A membrane material not affected by temperature and an analyte sensor containing the same

Abstract

Membrane materials that exhibit limited analyte permeability variation as a function of temperature, and analyte sensors incorporating such membrane materials, are provided. [Solution] A polymeric film composition having limited change in analyte permeability as a function of temperature may 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.

Description

Technical Field

[0001] The present invention relates to a film material not affected by temperature and an analyte sensor containing the same.

Background Art

[0002] The detection of various analytes within an individual can sometimes be essential for monitoring health status. Deviations from normal analyte levels can often indicate many 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, diabetic patients may be able to take corrective measures (e.g., injecting insulin to lower blood glucose levels or eating to raise blood glucose levels) before significant physiological harm occurs. Other analytes that may generally be desirably monitored for physiological dysregulation, which can include, but are not limited to, lactate, oxygen, pH, A1c, ketones, drug levels, etc.

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

[0004] For many individuals, periodic ex vivo analyte monitoring is sufficient to determine physiological status. However, ex vivo analyte monitoring can be inconvenient or painful for some people. Additionally, there is no way to recover lost data if analyte measurements are not obtained at the appropriate times.

[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. Continuous analyte monitoring by implanted sensors can be advantageous, but there are issues associated with these types of measurements. Intravascular analyte sensors have the advantage of providing analyte concentration directly from the blood, but are invasive and can be painful for an individual to wear for extended periods. Subcutaneous and transdermal analyte sensors are often less painful for an individual 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 operative portion of the sensor internally, along with one or more additional sensors (e.g., through a skin penetration), with the remaining components of the additional sensors remaining external to the individual's body. In certain examples, a sensor suitable for measuring analyte levels in vivo can extend from a sensor housing designed to be worn "on-body" for extended periods, such as on the skin. 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 can include a membrane disposed at least at the implanted portion of the sensor. In one aspect, the membrane can improve the biocompatibility of the sensor in vivo. In another aspect, the membrane can be permeable or semi-permeable to the analyte of interest, but restricts the overall flow of the analyte to the sensing portion during operation of the sensor. Restricting the access of the analyte to the operating sensing portion of the sensor helps to avoid overloading (saturating) the operating sensing components, thereby improving the performance and accuracy of the sensor. For example, in the case of a sensor employing enzyme-based detection, by restricting the access of the analyte to the sensor, the rate of the chemical reaction of the sensing process can be limited by the analyte rather than by the enzyme. The restricted analyte enzyme reaction enables easy calibration of the analyte sensor as a function of the sensor output. That is, when the enzyme reaction is limited by the analyte, the sensor output can correlate with the amount of analyte in some way. In many cases, the sensor response can vary linearly as a function of the analyte concentration in the biological fluid of interest when the enzyme reaction is limited by the analyte.

[0008] The drawings are included to illustrate particular aspects of the present disclosure and should not be regarded 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

Problems to be Solved by the Invention

[0009] One problem associated with incorporating a membrane into an analyte sensor is that the flux of analyte through the membrane can vary significantly as a function of temperature. A calibration factor or equation can be used to compensate for the variability of analyte flow as a function of temperature, but doing so can add significant complexity to the use of the sensor, especially when the analyte flow changes non-linearly with temperature. Additionally, the thermistors used in applying the calibration formula can be operationally complex and their size can impede efforts to miniaturize the sensor. As a further difficulty, the calibration temperature measurement location may not always be at the same temperature as the membrane covering the operative part of the sensor. Other parts of the sensor can likewise have performance that varies with temperature (e.g., the enzyme reaction rate in the case of an enzyme-based sensor), increasing the complexity of the components and the variability of their operating characteristics, which can make it quite difficult to separate and apply the calibration factor or equation for the membrane, resulting in higher costs and increased measurement errors.

Means for Solving the Problems

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

[0011] As described above, an in vivo analyte sensor can incorporate a membrane material to improve biocompatibility and to limit access of the analyte to the operative sensing region of the sensor. Limiting access to the detection region of the analyte to be detected can avoid saturation of the sensor and improve the characteristics and accuracy of the sensor. For example, in the case of an enzyme sensor, the membrane material can facilitate a detection process that is restricted by the analyte rather than the detection process restricted by the enzyme. Since the detection process is restricted by the analyte, easy calibration of the sensor can be achieved. In some cases, the sensor response can vary linearly as a function of analyte concentration in a detection process restricted by the analyte.

[0012] One problem associated with many membrane materials is that the permeability of their analytes can vary clinically significantly as a function of temperature. Variations in analyte permeability as a function of temperature can pose problems for sensor calibration, especially when the permeability variations are non-linear with respect to temperature. Certain membrane materials are known to have limited variations in analyte permeability as a function of temperature, but their biocompatibility may leave room for improvement. Furthermore, some membrane materials may be difficult to purify after synthesis.

[0013] The present disclosure provides, in certain embodiments, a polymeric membrane composition that can provide a desirable combination, such as limited analyte permeability variations as a function of temperature and having suitable biocompatibility characteristics. More particularly, the polymeric membrane compositions disclosed herein are polymers having one or more side chains containing a heterocycle Skeleton(also referred to herein as a heterocyclic polymer) and an amine-free polyether arm attached to at least a portion of one or more of the above 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. For example, other spacers such as carbonyl, carboxylic acid ester, or carboxamide can also be suitable in some embodiments. In some embodiments, a single polyethylene glycol moiety in the amine-free polyether arm can be joined to a single polypropylene glycol moiety in a diblock arrangement (e.g., in an A-B block pattern or a B-A block pattern where A is a polyethylene glycol block and B is a polypropylene glycol block). In other more specific embodiments, one or more polyethylene glycol moieties and one or more polypropylene glycol moieties can be present as alternating blocks without intervening functional groups (e.g., in an A-B-A pattern in some embodiments or B-A-B according to other embodiments when A is a polyethylene glycol block and B is a polypropylene glycol block). According to further embodiments of the present disclosure, the amine-free polyether arm can similarly include more than three alternating blocks. Both the block pattern and the number of ether units in each block can vary in the polymer film compositions disclosed herein. In some embodiments, the terminal polyethylene glycol unit within the amine-free polyether arm can be attached to the heterocycle or another side chain of the heterocyclic polymer via an alkyl spacer or a hydroxy-functionalized alkyl spacer, or an alternative spacer such as carbonyl, carboxyl ester, or carboxamide.In other embodiments, the terminal polypropylene glycol units within the amine-free polyether arms can be attached to the other side chains of the heterocycle or heterocyclic polymer via an alkyl spacer or a hydroxyl-functionalized alkyl spacer, or an alternative spacer such as a carbonyl, carboxylic acid ester, or carboxamide.

