Ion selecting film, ion selecting electrode, ion sensor, and specimen detector

Abstract

To reduce the influence of protein on an ISM using a metal porphyrin complex as an ionophore.SOLUTION: An ion selecting film of an embodiment includes a metal porphyrin compound, a polymer, and a film solvent. The film solvent is a compound satisfying CLogP≥9. The compound has a benzene ring. The 1-position of the benzene ring is an alkyl ester group having 5 or more and 19 or less carbon atoms which may have a substituent. At least one of the 3-position, 4-position, and 5-position of the benzene group is an alkyl ester group having 5 or more and 19 or less carbon atoms which may have the substituent.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The embodiments disclosed in the present specification and drawings relate to an ion selective membrane, an ion selective electrode, an ion sensor, and an analyte testing device. [Background technology]

[0002] An electrode that responds selectively to specific ions is called an ion-selective electrode (ISE). When an ISE is immersed in a solution, a potential difference corresponding to the activity of the target ion is generated at the interface between the ion-selective membrane and the solution, causing a change in the electrode potential. Ion concentration measuring devices (ion sensors) based on this phenomenon are widely used in fields such as physics and chemistry, agriculture, medicine, food, and the environment.

[0003] Ion-selective electrodes used in medical specimen testing equipment are widely used to measure sodium, potassium, and chloride ions. For the cations sodium and potassium ions, ionophore-type ISEs are widely used, which use ion-selective membranes (ISMs) that enclose ion-selective substances called ionophores in a matrix composed mainly of polymers and hydrophobic membrane solvents. For the anion chloride ion, on the other hand, there are no ionophores as good as those for sodium and potassium ions, so sparingly soluble salt-type ISEs, such as silver-silver chloride electrodes, or ion-exchanger-type ISEs using ion-exchange resins with immobilized ammonium salts, are often used.

[0004] Chloride ion ionophores can be broadly divided into three types: organometallic, organic, and metal complex. Of these, organometallic ionophores exhibit high chloride ion selectivity, but are difficult to use due to the toxicity of the chemicals involved, as they use organomercury and organotin compounds. Organic ionophores, such as bisthiourea, have the disadvantage of low chloride ion selectivity. Metal complex ionophores exhibit high chloride ion selectivity and are relatively easier to use as chemicals than organometallic ionophores. Furthermore, in ISMs using metal complex ionophores, membrane solvents with both hydrophobic and polar moieties within the molecule are often used as the membrane solvent for the hydrophobic membrane. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 3526677 Summary of the Invention [Problem to be solved by the invention]

[0006] In the conventional ISMs described above, metalloporphyrin complexes are used as chloride ion ionophores, and o-nitrophenyl octyl ether (NPOE) is a typical membrane solvent. The inventors investigated the properties of ISEs using metalloporphyrin complexes and NPOE and confirmed that they exhibit high chloride ion selectivity. However, they found that when an ISM containing NPOE was immersed in an aqueous solution containing a protein, the electromotive force response to ion concentration decreased.

[0007] The problem to be solved by the embodiments disclosed in this specification and the drawings is to suppress the effect of proteins on an ISM that uses a metalloporphyrin complex as an ionophore. However, the problem to be solved by the embodiments disclosed in this specification and the drawings is not limited to the above problem. Problems corresponding to the effects of each configuration shown in the embodiments described below can also be positioned as other problems. [Means for solving the problem]

[0008] The ion-selective membrane of the embodiment comprises a metalloporphyrin compound, a polymer, and a membrane solvent. The membrane solvent satisfies CLogP≧9 and contains a compound represented by the following general formula (1):

[0009] [ka]

[0010] In the general formula (1), X1 is an alkyl ester group having 5 to 19 carbon atoms which may have a substituent. X2 to X6 are each independently a hydrogen atom or a monovalent substituent. At least one of X3, X4, and X5 is the alkyl ester group having 5 to 19 carbon atoms which may have a substituent. In addition, the alkyl ester group having 5 to 19 carbon atoms which may have a substituent in the present application refers to an alkyl ester group having 5 to 19 carbon atoms excluding the carbon atoms of the substituent. [Brief explanation of the drawings]

[0011] [Figure 1] Schematic diagram explaining the outline of ISE. [Figure 2] Schematic diagram illustrating an overview of ISM. [Figure 3] Graph showing the relationship between membrane solvent CLogP and protein effect on ISM. [Figure 4] Schematic diagram illustrating an overview of an ion sensor using an ISE. [Figure 5] FIG. 1 is a schematic diagram illustrating an overview of a sample testing device. DETAILED DESCRIPTION OF THE INVENTION

[0012] Hereinafter, an ion selective membrane, an ion selective electrode, an ion sensor, and a specimen testing device according to embodiments will be described with reference to the drawings.

[0013] ·overview 1 is a schematic diagram illustrating an ion-selective electrode (ISE1000) equipped with an ion-selective membrane (ISM1002) according to this embodiment. In FIG. 1, the ISE1000 is composed of, for example, an electrode 1001 made of a conductor and an ISM 1002. The ISE1000 may have an internal electrolyte solution 1003.

[0014] The ISE 1000 is placed in contact with the measurement solution 1020 together with the reference electrode 1010 to be compared. The reference electrode 1010 may be in contact with the measurement solution 1020 through a salt bridge or a liquid junction. The ISM 1002 in contact with the measurement solution 1020 detects the concentration (more precisely, activity a I The membrane potential (E M ) is generated. M ) can be referred to the Nernst equation (eq.1) below:

[0015]

number

[0016] where E 0 is the standard electrode potential, R is the gas constant, T is the absolute temperature, z is the charge number of the ion, and F is the Faraday constant. In an ion sensor, the concentration of a target ion in a measurement solution is calculated by measuring the potential difference between the ISM and the reference electrode with a voltmeter for a solution with a known concentration of the target ion and the measurement solution. Each of the components shown in Figure 1 is explained in detail below.

