Method for manufacturing an analyte sensor cover membrane

Abstract

The present invention relates to a process for forming a film on an analyte sensor. The present invention further relates to an analyte sensor obtainable by said process. Furthermore, the present invention relates to a process for forming a sensing layer on an electrode of an analyte sensor, and an analyte sensor comprising a sensing layer obtainable by the process of the present invention as well as a film obtainable by the process of the present invention. The analyte sensors obtainable by the processes of the present invention can be primarily used to measure one or more analytes in the body fluids of a user or patient. The present invention can be applied to both the field of home care and professional medical fields such as hospitals. It can also be generally implemented in other application fields.

Description

Technology Field

[0001] The present invention relates to a process for forming a film on an analyte sensor. The present invention further relates to an analyte sensor obtainable by said process. Furthermore, the present invention relates to a process for forming a sensing layer on an electrode of an analyte sensor, and an analyte sensor comprising a sensing layer obtainable by the process of the present invention as well as a film obtainable by the process of the present invention. The analyte sensors obtainable by the processes of the present invention can be primarily used to measure one or more analytes in the body fluids of a user or patient. The present invention can be applied to both the field of home care and professional medical fields such as hospitals. It can also be generally implemented in other application fields. Background Technology

[0002] Biosensors designed to measure analytes of biological fluids, particularly those designed for implantation to measure body fluids, must perform various functions. Meanwhile, said sensors must provide specific and sensitive measurements without interference from specific components of the body fluid, such as cells. For this purpose, biosensors are often covered with a membrane that excludes specific compounds, allowing access to the actual detection site only for low-molecular-weight compounds. Furthermore, in the case of implantable sensors, it is desirable to have sensors that can remain in place for a long period without degradation of measurement, so that the patient does not have to replace the sensor frequently.

[0003] The implanted sensor comprises an electrode system that facilitates, for example, the measurement of physiologically significant analytes, such as glucose within the patient's body. The working electrode of the sensor has an electrically conductive enzyme layer to which enzyme molecules are bound, which release charge carriers by the catalytic conversion of analyte molecules. In this process, a current is generated as a measurement signal whose amplitude is correlated with the analyte concentration. This type of sensor is also referred to as an electrochemical sensor.

[0004] The electrochemical sensor described above is known, for example, in WO 2007 / 147475 and WO 2010 / 028708. The working electrode of the electrode system is provided with a diffusion barrier that controls the diffusion of an analyte to be measured from the body fluid or tissue surrounding the electrochemical sensor to enzyme molecules immobilized within the enzyme layer. WO 2007 / 147475 discloses a diffusion barrier made of a polymer having a binary ionic structure.

[0005] WO 2012 / 019083 discloses a diffusion-limiting membrane comprising polyurethane, siloxane, and hydrogel. The membrane is prepared by first mixing the polymers, then depositing the polymers onto a sensor, and then evaporating the solvent.

[0006] The sensor disclosed in the prior art has only limited long-term stability, particularly in in vivo applications. The problem to be solved

[0007] Accordingly, the object of the present invention is to provide improved means and methods for forming a film on an analyte sensor that at least partially prevent the disadvantages of the prior art, particularly with respect to long-term stability and film performance.

[0008] The above problem is solved by a process of forming a film on an analyte sensor, as well as an analyte sensor obtainable by said process, and a process of forming a sensing layer on an electrode of the analyte sensor, and an analyte sensor comprising a sensing layer obtainable by said process and a film obtainable by said process of the present invention. Preferred embodiments of the present invention that can be realized in separate ways or in any combination are disclosed throughout the dependent claims and the entirety of the present application. Specific details for implementing the invention

[0009] The terms "have," "comprise," or "include" used below, or any grammatical variations thereof, are used in an exclusive manner. Accordingly, the said terms may refer to both situations in which no further additional features exist within the entity described in the above context, in addition to the features introduced by the said terms, and situations in which one or more additional features exist. For example, the expressions "A has B," "A includes B," and "A includes B" may refer to both situations in which no other element exists within A other than B (i.e., situations consisting solely and exclusively of B) and situations in which one or more additional elements, such as elements C, C and D, or additional elements exist within entity A other than B.

[0010] Additionally, it should be noted that terms such as "at least one," "one or more," or similar expressions indicating that a feature or element may exist one or more times are generally used only once when introducing each feature or element. In the following, in most cases, when referring to each feature or element, the expressions "at least one" or "one or more" will not be repeated, despite the fact that each feature or element may exist one or more times.

[0011] Additionally, the terms “preferably,” “more preferably,” “in detail,” “in more detail,” “specifically,” “more specifically,” or similar terms used below are used with optional features without limiting alternative possibilities. Accordingly, features introduced by the above terms are optional features and are not intended to limit the scope of the claims in any way. As will be recognized by those skilled in the art, the present invention may be practiced using alternative features. Similarly, features introduced by “in an embodiment of the present invention” or similar expressions are intended to be optional features without any limitation to alternative embodiments of the present invention, without any limitation to the scope of the invention, and without any limitation to the possibility of combining features introduced in such a manner with optional or non-functional features of the present invention.

[0012] In a first aspect of the present invention, a process for forming a film on an analyte sensor is disclosed, and said process,

[0013] a) a step of providing the above-mentioned analyte sensor,

[0014] b) a step of providing a polymer solution,

[0015] (A) One or more first polymers comprising one or more first crosslinkable groups,

[0016] (B) One or more second polymers comprising one or more second crosslinkable groups, and

[0017] (C) a step of providing a polymer solution comprising one or more first solvent components,

[0018] c) a step of contacting the analyte sensor provided in step a) with the polymer solution provided in step b) to obtain an analyte sensor coated with said polymer solution,

[0019] d) drying the analyte sensor obtained in step c) to obtain a dried analyte sensor coated with a polymer blend comprising one or more first polymers and one or more second polymers, and

[0020] e) a step of curing a polymer blend that coats the dried analyte sensor obtained in step d), thereby crosslinking the one or more first polymers and the one or more second polymers to form a film on the analyte sensor.

[0021] In the present invention, the indicated steps may preferably be carried out in a given order, starting from process step a) and ending at process step e), but some or all of the indicated steps, particularly process step a) and process step b), may be carried out at least partially simultaneously, and / or step b) may be carried out prior to step a). Additionally, additional process steps may also be carried out, whether described herein or not.