[0014] The polymer membrane 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 a halogenated alkyl or a terminal epoxide. More specifically, a primary halogenated alkyl such as a primary alkyl bromide can terminate an amine-free polyether arm precursor and result in an alkyl spacer that attaches the amine-free polyether arm to the heterocycle. In contrast, the epoxide terminus of an amine-free polyether arm precursor allows the amine-free polyether arm to be attached to the heterocycle via a hydroxy-functionalized alkyl group, specifically an alkyl group having a secondary hydroxyl functional group. 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 in vivo properties of the resulting polymer. In a more detailed configuration, the primary halogenated alkyl or epoxide can be attached to the polyethylene glycol portion of the amine-free polyether arm precursor (i.e., via a terminal ether bond and an intervening spacer group). In other particular configurations, the primary halogenated alkyl or epoxide can be attached to the polypropylene glycol portion of the 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. The independent synthesis of the amine-free polyether arm precursors can provide greater compositional uniformity of the side chains in the resulting polymer membrane composition as compared to that obtained by the stepwise growth of the arms from the polymer backbone, where different arm lengths can be generated. Further, reacting the amine-free polyether arm precursors with the polymer backbone in one step can achieve improved yields, improved synthetic consistency, and improved throughput, and changes in the membrane properties can be more readily correlated with structural changes. A further advantage of the polymer membrane compositions disclosed herein is that they can often be synthesized with higher purity and compositional uniformity than equivalent polymer compositions having amine functional groups within the polyether arms.

[0016] A further advantage of the present disclosure is that the ratio of polyethylene oxide to polypropylene oxide within the polymer membrane composition of the present invention can be made far more diverse far more readily than in similar polymer compositions having amine functional groups within the polyether arms. More specifically, the distribution and ratio of polyethylene oxide to polypropylene oxide can be fixed within the amine-free polyether arm precursor before the attachment to the heterocyclic polymer occurs. Advantageously and surprisingly, this feature can, as further discussed herein, enable the adjustment of the polyethylene glycol to polypropylene glycol ratio to promote a desired biological response in vivo.

[0017] At least some of the polymer film compositions disclosed herein may exhibit low or no cytotoxicity in vivo, as well as other suitable biocompatibility characteristics. In certain embodiments, the ratio of polyethylene oxide to polypropylene oxide can be adjusted to obtain the resulting biocompatibility characteristics, such that the polymer film composition can be characterized as having a cytotoxicity score of 2 or less when measured by the minimum essential elution medium test. In some or other specific embodiments, the polymer film compositions described herein meet the biocompatibility requirements specified in International Organization for Standardization (ISO) 10993-1 when evaluated according to the specified test protocols.

[0018] Accordingly, the polymer film compositions disclosed herein can be particularly advantageous for use in various in vivo analyte sensors, especially when the analyte sensor is intended for long-term wear. However, it should be understood that the polymer film compositions disclosed herein can 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 can be temperature-insensitive with respect to the permeability of glucose. For example, other analytes such as lactate can 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 compositions of the present disclosure can include a polymer backbone comprising one or more side chains containing 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. Such amine-free polyether arms are distinguished from cross-linking agents (i.e., groups that covalently bond two or more polymer backbones) by the feature 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 and is a homopolymer or a heteropolymer. A homopolymer can be formed by the polymerization of a single type of monomer. A heteropolymer (also called a copolymer) includes two or more different types of monomers bonded to a single polymer chain. According to various embodiments, the copolymer can have a random, alternating, or block distribution of different monomer units.

[0021] Heterocycles suitable for incorporation within the polymer film compositions of the present disclosure can include any cyclic moiety containing one or more carbon atoms in combination with any combination of N, P, O, S, or Si atoms, and the cyclic moiety can be aromatic or aliphatic. Suitable functional groups for incorporating heteroatoms within aliphatic or heteroaromatic cyclic moieties include, for example, -O-, -S-, -S-S-, -O-S-, -NR 1 R 2 , =N-, =N-N=, -N=N-NR 1 R 2 , -PR 3 -, -P(O)2-, -P(O)R 3 -, -O-P(O)2-, -SO-, -S(O)-, -S(O)2-, etc. are included, 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. Optionally, any of R1 to R3 can be linear or branched. Substituted variants of R1 to R3 can include any of the above groups in which a carbon atom or a hydrogen atom is replaced by 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 a more detailed embodiment, the polymer Skeleton may include a heterocyclic or heteroaromatic nitrogen moiety within one or more side chains. In an even more detailed embodiment, the polymer Skeleton may include a heteroaromatic nitrogen moiety within one or more side chains. Suitable heteroaromatic nitrogen moieties 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, quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, triazole, and derivatives thereof.

[0023] According to some embodiments, one or more comonomers may be present in combination with a monomer unit having a heteroaromatic nitrogen moiety. Suitable comonomers for incorporation into the polymer film compositions 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 a more detailed embodiment, the polymer film compositions of the present disclosure may include polyvinylpyridine or polyvinylimidazole, and any copolymers thereof. In certain embodiments, the polymer film compositions of the present disclosure may include a copolymer of polyvinylpyridine, particularly vinylpyridine (particularly 4-vinylpyridine) and styrene, or a copolymer of polyvinylimidazole, particularly vinylimidazole (particularly 2-vinylimidazole) and styrene. In some embodiments, substituted styrene may be utilized.

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

[0026]

Chemical formula

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

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

[0029] According to some or various other embodiments, a suitable copolymer of 4-vinylpyridine and styrene can 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 detailed embodiments, a suitable copolymer of 4-vinylpyridine and styrene can have a molecular weight in the range of about 5 kDa to about 150 kDa, or about 10 kDa to about 125 kDa, or about 15 kDa to about 100 kDa, or about 20 kDa to about 80 kDa, or about 25 kDa to about 75 kDa, or about 30 kDa to about 60 kDa. Other polymers suitable for use in the polymer film compositions of the present disclosure can have molecular weight values within a similar range.

