7% of the available heterocycles in the heterocyclic polymer, or greater than or equal to about 0.8% of the available heterocycles in the heterocyclic polymer. or more than about 0.8% of the available heterocycles in the heterocyclic polymer, or more than about 0.9% of the available heterocycles in the heterocyclic polymer, or more than about 1.0% of the available heterocycles in the heterocyclic polymer, or more than 1.2% of the available heterocycles in the heterocyclic polymer, or more than about 1.4% of the available heterocycles in the heterocyclic polymer, or more than about 1.6% of the available heterocycles in the heterocyclic polymer, or more than about 1.8% of the available heterocycles in the heterocyclic polymer, or more than about 2.0% of the available heterocycles in the heterocyclic polymer, or more than about 2 ... or more than about 2.4% of the available heterocycles in the heterocyclic polymer, or more than about 2.6% of the available heterocycles in the heterocyclic polymer, or more than about 2.8% of the available heterocycles in the heterocyclic polymer, or more than about 3.0% of the available heterocycles in the heterocyclic polymer, or more than about 3.5% of the available heterocycles in the heterocyclic polymer, or more than about 4.0% of the available heterocycles in the heterocyclic polymer, or more than about 4.5% of the available heterocycles in the heterocyclic polymer, or more than about 5.0% of the available heterocycles in the heterocyclic polymer, or more than about 5.5% of the available heterocycles in the heterocyclic polymer or about 6.0% or more of the heterocycles available in the heterocyclic polymer, or about 6.5% or more of the heterocycles available in the heterocyclic polymer, or about 7.0% or more of the heterocycles available in the heterocyclic polymer, or about 7.5% or more of the heterocycles available in the heterocyclic polymer, or about 8.0% or more of the heterocycles available in the heterocyclic polymer, or about 8.5% or more of the heterocycles available in the heterocyclic polymer, or about 9.0% or more of the heterocycles available in the heterocyclic polymer, or about 9.5% or more of the heterocycles available in the heterocyclic polymer, or about 10% or more of the heterocycles available in the heterocyclic polymer.In more specific embodiments, amine-free polyether arms can be added to about 0.1% to about 5% of the heterocycles available on the heterocyclic polymer, or about 0.5% to about 4.5% of the heterocycles available on the heterocyclic polymer, or about 1.0% to about 4.0% of the heterocycles available on the heterocyclic polymer, or about 1.5% to about 3.0% of the heterocycles available on the heterocyclic polymer, or about 1.5% to about 2.5% of the heterocycles available on the heterocyclic polymer.

[0031] In an alternative embodiment, the amine-free polyether arms may be attached to non-heterocyclic side chains of the heterocyclic polymer, such as via a covalent bond to an optionally substituted phenyl group.

[0032] In some embodiments, at least a portion of the available heterocycles in the heterocyclic polymer may also have a crosslinker attached thereto. That is, in some embodiments, the polymer film composition of the present disclosure may further include a crosslinker attached to at least a portion of one or more side chains, juxtaposing a first polymer backbone to a second polymer backbone. The crosslinker may be attached to the heterocyclic polymer in addition to the amine-free polyether arms. In some embodiments, the crosslinker may itself be a polyether, such as polyethylene glycol or a copolymer of ethylene glycol and propylene glycol. Such crosslinkers are not limited with respect to the number of polyethylene glycol units that may be present. In some more detailed embodiments, the amount of heterocycles functionalized with the crosslinker may be greater than the amount of heterocycles functionalized with the amine-free polyether arms. In other embodiments, the amount of heterocycles functionalized with the crosslinker may be less than the amount of heterocycles functionalized with the amine-free polyether arms. In an exemplary embodiment, a bis-epoxide polyethylene glycol compound may be used to form the polymer film composition with a crosslinker.

[0033] In more specific embodiments, the percentage of side chains to which crosslinkers can be attached is about 0.1% or more of the available heterocycles in the heterocyclic polymer, or about 0.2% or more of the available heterocycles in the heterocyclic polymer, or 0.3% or more of the available heterocycles in the heterocyclic polymer, or about 0.4% or more of the available heterocycles in the heterocyclic polymer, or about 0.5% or more of the available heterocycles in the heterocyclic polymer, or about 0.6% or more of the available heterocycles in the heterocyclic polymer, or about 0.7% or more of the available heterocycles in the heterocyclic polymer, or about 0.8% or more of the available heterocycles in the heterocyclic polymer. or greater than about 0.8%, or greater than about 0.9% of the heterocycles available in the heterocyclic polymer, or greater than about 1.0% of the heterocycles available in the heterocyclic polymer, or greater than about 1.2% of the heterocycles available in the heterocyclic polymer, or greater than about 1.4% of the heterocycles available in the heterocyclic polymer, or greater than about 1.6% of the heterocycles available in the heterocyclic polymer, or greater than about 1.8% of the heterocycles available in the heterocyclic polymer, or greater than about 2.0% of the heterocycles available in the heterocyclic polymer, or greater than about 2.2% of the heterocycles available in the heterocyclic polymer, or greater than about 2.0% of the heterocycles available in the heterocyclic polymer, or greater than about 2.2% of the heterocycles available in the heterocyclic polymer or more than about 2.4% of the available heterocycles in the heterocyclic polymer, or more than about 2.6% of the heterocycles available in the heterocyclic polymer, or more than about 2.8% of the heterocycles available in the heterocyclic polymer, or more than about 3.0% of the heterocycles available in the heterocyclic polymer, or more than about 3.5% of the heterocycles available in the heterocyclic polymer, or more than about 4.0% of the heterocycles available in the heterocyclic polymer, or more than about 4.5% of the heterocycles available in the heterocyclic polymer, or more than 5.0% of the heterocycles available in the heterocyclic polymer, or more than about 5.5% of the heterocycles available in the heterocyclic polymer, or more than about 5.0% of the heterocycles available in the heterocyclic polymer, or more than about 5.5% of the heterocycles available in the heterocyclic polymer The heterocyclic polymer may have at least about 6.0% of the heterocycles available in the heterocyclic polymer, or at least about 6.5% of the heterocycles available in the heterocyclic polymer, or at least about 7.0% of the heterocycles available in the heterocyclic polymer, or at least about 7.5% of the heterocycles available in the heterocyclic polymer, or at least about 8.0% of the heterocycles available in the heterocyclic polymer, or at least about 8.5% of the heterocycles available in the heterocyclic polymer, or at least about 9.0% of the heterocycles available in the heterocyclic polymer, or at least about 9.5% of the heterocycles available in the heterocyclic polymer, or at least about 10% of the heterocycles available in the heterocyclic polymer.In more specific embodiments, the crosslinker may be loaded onto between about 1% and about 20% of the available heterocycles in the heterocyclic polymer, or about 2% and about 10% of the available heterocycles in the heterocyclic polymer, or about 3% and about 8% of the available heterocycles in the heterocyclic polymer, or about 4% and about 9% of the available heterocycles in the heterocyclic polymer, or about 5% and about 12% of the available heterocycles in the heterocyclic polymer.

