Glucose diffusion control membrane solution for continuous blood glucose measurement biosensor, glucose diffusion control membrane for continuous blood glucose measurement biosensor including the same, and continuous blood glucose measurement biosensor including the same

Abstract

The present invention relates to a glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor, a glucose diffusion control membrane for a continuous blood glucose measurement biosensor including the same, and a biosensor for continuous blood glucose measurement including the same, and more particularly to a glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor that can ensure stability even when inserted into a human body by using only materials with verified biocompatibility and can control glucose permeability and water absorbency, a glucose diffusion control membrane for a continuous blood glucose measurement biosensor including the same, and a biosensor for continuous blood glucose measurement including the same.

Description

Technical Field

[0001] The present invention relates to a glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor, a glucose diffusion control membrane for a continuous blood glucose measurement biosensor containing the same, and a biosensor for continuous blood glucose measurement containing the same. More specifically, even when inserted into the human body using only substances with verified biocompatibility, stability can be ensured, and a glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor that can control glucose permeability and water absorption, a glucose diffusion control membrane for a continuous blood glucose measurement biosensor containing the same, and a biosensor for continuous blood glucose measurement containing the same.

Background Art

[0002] According to the "IDF DIABETES ATLAS 9th Edition", a diabetes white paper published by the International Diabetes Federation (IDF) every two years, in 2019, the number of diabetic patients aged 20 to 79 years worldwide was 463 million (9.3%). Compared with 425 million reported in 2017, an increase of 39 million was observed.

[0003] Also, based on the 2019 standard, the number of diabetic patients aged 65 and above was 136 million, and one in five elderly people had diabetes.

[0004] It should be noted that the prevalence of diabetes is increasing rapidly every year.

[0005] Based on the current trend, it is predicted that by 2030, the number of diabetic patients worldwide will reach 578 million (10.2%), and by 2045, it will approach 700 million (10.9%), a 51% increase compared to 2019.

[0006] As a result, the 2021 revised version of the American Diabetes Association (ADA) guidelines explicitly recommends the use of a continuous glucose monitoring (CGM) system for patients undergoing multiple insulin therapies, regardless of age or diabetes type, and it can also be used during hospitalization.

[0007] Particularly, when programs such as education and training and follow-up management are provided together, blood glucose management via CGM was more effective in helping patients with blood glucose pattern management and improving glycated hemoglobin.

[0008] In the 2021 clinical practice guidelines of the Korean Diabetes Association (KDA), it is recommended that all adults with type 1 diabetes use real-time continuous glucose monitors to regulate blood glucose and reduce the risk of hypoglycemia, and it is specified that adults with type 2 diabetes receiving multiple insulin injection therapy can use real-time continuous glucose monitors for blood glucose regulation.

[0009] It is said that adults with type 2 diabetes who use other forms of insulin therapy or oral medications only instead of multiple insulin injections can periodically measure real-time continuous blood glucose for blood glucose regulation.

[0010] In addition, it is recommended to use continuous blood glucose measurement to optimize blood glucose while reducing the risk of hypoglycemia in pregnant women with type 1 diabetes and improve obstetric outcomes.

[0011] Such a sensor of a continuous glucose monitor may include a glucose diffusion control membrane on the outermost part of the sensor.

[0012] The glucose diffusion control membrane does not have a negative impact on the human body when the sensor is inserted into the human body, and prevents the sensor substance from being discharged into the human body. Moreover, it can control the diffusion of glucose flowing in from the human body.

[0013] Due to human movement, the inflow rate of glucose flowing into the outermost part of the sensor through the glucose diffusion control membrane can increase. As a result, it may be difficult to accurately measure blood glucose.

[0014] Therefore, as a result of research to overcome such problems, the inventors of the present invention have found that when manufacturing a glucose diffusion control membrane for a continuous blood glucose measurement biosensor using a glucose diffusion control membrane solution in which a specific hydrophilic substance and a specific hydrophobic substance are mixed, stability can be ensured even when only biocompatible substances are used and inserted into the human body, and it has been confirmed that the glucose permeability and water absorption can be controlled, thus completing the present invention.

Summary of the Invention

Problems to be Solved by the Invention

[0015] The present invention has been devised to solve the above problems, and the problem to be solved by the present invention is to ensure stability even when inserted into the human body using only biocompatible substances, and to provide a glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor that can control glucose permeability and water absorption, a glucose diffusion control membrane for a continuous blood glucose measurement biosensor containing the same, and a biosensor for continuous blood glucose measurement containing the same.

