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, 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 the human body 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 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), the number of people aged 20-79 years old worldwide with diabetes was 463 million (9.3%) in 2019. This is an increase of 39 million people compared to the 425 million reported in 2017.

[0003] In addition, as of 2019, the number of diabetes patients aged 65 or older was 136 million, 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 from 2019.

[0006] As a result, the American Diabetes Association (ADA) revised 2021 guidelines explicitly state 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 was helpful in improving glycemic patients' glycemic pattern management and glycosylated hemoglobin, and glycemic control via CGM was more effective when provided together with programs such as education and training and follow-up management.

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

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

[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 control and improving obstetric outcomes.

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

[0012] The glucose diffusion control membrane has no negative effect on the human body when the sensor is inserted into the human body, prevents the sensor material from being discharged into the human body, and can control the diffusion of glucose entering from the human body.

[0013] A person's movement can increase the rate at which glucose flows through the glucose diffusion control membrane to the outermost part of the sensor, which can make accurate blood glucose measurements difficult.

[0014] Therefore, the present inventors have conducted research to overcome these problems, and have confirmed that when a glucose diffusion control membrane for a continuous blood glucose measurement biosensor is manufactured 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 the membrane is inserted into the human body using only substances with verified biocompatibility, and glucose permeability and water absorbency 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 problems, and an object of the present invention is to provide a glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor, which can ensure stability even when inserted into the 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. [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 measurement biosensor of the present invention may contain an aliphatic polyester-based thermoplastic polyurethane as the hydrophilic substance, and may contain a styrene block copolymer as the hydrophobic substance.

[0017] In a preferred embodiment of the present invention, the aliphatic polyester-based thermoplastic polyurethane has a specific gravity of 1.0 to 1.2 g / cm according to the ASTM D792 measurement method. 3 may be also possible.

[0018] In a preferred embodiment of the present invention, the aliphatic polyester-based 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 polyester-based 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 polyester-based thermoplastic polyurethane may have an ultimate tensile of 1700 to 2700 psi in a dry state and an ultimate tensile of 900 to 1900 psi in a wet state, as measured by the ASTM D412 method.

[0021] In a preferred embodiment of the present invention, the aliphatic polyester-based 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, based on the ASTM D412 measurement method.

[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 also possible.

[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 based on the ISO 37 measurement method of 414 to 614%.

[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. Effect 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 including the same, and the continuous blood glucose measurement biosensor including the same can ensure stability even when inserted into the human body by using only materials whose biocompatibility has been verified, and can control glucose permeability and water absorbency. [Brief description of the drawings]

[0031] [Figure 1] FIG. 13 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. [Diagram 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 PREFERRED EMBODIMENTS

[0032] Hereinafter, the 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 carry out 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 related 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. In this case, the glucose diffusion control membrane for the continuous blood glucose measuring biosensor of the present invention can be produced by drying a glucose diffusion control membrane solution for the continuous blood glucose measuring 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] Such a biosensor for continuous blood glucose measurement may include, for example, 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 include an enzyme capable of oxidizing and reducing a liquid biological sample and a redox polymer. The enzyme layer may be an enzyme layer for an electrochemical biosensor containing an electron transfer mediator. The oxidoreductase is a general term for enzymes that catalyze oxidation-reduction reactions in living organisms. In the present invention, the oxidoreductase refers to an enzyme that reacts with a target substance to be measured, for example, in the case of a biosensor, and is reduced. The enzyme thus reduced reacts with an electron transfer mediator, and a signal such as a change in current generated at this time is measured to quantify the target substance. The oxidoreductase 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 an enzyme that uses the target substance as a substrate can be selected from the enzyme group according to the oxidation-reduction or the target substance to be detected.

[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, etc., which are group 8 elements, and the organic conductive salt may include ferrocene, quinone, a quinone derivative, methylene blue, etc.

[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] In addition, 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 act as a dispersant when dissolving the reagent, an adhesive when preparing the reagent, a stabilizer for long-term storage, etc.