[0034] Alternatively, in some embodiments, at least a portion of the non-heterocyclic side chains of the heterocyclic polymer, such as optionally substituted phenyl groups, may have a crosslinker attached thereto. According to various embodiments, the amine-free polyether arms can be attached to the polymer backbone of the polymer film compositions disclosed herein through heteroatoms in at least some of the heterocyclic rings in one or more side chains of the heterocyclic polymer. Alternative embodiments can include those in which the amine-free polyether arms are attached to the polymer backbone through carbon atoms in at least some of the heterocyclic rings in one or more side chains and / or through carbon atoms of an optionally substituted phenyl group in the polymer backbone. In more specific embodiments, the amine-free polyether arms can be attached to the polymer backbone through heteroaromatic or heteroaromatic nitrogen atoms in one or more side chains. For example, if the polymer backbone is polyvinylpyridine or a copolymer thereof, the amine-free polyether arms can be attached to the side chains through pyridine nitrogen atoms. Functionalization with the amine-free polyether arms or crosslinkers results in the pyridine nitrogen atoms being quaternized.

[0035] Thus, in more detailed embodiments, polymeric film compositions of the present disclosure having amine-free polyether arms attached to pyridine nitrogen atoms can have repeat units defined by the following formulas 2 and 3, where the variables a, b, and Q are defined above, and c is a positive integer less than or equal to a.

[0036] [ka]

[0037] Z is an amine-free polyether arm, a crosslinker, or any combination thereof. When both the amine-free polyether arm and the crosslinker are present, the polymeric film composition can have a structure defined by one or more of Formulas 4-7, where the variables a, b, and Q are as defined above.

[0038] [ka]

[0039] c1 and c2 are positive integers whose sum is less than or equal to a, d is as defined in Formula 1, Z1 is an amine-free polyether arm, and Z2 is The crosslinker is such that d=a-c1-c2 (Equation 1). Thus, the heteroaromatic (pyridine) rings of the heterocyclic polymer may be functionalized with Z1 and Z2 in any combination or pattern in various polymer film composition embodiments of the present disclosure. That is, the repeat units defined by Formulas 2-7 may be present in any combination with each other in defining heterocyclic polymers suitable for incorporation into the polymer film compositions of the present disclosure.

[0040] In other particular embodiments, polymeric film compositions having amine-free polyether arms attached to pyridine moieties without a pyridine nitrogen atom can be defined by the following formulas 8 and 9, where a, b, c, Q, and Z are defined above.

[0041] [ka]

[0042] Optionally, any of the pyridine nitrogen atoms in Formulas 8 and 9 can be quaternized with an alkyl group (e.g., via reaction with an alkyl halide) when an amine-free polyether arm is attached to a carbon atom of the pyridine. Any unsubstituted carbon atom in the pyridine group can be attached to an amine-free polyether arm and / or a crosslinker according to embodiments described herein. When both an amine-free polyether arm and a crosslinker are present, the amine-free polyether arm and the crosslinker can be on the same pyridine group or on different pyridine groups.

[0043] In various embodiments, the amine-free polyether arm can comprise at least one polyethylene oxide block and at least one polypropylene oxide block. According to some embodiments, the amine-free polyether arm can comprise a diblock arrangement of polyethylene oxide and polypropylene oxide. That is, in some embodiments, the amine-free polyether arm can comprise, in order, an alkyl spacer or a hydroxy-functionalized alkyl spacer, a polyethylene oxide block, and a polypropylene oxide block; in other embodiments, the amine-free polyether arm can comprise, in order, an alkyl spacer or a hydroxy-functionalized alkyl spacer, a polypropylene oxide block, and a polyethylene oxide block. In other more detailed embodiments, the amine-free polyether arm can consist, in order, of an alkyl spacer or a hydroxy-functionalized alkyl spacer, a first polyethylene oxide block, a polypropylene oxide block, and a second polyethylene oxide block (i.e., an ABA repeating pattern). In yet another, more detailed embodiment, the amine-free polyether arm may be composed, in order, of an alkyl spacer or a hydroxy-functionalized alkyl spacer, a first polypropylene oxide block, a polyethylene oxide block, and a second polypropylene oxide block (i.e., a BAB repeat pattern). The alkyl spacer or the hydroxy-functionalized alkyl spacer, according to various embodiments, can be attached to a heterocyclic or heteroaromatic nitrogen atom in the side chain of the polymer backbone. In some cases, alternative attachment to any carbon atom of the heterocyclic side chain or any carbon atom of the side chain phenyl group is also possible. The alkyl spacer or the hydroxy-functionalized alkyl spacer can also be attached to the first polyethylene oxide block of the amine-free polyether arm, according to various embodiments, such as via a terminal ether bond. According to some embodiments, the second polyethylene oxide block can be terminated with a methoxy group.Alternatively, according to some embodiments, the alkyl spacer of the hydroxy-functionalized alkyl spacer can also be attached to the first polypropylene oxide block of the amine-free polyether arm, and the second polypropylene oxide block can be terminated by a methoxy group.

[0044] Thus, in various embodiments of the present disclosure, the amine-free polyether arms may have a structure defined by Formula 10 or 11 below:

[0045] [ka]

[0046] Here, PE represents a polyethylene oxide block, PP represents a polypropylene oxide block, and L is a spacer group. Suitable spacer groups may include, but are not limited to, alkyl, hydroxy-functionalized alkyl, carbonyl, carboxylic acid ester, carboxamide, and the like. The variables q, r, s, and t are positive integers that define the number of monomer units in each block and the number of times the block is repeated. However, in the diblock configuration of polyethylene oxide and polypropylene oxide applicable to Formulas 10 and 11, the variable t may be 0. In Formula 10, when t≠0, the terminal polyethylene oxide monomer unit may be substituted with an alkoxy group, such as a methoxy group. Similarly, in Formula 11, where t≠0, the terminal polypropylene oxide monomer unit may be substituted with an alkoxy group, such as a methoxy group. The diblock configurations (t=0) related to Formulas 10 and 11 may similarly have alkoxy group terminations. According to some embodiments, the variable q is an integer ranging from about 2 to about 50 or from about 6 to about 20, the variable r is an integer ranging from about 2 to about 60 or from about 10 to about 40, and the variable t is an integer ranging from about 2 to about 50 or from about 10 to about 30. According to some or other various embodiments, the variable s is an integer ranging between 1 and about 20, or between 1 and about 10. In some embodiments, the variable s is equal to 1. Diblock configurations of polyethylene oxide and polypropylene oxide can include variables q and r within the same ranges as above, but with variable s equal to 1 and variable t equal to 0.