[0017] Ion selective electrodes (ISEs) The ISE 1000 of this embodiment is composed of an electrode 1001 made of at least one type of conductor and an ISM 1002. A known structure can be used as the structure of the ISE 1000. For example, there is a structure shown in FIG. 1 in which the internal electrode 1001 is in contact with the internal electrolyte 1003, the internal electrolyte 1003 is in contact with the ISM 1002, and the ISM 1002 is in contact with the measurement solution 1020.

[0018] The ISE1000 may be configured in any known manner except for the ISM1002. Examples of the cylindrical body of the ISE1000 include polymers such as polyvinyl chloride and polymethyl methacrylate. Examples of the internal electrolyte 1003 include aqueous solutions of sodium chloride, potassium chloride, and the like. Examples of the internal electrode 1001 include electrodes made of metals / poorly soluble metal chlorides, such as silver-silver chloride, and electrodes made of conductive materials, such as platinum, conductive carbon materials, and conductive polymers. A solid-state ISE1000 in which the internal electrolyte 1003 is omitted and the ISM1002 is applied to the electrode 1001 made of a conductor is also preferably used.

[0019] The ISE 1000 can be used, for example, as shown in FIG. 1. Specifically, it is placed in contact with the measurement solution 1020 together with a reference electrode 1010. The reference electrode 1010 may be in contact with the measurement solution 1020 through a salt bridge or a liquid junction. Any known reference electrode can be used as the reference electrode 1010. Specific examples include electrodes made of silver, metals such as silver chloride, or poorly soluble metal chlorides, and electrodes made of conductive materials such as conductive carbon materials, conductive polymers, and platinum.

[0020] Ion selective membrane (ISM) The ISM of this embodiment includes a metalloporphyrin compound, a polymer, and a membrane solvent. 2 is a schematic diagram illustrating an overview of the ISM 1002 of this embodiment. The ISM 1002 includes an ionophore 2001, a polymer 2002, and a membrane solvent 2003. The ISM 1002 may also include an ionic additive 2004. The ionophore 2001 selectively captures target ions 2005 from a measurement solution 1020 containing target ions 2005 and impurity ions 2006 into the ISM 1002 (the process indicated by the arrow in the figure), thereby enabling the generation of an ion-selective membrane potential.

[0021] ISM1002 can be produced by known methods. An example is described below. Ionophore 2001, polymer 2002, membrane solvent 2003, and ionic additive 2004 are dissolved in a process solvent, and the resulting solution is cast onto a substrate such as a glass plate and allowed to stand. After the process solvent evaporates, ISM1002 is molded into the desired shape. A process solvent that can dissolve the components of ISM1002 at a concentration sufficient for film formation and is suitable for film formation is preferably used. Examples include tetrahydrofuran, chloroform, acetone, methyl ethyl ketone, toluene, and ethyl acetate. The film thickness of ISM1002 can be adjusted by controlling the amount of process solvent. The appropriate film thickness varies depending on the mechanical strength and cost of the intended application, but can be between 1 μm and 5 mm. The components that make up ISM1002 are described below.

[0022] Membrane solvent The ISM 1002 of this embodiment includes a membrane solvent 2003. The membrane solvent 2003 is often the component that has the largest mass ratio among the components constituting the ISM 1002. The membrane solvent 2003 forms a flexible matrix together with the polymer 2002. The matrix retains other components such as the ionophore 2001, enabling the ISM 1002 to function. Because the measurement solution 1020 is typically an aqueous solution, the membrane solvent 2003 of the ISM 1002 has hydrophobicity that allows the components of the ISM 1002 to be retained and not eluted into the membrane. On the other hand, the membrane solvent 2003 preferably has a polarity sufficient to retain the ionophore 2001 and ionic additive 2004, which have a certain degree of polarity, and to incorporate the target ion 2005 into the membrane. In particular, it is preferable to use a solvent containing a benzene ring as the membrane solvent 2003 suitable for ISM1002, which uses a porphyrin complex as the ionophore 2001, in order to stably retain the porphyrin complex, which has a high degree of conjugation.

[0023] NPOE is a well-known representative membrane solvent, but when an ISM containing NPOE is immersed in an aqueous solution containing proteins, the electromotive force response to ion concentration decreases.

[0024] To solve this problem, the inventors investigated various membrane solvents. Among them, dioctyl phthalate (DOP), which has relatively small polarization and multiple hydrophobic alkyl chains, was found to exhibit relatively good properties. However, there was a demand for improved durability against repeated use when measuring the ion concentration of test solutions containing high concentrations of proteins. The inventors investigated the cause of the decrease in electromotive force response due to the influence of proteins. To suppress the influence of proteins on bio-related devices, a known method is to hydrophilize the device surface to suppress protein adsorption. However, hydrophilizing the surface of ion-selective membranes was not effective for ISMs that use porphyrin complexes as ionophores. Through further investigation, the inventors discovered that the cause of the decrease in electromotive force response due to the influence of proteins is the obscuring of the hydrophobic membrane / aqueous solution interface due to the surfactant function of proteins, resulting in the penetration of counterions and a reduction in the potential difference. To address this decrease in electromotive force response, the inventors attempted to form a hydrophobic membrane that suppresses the influence of the surfactant function of proteins by improving the membrane solvent. The following two specific methods were proposed and verified, leading to the completion of the present invention.

[0025] The first method is to strengthen the intermolecular hydrophobic interactions of the hydrophobic groups of the membrane solvent. In DOP, the two ester groups attached to the benzene ring are located at adjacent ortho positions. Therefore, the interactions of the alkyl chains of the ester groups, which express the hydrophobicity of the membrane solvent, are relatively expressed intramolecularly, and the intermolecular interactions that are important as a matrix are not easily expressed. To strengthen the intermolecular interactions of these alkyl chains, the ester groups were positioned at a distance to strengthen the intermolecular hydrophobic interactions, forming a hydrophobic membrane that suppresses the effects of the surfactant function of proteins.