[0030] In the polymer film composition of the present disclosure, the polyether arm without an amine can be attached to at least a part of the heterocyclic ring of the side chain of the heterocyclic polymer. For example, in the case of polyvinylpyridine, the polyether arm without an amine can be covalently bonded to the pyridine ring, particularly via the pyridine nitrogen atom.The proportion of side chains in the polymer film composition with amine-free polyether arms added can be 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 about 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 of the heterocyclic polymer, or about 0.7% or more of the available heterocycles of the heterocyclic polymer, or about 0.8% or more of the available heterocycles of the heterocyclic polymer, or about 0.9% or more of the available heterocycles in the heterocyclic polymer, or about 1.0% or more of the available heterocycles in the heterocyclic polymer, or 1.2% or more of the available heterocycles in the heterocyclic polymer, or about 1.4% or more of the available heterocycles of the heterocyclic polymer, or about 1.6% or more of the available heterocycles of the heterocyclic polymer, or about 1.8% or more of the available heterocycles of the heterocyclic polymer, or about 2.0% or more of the available heterocycles of the heterocyclic polymer, or about 2.2% or more of the available heterocycles of the heterocyclic polymer, or about 2.4% or more of the available heterocycles of the heterocyclic polymer, or about 2.6% or more of the available heterocycles in the heterocyclic polymer, or about 2.8% or more of the available heterocycles in the heterocyclic polymer, or about 3.0% or more of the available heterocycles in the heterocyclic polymer, or about 3.5% or more of the available heterocycles in the heterocyclic polymer, or about 4.0% or more of the available heterocycles in the heterocyclic polymer, or about 4.5% or more of the available heterocycles in the heterocyclic polymer, or about 5.0% or more of the available heterocycles in the heterocyclic polymer, or about 5.5% or more of the available heterocycles in the heterocyclic polymer, or about 6.0% or more of the available heterocycles in the heterocyclic polymer, or about 6.5% or more of the available heterocycles of the heterocyclic polymer, or about 7.0% or more of the available heterocycles of the heterocyclic polymer, or about 7.5% or more of the available heterocycles of the heterocyclic polymer, or about 8.0% or more of the heterocyclic polymer, or about 8.5% or more of the available heterocycles in the heterocyclic polymer, or about 9.0% or more of the available heterocycles in the heterocyclic polymer, or about 9.5% or more of the available heterocycles in the heterocyclic polymer, or about 10% or more of the available heterocycles in the heterocyclic polymer.In more detailed embodiments, the amine-free polyether arm can be added to the heterocyclic polymer in an amount of about 0.1% to about 5% of the heterocycles available in the heterocyclic polymer, or about 0.5% to about 4.5% of the heterocycles available in the heterocyclic polymer, or about 1.0% to about 4.0% of the heterocycles available in the heterocyclic polymer, or about 1.5% to about 3.0% of the heterocycles available in the heterocyclic polymer, or about 1.5% to about 2.5% of the heterocycles available in the heterocyclic polymer.

[0031] In alternative embodiments, the amine-free polyether arm can be added to a non-heterocyclic side chain 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 can also have a crosslinking agent attached thereto. That is, in some embodiments, the polymer film composition of the present disclosure can further include a crosslinking agent that is added to at least a portion of one or more side chains and that adjacent a first polymer backbone to a second polymer backbone. The crosslinking agent can be added to the heterocyclic polymer in addition to the amine-free polyether arm. In some embodiments, the crosslinking agent can itself be a polyether, such as polyethylene glycol or a copolymer of ethylene glycol and propylene glycol. Such crosslinking agents 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 crosslinking agent may be greater than the amount of heterocycles functionalized with the amine-free polyether arm. In other embodiments, the amount of heterocycles functionalized with the crosslinking agent may be less than the amount of heterocycles functionalized with the amine-free polyether arm. In an exemplary embodiment, a bisepoxide polyethylene glycol compound can be used to form a polymer film composition having a crosslinking agent.

[0033] In a more detailed embodiment, the proportion of side chains to which a crosslinking agent can be added 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, 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 about 0.9% or more of the available heterocycles in the heterocyclic polymer, or about 1.0% or more of the available heterocycles in the heterocyclic polymer, or about 1.2% or more of the available heterocycles in the heterocyclic polymer, or about 1.4% or more of the available heterocycles in the heterocyclic polymer, or about 1.6% or more of the available heterocycles in the heterocyclic polymer, or about 1.8% or more of the available heterocycles in the heterocyclic polymer, or about 2.0% or more of the available heterocycles in the heterocyclic polymer, or about 2.2% or more of the available heterocycles in the heterocyclic polymer, or about 2.4% or more of the available heterocycles in the heterocyclic polymer, or about 2.6% or more of the available heterocycles in the heterocyclic polymer, or about 2.8% or more of the available heterocycles in the heterocyclic polymer, or about 3.0% or more of the available heterocycles in the heterocyclic polymer, or about 3.5% or more of the available heterocycles in the heterocyclic polymer, or about 4.0% or more of the available heterocycles in the heterocyclic polymer, or about 4.5% or more of the available heterocycles in the heterocyclic polymer, or 5.0% or more of the available heterocycles in the heterocyclic polymer, or about 5.5% or more of the available heterocycles in the heterocyclic polymer, or about 6.0% or more of the available heterocycles in the heterocyclic polymer, or about 6.5% or more of the available heterocycles in the heterocyclic polymer, or about 7.0% or more of the available heterocycles in the heterocyclic polymer, or about 7.5% or more of the available heterocycles in the heterocyclic polymer, or about 8.0% or more of the available heterocycles in the heterocyclic polymer, or about 8.5% or more of the available heterocycles in the heterocyclic polymer, or about 9.0% or more of the available heterocycles in the heterocyclic polymer, or about 9.5% or more of the available heterocycles in the heterocyclic polymer, or about 10% or more of the available heterocycles in the heterocyclic polymer and may be.In more detailed embodiments, the crosslinking agent can be added at about 1% to about 20% of the available heterocycles in the heterocyclic polymer, or about 2% to about 10% of the available heterocycles in the heterocyclic polymer, or about 3% to about 8% of the available heterocycles in the heterocyclic polymer, or about 4% to about 9% of the available heterocycles in the heterocyclic polymer, or about 5% to 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 an optionally substituted phenyl group, can have a crosslinking agent attached thereto. According to various embodiments, the amine-free polyether arm can be attached to the polymer backbone of the polymer membrane composition disclosed herein via a heteroatom within at least a portion of the heterocycles of one or more side chains of the heterocyclic polymer. Alternative embodiments can include those in which the amine-free polyether arm is attached to the polymer backbone via at least a portion of the carbon atoms of the heterocycles of one or more side chains and / or via the carbon atoms of an optionally substituted phenyl group of the polymer backbone. In more detailed embodiments, the amine-free polyether arm is attached to the polymer Skeleton via a heterocyclic aromatic nitrogen atom or a heteroaromatic nitrogen atom within one or more side chains. For example, when the polymer Skeleton is polyvinylpyridine or a copolymer thereof, the amine-free polyether arm can be attached to the side chain via the pyridine nitrogen atom. When functionalized with an amine-free polyether arm or a crosslinking agent, the pyridine nitrogen atom is in a quaternized form.

[0035] Thus, in more detailed embodiments, the polymer membrane composition of the present disclosure in which the amine-free polyether arm is attached to the pyridine nitrogen atom can have repeating units defined by Chemical Formulas 2 and 3 below, where the variables a, b, and Q are defined as above, and c is a positive integer less than or equal to a.