[0022] As further used herein, the term “analyte” may refer to any element, component, or compound that may be present in body fluids and whose concentration may be of interest to the user. Preferably, said analyte may be or include any chemical substance or chemical compound that may participate in the user’s metabolism, such as at least one metabolite. As an example, said at least one analyte may be selected from the group consisting of glucose, cholesterol, triglycerides, and lactate. However, additionally or alternatively, other types of analytes may be used and / or any combination of analytes may be determined. Preferably, said analyte is glucose.

[0023] The commonly used term "analyte sensor" may refer to any device configured for the detection of an analyte. Preferably, the analyte sensor is a biosensor. More preferably, the analyte sensor is an electrochemical sensor. The term "electrochemical sensor" refers to a sensor suitable for performing one or more electrochemical measurements, particularly multiple or a series of electrochemical measurements, to detect one or more analytes contained in body fluids using amperometric methods. In particular, the term "electrochemical measurement" means detecting electrochemically detectable characteristics of an analyte, such as an electrochemical detection reaction, using amperometric methods. Thus, for example, the electrochemical detection reaction may be performed by applying and comparing one or more electrode potentials. Accordingly, the analyte sensor preferably comprises electrodes. Specifically, the electrochemical sensor may be configured to generate at least one electrical measurement signal capable of directly or indirectly indicating the presence and / or absence of an electrochemical detection reaction, such as at least one current signal and / or at least one voltage signal. The measurement may be qualitative and / or quantitative. Additionally, other embodiments are feasible.

[0024] In particular, the analyte sensor comprises an electrode. The electrode may be implemented in such a way that an oxidation process and / or a reduction process can occur on a selected surface of the electrode. In one embodiment, the electrode is a working electrode. In a particularly preferred embodiment used herein, the analyte sensor has a working electrode, a reference electrode and a counter electrode, and both the working electrode and the reference electrode may be covered with a membrane, the working electrode may further comprise an enzyme, and the working electrode may comprise the enzyme or be covered with an enzyme layer.

[0025] When the analyte sensor is an electrochemical sensor, it preferably includes an electrode system. In one embodiment, the analyte sensor includes a working electrode having immobilized enzyme molecules for the conversion of analytes that generate an electrical signal. The enzyme may be present in a layer covering the electrode. In one embodiment, the layer is a sensing layer. The process of forming the sensing layer is described in more detail below. Additionally, carbon particles and porous particles, as well as redox media and / or electrochemical catalysts, may be present inside or on the working electrode. Electrodes of this type are described, for example, in WO 2007 / 147475, the contents of which are incorporated herein by reference.

[0026] In a particularly preferred embodiment of the present invention, the analyte sensor may be wholly or partially implantable and thus configured to perform detection of analytes in body fluids within subcutaneous tissue, particularly interstitial fluid. As used herein, the terms “implantable” or “subcutaneous” refer to being wholly or at least partially arranged within the body tissue of a patient or user. For this purpose, the analyte sensor may comprise an implantable portion, the term “implantable portion” may generally refer to a part or component of an element configured to be implantable within any body tissue, while other parts or components may remain outside said body tissue. Preferably, the implantable portion may wholly or partially comprise a biocompatible surface, that is, a surface capable of having as little harmful effect as possible on the user, patient, or body tissue during at least a normal period of use. In one embodiment of the present invention, the biocompatible surface is a membrane obtainable by the process of the present invention.

[0027] The commonly used term "body fluid" may refer to a fluid, in particular, a fluid that may typically be present in or / or produced by the body of a user or patient within the body or body tissues. Preferably, said body fluid may be selected from the group consisting of blood and interstitial fluid. However, additionally or alternatively, one or more other types of body fluids, such as saliva, tears, urine, or other fluids may be used. While detecting said one or more analytes, said body fluid may be present in the body or body tissues. Accordingly, said analyte sensor may be configured to detect at least one or more analytes within body tissues. In one embodiment, said analyte sensor may be suitable for short-term application, e.g., 3 to 21 days, or long-term application, e.g., 1 to 12 months. During said application, said analytes may be determined by continuous or discontinuous measurements.

[0028] In step a) of the process of forming a film on the analyte sensor of the present invention, the analyte sensor is provided.

[0029] In one embodiment, the analyte sensor comprises one or more substrates and one or more first electrodes. In one embodiment, the one or more first electrodes are one or more working electrodes and are configured to detect the analyte. The analyte sensor may be dimensioned to enable transdermal insertion by providing a width in a direction perpendicular to the insertion direction, generally 5 mm or less, preferably 2 mm or less, more preferably 1.5 mm or less. The sensor may have a length of less than 50 mm, for example, 30 mm or less, for example, 5 mm to 30 mm. However, it should be noted that other dimensions are also possible.

[0030] The above-described analyte sensor may include a sensing layer obtainable by the process of the present invention for forming a sensing layer on the first electrode of the analyte sensor described below.

[0031] In step b), a polymer solution is provided. The polymer solution comprises one or more first polymer components (A) comprising one or more first crosslinkable groups, one or more second polymer components (B) comprising one or more second crosslinkable groups, and one or more first solvent components (C).

[0032] In the context of the present invention, the terms "component (A)" and "one or more first polymers comprising one or more first crosslinkable groups" are used as synonyms and thus have the same meaning.

[0033] Additionally, in the context of the present invention, the terms "component (B)" and "one or more second polymers comprising one or more second crosslinkable groups" are used as synonyms and thus have the same meaning.

[0034] Within the context of the present invention, the terms "component (C)" and "one or more solvents" are used synonyms and thus have the same meaning.

[0035] In step b), the polymer solution may be provided by any known method. For example, component (A) and component (B) may optionally be added to component (C) while stirring component (C). In one embodiment, component (C) is at a dissolution temperature (T) while component (A) and component (B) are added to component (C). S It is heated to the melting temperature (T). For example, the melting temperature (T S ) is in the range of 0 to 50°C.

[0036] In one embodiment, the polymer solution contains component (A) in a range of 30 to 99.5 mol%, preferably 50 to 99 mol%, based on the sum of the mol% of component (A) and component (B).