Means for Solving the Problems

[0016] In order to solve the above problems, the glucose diffusion control membrane solution of the present invention contains a hydrophilic substance and a hydrophobic substance. Specifically, the glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor of the present invention may contain an aliphatic Polyether thermoplastic polyurethane as the hydrophilic substance, and the hydrophobic substance may contain a styrene block copolymer.

[0017] In a preferred embodiment of the present invention, the aliphatic Polyether thermoplastic polyurethane may have a specific gravity based on the ASTM D792 measurement method of 1.0 to 1.2 g / cm 3 ³.

[0018] In a preferred embodiment of the present invention, the aliphatic PolyetherThe aliphatic thermoplastic polyurethane may have a shore hardness of 78 to 88A based on the ASTM D2240 measurement method.

[0019] In a preferred embodiment of the present invention, the aliphatic Polyether thermoplastic polyurethane may have a flexural modulus of 2400 to 3400 psi based on the ASTM D790 measurement method.

[0020] In a preferred embodiment of the present invention, the aliphatic Polyether thermoplastic polyurethane may have an ultimate tensile of 1700 to 2700 psi in the dry state and 900 to 1900 psi in the wet state based on the ASTM D412 measurement method.

[0021] In a preferred embodiment of the present invention, the aliphatic Polyether thermoplastic polyurethane may have an ultimate elongation of 540 to 1540 psi in the dry state and 320 to 920 psi in the wet state based on the ASTM D412 measurement method.

[0022] In a preferred embodiment of the present invention, the styrene block copolymer may have a specific gravity of 0.9 to 1.1 g / cm 3 according to the ISO1183-1 measurement method.

[0023] In a preferred embodiment of the present invention, the styrene block copolymer may have a shore hardness of 60 to 80A based on the ISO48-4 measurement method.

[0024] In a preferred embodiment of the present invention, the styrene block copolymer may have a tensile strength of 8.2 to 10.2 MPa based on the ISO37 measurement method.

[0025] In a preferred embodiment of the present invention, the styrene block copolymer may have an elongation at break of 414 to 614% based on the ISO37 measurement method.

[0026] In a preferred embodiment of the present invention, the styrene block copolymer may have a tear strength of 15 to 25 N / mm based on the ISO34-1 measurement method, preferably the ISO34-1 methode B(b)(Graves) measurement method.

[0027] In a preferred embodiment of the present invention, the hydrophilic substance and the hydrophobic substance may have a weight ratio of 1:0.1 to 4.

[0028] Note that the glucose diffusion control membrane for a continuous blood glucose measurement biosensor of the present invention can be produced by drying the glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor of the present invention.

[0029] Also, the biosensor for continuous blood glucose measurement of the present invention may include the glucose diffusion control membrane for a continuous blood glucose measurement biosensor of the present invention.

Advantages of the Invention

[0030] The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor of the present invention, the glucose diffusion control membrane for a continuous blood glucose measurement biosensor containing the same, and the biosensor for continuous blood glucose measurement containing the same can ensure stability even when inserted into the human body using only biocompatibility-verified substances, and can control glucose permeability and water absorption.

Brief Description of the Drawings

[0031]

Figure 1

Figure 2

Embodiments for Carrying Out the Invention

[0032] Hereinafter, embodiments of the present invention will be described in detail so that those having ordinary knowledge in the technical field to which the present invention pertains can easily implement them with reference to the accompanying drawings. The present invention can be embodied in various different forms and is not limited to the embodiments described herein. In the drawings, parts not related to the description are omitted for clarity in explaining the present invention, and the same reference numerals are added to the same or similar components throughout the specification.

[0033] The biosensor for continuous blood glucose measurement of the present invention may include a glucose diffusion control membrane for the continuous blood glucose measurement biosensor of the present invention. At this time, the glucose diffusion control membrane for the continuous blood glucose measurement biosensor of the present invention can be manufactured by drying the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention described later.

[0034] The biosensor for continuous blood glucose measurement of the present invention is an electrochemical sensor for measuring blood glucose.

[0035] As the configuration of such a biosensor for continuous blood glucose measurement, for example, it may include an electrode, an insulator, a substrate, an electron transfer mediator, an enzyme layer including an enzyme and a crosslinking agent, and a glucose diffusion control membrane.