[0042] In the case of electrodes, two types of electrodes such as a working electrode and a counter electrode may be included, or three types of electrodes such as a working electrode, a counter electrode, and a reference electrode may be included. In one embodiment, the biosensor according to the present invention may be an electrochemical biosensor fabricated by coating an enzyme solution containing an enzyme capable of oxidizing and reducing glucose, a crosslinker, and an electron transfer mediator on a substrate having at least two, preferably two or three, electrodes, and then drying the solution. For example, a planar electrochemical biosensor may be provided in which the working electrode, the counter electrode, and the reference electrode are arranged on the same surface of the substrate, the 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 control 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, or silver.

[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] In addition, the glucose diffusion control membrane solution for the continuous blood glucose measurement biosensor of the present invention contains a hydrophilic material and a hydrophobic material. As described above, since 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, it is possible to realize excellent control of glucose permeability even in the environment inside the human body and realize 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, there may be a problem that glucose permeates in an excessive amount at the outermost surface of the continuous blood glucose measurement biosensor, resulting in a decrease in sensor performance, and if it contains only a hydrophobic material, there may be a problem that glucose does not permeate at the outermost surface of the continuous blood glucose measurement biosensor, resulting in a failure to sense glucose.

[0048] First, an aliphatic polyester-based thermoplastic polyurethane may be included as a hydrophilic substance.

[0049] Specifically, the aliphatic polyester 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 also possible.

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

[0051] The aliphatic polyester 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] The aliphatic polyester-based thermoplastic polyurethane may have an ultimate tensile in a dry state of 1700 to 2700 psi, preferably 2000 to 2400 psi, as measured by the ASTM D412 measurement method.

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

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

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

[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 ISO 1183-1 measurement method. 3 , preferably 1.0 to 1.05 g / cm 3 may be also possible.

[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 based on the ISO 37 measurement method of 8.2 to 10.2 MPa, preferably 8.7 to 9.7 MPa.

[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 and 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, whereas 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] 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 may be adjusted using an organic solvent. The organic solvent of the present invention may be any organic solvent used in the art, and may preferably contain one or more selected from chloroform, cyclohexanone, cyclopentanone, dimethylacetamide, dimethylformamide, dioxane, dichloromethane, trichloroethane, tetrahydrofuran, xylene, and toluene, and more preferably may contain tetrahydrofuran.

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

[0065] Preparation Example 1: Preparation of hydrophilic solution 2,000 mg of aliphatic polyester-based thermoplastic polyurethane (HP-93A-100, Lubrizol) as a hydrophilic substance and 50 ml of tetrahydrofuran as an organic solvent were added to a homogenizer 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 prepared in Preparatory Example 1 and the hydrophobic solution prepared in Preparatory Example 2 was evaluated according to the ISO 10993-5 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 non-toxic.

[0068] Experimental Example 2: Skin sensitization experiment The hydrophilic solution prepared in Preparatory Example 1 and the hydrophobic solution prepared in Preparatory Example 2 were evaluated for skin sensitization according to the ISO 10993-10 evaluation method. As a result, it was confirmed that neither the hydrophilic solution prepared in Preparatory Example 1 nor the hydrophobic solution prepared in Preparatory 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 had no systemic toxicity.

[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 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 Preparation Example 2 were put into the stirrer and stirred to prepare 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 polyester 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 glucose diffusion control 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. At this time, the glucose diffusion control membrane solution contained aliphatic polyester thermoplastic polyurethane (HP-93A-100, Lubrizol) and styrene block copolymer (TM7APO, KRAIBURG) in a weight ratio of 1:1.

[0073] Example 3: Preparation of glucose diffusion control membrane solution for continuous blood glucose measurement biosensor A glucose diffusion control membrane solution with a concentration of 40 mg / mL was prepared by adding 4 mL of the hydrophilic solution prepared in Preparation Example 1 and 16 mL of the hydrophobic solution prepared in Preparation Example 2 to a stirrer and stirring them. At this time, the glucose diffusion control membrane solution contained an aliphatic polyester-based thermoplastic polyurethane (HP-93A-100, Lubrizol) and a 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 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 consisting of a working electrode (a carbon electrode), a reference electrode (a 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) Masking films were attached onto the working electrode, the reference electrode, and the 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 produce 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 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 concentrations were 50, 100, 200, 300, 400, and 500 mg / dL. The chronoamperometry (CA) condition was then measured using a potentiostat (Multi-Palmsens 4, applied voltage: 0.3 V). The results are shown in FIG. 1.