[0037] In one embodiment, the polymer solution contains component (B) in a range of 0.5 to 70 mol%, preferably 1 to 50 mol%, based on the sum of the mol% of component (A) and component (B).

[0038] The sum of the mole percentages of component (A) and component (B) is generally added up to 100 mole percentages.

[0039] In one embodiment, the polymer solution contains component (C) in a range of 1 to 50 weight%, preferably 5 to 30 weight%, based on the total weight of component (A), component (B), and component (C), preferably based on the total weight of the polymer solution.

[0040] It is obvious to those skilled in the art that the above mol% is related to the amounts of component (A) and component (B) before they react with each other. It is also obvious that the molar ratio between the components may change, for example, during drying in step d) and / or curing in step e).

[0041] The polymer solution may further comprise a component (Ba) which is one or more additional polymers comprising one or more third crosslinkable groups. For the one or more third crosslinkable groups, the embodiments and preferences described below for the one or more first crosslinkable groups are valid.

[0042] The optional component (Ba) is different from component (A) and component (B). One or more suitable additional polymers are, for example, polyethylene glycols having benzophenone as one or more crosslinking groups. Polyethylene glycols having benzophenone as one or more crosslinking groups are also referred to as PEG-BP. One suitable PEG-BP is shown in Fig. (I):

[0043] (I),

[0044] Here

[0045] n is in the range of 100 to 10000, preferably in the range of 200 to 5000.

[0046] In one embodiment, the polymer solution comprises one or more crosslinking agents. The one or more crosslinking agents are different from component (A), component (B), and optional component (Ba). The one or more crosslinking agents are oligomers or monomers, preferably monomer compounds. Suitable crosslinking agents are selected from the group consisting of, for example, epoxides, thiols containing crosslinking agents, benzophenones containing crosslinking agents, anhydrides, and imides.

[0047] Suitable epoxides are, for example, glycidyl glycerol ethers.

[0048] Suitable thiol-containing crosslinking agents are selected from the group consisting of, for example, 1,2-ethane dithiol, 1,3-propane trithiol, ethane-1,1,2,2-tetrathiol, ethene-1,1,2,2-tetrathiol, pentaerythryl tetrathiol (= 2,2-bis(mercaptomethyl)propane-1,3-dithiol), 2,2'-(ethylenedioxy)diethanethiol, tetra(ethylene glycol)dithiol, hexa(ethylene glycol)dithiol, 1,4-benzenedimethanethiol, 2,2-bis(sulfanylmethyl)propane-1,3-dithiol, benzene-1,2,4,5-tetrathiol, and SH-functionalized nanoparticles.

[0049] In one embodiment of the present invention, the polymer solution provided in step ii) does not contain one or more crosslinking agents. In one embodiment, the polymer solution provided in step ii) consists of component (A), component (B) and component (C), and optionally component (Ba).

[0050] In the context of the present invention, the term "polymer solution" refers not only to a solution in the ordinary and conventional sense but also to heterogeneous mixtures such as colloidal solutions or suspensions. "Solution" means that component (A), component (B), and component (C) form a homogeneous mixture (i.e., a single phase). The solution does not scatter light, and the solutes (components (A) and (B)) cannot be separated from the solvent (component (C)) by filtration. "Colloidal solution" and "suspension" mean that component (A) and component (B) are in a solid state and are suspended in component (C). Thus, component (A) and component (B) form a dispersed phase (suspended particles), and component (C) forms a continuous phase (suspension medium). In a colloidal solution, the particles of the dispersed phase have a diameter between about 1 and 1000 nm. In a suspension, the particles of the dispersed phase have a diameter greater than 1000 nm. Preferably, the term "polymer solution" relates to a solution in which component (A), component (B) and component (C) form a homogeneous mixture.

[0051] Component (A) is one or more first polymers comprising one or more first crosslinkable groups. For example, the one or more first polymers comprises the one or more first crosslinkable groups in a range of 0.5 to 20 mol% based on the sum of the mol% of the one or more first polymers and the one or more first crosslinkable groups, preferably in a range of 2 to 8 mol% based on the total amount of component (A).

[0052] The one or more first crosslinkable groups are directly connected to the one or more first polymers. In one embodiment, the one or more first crosslinkable groups are groups that form radicals when exposed to heating and / or light.

[0053] For example, the one or more first crosslinkable groups are selected from the group consisting of benzophenone groups, azide groups, anthraquinone groups, and psoralen.

[0054] Suitable azide groups are selected from the group consisting of, for example, sulfonyl azide groups, phenyl azide, ortho-hydroxyphenyl azide, meta-hydroxyphenyl azide, tetrafluorophenyl azide, ortho-nitrophenyl azide, meta-nitrophenyl azide, diazirin, and azido-methylcoumarin.

[0055] The above one or more first polymers are homopolymers or copolymers. Suitable copolymers are block copolymers or statistical copolymers. A block copolymer comprises two or more different blocks, each block being prepared from one or more types of monomers, whereas a statistical copolymer comprises a series of units prepared from different monomers according to statistical rules. If the copolymer is prepared from monomer X and monomer Y, the block copolymer comprises a block prepared only from monomer X and a block prepared only from monomer Y. In a statistical copolymer, for example, three units prepared from monomer X are followed by five units prepared from monomer Y, then two units prepared from monomer X, and then one unit prepared from monomer Y, etc.

[0056] For example, one or more of the first polymers mentioned above are hydrophobic polymers.

[0057] For example, the above one or more first polymers are ethyl acrylate (EA),

[0058] It is selected from the group consisting of n-propyl acrylate, i-propyl acrylate, n-butyl acrylate (n-BuA), sec-butyl acrylate (sec-BuA), i-butyl acrylate (i-BuA), 3-pentyl acrylate, n-pentyl acrylate, n-hexyl acrylate, n-hexyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, n-heptyl acrylate, n-heptyl methacrylate, n-octyl acrylate, n-octyl methacrylate, n-nonyl acrylate, n-nonyl methacrylate, n-decyl methacrylate, iso-decyl methacrylate, n-dodecyl methacrylate, n-dodecyl acrylate, polyurethane, styrene, and combinations thereof.

