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 including the same, and a continuous blood glucose measurement biosensor including the same. More specifically, the present invention relates to a glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor that uses only materials with verified biocompatibility, can ensure stability even when inserted into the human body, and can control glucose permeability and water absorption, a glucose diffusion control membrane for a continuous blood glucose measurement biosensor including the same, and a continuous blood glucose measurement biosensor including the same. [Background technology]

[0002] According to the 9th edition of the IDF Diabetes Atlas, a diabetes white paper published every two years by the International Diabetes Federation (IDF), there were 463 million people (9.3%) aged 20 to 79 worldwide with diabetes in 2019. This is an increase of 39 million people compared to the 425 million reported in 2017.

[0003] In addition, as of 2019, there were 136 million people aged 65 and over with diabetes, meaning that one in five elderly people had diabetes.

[0004] It is noteworthy that the prevalence of diabetes is increasing rapidly every year.

[0005] Based on current trends, the number of people with diabetes worldwide is expected to reach 578 million (10.2%) in 2030 and nearly 700 million (10.9%) in 2045, a 51% increase compared to 2019.

[0006] As a result, the American Diabetes Association (ADA) revised 2021 guidelines clarified that continuous glucose monitoring (CGM) systems can be used to recommend multiple insulin therapy to patients regardless of age or diabetes type, and can also be used during hospitalization.

[0007] In particular, it helps improve blood glucose pattern management and glycosylated hemoglobin in patients with diabetes, and blood glucose management via CGM is more effective when it is provided in conjunction with programs such as education and training and follow-up management.

[0008] The Korean Diabetes Association (KDA)'s 2021 clinical practice guidelines recommend the use of real-time continuous blood glucose monitors for all adults with type 1 diabetes to regulate blood glucose and reduce the risk of hypoglycemia, and explicitly state that adults with type 2 diabetes who receive multiple insulin injection therapy can use real-time continuous blood glucose monitors for blood glucose regulation.

[0009] Adults with type 2 diabetes who use only other forms of insulin therapy or oral medications, rather than multiple insulin injections, were told they could periodically use real-time continuous blood glucose monitoring for blood sugar control.

[0010] In addition, the authors recommended its use, saying that continuous blood glucose monitoring can reduce the risk of hypoglycemia in pregnant women with type 1 diabetes, while optimizing blood glucose regulation and improving obstetric outcomes.

[0011] The sensor of such a continuous blood glucose monitor may include a glucose diffusion control membrane at the outermost portion of the sensor.

[0012] The glucose diffusion control membrane does not negatively affect the human body when the sensor is inserted into the human body, prevents the sensor material from being excreted into the human body, and also controls the diffusion of glucose entering from the human body.

[0013] Movement can increase the rate at which glucose enters the outermost part of the sensor through the glucose diffusion-controlling membrane, which can make accurate blood glucose measurements difficult.

[0014] Therefore, the present inventors have conducted research to overcome these problems, and as a result, they have found that when a glucose diffusion-controlling membrane for a continuous blood glucose monitoring biosensor is manufactured using a glucose diffusion-controlling membrane solution in which a specific hydrophilic substance and a specific hydrophobic substance are mixed, stability can be ensured even when inserted into the human body using only substances whose biocompatibility has been verified, and glucose permeability and water absorption can be controlled, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0015] The present invention has been devised to solve the above-mentioned problems, and an object of the present invention is to provide a glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor that uses only materials with verified biocompatibility, can ensure stability even when inserted into the human body, 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 continuous blood glucose measurement biosensor including the same. [Means for solving the problem]

[0016] In order to solve the above-mentioned 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 measuring biosensor of the present invention contains an aliphatic acid as the hydrophilic substance. Polyether The hydrophobic material may comprise a thermoplastic polyurethane, and the hydrophobic material may comprise a styrene block copolymer.

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

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

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

[0020] In one preferred embodiment of the present invention, aliphatic Polyether The thermoplastic polyurethane may have an ultimate tensile strength of 1700 to 2700 psi in a dry state and an ultimate tensile strength of 900 to 1900 psi in a wet state, as measured by ASTM D412.