[0047] In more detailed embodiments of the present disclosure, the amine-free polyether arms may have a structure defined by formula 12, where the variable w is 0 or 1:

[0048] [ka]

[0049] The variable x is an integer ranging from about 4 to about 24, or from about 6 to about 20; the variable y is an integer ranging from about 8 to about 60, or from about 10 to about 40; and the variable z is an integer ranging from about 6 to about 36, or from about 10 to about 30. Alternatively, the variable z can be 0 in a diblock configuration, with the other variables remaining in the same ranges. In more specific embodiments, the variable x can be in the range from about 8 to about 16, or from about 9 to about 12, and the variable y can be in the range from about 10 to about 32, or from about 16 to about 30, or from about 12 to about 20. The variable z can be in the range from about 10 to about 20, or from about 14 to about 18. In still other more specific embodiments, x can be 10, y can be 20, and z can be 14. Alternatively, x can be 12, y can be 16, and z can be 16. Alternatively, x can be 14, y can be 12, and z can be 18. In some embodiments, x may be less than z, such that the second polyethylene oxide block is longer (larger) than the first polyethylene oxide block.

[0050] In some embodiments, the ratio of (x+z):y in Formula 12 can be at least about 1.4:1, or at least about 1.7:1, or at least about 2:1, or at least about 2.5:1, or at least about 3:1, or at least about 3.5:1. In more specific embodiments, the ratio of (x+z):y in Formula 12 can range from about 1.4:1 to about 5:1, or from about 1.7:1 to about 3.2:1, or from about 2.2:1 to about 3.0:1, or from about 2.6:1 to about 2.9:1, or from about 3:1 to about 5:1.

[0051] In some embodiments of the present disclosure, the amine-free polyether arms can have a structure defined by Formula 13, where the variable w is 0 or 1:

[0052] [ka]

[0053] The variable x is an integer ranging from about 4 to about 24, or from about 6 to about 20; the variable y is an integer ranging from about 8 to about 60, or from about 10 to about 40; and the variable z is an integer ranging from about 6 to about 36, or from about 10 to about 30. Alternatively, the variable z can be 0 in a diblock configuration, with the other variables in the same ranges. In more specific embodiments, the variable x can range from about 6 to about 16, or from about 9 to about 12, and the variable y can range from about 10 to about 40, or from about 16 to about 30, or from about 14 to about 32. The variable z can range from about 8 to about 20, or from about 12 to about 16.

[0054] The amine-free polyether arms described herein can be attached to the heterocycles of the side chains of the heterocyclic polymer through reactive functional groups of the amine-free polyether arm precursor. Suitable reactive functional groups can include, for example, halogens or epoxides, either of which can react via nucleophilic attack from the side chains of the heterocyclic polymer. Halogen-functionalized amine-free polyether arm precursors result in amine-free polyether arms where n is 0 (i.e., the spacer is an alkyl group), while epoxide-functionalized amine-free polyether arm precursors result in amine-free polyether arms where n is 1 (i.e., the spacer is a propyl group containing a secondary alcohol). In more specific embodiments, the alkyl spacer resulting from the halogen-functionalized amine-free polyether arm precursor can be linear or branched and include an alkyl group containing 2 to 20 carbon atoms. In more specific embodiments, halides that may be suitably included in the halogen-functionalized amine-free polyether arm precursor include chloride or bromide, with bromide being selected in even more specific embodiments.

[0055] Formulas 14 and 15 show the structures of exemplary amine-free polyether arm precursors that can be suitably reacted with heterocyclic polymers to form certain polymeric film compositions disclosed herein, where the variables x, y, and z are defined as above.

[0056] [ka]

[0057] In Formula 14, the variable A1 represents an alkyl group having 2 to about 20 carbon atoms, such as 2 to 4 carbon atoms, or 2 to about 6 carbon atoms, or 2 to about 8 carbon atoms, and X is a halide, such as chloride or bromide. The alkyl group of A1 can be branched or straight-chain and optionally includes heteroatom substitution. The halide X can be a primary alkyl halide, according to various embodiments. In Formula 15, the variable A2 represents an alkyl group having 1 to about 10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. In some embodiments, the alkyl group of A2 can be straight-chain; in other embodiments, the alkyl group A2 can include branching.

[0058] In more detailed embodiments, suitable amine-free polyether arm precursors for forming the polymeric film compositions disclosed herein can include those shown in Formulas 16 and 17, where the variables are defined as above.

[0059] [ka]

[0060] In some embodiments, sulfonate-containing arms can be attached to at least a portion of one or more side chains of the heterocyclic polymers disclosed herein. The sulfonate-containing arms can be present in any suitable ratio in combination with any of the amine-free polyether arms disclosed herein. In some embodiments, the polymeric film compositions disclosed herein can contain more amine-free polyether arms than sulfonate-containing arms.

[0061] According to more detailed embodiments, the sulfonate-containing arms can be attached to the heterocycles of the heterocyclic polymers via alkyl groups. According to various embodiments, the alkyl groups can contain from 1 to about 6 carbon atoms, or from 2 to about 4 carbon atoms. Suitable reagents for introducing sulfonate-containing arms into the heterocyclic polymers disclosed herein can include halosulfonic acid compounds, such as chloromethanesulfonic acid, bromoethanesulfonic acid, or cyclic sulfonates (sultones).

[0062] In some embodiments, amine-free polyether arms containing a single type of repeating ether unit may be attached to at least a portion of one or more side chains of the heterocyclic polymers disclosed herein. Such amine-free polyether arms may be present in combination with sulfonate-containing arms, and / or the amine-free polyether arms may have two or more different types of ether unit blocks, such as those set forth in Formulas 10-13.