[0036] The enzyme layer may contain an enzyme capable of oxidizing and reducing a liquid biological sample and a redox polymer. It may also be an enzyme layer for an electrochemical biosensor containing an electron transfer mediator. The redox enzyme is a general term for enzymes that catalyze the redox reactions in living organisms. In the present invention, for the substance to be measured, for example, in the case of a biosensor, it means an enzyme that reacts with the substance to be measured and is reduced. The enzyme reduced in this way reacts with the electron transfer mediator, and measures signals such as current changes generated at this time to quantify the target substance. The redox enzymes that can be used in the present invention may be one or more selected from the group consisting of various dehydrogenases, oxidases, esterases, etc., and depending on the redox or the substance to be detected, an enzyme using the target substance as a substrate can be selected from the enzymes belonging to the enzyme group and used.

[0037] More specifically, the redox enzyme may be one or more selected from the group consisting of glucose dehydrogenase, glutamate dehydrogenase, glucose oxidase, cholesterol oxidase, cholesterol esterase, lactate oxidase, ascorbic acid oxidase, alcohol oxidase, alcohol dehydrogenase, bilirubin oxidase, Uricase, etc.

[0038] Also, the electron transfer mediator may contain one or more selected from metal-containing complexes and organic conducting salts.

[0039] As the metal-containing complex, it may include ruthenium complex, osmium complex, ferricyanide complex, etc., which are Group 8 elements. As the organic conductive salt, it may include ferrocene, quinone, derivatives of quinone, methylene blue, etc.

[0040] In addition, the redox enzyme may also include a cofactor that plays a role in storing hydrogen taken from the substance to be measured (for example, the target substance) by the redox enzyme. For example, it may be one or more selected from the group consisting of flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD), pyrroloquinoline quinone (PQQ), etc.

[0041] Furthermore, the enzyme layer may further contain one or more additives selected from the group consisting of cross-linking agents, surfactants, water-soluble polymers, quaternary ammonium salts, fatty acids, thickeners, etc. for the roles of a dispersant during reagent dissolution, an adhesive during reagent production, a stabilizer for long-term storage, etc.

[0042] In the case of an electrode, it can also include two types of electrodes such as a working electrode and a counter electrode, or it can also include three types of electrodes such as a working electrode, a counter electrode, and a reference electrode. In one embodiment, the biosensor according to the present invention is an electrochemical biosensor produced by applying an enzyme solution containing an enzyme capable of oxidizing and reducing glucose, a crosslinking agent, and an electron transfer mediator to a substrate provided with at least two, preferably two or three electrodes, and then drying. For example, in an electrochemical biosensor, a working electrode, a counter electrode, and a reference electrode are arranged on the same surface of the substrate, an enzyme layer according to the present invention is laminated on the working electrode, an insulator is laminated on the substrate and the electrodes (working electrode, counter electrode, reference electrode), and a glucose diffusion control film is laminated on the electrodes, thereby providing a planar electrochemical biosensor.

[0043] As a specific embodiment, the substrate may be made of one or more materials selected from the group consisting of PDMS (polydimethylsiloxane), PI (polyimide), and PET (polyethylene terephthalate).

[0044] Also, for the working electrode, carbon, gold, platinum, silver, or an electrode can be used.

[0045] Also, in the case of an electrochemical biosensor having two electrodes, since the counter electrode also serves as a reference electrode, gold, platinum, silver, or a silver / silver chloride electrode can be used as the counter electrode. In the case of an electrochemical biosensor having three electrodes including a reference electrode, a silver / silver chloride electrode can be used as the reference electrode, and a carbon electrode can be used as the counter electrode.

[0046] As a non-limiting example, in the case of two electrodes, since the counter electrode also serves as a reference electrode, silver chloride or silver can be used. In the case of three electrodes, silver chloride or silver can be used for the reference electrode, and a carbon electrode can be used for the counter electrode.

[0047] In addition, the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention contains hydrophilic substances and hydrophobic substances. By including both hydrophilic and hydrophobic substances in the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention, it is excellent in controlling glucose permeability even in the human body environment and can embody glucose sensing sensitivity. If the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention contains only hydrophilic substances, there may be a problem that glucose permeates excessively at the outermost contour of the biosensor for continuous blood glucose measurement, resulting in a decrease in the performance of the sensor. If it contains only hydrophobic substances, there may be a problem that glucose is not sensed because glucose does not permeate at the outermost contour of the biosensor for continuous blood glucose measurement.