[0059] Component (B) is one or more second polymers comprising one or more second crosslinkable groups. For example, the one or more second polymers comprise the one or more second crosslinkable groups in a range of 0.5 to 20 mol%, preferably in a range of 2 to 8 mol%, based on the sum of the mol% of the one or more second polymers and the one or more second crosslinkable groups, and preferably based on the total amount of component (B).

[0060] In the case of the above one or more second crosslinkable groups, the above-described embodiments and preferences are valid for the above one or more first crosslinkable groups.

[0061] Accordingly, the one or more second crosslinkable groups are groups that form radicals when exposed to heating and / or light in one embodiment. The one or more second crosslinkable groups are directly connected to the one or more second polymers.

[0062] The above one or more second crosslinking groups are selected from the group consisting of, for example, benzophenone groups, azide groups, anthraquinone groups, and psoralen.

[0063] In the case of the azide group above, the embodiments described above are valid.

[0064] Accordingly, in one embodiment of the process of the present invention, the one or more first crosslinkable groups and the one or more second crosslinkable groups are independently selected from the group consisting of benzophenone groups, azide groups, anthraquinone groups and psoralen.

[0065] The one or more second polymers are different from the one or more first polymers. In the context of the present invention, "different" means that the one or more first polymers and the one or more second polymers are different, for example, in their characteristics and / or in the types of the one or more first polymers and the one or more second polymers.

[0066] The one or more second polymers mentioned above are homopolymers or copolymers. Suitable copolymers are block copolymers or statistical copolymers. In the case of the block copolymers and statistical copolymers, the embodiments and preferences described above are valid for the one or more first polymers.

[0067] In one embodiment, the one or more second polymers are hydrophilic polymers.

[0068] For example, the one or more second polymers are polyvinylpyrrolidone (PVP), side-chain functionalized polyvinylpyrrolidone, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate (HEMA), 2-methoxyethyl acrylate, 2-methoxyethyl methacrylate, 2-ethoxyethyl acrylate, 2-ethoxyethyl methacrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate (2-HPMA), 3-hydroxypropyl methacrylate (3-HPMA), 2-methoxypropyl acrylate, 3-methoxypropyl acrylate, 2-methoxypropyl methacrylate, 3-methoxypropyl methacrylate, 2-ethoxypropyl acrylate, 3-ethoxypropyl acrylate, 2-ethoxypropyl methacrylate, 3-ethoxypropyl acrylate. Selected from the group consisting of methacrylate, 1-glycerol acrylate, 2-glycerol acrylate, 1-glycerol methacrylate, 2-glycerol methacrylate, acrylamide, methacrylamide, N-alkyl acrylamide, N,N-dialkyl acrylamide, N-alkyl methacrylamide and N,N-dialkyl methacrylamide, wherein the alkyl includes methyl, ethyl or propyl, acrylic acid, methacrylic acid and combinations thereof.

[0069] In one embodiment, the one or more second polymers satisfy one or more of the following requirements:

[0070] - The above one or more second polymers further fine-tune the hydrophobicity of the membrane, and

[0071] - The above one or more second polymers reduce the diffusion of unwanted substances through the membrane, and

[0072] - The above one or more second polymers improve the bioactivity of the membrane, such as antifouling properties and / or biocompatibility.

[0073] Component (C) is one or more first solvents. Suitable first solvents are solvents in which components (A) and (B) can be dissolved or suspended. Accordingly, at least one first solvent is preferably selected from polar solvents.

[0074] Suitable polar solvents are selected from the group consisting of polar protic solvents and polar aprotic solvents.

[0075] Suitable polar protic solvents are selected from the group consisting of, for example, water, methanol, ethanol, and isopropyl alcohol.

[0076] Suitable polar aprotic solvents are selected from the group consisting of, for example, dichloromethane, tetrahydrofuran (THF), ethyl acetate, and dimethyl carbonate (DMC).

[0077] Accordingly, in one embodiment, the one or more first solvents are selected from the group consisting of water, methanol, ethanol, tetrahydrofuran (THF), and dimethyl carbonate (DMC).

[0078] Accordingly, in one embodiment of the process of the present invention for forming a film on an analyte sensor, the one or more first solvent components (C) are selected from the group consisting of water, methanol, ethanol, tetrahydrofuran (THF) and dimethyl carbonate (DMC).

[0079] In step c), the analyte sensor provided in step a) is brought into contact with the polymer solution provided in step b) to obtain an analyte sensor coated with said polymer solution.

[0080] The analyte sensor may come into contact with the polymer solution in any way. For example, the analyte sensor may come into contact with the polymer solution by immersing or submerging the analyte sensor in the polymer solution. Additionally, the analyte sensor may come into contact with the polymer solution by spray-coating the analyte sensor with the polymer solution or by performing doctor blading. Thus, in one embodiment, in step c), contact between the analyte sensor and the polymer solution is carried out by immersion, spray-coating, submersion, and / or doctor blading.

[0081] In step c), an analyte sensor coated with the polymer solution is obtained. This means that an analyte sensor coated with the polymer solution is obtained by contacting the analyte sensor with the polymer solution.

[0082] The analyte sensor is at least partially coated with the polymer solution. As described above, in one embodiment, the analyte sensor is an electrochemical sensor. In the above case, preferably, at least the working electrode is coated with the polymer solution. In one embodiment, the analyte sensor is an electrochemical sensor and only the working electrode is coated with the polymer solution. In one embodiment, the analyte sensor is completely coated with the polymer solution. In one embodiment, the analyte sensor is an electrochemical sensor and is completely coated with the polymer solution. In the context of the present invention, "completely coated" means that at least a portion of the sensor within the body of the subject is coated with the polymer solution while the sensor is in use.

[0083] The coating thickness of the polymer solution on the above-mentioned analyte sensor is, for example, in the range of 1 to 100 μm.

[0084] In step d), the analyte sensor obtained in step c) is dried to obtain a dried analyte sensor coated with a polymer blend. The polymer blend comprises the one or more first polymers and the one or more second polymers.

[0085] If the polymer solution provided in step b) further comprises a component (Ba) which is at least one additional polymer comprising one or more third crosslinkable groups, the polymer blend coating the dried analyte sensor further comprises said component (Ba).