[0026] The second approach is to increase the number of hydrophobic groups (e.g., alkyl groups) in the membrane solvent molecule. In order to form a hydrophobic membrane that can resist the surfactant function of proteins, it is effective to improve the hydrophobicity of the membrane solvent. One way to achieve this is to increase the proportion of hydrophobic functional groups in the molecule. Examples of hydrophobic functional groups include aromatic functional groups and aliphatic (alkyl chain) functional groups. After examining various membrane solvents, the inventors found that aliphatic functional groups are advantageous. There are two reasons for this: (i) Aliphatic functional groups have a stronger hydrophobic effect than aromatic functional groups. (ii) Aromatic functional groups have affinity with benzene rings contained in proteins through interactions such as ππ conjugation. From these findings, it is believed that it is effective to increase the proportion of alkyl groups contained in the carboxylic acid ester-based membrane solvent.

[0027] The ISM 1002 of this embodiment satisfies CLogP≧9 and includes a compound represented by the general formula (1) above as the membrane solvent 2003. The compound represented by the general formula (1) above has a benzene ring. The first position (X1) of the benzene ring is an alkyl ester group having 5 to 19 carbon atoms. Furthermore, at least one of the third position (X3), fourth position (X4), and fifth position (X5) of the benzene ring is an alkyl ester group having 5 to 19 carbon atoms.

[0028] Here, CLogP is a method that uses fragments, which is the most widely used of the octanol / water partition coefficient LogP, which is the most widely used parameter for describing the hydrophilicity and hydrophobicity of a compound. Specific CLogP values ​​can be easily calculated using commercially available software such as ChemDraw (registered trademark). The larger the CLogP value, the higher the hydrophobicity of the molecule. The inventors have found through their research that compounds with a CLogP of 9 or greater are significantly effective in suppressing the effects of proteins.

[0029] Figure 3 is a graph showing the relationship between the CLogP of a membrane solvent and the effect of a protein on an ISM. The horizontal axis of the graph represents the CLogP of the membrane solvent. The vertical axis (R) represents the ratio of the sensitivity (electromotive force response to Cl ion concentration) of an ISE prepared using the membrane solvent. More specifically, this R represents the ratio of the sensitivity after a series of measurements in a buffer solution containing protein to the initial sensitivity (sensitivity after measurement / initial sensitivity).

[0030] For use as a highly durable ISE in measuring Cl ion concentrations in protein-containing solutions, it is desirable for this ratio (R) to be 0.6 or greater, more preferably 0.8 or greater. In Figure 3, it can be seen that R within the desired range can be obtained when using the membrane solvents indicated by the ● legend. These membrane solvents satisfy CLogP ≥ 9 and are compounds represented by the general formula (1) above. The upper limit of CLogP is not particularly limited, but is usually 20.0 or less.

[0031] In the above general formula (1), X1 is an alkyl ester group, and when at least one of X3, X4, and X5 is an alkyl ester group, this corresponds to the first method (strengthening the intermolecular hydrophobic interaction of the hydrophobic groups of the membrane solvent). X3 and X5 are in the meta position relative to X1, and X4 is in the para position relative to X1. X2 and X6 may each independently be an alkyl ester group, a substituent that is not an alkyl ester group, or a hydrogen atom. X2 and X6 are located in the ortho position relative to X1.

[0032] Similarly, in the above general formula (1), when X1 is an alkyl ester group and at least two of X2, X3, X4, X5, and X6 are alkyl ester groups, this corresponds to the second method described above (increasing the intramolecular hydrophobic groups (alkyl groups) of the membrane solvent).

[0033] That is, in the ISM of this embodiment, the membrane solvent can include a compound in which X1, X2, X3, X4, X5, and X6 are each selected from the following options.

[0034] In the general formula (1), X1 is an alkyl ester group having 5 to 19 carbon atoms which may have a substituent. At least one of X3, X4, and X5 is an alkyl ester group having 5 to 19 carbon atoms which may have a substituent. The number of carbon atoms in the alkyl ester group, which may have a substituent, is the number of carbon atoms in the alkyl ester group excluding the substituent. In other words, the alkyl ester group, which may have a substituent, can be distinguished between the substituent and the alkyl ester group. For example, a branched side chain alkyl group (e.g., a 2-ethyl group) in a branched alkyl ester group (e.g., a 2-ethylhexyl ester group) does not become a substituent of the alkyl ester group. The substituents of the alkyl ester group are preferably each independently selected from the group consisting of an alkoxy group having from 1 to 4 carbon atoms, an alkylcarbonyl group having from 2 to 5 carbon atoms, an alkyloxycarbonyl group having from 2 to 5 carbon atoms, an alkylcarbonyloxy group having from 2 to 5 carbon atoms, an aryl group having from 6 to 20 carbon atoms, a cyano group, and a halogen atom. The number of carbon atoms in the alkylcarbonyl group, alkyloxycarbonyl group, and alkylcarbonyloxy group includes the carbon number of the carbonyl group, which is 1.