[0048] First, it may contain aliphatic Polyether thermoplastic polyurethane as a hydrophilic substance.

[0049] Specifically, the aliphatic Polyether thermoplastic polyurethane has a specific gravity of 1.0 - 1.2 g / cm 3 based on the ASTM D792 measurement method, preferably 3 1.1 - 1.16 g / cm.

[0050] Also, the aliphatic Polyether thermoplastic polyurethane may have a shore hardness of 78 - 88A, preferably 81 - 85A, based on the ASTM D2240 measurement method.

[0051] Also, the aliphatic Polyether thermoplastic polyurethane may have a flexural modulus of 2400 - 3400 psi, preferably 2700 - 3100 psi, based on the ASTM D790 measurement method.

[0052] Also, the aliphatic PolyetherThe thermoplastic polyurethane may have an ultimate tensile strength of 1700 - 2700 psi, preferably 2000 - 2400 psi, in the dry state based on the ASTM D412 measurement method.

[0053] Also, the aliphatic Polyether The thermoplastic polyurethane may have an ultimate tensile strength of 900 - 1900 psi, preferably 1200 - 1600 psi, in the wet state based on the ASTM D412 measurement method.

[0054] Also, the aliphatic Polyether The thermoplastic polyurethane may have an ultimate elongation of 540 - 1540 psi, preferably 840 - 1240 psi, in the dry state based on the ASTM D412 measurement method.

[0055] Also, the aliphatic Polyether The thermoplastic polyurethane may have an ultimate elongation of 320 - 920 psi, preferably 520 - 720 psi, in the wet state based on the ASTM D412 measurement method.

[0056] Next, it may contain a styrene block copolymer as a hydrophobic substance.

[0057] Specifically, the styrene block copolymer may have a specific gravity of 0.9 - 1.1 g / cm 3 , preferably 1.0 - 1.05 g / cm 3 based on the ISO1183 - 1 measurement method.

[0058] Also, the styrene block copolymer may have a shore hardness of 60 - 80 A, preferably 65 - 75 A, based on the ISO48 - 4 measurement method.

[0059] Also, the styrene block copolymer may have a tensile strength based on the ISO37 measurement method of 8.2 to 10.2 MPa, preferably 8.7 to 9.7 MPa.

[0060] Also, the styrene block copolymer may have an elongation at break based on the ISO37 measurement method of 414 to 614%, preferably 464 to 564%.

[0061] Also, the styrene block copolymer may have a tear strength based on the ISO34-1 measurement method, preferably the ISO34-1 methode B(b)(Graves) measurement method, of 15 to 25 N / mm, preferably 18 to 22 N / mm.

[0062] In addition, the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention may have a weight ratio of hydrophilic substance to hydrophobic substance of 1:0.1 to 4, preferably 1:0.1 to 3, more preferably 1:0.15 to 0.8. If the weight ratio is less than 1:0.1, there may be a problem that glucose permeates excessively at the outermost periphery of the biosensor for continuous blood glucose measurement, resulting in a decrease in the performance of the sensor. If the weight ratio exceeds 1:4, glucose may not permeate at the outermost periphery of the biosensor for continuous blood glucose measurement, so there may be a problem that glucose is not sensed.

[0063] In addition, the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention may further contain an organic solvent, and the concentration of the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention can be adjusted using the organic solvent. Any organic solvent used in the art can be used as the organic solvent of the present invention. Preferably, it may contain one or more selected from chloroform, cyclohexanone, cyclopentanone, dimethylacetamide, dimethylformamide, dioxane, methylene chloride, trichloroethane, tetrahydrofuran, xylene, and toluene, and more preferably, it may contain tetrahydrofuran.

[0064] Hereinafter, the present invention will be described based on the following examples. At this time, the following examples are merely presented to illustrate the invention, and the scope of the rights of the present invention is not limited by the following examples.

[0065] Preparation Example 1: Production of hydrophilic solution 2,000 mg of aliphatic Polyether thermoplastic polyurethane (HP-93A-100, Lubrizol) as a hydrophilic substance and 50 ml of tetrahydrofuran as an organic solvent were added and dissolved to produce a hydrophilic solution with a concentration of 40 mg / mL.