[0086] The above-mentioned analyte sensor can be dried under reduced pressure, for example, in a vacuum.

[0087] Alternatively or additionally, drying of the analyte sensor in step d) may be carried out by heating. For example, the analyte sensor obtained in step c) is dried at a drying temperature (T D It can be heated to the above drying temperature (T D ) is generally the curing temperature (T) at which the above polymer blend is cured. C It is lower than )

[0088] This is the above drying temperature (T D ) means that the temperature is lower than the temperature for forming radicals from the one or more first crosslinkable groups and / or the one or more second crosslinkable groups. For example, the drying temperature (T) of step d). D ) is in the range of 15 to 80°C.

[0089] During drying in step d), one or more solvents (component (C)) are evaporated. This means that one or more solvents are removed from the polymer solution. Thus, the polymer blend is obtained.

[0090] Preferably, during the drying step, the polymer blend is not cured. This means that during the drying step, preferably, the one or more first polymers and the one or more second polymers, as well as the one or more first crosslinkable groups and the second crosslinkable groups, do not react with each other.

[0091] In step e), the polymer blend coating the dried analyte sensor obtained in step d) is cured. Thereby, the one or more first polymers and the one or more second polymers are cross-linked to form a film on the analyte sensor.

[0092] During the curing of step e), one or more first crosslinkable groups included in the one or more first polymers and one or more second crosslinkable groups included in the one or more second polymers react. The one or more first crosslinkable groups and the one or more second crosslinkable groups can each be crosslinked to themselves and to each other. This means that the one or more first crosslinkable groups can be crosslinked to the one or more second crosslinkable groups as well as to other first crosslinkable groups. On the other hand, the one or more second crosslinkable groups can be crosslinked to the one or more first crosslinkable groups as well as to other second crosslinkable groups.

[0093] During the curing step, the one or more first polymers and the one or more second polymers are connected to each other. Additionally, the at least one first polymer is crosslinked with itself and with the second polymer. This is also valid for the at least one second polymer. The one or more second polymers are crosslinked with itself and with the one or more first polymers. In one embodiment, it is possible for the at least one first polymer and / or the at least one second polymer to also be connected to the analyte sensor. In one embodiment, the one or more first polymers and / or the one or more second polymers are connected to the analyte sensor through the one or more first crosslinkable groups and / or the one or more second crosslinkable groups.

[0094] Curing in step e) can be performed, for example, by heating the dried analyte sensor obtained in step d) or by exposing the analyte sensor obtained in step d) to light. This means that the polymer blend covering the dried analyte sensor is heated or exposed to light.

[0095] Accordingly, in an embodiment of the process of the present invention, the curing in step e) comprises at least one of the step of heating the polymer blend and the step of exposing the polymer blend to light.

[0096] If the curing of step e) is carried out by heating the polymer blend, the dried analyte sensor obtained in step d) (i.e., the polymer blend covering the dried analyte sensor) is at a curing temperature (T C It is heated to the above curing temperature (T C ) is generally the drying temperature (T) at step d). D It is higher than ). In one embodiment, the curing temperature (T CAt ), the one or more first crosslinkable groups and / or the one or more second crosslinkable groups generally form radicals. In particular, when one of the one or more first crosslinkable groups and the one or more second crosslinkable groups comprises N (nitrogen) and the other of the one or more first crosslinkable groups and the one or more second crosslinkable groups comprises an epoxide group, the curing temperature (T C In ), the one or more first crosslinkable groups react with the one or more second crosslinkable groups. Then, the formation of radicals is not necessary.

[0097] The above curing temperature (T C ) is generally in the range of 20 to 100°C.

[0098] If the curing of step e) is carried out by exposing the dried analyte sensor obtained in step d) (i.e., the polymer blend covering the dried analyte sensor) to light, any wavelength of light that does not cleave bonds within the one or more first polymers and / or the one or more second polymers may be used. Preferably, the wavelength is in the range of UV light. This means that it is preferable for the wavelength of the light to be in the range of 200 to 400 nm.

[0099] In step e), a membrane of the analyte sensor is obtained. In one embodiment, the membrane coats the analyte sensor at least partially. Generally, the membrane coats the analyte sensor in the same area as the polymer solution in step c). In one embodiment, where curing is performed by exposing the analyte sensor (i.e., the polymer blend covering the dried analyte sensor) to light, only selected areas of the analyte sensor are cured. In particular, preferably, when the analyte sensor is an electrochemical sensor, areas within the working electrode area are cured. In the above case, it is preferable that the curing be performed by light. The uncured areas of the analyte sensor (i.e., areas not exposed to light) are removed after step e).

[0100] The above film has a thickness in the range of, for example, 1 to 100 μm.

[0101] In an embodiment of the present invention, the membrane is a diffusion limiting membrane. The diffusion limiting membrane is also referred to as a diffusion barrier. The diffusion limiting membrane controls the diffusion of an analyte from a body fluid surrounding the analyte sensor to an enzyme molecule, which is an embodiment of the present invention, contained in the sensing layer of the analyte sensor.

[0102] Another objective of the present invention is an analyte sensor obtainable by the process of the present invention.

[0103] The process of the present invention is particularly advantageous because it facilitates the easy fabrication of a membrane on an analyte sensor. Preferably, the analyte sensor is coated with the membrane. Additionally, the properties of the membrane can be easily matched based on the one or more first polymers and the one or more second polymers. The obtained membrane has a well-defined and long-term stable structure. In particular, when the membrane is also covalently fixed to the sensor surface, the durability of the analyte sensor for in vivo application is particularly improved. Furthermore, it is easier to predict the properties of the obtained membrane.