[0035] X2 to X6 are each independently a hydrogen atom or a monovalent substituent. Examples of the monovalent substituent include saturated or unsaturated alkyl groups, alkoxy groups, alkylcarbonyl groups, aryl groups, aryloxy groups, aralkyl groups, halogen atoms, and alkyl ester groups. Two or more of X2 to X6 may be bonded to form a ring. For example, two of X2 to X6 may be bonded to form a divalent substituent selected from an alkylene group which may have a substituent, an arylene group which may have a substituent, and the like. It is preferable that X2 to X6 each independently represent a hydrogen atom, a saturated or unsaturated alkyl group having from 1 to 20 carbon atoms which may have a substituent, an alkoxy group having from 1 to 20 carbon atoms which may have a substituent, an alkylcarbonyl group having from 2 to 20 carbon atoms which may have a substituent, an aryl group having from 6 to 20 carbon atoms which may have a substituent, an aryloxy group having from 6 to 20 carbon atoms which may have a substituent, an aralkyl group having from 7 to 30 carbon atoms which may have a substituent, a halogen atom, or an alkyl ester group having from 5 to 19 carbon atoms which may have a substituent. The substituents of the alkyl group are preferably each independently selected from the group consisting of an alkoxy group having from 1 to 4 carbon atoms, an alkylcarbonyl group having from 2 to 5 carbon atoms, an alkyloxycarbonyl group having from 2 to 5 carbon atoms, an alkylcarbonyloxy group having from 2 to 5 carbon atoms, an aryl group having from 6 to 20 carbon atoms, a cyano group, and a halogen atom. It is preferable that the substituents of the alkoxy group, the alkylcarbonyl group, the aryl group, the aryloxy group, and the aralkyl group are each independently selected from the group consisting of a saturated or unsaturated alkyl group having from 1 to 20 carbon atoms, an alkoxy group having from 1 to 20 carbon atoms, an alkylcarbonyl group having from 2 to 20 carbon atoms, an alkyloxycarbonyl group having from 2 to 20 carbon atoms, an alkylcarbonyloxy group having from 2 to 20 carbon atoms, an aryl group having from 6 to 20 carbon atoms, a cyano group, and a halogen atom.

[0036] The arrangement of the alkyl ester groups on the benzene ring can be meta (1,3) or para (1,4) positions when there are two alkyl ester groups, 1,2,4 or 1,3,5 positions when there are three alkyl ester groups, or 1,2,3,5 or 1,2,4,5 positions when there are four alkyl ester groups.

[0037] Of X2, X3, X4, X5, and X6, the substituents that are not alkyl ester groups are preferably those whose aromatic substituent hydrophobicity constant π is 0 or more. Here, the hydrophobicity constant π of the aromatic substituent can be determined from the LogP of monosubstituted benzene. The hydrophobicity constant π of the aromatic substituent is the increment (logP) of the hydrophobicity index (log P) of the compound when converting a hydrogen atom H to a substituent X at a certain position of the reference substance. X -logP H ) π can be considered to be a value specific to the substituent. Details of the definition are also explained in Reference 1 below.

[0038] (Reference 1) Miki Akamatsu, “QSAR Parameters and Their Applications,” Journal of Pesticide Science, Japan, 2013, Vol. 38, No. 2, pp. 195-203

[0039] The reason why the substituent other than the alkyl ester group is preferably a substituent with a hydrophobicity constant π of the aromatic substituent of 0 or more is as follows: In order to suppress the influence of proteins, it is effective to improve the hydrophobicity of the membrane solvent. Therefore, it is preferable that the hydrophobicity constant π of the aromatic substituent is the same as that of a hydrogen atom (π is 0) or is a more hydrophobic substituent (π is greater than 0).

[0040] In the alkyl ester group of X1 and / or at least one alkyl ester group of X3, X4, and X5, the alkyl group of the alkyl ester group is preferably an alkyl group having from 4 to 18 carbon atoms, which may have a substituent and may be a linear alkyl group or a branched alkyl group. The alkyl group of the alkyl ester group is more preferably an alkyl group having from 6 to 14 carbon atoms (as an alkyl ester group, from 7 to 15 carbon atoms). The alkyl group of the alkyl ester group is even more preferably an alkyl group having from 6 to 12 carbon atoms (as an alkyl ester group, from 7 to 13 carbon atoms). X1 is preferably an alkyl ester group having from 7 to 13 carbon atoms, which may have a substituent. Furthermore, it is preferable that at least one of X3, X4, and X5 is an alkyl ester group having from 7 to 13 carbon atoms, which may have the substituent. The alkyl group of the alkyl ester group may be a straight-chain alkyl group or a branched alkyl group. Specific examples of the alkyl group of the alkyl ester group, which may be straight-chain or branched, include a butyl group (4 carbon atoms), a pentyl group (5 carbon atoms), a hexyl group (6 carbon atoms), a heptyl group (7 carbon atoms), an octyl group (8 carbon atoms), a nonyl group (9 carbon atoms), a decyl group (10 carbon atoms), an undecyl group (11 carbon atoms), a dodecyl group (12 carbon atoms), a tridecyl group (13 carbon atoms), a tetradecyl group (14 carbon atoms), a pentadecyl group (15 carbon atoms), a hexadecyl group (16 carbon atoms), a heptadecyl group (17 carbon atoms), and an octadecyl group (18 carbon atoms). The alkyl ester group may be an alkyloxycarbonyl group represented by -CO-OR when R is the alkyl group.

[0041] A larger number of carbon atoms in the alkyl group of the alkyl ester group is advantageous for improving hydrophobicity. However, if the number of carbon atoms is too large, it becomes difficult to form a membrane solvent (it becomes solid). If the membrane solvent becomes solid, it may lead to problems such as increased noise due to a significant increase in ISM resistance and reduced membrane flexibility.

[0042] For these reasons, the membrane solvent in the ISM of this embodiment is preferably a compound represented by any one of the following general formulas (2), (3), and (4).

[0043] [ka]

[0044] [ka]

[0045] [ka]

[0046] In the general formulae (2), (3), and (4), X7 to X 16are each independently a hydrogen atom or an aromatic substituent having a hydrophobicity constant π of 0 or more. R1 to R8 are each independently an alkyl group having 4 to 18 carbon atoms which may have a substituent. The substituents in R1 to R8 are each independently a substituent of the alkyl ester group. R1 to R8 may each independently be an alkyl ester group which does not have the substituent.