[0021] In one preferred embodiment of the present invention, aliphatic Polyether The thermoplastic polyurethane may have an ultimate elongation of 540 to 1540 psi in a dry state and an ultimate elongation of 320 to 920 psi in a wet state, as measured by ASTM D412.

[0022] In a preferred embodiment of the present invention, the styrene block copolymer has a specific gravity of 0.9 to 1.1 g / cm according to the ISO 1183-1 measurement method. 3 may be.

[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 ISO 48-4 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 ISO 37 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 ISO 37 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 ISO 34-1 measurement method, preferably the ISO 34-1 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 1:0.1-4.

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

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

[0030] The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor, the glucose diffusion control membrane for a continuous blood glucose measurement biosensor including the same, and the continuous blood glucose measurement biosensor including the same of the present invention are made using only materials whose biocompatibility has been verified, so that stability can be ensured even when inserted into the human body, and glucose permeability and water absorbency can be controlled. [Brief explanation of the drawings]

[0031] [Figure 1] FIG. 1 shows the results of measuring the current intensity over time for test sensors using the glucose diffusion control membrane solutions prepared in Examples 1 to 3, the hydrophilic solution prepared in Preparatory Example 1, and the hydrophobic solution prepared in Preparatory Example 2. [Figure 2]FIG. 1 is a graph showing the results of checking the current density over time for test sensors using the glucose diffusion control membrane solution prepared in Example 1 and the glucose diffusion control membrane solution prepared in Comparative Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0032] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily implement the present invention. The present invention may be embodied in various different forms and is not limited to the embodiments described herein. In the drawings, parts that are not relevant to the description will be omitted in order to clearly explain the present invention, and the same reference numerals will be used throughout the specification to refer to the same or similar components.

[0033] The continuous blood glucose measuring biosensor of the present invention may include a glucose diffusion control membrane for the continuous blood glucose measuring biosensor of the present invention, which can be produced by drying a glucose diffusion control membrane solution for the continuous blood glucose measuring biosensor of the present invention, which will be described later.

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

[0035] Such a biosensor for continuous blood glucose measurement may be configured, for example, to include an electrode, an insulator, a substrate, an electron transfer mediator, an enzyme layer containing an enzyme and a crosslinker, 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. "Oxidoreductase" is a general term for enzymes that catalyze oxidation-reduction reactions in living organisms. In the present invention, it refers to an enzyme that reacts with and is reduced by a target substance to be measured, e.g., in the case of a biosensor. The reduced enzyme reacts with the electron transfer mediator, and the resulting signal, such as a change in current, is measured to quantify the target substance. The oxidoreductase usable in the present invention may be one or more enzymes selected from the group consisting of various dehydrogenases, oxidases, esterases, etc. Depending on the oxidation-reduction or target substance to be detected, an enzyme that uses the target substance as a substrate can be selected from the enzyme group.

[0037] More specifically, the oxidoreductase 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, and the like.

[0038] The electron transfer mediator may also include one or more selected from a metal-containing complex and an organic conducting salt.

[0039] The metal-containing complex may include a ruthenium complex, an osmium complex, a ferricyanide complex, or the like, which are group 8 elements, and the organic conductive salt may include ferrocene, quinone, a quinone derivative, methylene blue, or the like.

[0040] The oxidoreductase may contain a cofactor that serves to store the hydrogen removed by the oxidoreductase from the target substance to be measured (e.g., the target substance), and the cofactor may be, for example, one or more selected from the group consisting of flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD), pyrroloquinoline quinone (PQQ), etc.

[0041] The enzyme layer may further contain one or more additives selected from the group consisting of crosslinkers, surfactants, water-soluble polymers, quaternary ammonium salts, fatty acids, thickeners, etc., to serve as a dispersant when dissolving the reagent, an adhesive when producing the reagent, a stabilizer for long-term storage, etc.

[0042] The electrodes may include two electrodes, such as a working electrode and a counter electrode, or three electrodes, such as a working electrode, a counter electrode, and a reference electrode. In one embodiment, the biosensor according to the present invention may be an electrochemical biosensor fabricated by coating a substrate having at least two, preferably two or three, electrodes with an enzyme solution containing an enzyme capable of oxidizing and reducing glucose, a crosslinker, and an electron transfer mediator, followed by drying. For example, a planar electrochemical biosensor may be provided in which the working electrode, counter electrode, and reference electrode are arranged on the same side 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, and reference electrode), and a glucose diffusion-controlling membrane is laminated on the electrodes.