[0104] In a second aspect of the present invention, a process of forming a sensing layer on a first electrode of an analyte sensor is disclosed, and the method is:

[0105] i) providing an analyte sensor comprising one or more first electrodes, wherein the first electrode comprises a first electrode material,

[0106] ii) a step of reacting one or more first electrodes of the analyte sensor provided in step i) with a functionalizing compound comprising one or more first groups reactive to the first electrode material and one or more crosslinkable second groups to obtain one or more functionalized first electrodes,

[0107] iii) a step of providing a polymer mixture,

[0108] (D) One or more mediating polymers comprising one or more crosslinkable groups, and

[0109] (E) a step of providing a polymer mixture comprising one or more second solvents,

[0110] iv) a step of contacting one or more functionalized first electrodes obtained in step ii) with a polymer mixture provided in step iii) to obtain one or more coated functionalized first electrodes,

[0111] v) drying one or more coated functionalized first electrodes obtained in step iv) to obtain one or more dried coated first electrodes coated with one or more mediating polymers, and

[0112] vi) The step of curing the one or more dried coated first electrodes to crosslink one or more second groups of the functionalized compound and one or more crosslinkable groups of the one or more mediating polymers to form a sensing layer on the electrode of the analyte sensor.

[0113] In the present invention, the indicated steps i) through vi) may preferably be carried out in a given order, starting from process step i) and ending at process step vi), but some or all of the indicated steps, in particular process step i) and process step iii) may be carried out at least partially simultaneously, and / or step iii) may be carried out before step i). Additionally, additional process steps may also be carried out, whether described herein or not.

[0114] An analyte sensor is provided in step i). For the analyte sensor, the embodiments and preferences described above are valid for the analyte sensor provided in step a) of the process of the present invention for forming a film on the analyte sensor. The analyte sensor comprises one or more first electrodes. In one embodiment, the one or more first electrodes are one or more working electrodes. The one or more first electrodes comprise a first electrode material. In one embodiment, the first electrode material comprises a conductive material. For example, the first electrode material is selected from the group consisting of metals, metal oxides, and carbon.

[0115] Preferably, the first electrode material is a metal. Suitable metals are selected from the group consisting of, for example, gold, copper, palladium, iridium, silver, and alloys thereof. Suitable metal oxides are selected from the group consisting of, for example, iridium-tin oxide.

[0116] In one embodiment of the process of forming a sensing layer on an electrode of an analyte sensor, the first electrode material comprises one or more metals. In a further embodiment of the process of forming a sensing layer on an electrode of an analyte sensor, the first electrode material comprises gold.

[0117] In a preferred embodiment, the analyte sensor is an electrochemical sensor arranged in the manner of an electrochemical cell. Accordingly, at least one pair of electrodes is used. The commonly used term "electrode" refers to an entity of the analyte sensor configured to come into contact with body fluids.

[0118] In step ii), one or more first electrodes of the analyte sensor provided in step i) react with a functionalizing compound to obtain one or more functionalized first electrodes. The functionalizing compound comprises one or more first groups that are reactive to the first electrode material and one or more second groups that are crosslinkable.

[0119] A first group that is reactive to the first electrode material is selected to react with the first electrode material. In one embodiment, the one or more first groups are selected from the group consisting of silane groups, thiol groups, and disulfide groups.

[0120] One or more crosslinkable second groups are groups that form radicals when exposed to heating and / or light in one embodiment. For the one or more second groups, the embodiments and preferences described above are valid for the one or more first crosslinkable groups and the one or more crosslinkable groups. Thus, for example, the one or more crosslinkable second groups are selected from the group consisting of benzophenone groups, azide groups, anthraquinone groups, and psoralen.

[0121] In the case of the azide group above, the above-described embodiment is valid.

[0122] In the functionalized compound, the one or more first groups are preferably connected to the one or more second groups through a spacer. Suitable spacers are, for example, substituted or unsubstituted C2-C 12 It is selected from a group composed of alkandiles.

[0123] Accordingly, in one embodiment of the present invention, the functionalized compound is selected from the group consisting of triethoxysilane benzophenone, (4-benzoylbenzoyl)aminopropyltrimethoxysilane, (4-benzoylbenzoyl)aminoethyltrimethoxysilane, 4-(3'-chlorodimethylsilyl)propyloxybenzophenone, and 4-hydroxybenzophenone 1,2-dithiolan-3-pentanoate (lipoic acid benzophenone ester).

[0124] In step ii), the reaction between the one or more first electrodes and the functionalized compound may be carried out by any method. For example, first, the one or more first electrodes may be coated with the functionalized compound in the presence of one or more solvents. Second, a reaction between the first electrode material and the first group of the functionalized compound may be initiated. The one or more solvents are, for example, nonpolar solvents such as toluene.

[0125] The temperature during the reaction in step ii) is, for example, in the range of 0 to 40°C.

[0126] During the reaction between one or more first electrodes of the analyte sensor and the functionalized compound, the first electrode material of the one or more first electrodes reacts with one or more first groups reactive to the first electrode material to form a covalent bond between the functionalized compound and the first electrode material. The obtained functionalized first electrode comprises one or more crosslinkable second groups of the functionalized compound on its surface. This implies that one or more crosslinkable second groups may further react. Preferably, one or more crosslinkable second groups do not react with the first electrode material.

[0127] In step iii), a polymer mixture is provided. The polymer mixture comprises one or more mediating polymer components (D) comprising one or more crosslinkable groups, and one or more second solvent components (E).

[0128] In the context of the present invention, the term “polymer mixture” relates to a solution in the ordinary and conventional sense, as well as to a colloidal solution or suspension of component (D) and component (E). The term “solution” means that component (D) and component (E) form a homogeneous mixture (i.e., a single phase). The solution does not scatter light, and the solute (component (D)) cannot be separated from the solvent (component (E)) by filtration. The terms “colloidal solution” and “suspension” mean that component (D) is in a solid state and is suspended within component (E). Thus, component (D) forms a dispersed phase (suspended particles) and component (E) forms a continuous phase (suspension medium). In a colloidal solution, the particles of the dispersed phase have a diameter between about 1 and 1000 nm. In a suspension, the particles of the dispersed phase have a diameter greater than 1000 nm. Preferably, the polymer mixture is a solution in which component (D) and component (E) form a homogeneous mixture.

[0129] For example, the polymer mixture contains component (D) in a range of 2 to 10 weight percent based on the total weight of component (D) and component (E), preferably based on the total weight of the polymer mixture.

[0130] For example, the polymer mixture contains component (E) in a range of 90 to 98 weight percent based on the total weight of component (D) and component (E), preferably based on the total weight of the polymer mixture.