[0063] According to more detailed embodiments, the amine-free polyether arm containing a single type of repeating ether unit can be a polyethylene oxide arm or a polypropylene oxide arm. In more specific embodiments, the amine-free polyether arm can be an amine-free polyethylene oxide arm attached to at least a portion of one or more side chain heterocycles via an alkyl spacer or a hydroxy-functionalized alkyl spacer. Between about 8 and about 25, between about 10 and about 22, or between about 12 and about 20 repeating ether units can be present in an amine-free polyether arm consisting of a single type of repeating ether unit. The repeating polyethylene oxide or polypropylene oxide ether units can be attached to one or more side chains of the heterocyclic polymer via an alkyl group or a hydroxyl-functionalized alkyl group. According to various embodiments, the alkyl group can contain 1 to about 6 carbon atoms or 2 to about 4 carbon atoms. The hydroxy-functionalized alkyl group can contain three carbon atoms with a hydroxyl group on the central carbon atom. An alkoxy group, particularly a methoxy group, can terminate the amine-free polyether arm opposite the point of attachment to the heterocyclic polymer. Such amine-free polyether arms can be introduced into heterocyclic polymers by reacting either alkyl halide or epoxide terminated polyethers with the heterocyclic polymer.

[0064] In some embodiments, the polymer film composition of the present disclosure can be crosslinked, as briefly referenced above. Crosslinked polymers suitable for incorporation into the polymer film composition can include a crosslinker that connects two or more polymer backbones together (intermolecular crosslinks) or connects different portions of the same polymer backbone together (intramolecular crosslinks). A "crosslinker" containing two or more reactive functional groups can facilitate such crosslinking. When crosslinking occurs, a portion of the crosslinker may remain as a crosslinker, linking polymer chains to each other intermolecularly or intramolecularly.

[0065] In some embodiments, suitable cross-linking agents include polyetherimines and glycidyl ethers, such as diglycidyl ethers. This combination of reagents forms cross-links containing amine groups. In other embodiments, suitable cross-linking agents may include polyethers and glycidyl ethers, such as diglycidyl ethers, which result in cross-links lacking amine groups. In more specific embodiments, suitable cross-linking agents for forming amine-free cross-links may include polyethylene oxide / polypropylene oxide copolymers and glycidyl ethers, such as diglycidyl ethers, or polyethylene oxide and glycidyl ethers.

[0066] In some or other embodiments, a suitable crosslinker may include a polyethylene oxide block having a terminal propylene oxide unit at each end of the polyethylene oxide block. Such a crosslinker may have the structure shown in Formula 18.

[0067] [ka]

[0068] wherein the variable n is a positive integer ranging from about 10 to about 500, or from about 10 to about 100, or from about 10 to about 50, or from about 12 to about 36, or from about 12 to about 30, or from about 12 to about 28, or from about 12 to about 26, or from about 12 to about 24, or from about 12 to about 22, or from about 12 to about 20, or from about 14 to about 28, or from about 14 to about 24, or from about 16 to about 30, or from about 16 to about 24. As will be understood by those skilled in the art, the crosslinker of formula 18 reacts to form crosslinks in which polyethylene oxide blocks are attached to the polymer backbone at each end through hydroxy-functionalized alkyl groups. Specifically, the crosslinker of formula 18, upon nucleophilic ring-opening of the epoxide ring in each terminal propylene oxide unit, produces a crosslinker of formula 19, where n is defined above.

[0069] [ka]

[0070] Thus, in more detailed embodiments of the present disclosure, a suitable crosslinker may comprise at least one polyethylene oxide block attached to opposite ends of a first heterocycle of a first polymer backbone and a second heterocycle of a second polymer backbone, each via a hydroxyl-functionalized alkyl group. In such embodiments, the method of crosslinking is intermolecular. In some or other embodiments of the present disclosure, such crosslinkers may be attached at opposite ends to a first and second heterocycle within the same polymer backbone, each via a hydroxyl-functionalized alkyl group, in which case the method of crosslinking is intramolecular.

[0071] Crosslinkers with additional epoxide groups can also be used in some embodiments, such as the exemplary tris-epoxide compound shown in Formula 20. Such crosslinkers can result in the formation of crosslinks between three or more polymer backbones.

[0072] [ka]

[0073] Optionally, such cross-linkers can be further reacted with polyethylene glycol, polypropylene glycol, or ethylene glycol / propylene glycol copolymers to form the desired cross-links.

[0074] Advantageously, the polymer film composition of the present disclosure, according to various embodiments, can form a temperature-insensitive membrane. As used herein, the term "temperature-insensitive" refers to the state of a parameter of interest that changes in a clinically or statistically insignificant manner as a function of temperature over a given range. In more detailed embodiments, the temperature-insensitive membrane of the present disclosure can be temperature-insensitive with respect to analyte permeability, particularly glucose. Other analytes may also exhibit temperature-independent membrane permeability, with permeation rates that may be the same as or different from that of glucose. Thus, limited variations in analyte permeability may result in little or no change in sensor response when analyzing a constant concentration of the analyte over a given temperature range where the polymer film composition is temperature-insensitive.

[0075] In more specific embodiments, the polymeric film compositions of the present disclosure can be temperature insensitive to analyte permeability (e.g., glucose) over a temperature range of about 10° C. to about 70° C., or about 15° C. to about 65° C., or about 20° C. to about 60° C., or about 25° C. to about 50° C., or about 15° C. to about 45° C., or about 15° C. to about 40° C., or about 20° C. to about 45° C., or about 25° C. to about 40° C. In some or other more specific embodiments, the variability in analyte permeability (e.g., glucose) of the polymeric film compositions can be about 10% or less over the temperature range, or about 5% or less over the temperature range, or about 2% or less over the temperature range, or about 1% or less over the temperature range, or about 0.5% or less over the temperature range, or about 0.1% or less over the temperature range, or about 0.05% or less over the temperature range, or about 0.01% or less over the temperature range. Within a subrange of the wider temperature range (e.g., from about 15° C. to about 45° C.), the variation in analyte permeability of the polymeric film composition can be about 2% or less, or about 1% or less, over a given temperature increment of 5° C. Determining the effect of polymeric film composition on analyte permeability can be confirmed by measuring the difference in sensor response over a particular temperature range at a constant concentration of analyte (see Figure 4 herein).

[0076] The polymeric film compositions described herein can be further characterized with respect to their biocompatibility properties. In various embodiments, the polymeric film compositions can be characterized as having a cytotoxicity score of 2, a cytotoxicity score of 1, or a cytotoxicity score of 0. Such cytotoxicity scores can exist in combination with other properties, such as lack of hemolysis, mutagenicity, irritation, and similar properties. In some embodiments, the polymeric film compositions of the present disclosure meet or exceed the ISO 10993-1 standard. The ISO 10993-1 standard for tissue implant devices includes a clinical lack of cytotoxicity, sensitization, irritation or intracutaneous reactivity, acute systemic toxicity, pyrogenicity, subacute or subchronic toxicity, genotoxicity, and implantation problems.