[0047] More preferred membrane solvents include alkyl ester compounds of isophthalic acid, terephthalic acid, and pyromellitic acid. The alkyl ester compounds of isophthalic acid are those represented by the general formula (2) in which X7 to X 10 are both hydrogen atoms. R1 and R2 may be the same or different. The alkyl ester compound of terephthalic acid is a compound represented by the general formula (3) above, 11 From X 14 are both hydrogen atoms. R3 and R4 may be the same or different. The alkyl ester compound of pyromellitic acid is a compound represented by the general formula (4) in which X 15 and X 16 are all hydrogen atoms. R5, R6, R7 and R8 may be the same or different from each other. Further preferred membrane solvents include bis(2-ethylhexyl) isophthalate (DOIP) alone, bis(2-ethylhexyl) terephthalate (DOTP) alone, tetra(2-ethylhexyl) pyromellitic acid (TOP) alone, or mixtures of two or more of these (i.e., a two-component mixture of DOIP and DOTP, a two-component mixture of DOIP and TOP, a two-component mixture of DOTP and TOP, or a three-component mixture of DOIP, DOTP, and TOP).

[0048] The composition ratio of the membrane solvent in the ISM can be appropriately selected depending on the application of the ISM, and can be, for example, 30% by mass or more and 95% by mass or less of the mass of the ISM.

[0049] ·polymer The ISM 1002 of this embodiment includes a polymer 2002. Of the components constituting the ISM 1002, the polymer 2002 often has the second largest mass ratio after the membrane solvent 2003. The polymer 2002 forms a matrix together with the membrane solvent 2003 and functions to maintain the shape of the solid membrane. The polymer 2002 forms the ISM 1002 that comes into contact with the aqueous solution of the measurement solution 1020, and is preferably one with low water solubility in order to form a matrix together with the hydrophobic membrane solvent 2003.

[0050] Specific examples of the polymer include at least one selected from the group consisting of ethylene polymers which may have a substituent, polymers of diene compounds, polymers having a urethane bond, polymers having a siloxane bond, cellulose derivatives, and polymers of organosilicon compounds. The ethylene which may have a substituent may be one or more selected from the group consisting of α-olefins, vinyl halides, styrene and its substitution products, acrylic esters, methacrylic esters, vinyl esters, etc. Examples of the substituent of styrene include alkyl groups such as methyl groups, and halogen atoms such as chloro groups. More specific examples include polyvinyl chloride, polystyrene, polymethyl acrylate, polymethyl methacrylate, polyvinyl acetate, polybutadiene, polyisoprene, polyacrylonitrile, cellulose acetate, and silicone. The chain structure of the polymer can be either linear or branched. In particular, polymers with crosslinking groups and a three-dimensional network structure can form a reinforced hydrophobic membrane matrix for ISMs together with the membrane solvent. This reinforced hydrophobic membrane matrix is ​​advantageous in that it forms a hydrophobic membrane that is less affected by the surfactant function of proteins.

[0051] Ionophores The ISM 1002 of this embodiment includes an ionophore 2001. The ionophore 2001 is a compound that selectively incorporates a target ion 2005 from the measurement solution 1020 into the ISM 1002, thereby enabling the generation of an ion-selective membrane potential.

[0052] The ionophore in this embodiment is a metal porphyrin complex. Three types of chloride ionophores are known: organometallic, organic, and metal complex. Of these, the organometallic type is harmful, while the organic type has low ion selectivity, which poses a problem for practical use. Porphyrin complexes, known as metal complex types, are less subject to regulations as chemical substances and are easier to use than organometallic types.

[0053] The central metal of metalloporphyrins as ionophores is not particularly limited, but examples include the Group 13 metal elements manganese, cobalt, and tin. Among the Group 13 elements, aluminum functions as an ionophore for fluoride ions, gallium functions as an ionophore for chloride ions and bromide ions, indium functions as an ionophore for chloride ions, and thallium functions as an ionophore for chloride ions, bromide ions, and iodide ions. Manganese functions as an ionophore for chloride ions, tin functions as an ionophore for salicylic acid, and cobalt functions as an ionophore for nitrite and thiocyanate. Among these, thallium and indium complexes are particularly useful as ionophores for the widely used chloride ion. Thallium complexes, in particular, are advantageous in that they are less harmful than indium complexes, are less subject to chemical regulations, and are easier to use.

[0054] The porphyrin, which is a ligand of the metalloporphyrin, is not particularly limited, but examples thereof include porphyrins having a substituent. Examples of the substituent include an aryl group such as a phenyl group, a saturated or unsaturated alkyl group, an alkoxy group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylcarbonyloxy group, an aryloxy group, an aralkyl group, or a halogen atom. Among these substituents, the carbon numbers of the alkyl group and the alkoxy group are each 1 to 20, the carbon numbers of the alkylcarbonyl group, the alkyloxycarbonyl group, and the alkylcarbonyloxy group are each 2 to 20, the carbon numbers of the aryl group and the aryloxy group are each 6 to 20, and the carbon numbers of the aralkyl group are each 7 to 30.

[0055] Porphyrins having hydrophobic groups as substituents are preferred as ionophores that are isolated from aqueous solutions and retained in a hydrophobic matrix, such as tetraphenylporphyrin and its derivatives, and octaalkylporphyrin and its derivatives.

[0056] Tetraphenylporphyrin derivatives include compounds having a substituent on any of the phenyl groups bonded to the porphyrin. The substituent on the phenyl group can be selected from the group consisting of saturated or unsaturated alkyl groups having from 1 to 20 carbon atoms, alkoxy groups having from 1 to 20 carbon atoms, alkylcarbonyl groups having from 2 to 20 carbon atoms, alkyloxycarbonyl groups having from 2 to 20 carbon atoms, alkylcarbonyloxy groups having from 2 to 20 carbon atoms, aryl groups having from 6 to 20 carbon atoms, cyano groups, and halogen atoms.

[0057] Derivatives of octaalkylporphyrin include compounds having a substituent on any of the alkyl groups bonded to the porphyrin. The substituent on the alkyl group may be selected from the group consisting of an alkoxy group having from 1 to 4 carbon atoms, an alkylcarbonyl group having from 2 to 5 carbon atoms, an alkyloxycarbonyl group having from 2 to 5 carbon atoms, an alkylcarbonyloxy group having from 2 to 5 carbon atoms, an aryl group having from 6 to 20 carbon atoms, a cyano group, and a halogen atom.