[0077] 1, it was confirmed that the change in current value due to the change in glucose concentration was greater in the order of using the hydrophilic solution produced in Preparatory 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. In addition, when only the hydrophobic solution produced in Preparatory Example 2 was used, there was almost no change in current value due to the change in glucose concentration.

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

[0079] Experimental Example 6: Measurement of water absorption rate 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 each dispensed in 3 mL portions 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 control membrane thus prepared was left in ultrapure water (DI water) for 24 hours, and then the final weight of each membrane was measured.

[0081] Using the measured initial weights and final weights, the water absorption rates 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 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] From these 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 2,000 mg of aliphatic polyester-based thermoplastic polyurethane (SG-80A, Lubrizol) as a hydrophobic material and 50 ml of tetrahydrofuran as an organic solvent were added to a homogenizer 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, it took 30 minutes to dissolve the styrene block copolymer used in Preparation Example 2, whereas it took 60 minutes to dissolve the aliphatic polyester-based thermoplastic polyurethane used in Comparative Preparation Example 1. Thus, it was confirmed that using the hydrophobic solution prepared in Preparation Example 2 as the hydrophobic solution during preparation of the glucose diffusion control membrane solution shortens the preparation time compared to using the hydrophobic solution prepared in Comparative Preparation Example 1, and is easy for mass production.

[0087] Comparative Example 1: Preparation of glucose diffusion control membrane solution for continuous blood glucose measurement biosensor A glucose diffusion control membrane solution with a concentration of 40 mg / mL was prepared by adding 16 mL of the hydrophilic solution prepared in Preparation Example 1 and 4 mL of the hydrophobic solution prepared in Comparative Preparation Example 1 to the stirrer and stirring them. At this time, the glucose diffusion control membrane solution contained aliphatic polyester thermoplastic polyurethane (HP-93A-100, Lubrizol) and aliphatic polyester thermoplastic polyurethane (SG-80A, Lubrizol) 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 consisting of a working electrode (a carbon electrode), a reference electrode (a 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 test electrode was dried in a dryer at 35° C. for 30 minutes. (4) Masking films were attached on the working electrode, the reference electrode, and the 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 on the masking films, respectively, and then dried 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 of the test sensors produced in Production Example 2 was supported in the PBS solution.

[0090] Glucose was provided to the PBS solution using a glucose stock solution (in 10 mM PBS solution) so that the glucose concentration was 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 current density was measured to be 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 a person having ordinary skill in the art, and all such modifications and variations are deemed to be included within the scope of the present invention.

Claims

1. A glucose diffusion control membrane solution comprising a hydrophilic material and a hydrophobic material, The hydrophilic material includes an aliphatic polyester-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 polyester thermoplastic polyurethane has a specific gravity of 1.0 to 1.2 g / cm according to the ASTM D792 measurement method. ３ and the shore hardness based on the ASTM D2240 measurement method is 78 to 88A; 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 The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor according to claim 1, characterized in that the Shore hardness based on the ISO 48-4 measurement method is 60 to 80A.

3. The aliphatic polyester-based thermoplastic polyurethane is A flexural modulus based on the ASTM D790 measurement method is 2400 to 3400 psi; The ultimate tensile strength in a dry state is 1700 to 2700 psi and the ultimate tensile strength in a wet state is 900 to 1900 psi according to the ASTM D412 measurement method; The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor according to claim 2, characterized in that 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 based on the ASTM D412 measurement method.

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 ISO 37 measurement method is 414 to 614%, 3. The glucose diffusion control membrane solution for a continuous blood glucose measurement biosensor according to claim 2, characterized in that 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 1:0.1-4.

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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