[0043] In 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] The working electrode may be made of carbon, gold, platinum, silver, or other metals.

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

[0047] The glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention contains both a hydrophilic material and a hydrophobic material. By including both a hydrophilic material and a hydrophobic material, the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention can effectively control glucose permeability even in the human body environment, thereby achieving high glucose sensing sensitivity. If the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention contains only a hydrophilic material, excessive glucose permeates through the outermost layer of the continuous blood glucose measurement biosensor, resulting in reduced sensor performance. If the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor contains only a hydrophobic material, glucose cannot permeate through the outermost layer of the continuous blood glucose measurement biosensor, resulting in a lack of glucose sensing.

[0048] First, aliphatic substances are used as hydrophilic substances. Polyether The thermoplastic polyurethane may also be included.

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

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

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

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

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

[0054] In addition, aliphatic Polyether The thermoplastic polyurethane may have an ultimate elongation in a dry state of 540 to 1540 psi, preferably 840 to 1240 psi, measured according to the ASTM D412 measurement method.

[0055] In addition, aliphatic Polyether The thermoplastic polyurethane may have an ultimate elongation in a wet state of 320 to 920 psi, preferably 520 to 720 psi, measured according to the ASTM D412 measurement method.

[0056] Secondly, the hydrophobic material may include a styrene block copolymer.

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

[0058] The styrene block copolymer may have a shore hardness of 60 to 80A, preferably 65 to 75A, based on the ISO 48-4 measurement method.

[0059] The styrene block copolymer may have a tensile strength of 8.2 to 10.2 MPa, preferably 8.7 to 9.7 MPa, based on the ISO 37 measurement method.

[0060] The styrene block copolymer may have an elongation at break based on the ISO 37 measurement method of 414 to 614%, preferably 464 to 564%.

[0061] The styrene block copolymer may have a tear strength of 15 to 25 N / mm, preferably 18 to 22 N / mm, based on the ISO 34-1 measurement method, preferably the ISO 34-1 methode B(b) (Graves) measurement method.

[0062] The glucose diffusion control membrane solution for a continuous blood glucose measuring 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, and more preferably 1:0.15 to 0.8. If the weight ratio is less than 1:0.1, an excessive amount of glucose may permeate the outermost surface of the continuous blood glucose measuring biosensor, resulting in a problem of reduced sensor performance, while if the weight ratio exceeds 1:4, glucose may not permeate the outermost surface of the continuous blood glucose measuring biosensor, resulting in a problem of glucose not being sensed.

[0063] Furthermore, the glucose diffusion control membrane solution for the continuous blood glucose monitoring 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 monitoring biosensor of the present invention can be adjusted using an organic solvent. The organic solvent of the present invention may be any organic solvent commonly used in the art, and preferably may include one or more selected from chloroform, cyclohexanone, cyclopentanone, dimethylacetamide, dimethylformamide, dioxane, dichloromethane, trichloroethane, tetrahydrofuran, xylene, and toluene, and more preferably may include tetrahydrofuran.

[0064] The present invention will now be described with reference to the following examples, which are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

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

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

[0067] Experimental Example 1: Cytotoxicity experiment The cytotoxicity of the hydrophilic solution produced in Preparatory Example 1 and the hydrophobic solution produced in Preparatory Example 2 was evaluated using the ISO 10993-5 evaluation method. As a result, it was confirmed that both the hydrophilic solution produced in Preparatory Example 1 and the hydrophobic solution produced in Preparatory Example 2 were non-toxic.

[0068] Experimental Example 2: Skin sensitization experiment The hydrophilic solution prepared in Preparative Example 1 and the hydrophobic solution prepared in Preparative Example 2 were evaluated for skin sensitization according to the ISO10993-10 evaluation method. As a result, it was confirmed that neither the hydrophilic solution prepared in Preparative Example 1 nor the hydrophobic solution prepared in Preparative Example 2 induced irritation or skin sensitivity.