[0058] The metalloporphyrin content in the ISM of this embodiment can be appropriately selected depending on the application of the ISM. For example, it can be 0.1% by mass or more and 20% by mass or less of the mass of the ISM. Preferably, it can be 0.5% by mass or more and 10% by mass or less. If the metalloporphyrin content is less than 0.1% by mass, the electromotive force response to target ions may decrease. On the other hand, if the metalloporphyrin content is more than 20% by mass, the metalloporphyrin may precipitate, inhibiting the incorporation of target ions into the membrane.

[0059] The ISM of this embodiment uses a metalloporphyrin complex as the ionophore, thereby exhibiting high selectivity for various anions, particularly halide ions, especially chloride ions. Specifically, it exhibits high selectivity for bicarbonate ions, phosphate ions, nitrate ions, and other interfering ions present in biological fluids such as blood and urine. Therefore, by using the ISM of this embodiment, an ISE with high selectivity for anions, particularly halide ions such as chloride ions, can be constructed. The ISM of this embodiment may also be a halide ion-selective membrane, such as a chloride ion-selective membrane.

[0060] Ionic additives The ISM of this embodiment may contain an ionic additive. Ionic additives are said to have the effect of preventing the intrusion of contaminating ions into the membrane that interfere with the detection of target ions. For metalloporphyrins, an ionic additive consisting of a hydrophilic cation and a hydrophobic anion is preferably used. Known hydrophobic anions can be used. Here, one method for confirming hydrophobicity is to confirm whether the anion is insoluble in water when its counter cation is tetrabutylammonium ion.

[0061] Examples of compounds having hydrophobic anions include tetraphenyl borate compounds, long-chain alkyl sulfonic acid compounds, long-chain dialkyl sulfosuccinic acid compounds, long-chain alkyl phosphate compounds, long-chain dialkyl phosphate compounds, and long-chain dialkyl phosphosuccinic acid compounds. Specific examples of tetraphenyl borate compounds include tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB), tetrakis(4-chlorophenyl)borate, tetrakis(4-fluorophenyl)borate, and tetraphenylborate. Specific examples of long-chain alkyl sulfonic acid compounds include decyl sulfonic acid, dodecyl sulfonic acid, dodecyl benzene sulfonic acid, octadecyl sulfonic acid, and oleyl sulfonic acid. Specific examples of long-chain dialkyl sulfosuccinic acids include bismethylhexyl sulfosuccinic acid, dioctyl sulfosuccinic acid, didecyl sulfosuccinic acid, and didodecyl sulfosuccinic acid. Specific examples of long-chain alkyl phosphate compounds include decyl phosphonic acid, dodecyl phosphonic acid, dodecyl benzene phosphonic acid, octadecyl phosphonic acid, oleyl phosphonic acid, etc. Specific examples of long-chain dialkyl phosphate compounds include bismethylhexyl phosphonic acid, dioctyl phosphonic acid, didecyl phosphonic acid, didodecyl phosphonic acid, etc. Specific examples of long-chain dialkyl phosphosuccinic acid compounds include bismethylhexyl phosphosuccinic acid, dioctyl phosphosuccinic acid, didecyl phosphosuccinic acid, didodecyl phosphosuccinic acid, etc.

[0062] A hydrophilic cation is used as the cation of the ionic additive. One method for confirming hydrophilicity is to confirm whether the cation is soluble in water when its counter anion is a hexafluorophosphate ion. Known cations can be used as such cations. Specific examples include alkali metal ions, alkaline earth metal ions, and ammonium ions. More specific examples include sodium ions, potassium ions, and ammonium ions.

[0063] The composition ratio of the ionic additive to the metal porphyrin in the ISM of this embodiment can be appropriately selected depending on the application of the ISM. For example, the ratio of the number of molecules to the metal porphyrin can be in the range of 1 to 100 mol %. If the amount of the ionic additive added is less than 1 mol %, the electromotive force response to ions may be slow. On the other hand, if the amount of the ionic additive added is more than 100 mol %, the function as a cation exchanger may be more pronounced than the electromotive force response to anions, and the electromotive force response to cations may be strong. A more preferable concentration of the ionic additive to the metal porphyrin is in the range of 10 to 50 mol %.

[0064] In conventional anion-selective electrodes (e.g., bisthiourea), a combination of a hydrophobic cation and a hydrophilic anion is often selected as the ionic additive. In metalloporphyrins, a combination of a hydrophilic cation and a hydrophobic anion is preferred. This is thought to be because the interaction between the hydrophobic anion and the metalloporphyrin activates the ion selectivity of the ionophore.

[0065] Ion sensor This embodiment provides an ion sensor comprising the ion selective electrode of this embodiment, a reference electrode, and a measuring device, which measures the potential difference between the ion selective electrode and the reference electrode.

[0066] An ion sensor is a sensor that measures the concentration of a target ion contained in a sample. FIG. 4 is a schematic diagram illustrating an outline of an ion sensor 3050 (ion concentration measuring device) that uses an ISE 1000 equipped with an ISM 1002 of this embodiment. In FIG. 3, the ISE 1000 is placed in contact with a measurement solution 1020 together with a reference electrode 1010 to be used for comparison. The reference electrode 1010 may be in contact with the measurement solution 1020 through a salt bridge or a liquid junction. The ISM 1002 in contact with the measurement solution 1020 detects the concentration of the target ion in the measurement solution 1020 (more precisely, the activity a I The membrane potential (E M) occurs (the Nernst equation mentioned above).