[0036]

Chemical formula

[0037] Z is a polyether arm without amine, a crosslinking agent, or any combination thereof. When both a polyether arm without amine and a crosslinking agent are present, the polymer film composition may have a structure defined by one or more of Chemical Formulas 4 to 7, where the variables a, b, and Q are as defined above.

[0038]

Chemical Formula

[0039] c1 and c2 are positive integers whose sum is not more than a, d is as defined in Chemical Formula 1, Z1 is a polyether arm without amine, and Z2 is d = a - c1 - c2 (Equation 1) a crosslinking agent such that. Accordingly, the heteroaromatic (pyridine) ring of the heterocyclic polymer can be functionalized with Z1 and Z2 in any combination or pattern in various embodiments of the polymer film compositions of the present disclosure. That is, the repeating units defined by Chemical Formulas 2 to 7 can be present in any combination with each other when defining a heterocyclic polymer suitable for incorporation into the polymer film compositions of the present disclosure.

[0040] In other specific embodiments, a polymer film composition having a polyether arm without amine bonded to a pyridine moiety without passing through a pyridine nitrogen atom can be defined by the following Chemical Formulas 8 and 9, where a, b, c, Q, and Z are as defined above.

[0041]

Chemical Formula

[0042] Optionally, either of the pyridine nitrogen atoms in Chemical Formulas 8 and 9 can be quaternized with an alkyl group (e.g., via reaction with an alkyl halide) when a polyether arm without an amine is bonded to a carbon atom of the pyridine. Any unsubstituted carbon atom in the pyridine group can be bonded to a polyether arm without an amine and / or a crosslinking agent according to the embodiments described herein. When both a polyether arm without an amine and a crosslinking agent are present, the polyether arm without an amine and the crosslinking agent may be present on the same pyridine group or on different pyridine groups.

[0043] In various embodiments, the amine-free polyether arm may include at least one polyethylene oxide block and at least one polypropylene oxide block. According to some embodiments, the amine-free polyether arm may include a diblock arrangement of polyethylene oxide and polypropylene oxide. That is, in some embodiments, the amine-free polyether arm may include, in order, an alkyl spacer or a hydroxy-functionalized alkyl spacer, a polyethylene oxide block, and a polypropylene oxide block, and in other embodiments, the amine-free polyether arm may include, 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 may consist of, in order, 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 A-B-A repeating pattern). In yet other different more detailed embodiments, the amine-free polyether arm may consist of, in order, 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 B-A-B repeating pattern). The alkyl spacer or the hydroxy-functionalized alkyl spacer may, according to various embodiments, be a polymer SkeletonIt can be attached to a heterocyclic or heteroaromatic nitrogen atom in the side chain. 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. According to various embodiments such as via a terminal ether bond, the alkyl spacer or hydroxy-functionalized alkyl spacer can also be attached to the first polyethylene oxide block of the amine-free polyether arm. According to some embodiments, the second polyethylene oxide block can be terminated by 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 arm can have a structure defined by the following Chemical Formula 10 or 11.

[0045]

Chemical Formula

[0046] Here, PE represents a polyethylene oxide block, PP represents a polypropylene oxide block, and L is a spacer group. Suitable spacer groups can include, but are not limited to, alkyl, hydroxy-functionalized alkyl, carbonyl, carboxylic acid ester, carboxamide, etc. 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 arrangement of polyethylene oxide and polypropylene oxide applicable to Chemical Formulas 10 and 11, the variable t can be 0. In Formula 10, when t ≠ 0, the terminal polyethylene oxide monomer unit can be substituted with an alkoxy group such as a methoxy group. Similarly, in Chemical Formula 11 where t ≠ 0, the terminal polypropylene oxide monomer unit can be substituted with an alkoxy group such as a methoxy group. The diblock arrangements (t = 0) related to Chemical Formulas 10 and 11 can similarly have alkoxy group termini. According to some embodiments, the variable q is an integer in the range of about 2 to about 50 or about 6 to about 20, the variable r is an integer in the range of about 2 to about 60 or about 10 to about 40, and the variable t is an integer in the range of about 2 to about 50 or about 10 to about 30. According to some or various other embodiments, the variable s is an integer in the range between 1 and about 20, or between 1 and about 10. In some embodiments, the variable s is equal to 1. The diblock arrangements of polyethylene oxide and polypropylene oxide can include variables q and r within the same ranges as described above, but the variable s is equal to 1 and the variable t is equal to 0.

[0047] In a more detailed embodiment of the present disclosure, the amine-free polyether arm can have a structure defined by Chemical Formula 12, where the variable w is 0 or 1,

[0048]

Chemical Formula

[0049] The variable x is an integer in the range of about 4 to about 24, or about 6 to about 20, the variable y is an integer in the range of about 8 to about 60, or about 10 to about 40, and the variable z is an integer in the range of about 6 to about 36, or about 10 to about 30. Alternatively, the variable z can be set to 0 in a diblock arrangement while the other variables are in the same range. In a more detailed embodiment, the variable x can be in the range of about 8 to about 16 or about 9 to about 12, and the variable y can be in the range of about 10 to about 32, or about 16 to about 30, or about 12 to about 20. The variable z can be in the range between about 10 and about 20, or between about 14 and about 18. In yet other more detailed 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 smaller 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 Chemical 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 a more detailed embodiment, the ratio of (x + z):y in Chemical Formula 12 can be in the range between about 1.4:1 and about 5:1, or between about 1.7:1 and about 3.2:1, or between about 2.2:1 and about 3.0:1, or between about 2.6:1 and about 2.9:1, or between about 3:1 and about 5:1.

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

[0052]

Chemical Formula

[0053] The variable x is an integer in the range of about 4 to about 24, or about 6 to about 20, the variable y is an integer in the range of about 8 to about 60, or about 10 to about 40, and the variable z is an integer in the range of about 6 to about 36, or about 10 to about 30. Alternatively, the variable z can be set to 0 in a diblock configuration while the other variables are in the same range. In a more detailed embodiment, the variable x can be in the range between about 6 and about 16 or between about 9 and about 12, and the variable y can be in the range between about 10 and about 40, or between about 16 and about 30, or between about 14 and about 32. The variable z can be in the range between about 8 and about 20, or between about 12 and about 16.

[0054] The amine-free polyether arm described herein can be bonded to the heterocycle of the side chain of the heterocyclic polymer via the reactive functional group of the amine-free polyether arm precursor. Suitable reactive functional groups can include, for example, halogen or epoxide, either of which can be reacted via a nucleophilic attack from the side chain of the heterocyclic polymer. The halogen-functionalized amine-free polyether arm precursor becomes an amine-free polyether arm where n is 0 (i.e., the spacer is an alkyl group), while the epoxide-functionalized amine-free polyether arm precursor becomes an amine-free polyether arm where n is 1 (i.e., the spacer is a propyl group containing a secondary alcohol). In a more detailed embodiment, the alkyl spacer resulting from the halogen-functionalized amine-free polyether arm precursor can be linear or branched and can include an alkyl group containing 2 to 20 carbon atoms. In a more detailed embodiment, the halides that can be suitably included in the halogen-functionalized amine-free polyether arm precursor include chloride or bromide, and bromide is selected in a more detailed embodiment.