[0077] According to various embodiments, the polymer film compositions disclosed above can be present in an analyte sensor. Thus, the analyte sensor of the present disclosure can include a sensing region (i.e., the working portion of the sensor) and a polymer film composition covering the sensing region. The polymer film composition can include a polymer backbone including one or more side chains including a heterocycle and amine-free polyether arms attached to at least a portion of the heterocycles of the one or more side chains via an alkyl spacer or a hydroxyl-functionalized alkyl spacer. As discussed further herein, any polymer film composition can be utilized in combination with an analyte sensor.

[0078] In some embodiments, the sensing region of an analyte sensor of the present disclosure can include an enzyme. The enzyme can catalyze a reaction that consumes the analyte of interest or produce a product detectable by the analyte sensor. According to some embodiments, the enzyme can be covalently attached to a polymer that forms at least a portion of the sensing region. The selection of a particular enzyme can be determined by the analyte of interest to be detected. If the analyte of interest is glucose, glucose oxidase or glucose dehydrogenase (e.g., pyrroloquinoline quinone (PQQ)-dependent glucose dehydrogenase, flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenase, or nicotinamide adenine dinucleotide (NAD)-dependent glucose dehydrogenase) can be used. If the analyte of interest is lactate, lactate oxidase or lactate dehydrogenase can be used. Laccase can be used if the analyte of interest is oxygen or if oxygen is produced or consumed in response to the analyte reaction. As will be understood by one of ordinary skill in the art and with the benefit of this disclosure, other enzymes can similarly be used to detect other analytes of interest. Any of the substrates acted upon by the above enzymes or other enzymes may be suitable analytes for analysis using the analyte sensors disclosed herein.

[0079] Further details of exemplary analyte sensors that can be used in conjunction with the polymeric film compositions of the present disclosure are described in more detail below, however, it should be understood that analyte sensors having different designs and components other than those explicitly disclosed herein may also be suitably used. [Brief explanation of the drawings]

[0080] [Figure 1] FIG. 1 illustrates an exemplary analyte monitoring system that can incorporate an analyte sensor of the present disclosure. [Figure 2] FIG. 1 is a diagram of an exemplary two-electrode sensor configuration compatible with the disclosure herein. [Figure 3A] FIG. 1 is a diagram of an exemplary three-electrode sensor configuration compatible with the present disclosure. [Figure 3B] FIG. 10 is a diagram of another configuration of an exemplary three-electrode sensor compatible with the disclosure herein. [Figure 4] Graph showing an exemplary plot of sensor response over a temperature range of 17° C. to 42° C. at a fixed glucose concentration (sensing area overcoated with a polymer film composition described herein). [Figure 5] 1 is an exemplary bar graph showing temperature change over 5° C. increments for a sensor operating over a temperature range of 17° C. to 42° C. at a fixed glucose concentration (the sensing area is overcoated with a polymeric film composition described herein). [Figure 6] Graph showing an exemplary plot of sensor response versus glucose concentration at constant temperature (sensing area is overcoated with a polymer film composition described herein). DETAILED DESCRIPTION OF THE INVENTION

[0081] FIG. 1 shows a diagram of an exemplary analyte monitoring system that can incorporate analyte sensors of the present disclosure. As shown, analyte monitoring system 100 includes a sensor control device 102 and a reader device 120 configured to communicate with each other over a local communication path or link, which may be wired or wireless, unidirectional or bidirectional, and encrypted or unencrypted. Reader device 120 may also communicate with remote terminal 170 and / or trusted computer system 180 over communication paths / links 141 and / or 142, respectively, which may be wired or wireless, unidirectional or bidirectional, and encrypted or unencrypted. Any suitable electronic communication protocol may be used for each of the local communication paths or links. Reader device 120 may include a display 122 and optional input components 121.

[0082] Sensor control device 102 includes a sensor housing 103, which may house circuitry and a power source for operating sensor 104. Sensor 104 protrudes from sensor housing 103 and extends through adhesive layer 105. Suitable adhesives for adhesive layer 105 will be known to those skilled in the art.

[0083] The sensor 104 is adapted to be at least partially inserted into a tissue of interest, such as the dermis layer of the skin. The sensor 104 may include a sensor tail of sufficient length to insert to a desired depth within a given tissue. The sensor tail, according to one or more embodiments, may include a sensing region operative for sensing and may include an enzyme. The sensing region includes a polymer film composition of the present disclosure, according to various embodiments. According to one or more embodiments, one or more analyte levels can be determined using the sensor 104 and communicated to a reader device 120. Analytes can be monitored in any biological fluid, such as dermal fluid, plasma, blood, lymph, etc. Analytes that may be monitored are not particularly limited. In certain embodiments, the analyte can be glucose. Other analytes of interest in human physiology may include, for example, lactate, oxygen, pH, A1c, ketones, drug levels, etc. Any of these analytes may exhibit temperature-insensitive permeability through the polymer film compositions disclosed herein. Both single analytes and any combination of the aforementioned analytes can be assayed.

[0084] The introducer may be temporarily present to facilitate the introduction of the sensor 104 into the tissue. In an exemplary embodiment, the introducer may include a needle 190. It should be appreciated that in alternative embodiments, other types of introducers, such as a sheath or blade, may be present. More particularly, the needle or similar introducer may be temporarily present near the sensor 104 prior to insertion and then removed. While present, the needle or other introducer may facilitate the insertion of the sensor 104 into the tissue by opening an access path for the sensor 104 to follow. For example, according to one or more embodiments, the needle may facilitate penetration of the epidermis as an access path to the dermis, allowing implantation of the sensor 104 to occur. After opening the access path, the needle or other introducer may be withdrawn to avoid posing a sharps hazard. In an exemplary embodiment, the needle may be solid or hollow, beveled or non-beveled, and / or circular or non-circular in cross-section. In more particular embodiments, the needle may be comparable in cross-sectional diameter and / or tip design to an acupuncture needle, which may have a cross-sectional diameter of approximately 250 microns. However, it should be recognized that a suitable needle may have a larger or smaller cross-sectional diameter as needed for a particular application. In alternative embodiments, a needle 109 or similar introducer may be absent, provided that the sensor 104 is sufficiently robust to penetrate tissue and establish communication with the subject's bodily fluids.

[0085] In some embodiments, the tip of the needle may be angled on the end of the sensor 104 so that the needle penetrates the tissue first, opening an access path for the sensor 104. In other exemplary embodiments, the sensor 104 may reside within a lumen or channel of the needle 109, which similarly opens an access path for the sensor 104. In either case, after facilitating insertion, the needle is then withdrawn.