[0067] The ion sensor 3050 calculates the concentration of a target ion in a measurement solution 1020 by measuring the potential difference between the ISM 1002 and the reference electrode 1010 with a measuring device 1030 such as a voltmeter for a solution with a known concentration of the target ion and the measurement solution 1020. The reference electrode 1010 is preferably the one described above. A general measuring device can be used for the measuring device 1030. For example, a voltmeter with a large input resistance or the electrometer mode of a potentiostat can be used. The input resistance is preferably 10 9 Ω, more preferably 10 12 Ω or more is preferable.

[0068] Sample testing equipment This embodiment provides a sample testing device including the ion selective electrode of this embodiment and a mechanism for supplying a sample to the ion selective electrode.

[0069] An example of the specimen testing apparatus of this embodiment will be described with reference to FIG. 5 . The specimen testing apparatus 4000 takes in a specimen from a specimen inlet 4001 into a flow path 4003 or the like within the apparatus. The taken-in specimen is supplied to the ISE 1000 and reference electrode 1010 in the ISE unit 4004 through the flow path 4003 or the like by power from a pump 4002 or the like. The electromotive force generated by the ISE 1000 is measured and recorded by a measurement unit 4005. The specimen used for the measurement is collected in a collection container 4006. The specimen testing apparatus 4000 may also include a unit for supplying and mixing a liquid to dilute the specimen, a unit for measuring other test items, and the like. The specimen testing apparatus 4000 of this embodiment uses an ISE that uses a metalloporphyrin as an ionophore, enabling highly accurate analysis of anions such as chloride ions.

[0070] Effects and uses The ISM of this embodiment uses a metalloporphyrin as the ionophore and a compound represented by the general formula (1) above, which satisfies CLogP≧9, as the membrane solvent. As a result, even when the ISM is brought into contact with an aqueous solution containing a protein, it is possible to suppress a decrease in the electromotive force response to ion concentration. As a result, an ISE and ion sensor with improved protein resistance can be realized. An ion sensor using this highly protein-resistant ISE has improved durability as an ion sensor for protein-containing test subjects, particularly those related to living organisms. As a result, a sample testing device using this can test the concentration of target ions and samples for a long period of time. [Example]

[0071] The present embodiment will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0072] (1) Synthesis of metalloporphyrins As an example compound, a metalloporphyrin represented by P-1 in the following reaction scheme was synthesized by the reaction shown in the following scheme (A) with reference to a non-patent document (Polyhedron, 1986, Vol. 5, pp. 1157-1164).

[0073] [ka]

[0074] (2) Preparation of ISM The preparation methods of the ISMs used in the Examples and Comparative Examples are described below. The following materials were used for these ISMs. Bis(2-ethylhexyl) isophthalate (DOIP), bis(2-ethylhexyl) terephthalate (DOTP), and tetra(2-ethylhexyl) pyromellitic acid (TOP) were used as membrane solvents in the Examples. 2-Nitrophenyl octyl ether (NPOE) and bis(2-ethylhexyl) phthalate (DOP) were used as membrane solvents in the Comparative Examples. The CLogP of each membrane solvent was calculated using commercially available software (ChemDraw). The 2-ethylhexyl group is an alkyl group with 8 carbon atoms.

[0075] In both the Examples and Comparative Examples, the polymer used was polyvinyl chloride (PVC) or cross-linked PVC (CL-PVC), the metalloporphyrin compound P-1 was used as the ionophore, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB) was used as the ionic additive, and tetrahydrofuran (THF) was used as the process solvent. The membrane solvent, PVC, metalloporphyrin, and NaTFPB were dissolved in THF by heating, and the solution was cast onto a glass plate, allowing the THF to evaporate, to prepare an ISM. The mass ratio in a typical membrane was membrane solvent / PVC / metalloporphyrin = 66 / 33 / 1. The concentration of the ionic additive relative to the metalloporphyrin was 5.6 mol% in terms of molecular number ratio. The membrane thickness of the prepared ISM was approximately 0.4 mm.

[0076] (3) Preparation of ISE The preparation method of the ISE used in the Examples and Comparative Examples is described below. The ISM was cut to the electrode size and attached to a PVC electrode case with THF. After conditioning the ISM overnight in a 10 mM NaCl aqueous solution, it was placed between a silver / silver chloride (Ag / AgCl) electrode and the sample solution via an internal solution of 10 mM NaCl aqueous solution, as shown in Figure 1.

[0077] (4) Evaluation Electromotive force evaluation The ISE and the reference electrode (Ag / AgCl) were connected to the measuring instrument with an input resistance of 10 12The electromotive force (EMF) was measured by varying the Cl ion concentration in tris(hydroxymethyl)aminomethane (Tris)-acetate buffer solution. The slope of the EMF versus the logarithm of the Cl ion concentration was calculated in the range of 1.8 to 7.1 mM. Measurements were performed at 23°C.

[0078] Protein tolerance assessment The electromotive force was evaluated before and after immersion of the ISE in Tris-acetate buffer containing bovine serum albumin (BSA) for 8 cycles for 3 minutes. The ratio of the slope of the electromotive force versus the logarithm of the Cl ion concentration (after immersion / before immersion) was calculated to evaluate the protein resistance.

[0079] (5) Results Table 1 shows the CLogP of each membrane solvent constituting the ISM, the initial slope (sensitivity) of the ISE using that ISM, and the ratio of the initial slope to the slope after protein resistance evaluation (slope ratio). Table 1 shows that the CLogP of the membrane solvent of the Example shows a value of 9 or more. In contrast, it was found that the CLogP of the membrane solvent of the Comparative Example shows a value of less than 9. In the ISE, the EMF changes linearly with the logarithm of the target ion concentration, and the slope represents the sensitivity to the target ion. Furthermore, in the case of an anion ISE, the slope is a negative slope. Table 1 shows that the initial slope obtained for both the membrane solvent of the Example and the membrane solvent of the Comparative Example is -40 mV dec -1 The negative values ​​were smaller than the EMF change (in mV) when the concentration was changed by one digit. The electromotive force was evaluated after immersion of the ISE in the BSA-added buffer solution, and the calculated slope ratio (after immersion / before immersion) was 0.6 or higher for the membrane solvent of the example. In contrast, the slope ratio for the comparative example was less than 0.6.