[0069] Experimental Example 3: Systemic Toxicity Experiment The systemic toxicity of the hydrophilic solution produced in Preparatory Example 1 and the hydrophobic solution produced in Preparatory Example 2 was evaluated using the ISO 10993-11 evaluation method. As a result, it was confirmed that both the hydrophilic solution produced in Preparatory Example 1 and the hydrophobic solution produced in Preparatory Example 2 were not systemic toxic.

[0070] Experimental Example 4: Blood compatibility experiment The hydrophilic solution prepared in Preparatory Example 1 and the hydrophobic solution prepared in Preparatory Example 2 were evaluated for blood compatibility using the ISO 10993-4 evaluation method. As a result, it was confirmed that both the hydrophilic solution prepared in Preparatory Example 1 and the hydrophobic solution prepared in Preparatory Example 2 were blood compatible.

[0071] Example 1: Preparation of glucose diffusion-controlling 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 Preparation Example 2 were charged into a stirrer and stirred to prepare a glucose diffusion control membrane solution with a concentration of 40 mg / mL. Polyether The system contained thermoplastic polyurethane (HP-93A-100, Lubrizol) and styrene block copolymer (TM7APO, KRAIBURG) in a weight ratio of 1:0.25.

[0072] Example 2: Preparation of glucose diffusion-controlling membrane solution for continuous blood glucose measurement 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 charged into a stirrer and stirred to prepare a glucose diffusion control membrane solution with a concentration of 40 mg / mL. Polyether The thermoplastic polyurethane (HP-93A-100, Lubrizol) and styrene block copolymer (TM7APO, KRAIBURG) were contained in a weight ratio of 1:1.

[0073] Example 3: Preparation of glucose diffusion-controlling membrane solution for continuous blood glucose measurement 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 charged into a stirrer and stirred to prepare a glucose diffusion control membrane solution with a concentration of 40 mg / mL. Polyether The system contained thermoplastic polyurethane (HP-93A-100, Lubrizol) and styrene block copolymer (TM7APO, KRAIBURG) in a weight ratio of 1:4.

[0074] Manufacturing example 1: Manufacturing a test sensor (1) An enzyme solution was prepared by mixing an electron transfer mediator, an enzyme, and a cross-linker 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 consisting of a working electrode (carbon electrode), a reference electrode (AgCl electrode), and a counter electrode (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) Masking films were attached to the working electrode, reference electrode, and counter electrode of the test electrode, and the glucose diffusion control membrane solutions prepared in Examples 1 to 3, the hydrophilic solution prepared in Preparatory Example 1, and the hydrophobic solution prepared in Preparatory Example 2 were drop-cast onto the masking films, followed by drying to prepare test sensors each having a glucose diffusion control membrane formed thereon.

[0075] Experimental Example 5: Measurement of glucose permeability 2 mL of PBS solution was placed in a glass cell for electrochemical measurement, and each test sensor prepared in Preparation Example 1 was supported in the PBS solution.

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

[0077] 1, it was confirmed that the change in current value due to a change in glucose concentration increased in the order of use of the hydrophilic solution prepared in Preparatory Example 1, the glucose diffusion control membrane solution prepared in Example 1, the glucose diffusion control membrane solution prepared in Example 2, and the glucose diffusion control membrane solution prepared in Example 3. Furthermore, when only the hydrophobic solution prepared in Preparatory Example 2 was used, there was almost no change in current value due to a change in glucose concentration.

[0078] These results confirm that the glucose sensing sensitivity can be selectively controlled by controlling the ratio of hydrophobic substances contained in the glucose diffusion control membrane.

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

[0080] The glucose diffusion-controlling membranes thus prepared were left in ultrapure water (DI water) for 24 hours, and then their final weights were measured.

[0081] Using the measured initial weights and final weights, the water absorption rates of the glucose diffusion-controlling membrane solutions prepared in Examples 1 to 3, the hydrophilic solution prepared in Preparatory Example 1, and the hydrophobic solution prepared in Preparatory Example 2 were calculated and are shown in Table 1 below.