[0055] Chemical formulas 14 and 15 show the structures of exemplary amine-free polyether arm precursors that can react appropriately with the heterocyclic polymer to form the specific polymer membrane compositions disclosed herein, where the variables x, y, and z are defined as above.

[0056] [Chem.]

[0057] In Chemical 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 is branched or linear and may contain heteroatom substitution as necessary. According to various embodiments, the halide X can be a primary alkyl halide. In Chemical 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 linear, and in other embodiments, the alkyl group A2 can contain branches.

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

[0059] [Chem.]

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

[0061] According to more detailed embodiments, the sulfonate-containing arm can be attached to the heterocycle of the heterocyclic polymer via an alkyl group. According to various embodiments, the alkyl group can contain from 1 to about 6 carbon atoms, or from 2 to about 4 carbon atoms. Suitable reagents for introducing a sulfonate-containing arm 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, an amine-free polyether arm containing a single type of repeating ether unit can be attached to at least a portion of one or more side chains of the heterocyclic polymers disclosed herein. Such amine-free polyether arms can be present in combination with sulfonate-containing arms, and / or the amine-free polyether arms can have two or more different types of ether unit blocks such as those described in Chemical Formulas 10-13.

[0063] According to more detailed embodiments, the amine-free polyether arm comprising 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 a heterocycle of at least a portion of one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer. Between about 8 and about 25, or between about 10 and about 22, or between about 12 and about 20 repeating ether units can be present in the 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 from 1 to about 6 carbon atoms, or from 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 on the opposite side of the attachment point to the heterocyclic polymer. Such amine-free polyether arms can be introduced into the heterocyclic polymer by reacting a polyether terminated with either a halogenated alkyl or an epoxide with the heterocyclic polymer.

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

[0065] In some embodiments, suitable crosslinking agents include glycidyl ethers such as polyetherimine and diglycidyl ether. This combination of reagents forms crosslinks containing amine groups. In other embodiments, suitable crosslinking agents may include glycidyl ethers such as polyether and diglycidyl ether, which result in crosslinks lacking amine groups. In more specific embodiments, suitable crosslinking agents for forming amine-free crosslinks may include glycidyl ethers such as polyethylene oxide / polypropylene oxide copolymer and diglycidyl ether, or glycidyl ethers such as polyethylene oxide and diglycidyl ether.

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

[0067]

Chemical formula

[0068] Here, the variable n is a positive integer ranging from about 10 to about 500, or about 10 to about 100, or about 10 to about 50, or about 12 to about 36, or about 12 to about 30, or about 12 to about 28, or about 12 to about 26, or about 12 to about 24, or about 12 to about 22, or about 12 to about 20, or about 14 to about 28, or about 14 to about 24, or about 16 to about 30, or about 16 to about 24. As will be understood by those skilled in the art, the crosslinking agent of Chemical Formula 18 reacts to form a crosslink in which the polyethylene oxide block is bonded to the polymer backbone at each end via a hydroxy-functionalized alkyl group. Specifically, the crosslinking agent of Chemical Formula 18 generates the crosslinking agent of Chemical Formula 19 upon nucleophilic ring opening of the epoxide ring in each terminal propylene oxide unit, where n is defined as above.

[0069]

Chemical formula

[0070] Thus, in more detailed embodiments of the present disclosure, suitable crosslinks may each include at least one polyethylene oxide block that is attached to opposite ends of a first heterocyclic ring of a first polymer backbone and a second heterocyclic ring of a second polymer backbone via a hydroxy-functionalized alkyl group. In such embodiments, the method of crosslinking is intermolecular. In some or other embodiments of the present disclosure, such a crosslinking agent may be attached to opposite ends of the first and second heterocyclic rings within the same polymer Skeleton in which case the method of crosslinking is intramolecular.

[0071] In some embodiments, such as the exemplary trisepoxide compound shown in Chemical Formula 20, crosslinking agents having additional epoxide groups can also be used. Such crosslinking agents can result in the formation of crosslinks between three or more polymer backbones.

[0072]

Chemical formula

[0073] Optionally, such crosslinking agents can be further reacted with polyethylene glycol, polypropylene glycol, or ethylene glycol / propylene glycol copolymers to form a given crosslink.

[0074] Advantageously, according to various embodiments, the polymer membrane compositions of the present disclosure can form temperature-insensitive membranes. 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 membranes of the present disclosure can be temperature-insensitive with respect to the permeability of analytes, particularly glucose. Other analytes also exhibit membrane permeability that is not affected by temperature, and the permeation rate may be the same as or different from the permeation rate of glucose. Thus, limited variations in analyte permeability may result in little or no change in sensor response when analyzing a constant concentration of analyte over a given temperature range in which the polymer membrane composition is not affected by temperature.

[0075] In more detailed embodiments, the polymer membrane compositions of the present disclosure can be temperature-insensitive with respect 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, about 20°C to about 45°C, or about 25°C to about 40°C. In some or other more detailed embodiments, the variation in analyte permeability (e.g., glucose) of the polymer membrane composition can be about 10% or less over the entire temperature range, or about 5% or less over the entire temperature range, or about 2% or less over the entire temperature range, about 1% or less over the entire temperature range, or about 0.5% or less over the entire temperature range, or about 0.1% or less over the entire temperature range, or about 0.05% or less over the entire temperature range, or about 0.01% or less over the entire temperature range. Within a subrange of a wider temperature range (e.g., about 15°C to about 45°C), the variation in analyte permeability of the polymer membrane composition can be about 2% or less or about 1% or less during a given 5°C temperature increment. The determination of the change in polymer membrane composition with respect to analyte permeability can be confirmed by measuring the difference in sensor response over a specific temperature range at a constant concentration of analyte (see FIG. 4 of this case).

[0076] The polymer film compositions described herein can be further characterized with respect to their biocompatibility properties. In various embodiments, the polymer film compositions can be characterized as having a cytotoxicity score of 2, or a cytotoxicity score of 1, or a cytotoxicity score of 0. Such cytotoxicity scores can be present in combination with properties such as absence of hemolysis, mutagenicity, irritation, and similar properties. In some embodiments, the polymer film compositions of the present disclosure meet or exceed the ISO 10993-1 standard. The ISO 10993-1 standard for tissue implant devices includes the clinical absence 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 operating portion of the sensor), and a polymer film composition that covers the sensing region. The polymer film composition can include a polymer containing one or more side chains containing a heterocycle Skeleton and a polyether arm not containing an amine attached to at least a portion of the heterocycle of the one or more side chains via an alkyl spacer or a hydroxyl-functionalized alkyl spacer. As further discussed herein, any polymer film composition can be utilized in combination with an analyte sensor.