[0086] It should be appreciated that analyte monitoring system 100 may include additional features and functionality not necessarily described herein for the sake of brevity. Accordingly, the above description of analyte monitoring system 100 should be considered exemplary and non-limiting in nature.

[0087] Analyte sensors of the present disclosure may include, according to various embodiments, a two-electrode or three-electrode detection motif. A three-electrode motif may include a working electrode, a counter electrode, and a reference electrode. A two-electrode motif may include a working electrode and a second electrode, with the second electrode functioning as both a counter electrode and a reference electrode (i.e., a counter / reference electrode). In both two-electrode and three-electrode detection motifs, the sensing region of the analyte sensors described herein may be in contact with the working electrode. In various embodiments, the various electrodes may be at least partially stacked on top of one another, as described in further detail below. In alternative embodiments, the various electrodes may be spaced apart from one another on the insertion tail of the analyte sensor.

[0088] FIG. 2 shows a diagram of an exemplary two-electrode sensor configuration compatible with the disclosure 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 may be disposed on the same side of the substrate 212 with a dielectric material interposed therebetween. A sensing area 218 is disposed as at least one spot on at least a portion of the working electrode 214. A membrane 220 overcoats at least the sensing area 218 and, optionally, in some embodiments, can overcoat some or all of the working electrode 214 and / or the counter / reference electrode 216. One or both sides of the sensor 200 may be overcoated with the membrane 220. The membrane 220 may comprise any of the polymeric film compositions disclosed herein.

[0089] A three-electrode sensor configuration can be similar to analyte sensor 200, except that it includes an additional electrode (FIGS. 3A and 3B). With additional electrode 217, counter / reference electrode 216 then functions as either a counter electrode or a reference electrode, and additional electrode 217 (FIGS. 3A and 3B) serves another function not otherwise served. Additional electrode 217 can be positioned on either working electrode 214 or counter / reference electrode 216, with a dielectric separation layer between them. For example, as shown in FIG. 3A, dielectric layers 219a, 219b, and 219c separate electrodes 214, 216, and 217 from one another. Alternatively, at least one of electrodes 214, 216, and 217 can be positioned on the opposite side of substrate 212 (FIG. 3B). Thus, in some embodiments, electrode 214 (working electrode) and electrode 216 (counter electrode) can be disposed on opposite sides of substrate 212, with electrode 217 (reference electrode) disposed on one of electrodes 214 or 216 and separated therefrom by a dielectric. According to some embodiments, a conductive layer 222, such as a silver / silver chloride reference, can be disposed on electrode 217 (reference electrode). Similar to sensor 200 shown in FIG. 2, sensing region 218 can include a single spot or multiple spots configured to detect an analyte of interest.

[0090] In some embodiments, the additional electrode 217 may optionally be overcoated with a film 220. It should be appreciated that while Figures 3A and 3B depict all of the electrodes 214, 216, and 217 as being overcoated with a film 220, only the sensing region 218 need be overcoated to achieve the benefits described herein. As such, the configurations shown in Figures 3A and 3B should be understood as not limiting the embodiments disclosed herein. As with the two-electrode configuration, one or both sides of the sensor 200 may be overcoated with a film 220.

[0091] When coating the sensing region 218, the membrane 220 can have a thickness ranging from about 0.1 microns to about 1000 microns, or from about 1 micron to about 500 microns, or from about 10 microns to about 100 microns.

[0092] In some embodiments, the sensing region 218 may include a polymer bound to glucose oxidase or another enzyme and a low-potential osmium complex electron transfer mediator, as disclosed, for example, in U.S. Patent No. 6,134,461, which is incorporated herein by reference in its entirety. Other suitable electron transfer mediators may include, for example, metal compounds or complexes of ruthenium, iron, or cobalt. Suitable ligands for metal complexes may include, for example, bidentate or higher dentate ligands, such as bipyridine, biimidazole, or pyridyl (imidazole). Other suitable bidentate ligands may include, for example, amino acids, oxalic acid, acetylacetone, diaminoalkanes, or o-diaminoarenes. Any combination of monodentate, bidentate, tridentate, tetradentate, or higher dentate ligands may be present in the metal complex to achieve a complete coordination sphere.

[0093] The enzyme in sensing region 218 may be covalently attached to a polymer or other suitable matrix via a cross-linking agent. Cross-linking agents suitable for reaction with free amino groups in the enzyme (e.g., with the free amine in lysine) may include, for example, polyethylene glycol diglycidyl ether (PEGDGE) or other polyepoxides, cyanuric chloride, N-hydroxysuccinimide, imidoesters, or derivatized variants thereof. Cross-linking agents suitable for reaction with free carboxylic acid groups in the enzyme may include, for example, carbodiimides.

[0094] A variety of approaches can be employed to determine the concentration of an analyte using analyte sensor 200. For example, the concentration of the analyte can be monitored using any of the following electrochemical detection techniques: coulometric, amperometric, voltammetric, or potentiometric.

[0095] Embodiments disclosed herein include the following: A. Polymeric Film Composition The polymeric film composition comprises: a polymer backbone comprising one or more side chains comprising a heterocycle; and amine-free polyether arms attached to at least some of the heterocycles of the one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer.

[0096] B. Analyte Sensor The analyte sensor comprises: a sensing region; and a polymeric film composition covering the sensing region, wherein the polymeric film composition comprises a polymer backbone comprising one or more side chains comprising a heterocycle, and amine-free polyether arms attached to at least a portion of the heterocycles of the one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer.

[0097] C. Polymeric Film Compositions with Temperature Insensitivity to Glucose or Other Potential Analytes The polymeric film compositions are temperature insensitive at least in glucose permeability over a temperature range of about 15°C to about 45°C and meet or exceed ISO 10993-1 standards.

[0098] Each of embodiments A and B may have one or more of the following additional elements in any combination. Element 1: The polymer backbone comprises polyvinylpyridine or polyvinylimidazole.

[0099] Element 2: Wherein the polymer backbone comprises a copolymer of vinylpyridine and styrene. Element 3: The amine-free polyether arm comprises at least one polyethylene oxide block and at least one polypropylene oxide block, and the amine-free polyether arm is attached to a heterocyclic or heteroaromatic nitrogen atom in a side chain of the polymer backbone.

[0100] Element 4: The amine-free polyether arms are

[0101] [ka]

[0102] where w is 0 or 1, x is in the range of about 4 to about 24, y is in the range of about 8 to about 60, and z is in the range of about 6 to about 36. Element 5: where x is in the range of about 8 to about 16, y is in the range of about 10 to about 32, and z is in the range of about 10 to about 20.

[0103] Element 6: where x≦z. Element 7: wherein the ratio of (x+z):y is at least about 1.7:1. Element 8: wherein the ratio of (x+z):y ranges from about 1.7:1 to about 5:1.