[0082] [Table 1]

[0083] As can be seen from Table 1, the water absorption rate was measured to be higher in the following order: hydrophilic solution prepared in Preparatory Example 1, glucose diffusion control membrane solution prepared in Example 1, glucose diffusion control membrane solution prepared in Example 2, and glucose diffusion control membrane solution prepared in Example 3. In addition, when only the hydrophobic solution prepared in Preparatory Example 2 was used, almost no water was absorbed.

[0084] These results confirm that the water absorption rate can be selectively controlled by controlling the ratio of hydrophobic substances contained in the glucose diffusion control membrane.

[0085] Comparative Preparation Example 1: Preparation of Hydrophobic Solution Aliphatic compounds 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 is 30 minutes, while the time for dissolving the aliphatic block copolymer used in Comparative Preparation Example 1 is 30 minutes. Polyether It was confirmed that it took 60 minutes to dissolve the thermoplastic polyurethane. Therefore, it was confirmed that using the hydrophobic solution prepared in Preparative Example 2 as the hydrophobic solution in preparing the glucose diffusion control membrane solution shortens the preparation time compared to using the hydrophobic solution prepared in Comparative Preparative 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 charged into a 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 A thermoplastic polyurethane (SG-80A, Lubrizol) was included in the mixture at 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 cross-linker 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 consisting of a working electrode (carbon electrode), a reference electrode (AgCl electrode), and a counter electrode (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 test electrode was dried in a dryer at 35°C for 30 minutes. (4) Masking films were attached to the working electrode, reference electrode, and counter electrode of the test electrode, and the glucose diffusion control membrane solution prepared in Example 1 and the glucose diffusion control membrane solution prepared in Comparative Example 1 were drop-cast onto the masking films, followed by drying to prepare test sensors each having a glucose diffusion control membrane formed thereon.

[0089] Experimental Example 7: Measurement of glucose permeability 2 mL of PBS solution was placed in a glass cell for electrochemical measurement, and each test sensor prepared in Preparation Example 2 was supported in the PBS solution.

[0090] Glucose was added to the PBS solution using a glucose stock solution (in 10 mM PBS solution) to adjust the glucose concentration to 200 mg / dL, and then the chronoamperometry (CA) condition was measured using a potentiostat (Multi-Palmsens 4, applied voltage: 0.3 V). The results are shown in Figure 2.

[0091] As can be seen from FIG. 2, when the glucose diffusion control membrane solution prepared in Example 1 was used, the measured current density was higher than when the glucose diffusion control membrane solution prepared in Comparative Example 1 was used.

[0092] Simple modifications and variations of the present invention can be easily implemented by those skilled in the art, and all such modifications and variations are considered to be included within the scope of the present invention.

Claims

1. A glucose diffusion-controlling membrane solution comprising a hydrophilic substance and a hydrophobic substance, the hydrophilic material comprises an aliphatic polyether-based thermoplastic polyurethane; A glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor, wherein the hydrophobic substance contains a styrene block copolymer.

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

3. The aliphatic polyether-based thermoplastic polyurethane is a flexural modulus based on ASTM D790 measurement method of 2400 to 3400 psi; Ultimate tensile strength in a dry state is 1700 to 2700 psi, and in a wet state is 900 to 1900 psi, based on the ASTM D412 measurement method; 3. The glucose diffusion control membrane solution for a continuous blood glucose monitoring biosensor according to claim 2, wherein the ultimate elongation in a dry state is 540 to 1540 psi and the ultimate elongation in a wet state is 320 to 920 psi, as measured by ASTM D412.

4. The styrene block copolymer is The tensile strength based on the ISO37 measurement method is 8.2 to 10.2 MPa, The elongation at break based on the ISO37 measurement method is 414 to 614%, 3. The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor according to claim 2, wherein the tear strength based on the ISO 34-1 measurement method is 15 to 25 N / mm.

5. 2. The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor according to claim 1, wherein the hydrophilic substance and the hydrophobic substance have a weight ratio of 1:0.1 to 1:

4.

6. A glucose diffusion control membrane for a continuous blood glucose measurement biosensor, produced by drying the glucose diffusion control membrane solution for a biosensor according to claim 1.

7. A biosensor for continuous blood glucose measurement, comprising the glucose diffusion control membrane according to claim 6.

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