[0078] In some embodiments, the sensing region of the analyte sensor of the present disclosure may include an enzyme. The enzyme may catalyze a reaction that consumes the analyte of interest or produce a product that can be detected by the analyte sensor. According to some embodiments, the enzyme may be covalently bound to a polymer that forms at least a portion of the sensing region. The selection of a particular enzyme may 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 when the analyte of interest is oxygen or when oxygen is generated or consumed in response to the reaction of the analyte. As will be understood by those skilled in the art and the advantages of the present disclosure, other enzymes can be similarly used to detect other analytes of interest. Any of the substrates acted upon by the above enzymes or other enzymes can be an analyte suitable for analysis using the analyte sensors disclosed herein.

[0079] Further details of exemplary analyte sensors that can be used in conjunction with the polymer 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 can also be suitably used.

Brief Description of the Drawings

[0080]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 4

Figure 5

Figure 6

DETAILED DESCRIPTION OF THE INVENTION

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

[0082] The sensor control device 102 includes a sensor housing 103, and the sensor housing 103 can accommodate a circuit and a power source for operating the sensor 104. The sensor 104 protrudes from the sensor housing 103 and extends through the adhesive layer 105. Adhesives suitable for the 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 target tissue such as the dermis layer of the skin. The sensor 104 may include a sensor tail of sufficient length to be inserted to a desired depth within a given tissue. The sensor tail may, according to one or more embodiments, include a sensing region operative for sensing and may include an enzyme. The sensing region includes the polymer membrane 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. The analyte can be monitored in any biological fluid such as interstitial fluid, plasma, blood, lymph fluid, etc. The analyte that may be monitored is not particularly limited. In certain embodiments, the analyte can be glucose. Other analytes of interest regarding 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 membrane composition disclosed herein. Both a single analyte and any combination of the foregoing analytes can be assayed.

[0084] The introducer may be present temporarily to facilitate introduction of the sensor 104 into tissue. In an exemplary embodiment, the introducer may include a needle 190. It should be recognized that in alternative embodiments, other types of introducers, such as sheaths or blades, may exist. More particularly, the needle or similar introducer may be present temporarily near the sensor 104 prior to insertion and may then be removed. While present, the needle or other introducer can facilitate insertion of the sensor 104 into tissue by opening an access path for the sensor 104 to follow. For example, according to one or more embodiments, the needle can facilitate penetration of the epidermis as an access path to the dermis, enabling implantation of the sensor 104. After opening the access path, the needle or other introducer can be withdrawn so as not to pose a danger from sharp objects. In an exemplary embodiment, the needle can be solid or hollow, beveled or non-beveled, and / or have a circular or non-circular cross-section. In a more particular embodiment, the needle can be comparable to a needle therapy needle that can have a cross-sectional diameter of about 250 microns in cross-sectional diameter and / or tip design. However, it should be recognized that appropriate needles can have larger or smaller cross-sectional diameters if required for a particular application. In an alternative embodiment, the needle 109 or similar introducer may not be necessary provided that the sensor 104 is strong enough to penetrate tissue and establish communication with the subject's body fluid.

[0085] In some embodiments, the tip of the needle can be angled on the end of the sensor 104 such that the needle first penetrates the tissue and opens an access path for the sensor 104. In other exemplary embodiments, the sensor 104 can be present within the lumen or groove of the needle 109 and the needle likewise opens an access path for the sensor 104. In either case, after facilitating insertion, the needle is then removed.

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

[0087] According to various embodiments, the analyte sensor of the present disclosure may include a two-electrode or three-electrode detection motif. The three-electrode motif may include a working electrode, a counter electrode, and a reference electrode. The two-electrode motif may include a working electrode and a second electrode, and the second electrode functions as both a counter electrode and a reference electrode (i.e., a counter / reference electrode). In both the two-electrode and three-electrode detection motifs, the sensing region of the analyte sensor 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 each other, as described in more detail below. In alternative embodiments, the various electrodes may be spaced apart from each other on the insertion tail of the analyte sensor.

[0088] FIG. 2 shows a diagram of an exemplary two-electrode sensor configuration that is 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 inserted therebetween. The sensing region 218 is disposed as at least one spot on at least a portion of the working electrode 214. The membrane 220 overcoats at least the sensing region 218 and, optionally, in some embodiments, may 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 include any of the polymer membrane compositions disclosed herein.

[0089] The three - electrode sensor configuration can be similar to the analyte sensor 200, except that it includes additional electrodes (Figs. 3A, 3B). Using the additional electrode 217, the counter / reference electrode 216 then functions as either a counter electrode or a reference electrode, and the additional electrode 217 (Figs. 3A and 3B) serves other functions not performed otherwise. The additional electrode 217 can be disposed either on the working electrode 214 or the counter / reference electrode 216 with a dielectric separation layer sandwiched therebetween. For example, as shown in Fig. 3A, dielectric layers 219a, 219b, and 219c separate electrodes 214, 216, and 217 from each other. Alternatively, at least one of electrodes 214, 216, and 217 can be disposed on the opposite surface of the substrate 212 (Fig. 3B). Thus, in some embodiments, the electrode 214 (working electrode) and the electrode 216 (counter electrode) can be disposed on opposite surfaces of the substrate 212, and the electrode 217 (reference electrode) is disposed on one of the 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 the electrode 217 (reference electrode). Similar to the sensor 200 shown in Fig. 2, the sensing region 218 can include a single spot or multiple spots configured to detect the target analyte.

[0090] In some embodiments, the additional electrode 217 can optionally be overcoated with a film 220. Figs. 3A and 3B are depicted as if all of the electrodes 214, 216, and 217 are overcoated with the film 220, and it should be recognized that only the sensing region 218 needs to be overcoated to achieve the advantages described herein. Thus, the configurations shown in Figs. 3A and 3B should be understood not to limit the embodiments disclosed herein. Similar to the two - electrode configuration, one or both sides of the sensor 200 can be overcoated with the film 220.

[0091] When coating the sensing region 218, the membrane 220 can have a thickness in the range of from about 0.1 micron 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 can include a polymer bound to glucose oxidase or another enzyme, and a low-potential osmium complex electron transfer medium, as disclosed, for example, in U.S. Patent No. 6,134,461, which is hereby incorporated by reference in its entirety. Other suitable electron transfer media can include, for example, metal compounds or complexes of ruthenium, iron, or cobalt. Ligands suitable for metal complexes can include, for example, bidentate or higher denticity ligands, such as bipyridine, biimidazole, 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 to achieve a complete coordination sphere.