[0131] In one embodiment, the polymer mixture provided in step iii) further comprises one or more enzymes. For example, the polymer mixture then comprises the one or more enzymes in a range of 2 to 10 weight percent based on the total weight of the polymer mixture.

[0132] The weight percentages of component (D) and component (E) are generally added up to a maximum of 100 weight%. If the polymer mixture additionally contains one or more enzymes, the weight percentages of component (D) and component (E) and the weight percentages of said one or more enzymes are added up to 100 weight%.

[0133] Typically, the at least one enzyme is an oxidoreductase, that is, an enzyme that catalyzes a redox reaction. In particular, the enzyme catalyzes a redox reaction in which H2O2 is produced and / or consumed. More specifically, the enzyme catalyzes a reaction in which H2O2 is produced, for example, from O2 as a co-substrate. Specific examples of the enzyme include glucose oxidase (EC 1.1.3.4), hexose oxidase (EC 1.1.3.5), cholesterol oxidase (EC 1.1.3.6), galactose oxidase (EC 1.1.3.9), alcohol oxidase (EC 1.1.3.13), (S)-2 hydroxy acid oxidase (EC 1.1.3.15), L-glutamate oxidase (EC 1.4.3.11), or L-aspartate oxidase (EC 1.4.3.16). In particular, the enzyme is a glucose oxidase, such as the glucose oxidase of Aspergillus or Penicillium.

[0134] Component (E) is one or more second solvents. A suitable second solvent is a solvent in which component (D) can be dissolved or suspended. Accordingly, the at least one second solvent is preferably selected from protic polar solvents.

[0135] Suitable protic polar solvents are selected from the group consisting of water, methanol, and ethanol.

[0136] Component (D) is one or more mediating polymers comprising one or more crosslinkable groups. For one or more crosslinkable groups included in the one or more mediating polymers, the embodiments and preferences described for one or more second groups included in the functionalized compound that are crosslinkable are valid. Accordingly, the one or more crosslinkable groups are preferably selected from the group consisting of benzophenone groups, azide groups, anthraquinone groups, and psoralen.

[0137] In the case of the azide group above, the above-described embodiment is valid.

[0138] In the context of the present invention, "one or more mediating polymers" means a polymer comprising a mediating compound. In one embodiment, the mediating compound is a redox mediator.

[0139] In the context of the present invention, the "redox mediator" is understood to transfer electrons from an enzyme active center to the surface of the at least one first electrode.

[0140] In one embodiment, the one or more mediating polymers comprise a mediating compound selected from the group consisting of ruthenium-containing complexes and osmium-containing complexes. Accordingly, in one embodiment, the present invention relates to a process for forming a sensing layer on an electrode of an analyte sensor, wherein the component (D), which is one or more mediating polymers, comprises a redox mediator selected from the group consisting of ruthenium-containing complexes and osmium-containing complexes.

[0141] Preferably, the one or more mediating polymers are statistical copolymers of two or more different types of polymers.

[0142] The polymer mixture provided in step iii) may further comprise a component (Da) which is one or more second additional polymers comprising one or more second additional crosslinkable groups. For the one or more second additional crosslinkable groups, the embodiments and preferences described above are valid for the one or more crosslinkable groups included in the one or more mediating polymers.

[0143] The above one or more second additional polymers are different from the above one or more mediating polymers.

[0144] Preferably, the polymer mixture does not additionally include one or more second additional polymer components (Da).

[0145] In step iv), one or more functionalized first electrodes obtained in step ii) are brought into contact with the polymer mixture provided in step iii). Thereby, one or more coated functionalized first electrodes are obtained.

[0146] The one or more functionalized first electrodes may be brought into contact with the polymer mixture by any known method. For example, the one or more functionalized first electrodes may be brought into contact with the polymer mixture by immersing or submerging the one or more functionalized first electrodes in the polymer mixture. The functionalized first electrodes may be brought into contact with the polymer mixture by spray coating or doctor blading. Additionally, it is possible to bring the one or more functionalized first electrodes into contact with the polymer mixture by bringing the analyte sensor into contact with the polymer mixture.

[0147] In step iv), one or more coated functionalized first electrodes are obtained. This means that the coated functionalized first electrodes are obtained by contacting the functionalized first electrodes with the polymer mixture.

[0148] The thickness of the polymer mixture coating the one or more functionalized first electrodes is, for example, in the range of 0.1 to 5 μm.

[0149] In step v), the one or more coated functionalized first electrodes are dried to obtain a dried coated first electrode coated with one or more mediating polymers.

[0150] The above-mentioned coated functionalized first electrode can be dried under reduced pressure, for example, in a vacuum.

[0151] Alternatively or additionally, drying of the coated functionalized first electrode in step v) may be carried out by heating. For example, the coated functionalized first electrode obtained in step iv) is dried at a drying temperature (T D2 It can be heated to the above drying temperature (T D2 ) is generally lower than the temperature at which the dried coated first electrode is cured. This is because the drying temperature (T D2 ) is the above curing temperature (T C2 It means lower than ). For example, the drying temperature (T) of step v). D2 ) is in the range of 0 to 40°C.

[0152] During drying in step v), one or more of the second solvents (components (E)) are evaporated. This means that one or more of the second solvents are removed from the polymer mixture. Thus, a coating of one or more of the mediating polymers is obtained.

[0153] The coating of the one or more mediating polymers may further include residues of the one or more second solvent components (E). For example, the coating of the one or more mediating polymers may include the one or more second solvents in a range of <1 weight% based on the total weight of the coating of the one or more mediating polymers.

[0154] Preferably, during the drying of step v), the mediating polymer and / or the one or more dried coated first electrodes are not cured. This means that, preferably, during the drying step, the one or more dried coated first electrodes and the one or more mediating polymers do not react with each other.

[0155] In step vi), the one or more dried coated first electrodes are cured. This allows one or more second groups of the functionalized compound and one or more crosslinkable groups of the one or more mediating polymers to be crosslinked to form a sensing layer on the electrode of the analyte sensor.

[0156] During the curing of step vi), one or more second groups of the functionalized compound and one or more crosslinkable groups of the one or more mediating polymers react with each other. One or more second groups of the functionalized compound and one or more crosslinkable groups of the one or more mediating polymers can each be crosslinked to themselves and to each other.