[0066] Preparation Example 2: Production of hydrophobic solution 2,000 mg of a styrene block copolymer (TM7APO, KRAIBURG) as a hydrophobic substance and 50 ml of tetrahydrofuran as an organic solvent were added to a homogenizer and dissolved for 30 minutes to produce a hydrophobic solution with a concentration of 40 mg / mL.

[0067] Experimental Example 1: Cytotoxicity Experiment The cytotoxicity of the hydrophilic solution prepared in Preparation Example 1 and the hydrophobic solution prepared in Preparation Example 2 was evaluated according to the ISO10993-5 evaluation method. As a result, it was confirmed that both the hydrophilic solution prepared in Preparation Example 1 and the hydrophobic solution prepared in Preparation Example 2 were non-toxic.

[0068] Experimental Example 2: Skin Sensitization Experiment The skin sensitization of the hydrophilic solution prepared in Preparation Example 1 and the hydrophobic solution prepared in Preparation Example 2 was evaluated according to the ISO10993-10 evaluation method. As a result, it was confirmed that both the hydrophilic solution prepared in Preparation Example 1 and the hydrophobic solution prepared in Preparation Example 2 did not induce irritation and skin sensitivity.

[0069] Experimental Example 3: Systemic Toxicity Experiment The systemic toxicity of the hydrophilic solution prepared in Preparation Example 1 and the hydrophobic solution prepared in Preparation Example 2 was evaluated according to the ISO10993-11 evaluation method. As a result, it was confirmed that both the hydrophilic solution prepared in Preparation Example 1 and the hydrophobic solution prepared in Preparation Example 2 were non-systemically toxic.

[0070] Experimental Example 4: Blood Compatibility Experiment The blood compatibility of the hydrophilic solution prepared in Preparation Example 1 and the hydrophobic solution prepared in Preparation Example 2 was evaluated according to the ISO10993-4 evaluation method. As a result, it was confirmed that both the hydrophilic solution prepared in Preparation Example 1 and the hydrophobic solution prepared in Preparation Example 2 had blood compatibility.

[0071] Example 1: Preparation of a Glucose Diffusion Control Membrane Solution for a Continuous Glucose Monitoring Biosensor 16 mL of the hydrophilic solution prepared in Preparation Example 1 and 4 mL of the hydrophobic solution prepared in Preparation Example 2 were put into a stirrer and stirred to produce a glucose diffusion control membrane solution with a concentration of 40 mg / mL. At this time, the glucose diffusion control membrane solution contained an aliphatic Polyether thermoplastic polyurethane (HP-93A-100, Lubrizol) and a styrene block copolymer (TM7APO, KRAIBURG) in a weight ratio of 1:0.25.

[0072] Example 2: Preparation of a Glucose Diffusion Control Membrane Solution for a Continuous Glucose Monitoring Biosensor 10 mL of the hydrophilic solution prepared in Preparation Example 1 and 10 mL of the hydrophobic solution prepared in Preparation Example 2 were put into a stirrer and stirred to produce a glucose diffusion control membrane solution with a concentration of 40 mg / mL. At this time, the glucose diffusion control membrane solution contained an aliphatic Polyether thermoplastic polyurethane (HP-93A-100, Lubrizol) and a styrene block copolymer (TM7APO, KRAIBURG) in a weight ratio of 1:1.

[0073] Example 3: Preparation of a Glucose Diffusion Control Membrane Solution for a Continuous Glucose Monitoring Biosensor 4 mL of the hydrophilic solution prepared in Preparation Example 1 and 16 mL of the hydrophobic solution prepared in Preparation Example 2 were put into a stirrer and stirred to produce a glucose diffusion control membrane solution with a concentration of 40 mg / mL. At this time, the glucose diffusion control membrane solution contained an aliphatic Polyether thermoplastic polyurethane (HP-93A-100, Lubrizol) and a styrene block copolymer (TM7APO, KRAIBURG) in a weight ratio of 1:4.

[0074] Production Example 1: Production of a Test Sensor (1) An osmium complex was used as an electron transfer mediator, and glutamate dehydrogenase was used as an enzyme. An enzyme solution was prepared by mixing an electron transfer mediator, an enzyme, and a crosslinking agent at a volume ratio of 4:4:1. (2) A test electrode composed of a working electrode (using a carbon electrode), a reference electrode (using an AgCl electrode), and a counter electrode (a carbon electrode) was prepared, and 2.5 μL of the enzyme solution was drop-cast onto the working electrode of the test electrode. (3) The test electrode was dried in a dryer at 35 °C for 30 minutes. (4) A masking film was attached to the working electrode, reference electrode, and counter electrode of the test electrode, and the glucose diffusion control film solution produced in Examples 1 to 3, the hydrophilic solution produced in Preparation Example 1, and the hydrophobic solution produced in Preparation Example 2 were each drop-cast onto the masking film and then dried to produce test sensors on which glucose diffusion control films were formed.