[0104] Element 9: Wherein the polymeric film composition further comprises a sulfonate-containing arm attached to at least a portion of one or more side chains. Element 10: Wherein the polymeric film composition further comprises a crosslinker attached to at least a portion of the one or more side chains, linking the first polymer backbone to the second polymer backbone.

[0105] Element 11: Wherein the sensing region comprises an enzyme. Element 12: Wherein the polymer film composition further comprises amine-free polyethylene oxide arms attached to at least some of the heterocycles of one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer.

[0106] By way of non-limiting example, exemplary combinations applicable to A and B include: Elements 1,2;Element 1,3;Element 1,4;Element 1,4,5;Element 1,4,6;Element 1,4,5,6;Element 1,4,7;Element 1,4,5,7;Element 1,4,8;Element 1,4,5,8;Element 1,9;Element 1,10;Element 1,12;Element 1,9,10;Element 2,3;Element 2,4;Element 2,4,5;Element 2,4,6;Element 2,4,5,6;Element 2,4,7;Element 2,4,5,7;Element 2,4,8;Element 2,4,5,8;Element 2,9;Element 2,10;Element 2,9,1 Composition A in combination with 0; elements 3,4; elements 3,4,5; elements 3,4,6; elements 3,4,5,6; elements 3,4,7; elements 3,4,5,7; elements 3,4,8; elements 3,4,5,9; elements 3,9; elements 3,103,9,10; elements 4,5; elements 4,6; elements 4,5,6; elements 4,7; elements 4,5,7; elements 4,8; elements 4,5,8; elements 4,9; elements 4,10; elements 4,9,10; elements 4,12; elements 9,10; elements 10,12; elements 11,12. Elements 1,2; Elements 1,3; Elements 1,4; Elements 1,4,5; Elements 1,4,6; Elements 1,4,5,6; Elements 1,4,7; Elements 1,4,5,7; Elements 1,4,8; Elements 1,4,5,8; Elements 1,9; Elements 1,10; Elements 1,12; Elements 1,9,10; Elements 2,3; Elements 2,4; Elements 2,4,5; Elements 2,4,6; Elements 2,4,5,6; Elements 2,4,7; Elements 2,4,5,7; Elements 2,4,8; Elements 2,4,5,8; Elements 2,9; Elements 2,10; Elements 2,9,10; Elements 3,4; Elements 3,4,5; Elements The analyte sensor of B in combination with elements 3, 4, 6; elements 3, 4, 5, 6; elements 3, 4, 7; elements 3, 4, 5, 7; elements 3, 4, 8; elements 3, 4, 5, 9; elements 3, 9; elements 3, 10, 3, 9, 10; elements 4, 5; elements 4, 6; elements 4, 5, 6; elements 4, 7; elements 4, 5, 7; elements 4, 8; elements 4, 5, 8; elements 4, 9; elements 4, 10; elements 4, 9, 10; elements 4, 12; elements 9, 10; elements 10, 12; elements 11, 12, and optionally with element 11. The composition of C can be used in combination with any of the elements applicable to A.

[0107] To facilitate a better understanding of the embodiments described herein, the following examples of various representative embodiments are given. The following examples should not be read to limit or define the scope of the invention.

[0108] (Example) Example 1: Temperature Variability. A polyvinylpyridine copolymer with styrene having amine-free polyether arms and a structure corresponding to Formula 12 (w=1, x=14, y=12, z=18) was coated onto a glucose-responsive sensor. The coated sensor was then exposed to a fixed concentration of glucose solution, and the sensor response was measured over a range of temperatures. Figure 4 shows a plot of the sensor response data over a temperature range of 17°C to 42°C. As shown in Figure 4, the sensor response exhibited minimal variation over a significant portion of the temperature range that includes normal physiological temperatures in humans. Even at temperatures where the onset of response variation began to be observed (i.e., above 37°C), the response variation was less than 2% over the entire 5°C measurement interval, as shown in the bar graph in Figure 5.

[0109] Example 2: Glucose response. The coated sensor of Example 1 was tested at room temperature with various glucose concentrations. As shown in Figure 6, the sensor response as a function of glucose concentration was nearly linear at constant temperature.

[0110] Example 3: Biocompatibility Testing. A polyvinylpyridine copolymer with styrene having amine-free polyether arms corresponding to formula 12 (w=1) and having a structure defined by the variables x, y, and z as specified in Table 1 below was used to perform several biocompatibility tests. The tests were performed according to the ISO 10993-1 protocol and are briefly described below.

[0111] Cytotoxicity. Polymers with amine-free polyether arms were tested for cytotoxicity under standard conditions using the minimum essential dissolution medium test. The results are shown in Table 1. Cytotoxicity testing was performed by applying an extract of the polymer (glucose-free minimum essential medium) to test cell monolayers, incubating, and scoring based on the degree of monolayer disruption and the amount of cell lysis. A score of "0" represents no observable monolayer disruption or cell lysis. Mild cytotoxicity is classified as a score of "2" or less (<50% monolayer disruption without extensive cell lysis). A score of 2 or less meets current United States Pharmacopeia and National Formulary requirements ( <usp87>) are considered acceptable standards for certain purposes.

[0112] [Table 1]

[0113] As shown in Table 1, increasing the ratio of polyethylene oxide to polypropylene oxide improved the cytotoxic response. Hemolysis. A hemolysis study was performed on the polymer from entry 3 using the extraction method (phosphate buffered saline) specified in ASTM F756. There was no difference in hemolysis between the extract and the negative control, meaning that the polymer from entry 3 was non-hemolytic, with a hemolysis index of 2 or less.

[0114] Mutagenicity: Mutagenicity testing was performed on the polymer from entry 3 using the Ames test. Extracts of the polymer did not meet the mutagenicity requirements of this test. Single-dose systemic irritation test. The polymer extract of entry 3 was injected intravenously or intraperitoneally. No signs of toxicity were observed during the observation period compared with the control.

[0115] Skin Irritation Test: The skin irritation test of the polymer extract of entry 3 gave a sensitization response score of 0, which means no visible erythema or edema. Intradermal Irritation Test. Intradermal irritation testing of the polymer extract of Entry 3 did not produce any abnormal clinical signs compared to the vehicle control over the 72-hour observation period. Calculated erythema and edema scores compared to the control were less than 1 (no barely perceptible erythema or edema).