[0157] During the above curing step, the one or more mediating polymers are connected to the surface of the one or more first electrodes.

[0158] In one embodiment of the present invention, if the polymer mixture provided in step iii) comprises a component (Da) which is one or more second additional polymers, said one or more second additional polymers also react with said one or more mediating polymers and one or more second groups of said functionalized compound. In said embodiment, said one or more second additional polymers and said one or more mediating polymers are typically crosslinked.

[0159] If the polymer mixture comprises one or more enzymes, the obtained sensing layer generally also comprises said one or more enzymes. In one embodiment, said one or more enzymes are dispersed within a layer of said mediator polymer and optionally said one or more second additional polymers.

[0160] Curing of step vi) may be carried out, for example, by heating one or more dried coated first electrodes obtained in step v) or by exposing one or more dried coated first electrodes obtained in step v) to light. This means that the mediating polymer coating the one or more dried coated first electrodes is heated or exposed to light.

[0161] Accordingly, in an embodiment of the process of the present invention, the curing of step vi) comprises at least one of the steps of heating the one or more dried coated first electrodes and exposing the one or more dried coated first electrodes to light.

[0162] If the curing of step vi) is carried out by heating the one or more dried coated first electrodes, the one or more dried coated first electrodes obtained in step v) are at a curing temperature (T C2 It is heated to the above curing temperature (T C2 ) is generally the drying temperature (T) at step v). D2 It is higher than the above curing temperature (T C2 In ), one or more second groups of the functionalized compound and / or one or more crosslinkable groups generally form radicals.

[0163] The above curing temperature (T C2 ) is generally in the range of 20 to 100°C.

[0164] When the curing of step vi) is carried out by exposing one or more dried coated first electrodes obtained in step v) to light, any wavelength of light that does not cleave bonds within the functionalized compound and / or the one or more mediating polymers may be used. Preferably, the wavelength is in the range of UV light. This means that it is preferable for the wavelength of the light to be in the range of 200 to 400 nm.

[0165] In one embodiment of the present invention, in a first step, a sensing layer is formed on an electrode of an analyte sensor according to a process of the present invention for forming a sensing layer on an electrode of an analyte sensor. In a second step, a film is formed on an analyte sensor including a sensing layer on an electrode according to a process of the present invention for forming a film on an analyte sensor.

[0166] Accordingly, the present invention also discloses an analyte sensor comprising a sensing layer obtainable by a process of forming a sensing layer on a first electrode of the analyte sensor according to the present invention and a film obtainable by a process of forming a film on the analyte sensor.

[0167] In one embodiment, the membrane covers at least partially the sensing layer of the analyte sensor.

Claims

Claim 1 A process for forming a film on an analyte sensor comprising: a) a step of providing said analyte sensor, wherein said analyte sensor comprises one or more substrates and one or more first electrodes; b) a step of providing a polymer solution, wherein (A) one or more first polymers comprising one or more first crosslinkable groups, wherein said one or more first polymers are hydrophobic polymers; (B) one or more second polymers comprising one or more second crosslinkable groups, wherein said one or more second polymers are hydrophilic polymers; and (C) a step of providing a polymer solution comprising one or more first solvent components; c) a step of contacting the analyte sensor provided in step a) with the polymer solution provided in step b) to obtain an analyte sensor coated with said polymer solution; d) a step of drying the analyte sensor obtained in step c) to obtain a dried analyte sensor coated with a polymer blend comprising said one or more first polymers and said one or more second polymers; and e) a step of curing the polymer blend coating the dried analyte sensor obtained in step d), thereby such that said one or more first A process comprising the step of forming a film on the analyte sensor by crosslinking a polymer and one or more second polymers, wherein the one or more first crosslinkable groups and the one or more second crosslinkable groups are independently selected from the group consisting of benzophenone groups, azide groups, anthraquinone groups and psoralen, and wherein the one or more second polymers are different from the one or more first polymers. Claim 2 A process according to claim 1, wherein the curing in step e) comprises at least one of the step of heating the polymer blend and the step of exposing the polymer blend to light. Claim 3 In claim 1, the process wherein one or more first solvent components (C) are selected from the group consisting of water, methanol, ethanol, tetrahydrofuran and dimethyl carbonate. Claim 4 In claim 1, the process wherein one or more first polymers are homopolymers. Claim 5 In claim 1, the process wherein one or more of the second polymers are homopolymers. Claim 6 A process for forming a sensing layer on a first electrode of an analyte sensor and forming a film on an analyte sensor including the sensing layer on the first electrode, wherein the process comprises the following steps for forming a sensing layer on the first electrode of an analyte sensor: a first step of: i) providing an analyte sensor including one or more first electrodes, wherein the one or more first electrodes include a first electrode material; ii) reacting one or more first electrodes of the analyte sensor provided in step i) with a functionalizing compound including one or more first groups reactive to the first electrode material and one or more crosslinkable second groups to obtain one or more functionalized first electrodes; iii) providing a polymer mixture, wherein (D) one or more mediating polymers including one or more crosslinkable groups, and (E) one or more second solvent components; iv) contacting one or more functionalized first electrodes obtained in step ii) with the polymer mixture provided in step iii) to obtain one or more coated functionalized first electrodes; v) one or more coated A process comprising: a step of drying a functionalized first electrode to obtain one or more dried coated first electrodes coated with one or more mediating polymers; and vi) curing the one or more dried coated first electrodes so that one or more second groups of the functionalized compound and one or more crosslinkable groups of the one or more mediating polymers are crosslinked to form a sensing layer on the first electrode of the analyte sensor; and a second step of forming a film on the analyte sensor comprising the sensing layer on the first electrode according to any one of claims 1 to 5. Claim 7 In claim 6, the process wherein the first electrode material comprises one or more metals. Claim 8 In claim 6, the polymer mixture provided in step iii) further comprises one or more enzymes. Claim 9 In claim 6, the process comprises one or more mediating material polymer components (D) including a redox mediating material selected from the group consisting of ruthenium-containing complexes and osmium-containing complexes. Claim 10 In claim 6, the process wherein one or more of the second solvent components (E) are selected from the group consisting of water, methanol and ethanol. Claim 11 delete Claim 12 delete Claim 13 delete