[0075] Experimental Example 5: Measurement of Glucose Permeability 2 mL of PBS solution was put into an electrochemical measurement glass cell, and each of the test sensors produced in Production Example 1 was supported in the PBS solution.

[0076] Glucose was provided to the PBS solution using a glucose stock solution (in 10 mM PBS solution) so that the glucose concentration became 50, 100, 200, 300, 400, 500 mg / dL, and then the CA (chronoamperometry) condition was measured via a potentiostat (Multi-Palmsens 4, applied voltage: 0.3 V), and the results are shown in Figure 1.

[0077] As can be confirmed from Figure 1, it was confirmed that the change in the current value due to the change in glucose concentration was measured in descending order when using the hydrophilic solution produced in Preparation Example 1, the glucose diffusion control film solution produced in Example 1, the glucose diffusion control film solution produced in Example 2, and the glucose diffusion control film solution produced in Example 3. Also, when only the hydrophobic solution produced in Preparation Example 2 was used, there was almost no change in the current value due to the change in glucose concentration.

[0078] Through such results, it was confirmed that the glucose sensing sensitivity can be selectively controlled by controlling the ratio of the hydrophobic substance contained in the glucose diffusion control membrane.

[0079] Experimental Example 6: Measurement of water absorption rate 3 mL of the glucose diffusion control membrane solution produced in Examples 1 to 3, the hydrophilic solution produced in Preparation Example 1, and the hydrophobic solution produced in Preparation Example 2 were each dispensed into a glass Petri dish and dried at room temperature (25°C) for 24 hours to produce a glucose diffusion control membrane, and the initial weight was measured for each.

[0080] After the produced glucose diffusion control membranes were supported in ultrapure water (D.I water) for 24 hours, the final weight was measured for each.

[0081] Using the measured initial weight and final weight, the water absorption rate of each of the glucose diffusion control membrane solution produced in Examples 1 to 3, the hydrophilic solution produced in Preparation Example 1, and the hydrophobic solution produced in Preparation Example 2 was calculated and shown in Table 1 below.

[0082] [Table 1]

[0083] As can be confirmed from Table 1, it was confirmed that the water absorption rate was measured to be high in the order of using the hydrophilic solution produced in Preparation Example 1, the glucose diffusion control membrane solution produced in Example 1, the glucose diffusion control membrane solution produced in Example 2, and the glucose diffusion control membrane solution produced in Example 3. Also, when only the hydrophobic solution produced in Preparation Example 2 was used, almost no water was absorbed.

[0084] Through such results, it was confirmed that the water absorption rate can be selectively controlled by controlling the ratio of the hydrophobic substance contained in the glucose diffusion control membrane.

[0085] Comparative Preparation Example 1: Preparation of a hydrophobic solution Aliphatic substances as hydrophobic substances in homogenizers Polyether 2,000 mg of thermoplastic polyurethane (SG-80A, Lubrizol) and 50 ml of tetrahydrofuran as an organic solvent were added and dissolved for 60 minutes to prepare a hydrophobic solution with a concentration of 40 mg / mL.

[0086] As can be seen from the process of preparing the hydrophobic solution of Comparative Preparation Example 1, the time for dissolving the styrene block copolymer used in Preparation Example 2 was 30 minutes, whereas the time for dissolving the aliphatic block copolymer used in Comparative Preparation Example 1 was 30 minutes. Polyether It was confirmed that it took 60 minutes to dissolve the thermoplastic polyurethane-based polymer. Thus, it was confirmed that the use of the hydrophobic solution prepared in Preparation Example 2 as a hydrophobic solution in preparing a glucose diffusion control membrane solution shortens the preparation time compared to the use of the hydrophobic solution prepared in Comparative Preparation Example 1, and that it is easy to mass-produce.