[0116] Implantation Study. The polymer in entry 3 produced an irritation score of 0.2 upon implantation and was thereby classified as non-irritating. Unless otherwise indicated, all numbers expressing quantities and the like in this specification and the related claims should be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by embodiments of the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0117] One or more exemplary embodiments incorporating various features are presented herein. For clarity, not all functionality of a physical implementation is described or shown herein. It is understood that the development of a physical implementation incorporating embodiments of the present invention involves numerous implementation-specific decisions to achieve the developer's goals, such as system-related, business-related, governmental, and other compliance requirements. Constraints vary from implementation to implementation and over time. While the developer's efforts may be time-consuming, such efforts are nevertheless routine for those skilled in the art and having the benefit of this disclosure. While various systems, tools, and methods are described herein in terms of "including" various components or steps, the systems, tools, and methods can also be "consisting essentially of" or "consisting of" the various components and steps.

[0118] As used herein, the phrase "at least one of" preceding a list of items, together with the term "and" or "or" separating any of the items, modifies the list as a whole (i.e., each item), not each member of the list. The phrase "at least one of" allows for the meaning to include at least one of any one of the items, and / or at least one of any combination of the items, and / or at least one of each of the items. By way of example, the phrases "at least one of A, B, and C" or "at least one of A, B, or C" refer to A only, B only, or C only, any combination of A, B, and C, and / or at least one of each of A, B, and C, respectively.

[0119] Thus, the disclosed systems, tools, and methods are well adapted to achieve the objects and advantages mentioned, as well as those inherent therein. The specific embodiments disclosed above are merely illustrative, as the teachings of the present invention may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Moreover, no limitations to the details of construction or design shown herein are intended, except as set forth in the appended claims. It is therefore evident that the specific exemplary embodiments disclosed above may be altered, combined, or modified, and all such variations are considered to be within the scope of the present invention. The systems, tools, and methods illustratively disclosed herein may suitably be practiced in the absence of elements not specifically disclosed herein and / or any elements disclosed herein. Although systems, tools, and methods may be described in terms of "comprising," "including," or "comprising" various elements or steps, the systems, tools, and methods may also "consist essentially of" or "consist of" the various elements. All numbers and ranges disclosed above may vary to some extent. Whenever a numerical range with a lower and upper limit is disclosed, any number and any included range within that range is specifically disclosed. In particular, all range values ​​disclosed herein (in the form "about a to about b," or equivalently, "about a to b," or equivalently, "about a b") should be understood as follows: Denotes all numbers and ranges that fall within the broader range value. Also, claim terms have their plain and ordinary meaning unless expressly and clearly defined otherwise by the patent owner. Furthermore, the indefinite article "a" or "an," as used in the claims, is defined herein to mean one or more of the elements it introduces. In the event of a discrepancy in a term or usage of a term in this specification and one or more patents or other documents that may be incorporated herein by reference, the consistent definition in this specification should prevail.

Claims

1. A polymeric film material, comprising: a polymer backbone having one or more side chains comprising a heterocycle; an amine-free polyether arm attached to at least one of the side chain heterocycles via an alkyl spacer or a hydroxy-functionalized alkyl spacer; Including, wherein the amine-free polyether arms have a structure shown by formula 13: 【Chemistry 1】 wherein w is 0 or 1, x is in the range of about 4 to about 24, y is in the range of about 8 to about 60, and z is in the range of about 6 to about 36.

2. The polymer film material described in claim 1, wherein the polymer backbone comprises polyvinylpyridine or polyvinylimidazole.

3. The polymer film material described in claim 1, wherein the polymer backbone comprises a polyvinylpyridine homopolymer.

4. The polymer film material of claim 1, wherein the polymer backbone comprises a copolymer of vinylpyridine and styrene.

5. The polymeric film material of claim 1, wherein x is in the range of about 6 to about 20, y is in the range of about 10 to about 40, and z is in the range of about 10 to about 30.

6. The polymeric film material of claim 1, wherein x is in the range of about 9 to about 12, y is in the range of about 16 to about 30, and z is in the range of about 12 to about 16.

7. The polymeric membrane material of claim 1, further comprising a sulfonate-containing arm attached to at least a portion of said one or more side chains.

8. The polymer film material of claim 1, further comprising an amine-free polyethylene oxide arm attached to at least some of the heterocycles of the one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer.

9. The polymer film material of claim 1, comprising a crosslinking agent attached to at least a portion of the one or more side chains, linking the first polymer backbone to the second polymer backbone.

10. The polymeric film material of claim 1, wherein the polymeric film material exhibits a cytotoxicity score of 2 or less under the requirements of the United States Pharmacopeia and National Formulary, USP 87.

11. The polymeric membrane material of claim 1, wherein the polymeric membrane material is temperature insensitive at least in glucose permeability over a temperature range of about 15°C to about 45°C.

12. A polymer comprising one or more side chains containing a heterocyclic or heteroaromatic nitrogen atom; an amine-free polyether arm precursor comprising at least one polyethylene oxide block and at least one polypropylene oxide block; A method for producing a polymeric membrane material comprising reacting 13. The amine-free polyether arm precursor has a structure represented by Formula 14: 【Chemistry 2】 13. The method of claim 12, wherein x ranges from about 4 to about 24, y ranges from about 8 to about 60, z ranges from about 6 to about 36, A1 is an alkyl group having from about 2 to about 20 carbon atoms, and X is a halide.

14. The amine-free polyether arm precursor has a structure represented by Formula 15: 【Transformation 3】 13. The method of claim 12, wherein x is in the range of from about 4 to about 24, y is in the range of from about 8 to about 60, z is in the range of from about 6 to about 36, and A2 is an alkyl group having 1 to about 10 carbon atoms.

15. The method of claim 12, wherein the polymer is a copolymer of vinylpyridine and styrene.

16. The method of claim 13, wherein X is Br.

17. The method of claim 14, wherein A2 is methylene.

18. The method of claim 12, further comprising crosslinking the polymeric film material using a crosslinking agent.

19. An in vivo analyte sensor for measuring an analyte concentration in a bodily fluid of a user, comprising: a first portion coupled to an analyte monitoring system, the first portion positionable on a surface of the skin; a second portion positionable below the surface of the skin, the second portion configured to contact bodily fluid and monitor an analyte concentration in the bodily fluid, the second portion including an electrode connected to a contact portion disposed on the first portion; and Including, wherein the analyte monitoring system includes: a) a sensor control device configured to correlate a sensor output with an analyte concentration and transmit the analyte concentration to a reader device according to an electronic communication protocol via a transmitter connected to the sensor control device; and b) a power source for operation of the sensor control device; the electrodes of the second portion include a working electrode including at least one sensing area; The in vivo analyte sensor further comprises the polymeric membrane material of claim 1 covering the at least one sensing area.

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