[0093] The enzyme of the sensing region 218 can be covalently bound to a polymer or other suitable matrix via a crosslinking agent. Crosslinking agents suitable for reaction with free amino groups in the enzyme (e.g., with free amines in lysine) can include, for example, polyethylene glycol diglycidyl ether (PEGDGE) or other polyepoxides, cyanuric chloride, N-hydroxysuccinimide, imido esters, or derivatized variants thereof. Crosslinking agents suitable for reaction with free carboxylic acid groups in the enzyme can include, for example, carbodiimides.

[0094] To determine the concentration of an analyte using the analyte sensor 200, various approaches can be employed. For example, the concentration of the analyte can be monitored using any of the electrochemical detection techniques of coulometry, amperometry, voltammetry, or potentiometry.

[0095] The embodiments disclosed in this specification include the following. A. Polymer Membrane Composition The polymer membrane composition includes: a polymer backbone including one or more side chains containing a heterocyclic ring; a polyether arm not containing an amine, which is attached to a heterocyclic ring of at least a part of one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer.

[0096] B. Analyte Sensor The analyte sensor includes: a sensing region; and a polymer membrane composition covering the sensing region. Here, the polymer membrane composition includes a polymer including one or more side chains containing a heterocyclic ring Skeleton and a polyether arm not containing an amine, which is attached to a heterocyclic ring of at least a part of one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer.

[0097] C. Polymer Membrane Composition Having Temperature Insensitivity to Glucose or Other Potential Analytes The polymer membrane composition is temperature-insensitive at least in terms of glucose permeability over a temperature range of about 15 °C to about 45 °C and meets or exceeds the ISO10993-1 standard.

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

[0099] Element 2: Here, the polymer Skeleton includes a copolymer of vinylpyridine and styrene. Element 3: The polyether arm not containing an amine includes at least one polyethylene oxide block and at least one polypropylene oxide block, and the polyether arm not containing an amine is bonded to a heterocyclic or heteroaromatic nitrogen atom of a side chain of the polymer Skeleton and is bonded to a heterocyclic or heteroaromatic nitrogen atom of a side chain of the polymer.

[0100] Element 4: The polyether arm without amine has the structural formula of

[0101] [Chemical formula]

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

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

[0104] Element 9: Here, the polymer membrane composition further includes a sulfonate-containing arm attached to at least a part of one or more side chains. Element 10: Here, the polymer membrane composition further includes a cross-linking agent attached to at least a part of one or more side chains to bind the first polymer backbone to the second polymer backbone.

[0105] Element 11: Here, the sensing region contains an enzyme. Element 12: Here, the polymer membrane composition further includes a polyethylene oxide arm without amine attached to a heterocycle of at least a part of one or more side chains via an alkyl spacer or a hydroxy-functionalized alkyl spacer.

[0106] As non-limiting examples, exemplary combinations applicable to A and B include the following. A composition of A in combination with Element 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; 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, 10; Element 3, 4; Element 3, 4, 5; Element 3, 4, 6; Element 3, 4, 5, 6; Element 3, 4, 7; Element 3, 4, 5, 7; Element 3, 4, 8; Element 3, 4, 5, 9; Element 3, 9; Element 3, 103, 9, 10; Element 4, 5; Element 4, 6; Element 4, 5, 6; Element 4, 7; Element 4, 5, 7; Element 4, 8; Element 4, 5, 8; Element 4, 9; Element 4, 10; Element 4, 9, 10; Element 4, 12; Element 9, 10; Element 10, 12; Element 11, 12. An analyte sensor of B in combination with Element 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; 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, 10; Element 3, 4; Element 3, 4, 5; Element 3, 4, 6; Element 3, 4, 5, 6; Element 3, 4, 7; Element 3, 4, 5, 7; Element 3, 4, 8; Element 3, 4, 5, 9; Element 3, 9; Element 3, 103, 9, 10; Element 4, 5; Element 4, 6; Element 4, 5, 6; Element 4, 7; Element 4, 5, 7; Element 4, 8; Element 4, 5, 8; Element 4, 9; Element 4, 10; Element 4, 9, 10; Element 4, 12; Element 9, 10; Element 10, 12; Element 11, 12, which can also be combined with Element 11. The composition of C can be used in combination with any element applicable to A.

[0107] For the purpose of facilitating 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 present invention.

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

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

[0110] Example 3: Biocompatibility Test. A polyvinylpyridine copolymer with styrene having an amine-free polyether arm corresponding to Chemical 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 conduct several biocompatibility tests. The tests were carried out in accordance with the ISO10993-1 protocol and are briefly described below.

[0111] Cytotoxicity. Polymers having polyether arms without amines were tested for cytotoxicity under standard conditions using the minimum essential elution medium test. The results are shown in Table 1. The cytotoxicity test was performed by applying an extract of the polymer (minimum essential medium without glucose) to a monolayer of test cells, culturing, and scoring based on the degree of monolayer disruption and the amount of cell lysis. A score of "0" indicates no observable monolayer disruption or cell lysis. Mild cytotoxicity is classified with a score of "2" or less (<50% monolayer disruption without extensive cell lysis). A score of 2 or less meets the requirements of the current US Pharmacopeia and the US National Formulary ( <usp87>) is regarded as an acceptable criterion for a specific purpose.

[0112]

Table 1

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

[0114] Mutagenicity. The Ames test was used to perform a mutagenicity test on the polymer of Entry 3. The extract of the polymer did not meet the mutagenicity requirements in this test. Single-dose systemic irritation test. The extract of the polymer of Entry 3 was injected intravenously or intraperitoneally. No signs of toxicity were observed during the observation period compared to the control.

[0115] Skin irritation test. In the skin irritation test of the extract of the polymer of Entry 3, a sensitization reaction score of 0 was obtained, which means there was no visible erythema or edema. Intradermal irritation test. In the intradermal irritation test of the extract of the polymer of Entry 3, no abnormal clinical signs occurred over the 72-hour observation period compared to the vehicle control. The calculated erythema and edema scores were less than 1 compared to the control (there was no erythema or edema that was hardly perceptible).

[0116] Transplantation study. The polymer of Entry 3 produced an irritation score of 0.2 at the time of transplantation and was thus classified as non-irritating. Unless otherwise specified, all numbers expressing quantities or the like in this specification and the related claims are to 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 be construed in light of the reported significant digits and by applying ordinary rounding techniques.