[0087] Comparative Example 1: Preparation of glucose diffusion control membrane solution for continuous blood glucose measurement biosensor 16 mL of the hydrophilic solution prepared in Preparation Example 1 and 4 mL of the hydrophobic solution prepared in Comparative Preparation Example 1 were put into the stirrer and stirred to prepare a glucose diffusion control membrane solution with a concentration of 40 mg / mL. Polyether Thermoplastic polyurethane (HP-93A-100, Lubrizol) and aliphatic Polyether The thermoplastic polyurethane (SG-80A, Lubrizol) was included in a weight ratio of 1:0.25.

[0088] Manufacturing example 2: Manufacturing a test sensor (1) An enzyme solution was prepared by mixing an electron transfer mediator, an enzyme, and a crosslinker in a volume ratio of 4:4:1. In this case, an osmium complex was used as the electron transfer mediator, and glutamate dehydrogenase was used as the enzyme. (2) A test electrode composed of a working electrode (using a carbon electrode), a reference electrode (using an AgCl electrode), and a counter electrode (a carbon electrode) was prepared, and 2.5 μL of the above enzyme solution was drop-cast onto the working electrode of the test electrode. (3) The above test electrode was dried in a dryer at 35 °C for 30 minutes. (4) A masking film was attached to the working electrode, reference electrode, and counter electrode of the test electrode, and the glucose diffusion control film solution prepared in Example 1 and the glucose diffusion control film solution prepared in Comparative Example 1 were each drop-cast onto the masking film and then dried to produce test sensors with glucose diffusion control films formed respectively.

[0089] Experimental Example 7: Measurement of Glucose Permeability 2 mL of PBS solution was put into an electrochemical measurement glass cell, and each of the test sensors prepared in Production Example 2 was supported in the PBS solution.

[0090] After providing glucose to the PBS solution using a glucose stock solution (in 10 mM PBS solution) so that the concentration of glucose became 200 mg / dL, the CA (chronoamperometry) condition was measured via a potentiostat (Multi-Palmsens 4, applied voltage: 0.3 V), and the results are shown in Figure 2.

[0091] As can be confirmed from Figure 2, it was confirmed that when the glucose diffusion control film solution prepared in Example 1 was used, the current density was measured higher than when the glucose diffusion control film solution prepared in Comparative Example 1 was used.

[0092] Simple modifications and changes to the present invention can be easily implemented by those with ordinary knowledge in this field, and such modifications and changes can be regarded as being all included in the scope of the present invention.

Claims

1. A glucose diffusion control membrane solution containing a hydrophilic substance and a hydrophobic substance, wherein the hydrophilic substance includes an aliphatic polyether-based thermoplastic polyurethane, and the hydrophobic substance includes a styrene block copolymer. A glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor, characterized in that it contains the above components.

2. The aliphatic polyether-based thermoplastic polyurethane has a specific gravity based on the ASTM D792 measurement method of 1.0 to 1.2 g / cm ３ and a shore hardness based on the ASTM D2240 measurement method of 78 to 88 A, The styrene block copolymer has a specific gravity of 0.9 to 1.1 g / cm ３ based on the ISO 1183-1 measurement method, and a shore hardness of 60 to 80 A based on the ISO 48-4 measurement method. The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor according to claim 1, characterized in that it is as described above.

3. The aliphatic polyether-based thermoplastic polyurethane has a flexural modulus of 2400 to 3400 psi based on the ASTM D790 measurement method, has an ultimate tensile strength of 1700 to 2700 psi in the dry state and 900 to 1900 psi in the wet state based on the ASTM D412 measurement method, and has an ultimate elongation of 540 to 1540 psi in the dry state and 320 to 920 psi in the wet state based on the ASTM D412 measurement method. The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor according to Claim 2, characterized by the above properties.

4. The styrene block copolymer has a tensile strength of 8.2 to 10.2 MPa based on the ISO37 measurement method, has an elongation at break of 414 to 614% based on the ISO37 measurement method, and has a tear strength of 15 to 25 N / mm based on the ISO34-1 measurement method. The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor according to Claim 2, characterized by the above properties.

5. The hydrophilic substance and the hydrophobic substance have a weight ratio of 1:0.1 to 4. The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor according to Claim 1, characterized by the above weight ratio.

6. A glucose diffusion control membrane for a continuous blood glucose measurement biosensor, which is manufactured by drying the glucose diffusion control membrane solution for a biosensor according to Claim 1.

7. A continuous blood glucose measurement biosensor including the glucose diffusion control membrane according to Claim 6.

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