[0117] This specification presents one or more exemplary embodiments incorporating various features. For clarity, not all functions of a physical implementation are described or shown in this application. It is understood that in developing a physical implementation incorporating embodiments of the present invention, numerous implementation-specific decisions must be made to achieve the developer's goals, such as system-related, business-related, government-related, and compliance. Constraints vary by implementation and over time. Although the developer's efforts may be time-consuming, such efforts are routine for those of ordinary skill in the art and are benefited by this disclosure. Various systems, tools, and methods are described herein from the perspective of "including" various components or steps, but the systems, tools, and methods can also "consist essentially of" or "consist of" various components and steps.

[0118] As used herein, the phrase "at least one" before a series of items, together with the term "and" or "or" separating any of the items, modifies the list as a whole (i.e., each item), rather than each member of the list. The phrase "at least one of" enables the meaning of including 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" each refer to only A, only B, or only C, any combination of A, B, and C, and / or at least one of each of A, B, and C.

[0119] Accordingly, the disclosed systems, tools, and methods are well adapted to attain the recited objects and advantages, as well as those inherent therein. The teachings of the present invention may be modified and practiced in different but equivalent manners that will be apparent to those skilled in the art having the benefit of the teachings herein, and the specific embodiments disclosed above are merely exemplary. Further, no limitations are intended as to the details of the structure or design shown herein, other than as described in the appended claims. Accordingly, it is evident that the specific exemplary embodiments disclosed above may be varied, combined, or modified, and all such variations are considered to be within the scope of the present invention. The systems, tools, and methods exemplified herein may be suitably practiced without the elements specifically disclosed herein and / or in the absence of any of the elements disclosed herein. The systems, tools, and methods are described from the perspective of including, containing, or comprising various members or steps, but the systems, tools, and methods may also consist essentially of or consist of various members. All of the numbers and ranges disclosed above may vary to some extent. When a numerical range with a lower limit and an upper limit is disclosed, any number and any included range within that range are always specifically disclosed. In particular, all range values disclosed herein (in the form of "about a to about b", or equivalently "about a to b", or equivalently "about ab") should be understood as follows. It indicates all numbers and ranges included within the broader range of values. Also, the terms of the claims have their plain and ordinary meaning unless explicitly and clearly defined by the patentee. Further, the indefinite article "a" or "an" used in the claims is defined herein to mean one or more of the elements it introduces. In the event of any conflict in the use of terms or terminology in this specification and one or more patents or other documents incorporated herein by reference, the definitions consistent with this specification should be adopted.

Claims

1. An analyte sensor comprising a sensing region and a polymer membrane material covering the sensing region, wherein the polymer membrane material comprises a first polymer backbone containing polyvinylpyridine, and a part of a plurality of pyridine rings of the polyvinylpyridine is functionalized by a polyether arm without amine, which is attached to a nitrogen atom of the part of the pyridine rings via an alkyl spacer or a hydroxy-functionalized alkyl spacer, the polyether arm without amine comprises at least one polyethylene oxide block and at least one polypropylene oxide block, and the polymer membrane material is at least insensitive to temperature with respect to glucose permeability over a temperature range of 15 °C to 45 °C. The analyte sensor as claimed in claim 1.

2. The analyte sensor according to claim 1, wherein the first polymer backbone of the polymer membrane material comprises a polyvinylpyridine homopolymer.

3. The analyte sensor according to claim 1, wherein the first polymer backbone of the polymer membrane material comprises a copolymer of vinylpyridine and styrene.

4. The analyte sensor according to claim 1, wherein the sensing region comprises an analyte-responsive enzyme.

5. The analyte sensor according to claim 4, wherein the analyte-responsive enzyme is a glucose-responsive enzyme.

6. The analyte sensor according to claim 5, wherein the glucose-responsive enzyme is glucose oxidase or glucose dehydrogenase.

7. The analyte sensor according to claim 4, wherein the analyte-responsive enzyme is a lactate-responsive enzyme.

8. The analyte sensor according to claim 7, wherein the lactate-responsive enzyme is lactate oxidase or lactate dehydrogenase.

9. The analyte sensor according to claim 4, wherein the analyte-responsive enzyme is covalently bonded to the polymer membrane material.

10. The polyether arm without amine of the polymer membrane material has the following structure: wherein w is 0 or 1, x ranges from 4 to 24, y ranges from 8 to 60, and z ranges from 6 to 36. The analyte sensor as claimed in claim 1. 【Chemical 1】

11. The analyte sensor according to claim 10, wherein x ranges from 6 to 16, y ranges from 10 to 40, and z ranges from 8 to 20.

12. ​ The analyte sensor according to claim 10, wherein x is in the range between 9 and 12, y is in the range between 16 and 30, and z is in the range between 12 and 16.

13. The analyte sensor according to claim 1, wherein the polymer film material further comprises a sulfonate-containing arm attached to a part of a plurality of pyridine rings of the polyvinylpyridine.

14. The analyte sensor according to claim 1, wherein the polymer film material further comprises a crosslinking agent that binds the first polymer backbone to a second polymer backbone, the crosslinking agent being added to a part of a plurality of pyridine rings of the polyvinylpyridine of the first polymer backbone, and the crosslinking agent comprising a first part bound to the first polymer backbone and a second part bound to the second polymer backbone.

15. The analyte sensor according to claim 1, wherein the polymer film material exhibits a cytotoxicity score of 2 or less under the requirements of the United States Pharmacopeia and the National Formulary of the United States (<USP 87>).

16. An in vivo analyte sensor for measuring the concentration of an analyte in a user's body fluid, A first part connected to an analyte monitoring system, the first part being positionable on the surface of the skin, the first part, A second part positionable under the surface of the skin, the second part being in contact with the body fluid and configured to monitor the concentration of the analyte in the body fluid, the second part including an electrode connected to a contact part located on the first part, the second part, The analyte monitoring system includes a sensor control device configured to measure data indicating the analyte concentration and transmit the data indicating the analyte concentration to a reader device via an electronic communication protocol through a transmitter connected to the sensor control device, and a power source for operating the sensor control device. The electrode of the second part includes a working electrode including at least one sensing region and a polymer film material covering the sensing region. The polymer film material includes a polymer backbone containing polyvinylpyridine, and a part of a plurality of pyridine rings of the polyvinylpyridine is functionalized by a polyether arm containing no amine, which is added to a nitrogen atom of the part of the pyridine rings via an alkyl spacer or a hydroxy-functionalized alkyl spacer. The analyte sensor, wherein the amine-free polyether arm comprises at least one polyethylene oxide block and at least one polypropylene oxide block. **Claim 17** The amine-free polyether arm of the polymer film material has the following structure: [Chemical 2] wherein w is 0 or 1, x ranges from 4 to 24, y ranges from 8 to 60, z ranges from 6 to 36, or has the following structure: 【Chemical Formula 3】 wherein w is 0 or 1, x ranges from 4 to 24, y ranges from 8 to 60, z ranges from 6 to 36, the analyte sensor according to claim 16.

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