[0080] Table 1: List of CLogP of membrane solvents in Examples and Comparative Examples, and the initial EMF response (initial slope) and EMF response (slope ratio) after protein resistance evaluation of ISEs using them.

[0081] [Table 1]

[0082] Table 2: CLogP of the example membrane solvents and the EMF response after initial and protein resistance evaluation of ISE using CL-PVC.

[0083] [Table 2]

[0084] (6) Discussion The CLogP of the membrane solvent used in the ISM of the Example exhibited a value of 9 or higher, indicating a higher hydrophobicity than the membrane solvent used in the ISM of the Comparative Example. The TOP, which has a large number of alkyl chains, exhibited a particularly high CLogP value. The initial slope value was sufficient for measuring ion concentrations in both the ISE using the membrane solvent of the Example and the Comparative Example. In contrast, the slope ratio (after immersion / before immersion), an evaluation parameter for protein resistance, was high in the ISE using the membrane solvent of the Example and low in the ISE using the membrane solvent of the Comparative Example. This indicates that the ISM using the membrane solvent of the Example exhibits high protein resistance. This is thought to be due to the fact that the decrease in electromotive force response caused by proteins is due to the obscuring of the hydrophobic membrane / aqueous solution interface caused by the surfactant function of the protein. By improving the hydrophobicity of the membrane solvent, a hydrophobic membrane was formed that suppressed the effects of the surfactant function of the protein.

[0085] The membrane solvents DOIP and DOTP used in the ISMs of Examples 1 and 2 have a molecular structure in which the two ester groups are spaced apart, compared to the molecular structure of the membrane solvent DOP used in the ISM of Comparative Example 2. This is thought to have strengthened the intermolecular hydrophobic interactions in the ISMs of Examples 1 and 2, enabling the formation of hydrophobic membranes that suppress the effects of the surfactant function of proteins.

[0086] The membrane solvent TOP used in the ISM of Example 3 has four hydrophobic ester groups in its molecule. This is thought to have enabled the ISM of Example 3 to form a hydrophobic membrane that suppresses the effects of the surfactant function of proteins, thereby demonstrating the highest protein resistance.

[0087] The polymer CL-PVC used in the ISMs of Examples 4 and 5 has a three-dimensional network structure in which crosslinking groups have been introduced into the PVC chains. This strengthens the hydrophobic membrane matrix, consisting of the membrane solvent and polymer, compared with the chain-like structure of PVC, and is thought to have enabled the formation of a hydrophobic membrane that is less susceptible to the effects of the surfactant function of proteins.

[0088] (6) Summary From this example, the following was found in an ISM containing a metalloporphyrin compound, a polymer, and a membrane solvent made of an aromatic alkyl ester compound. By using a compound with a CLogP of 9 or more as a membrane solvent, it is possible to provide an ISM with reduced protein influence. By using a compound with alkyl ester groups attached to two or more non-adjacent carbon atoms of the benzene ring as the membrane solvent, it is possible to provide an ISM with reduced protein influence. By using a compound with four alkyl ester groups as a membrane solvent, it is possible to provide an ISM that suppresses the influence of proteins. By using a polymer with a cross-linked structure, it is possible to provide an ISM that suppresses the effects of proteins. These findings demonstrate that the value of devices using ISE, including ion sensors and sample testing devices, can be improved.

[0089] According to at least one of the embodiments described above, by using a compound represented by the general formula (1) above that satisfies CLogP≧9 as a membrane solvent, it is possible to suppress the effect of proteins on an ISM that uses a metalloporphyrin complex as an ionophore.

[0090] Although several embodiments of the present invention have been described, these embodiments are presented as examples and are not intended to limit the scope of the invention. These embodiments can be implemented in various other forms, and various omissions, substitutions, and modifications can be made without departing from the spirit of the invention. These embodiments and their modifications are included within the scope and spirit of the invention, as well as within the scope of the invention described in the claims and their equivalents. [Explanation of symbols]

[0091] 1000: Ion selective electrode (ISE) 1001: Electrode 1002: Ion selective membrane (ISM) 1003: Internal electrolyte 1010:Reference electrode 1020: Measurement solution 1030: Measuring instrument 2001: Ionophore 2002: Polymer 2003: Membrane Solvent 2004: Ionic Additives 2005: Target ions 2006: Impurity ions 3050: Ion sensor 4000: Sample testing equipment 4001: Sample intake port 4002: Pump 4003: Flow path 4004: Ion selective electrode (ISE) unit 4005: Measuring unit 4006: Collection container

Claims

1. An ion-selective membrane comprising a metalloporphyrin compound, a polymer, and a membrane solvent, wherein the membrane solvent satisfies CLogP≧9 and comprises a compound represented by the following general formula (1): 【Chemical 1】 In the general formula (1), X １ represents an alkyl ester group having from 5 to 19 carbon atoms which may have a substituent, X ２ From X ６ are each independently a hydrogen atom or a monovalent substituent, X ３ , X ４ , X ５ at least one of the above is an alkyl ester group having 5 to 19 carbon atoms which may have a substituent.

2. In the general formula (1), X １ represents an alkyl ester group having 7 to 13 carbon atoms which may have a substituent, X ３ , X ４ , X ５ 2. The ion-selective membrane according to claim 1, wherein at least one of the groups is an alkyl ester group having 7 to 13 carbon atoms, which may have a substituent.

3. In the general formula (1), X ２ From X ６ are each independently a hydrogen atom, a saturated or unsaturated alkyl group having from 1 to 20 carbon atoms which may have a substituent, an alkoxy group having from 1 to 20 carbon atoms which may have a substituent, an alkylcarbonyl group having from 2 to 20 carbon atoms which may have a substituent, an aryl group having from 6 to 20 carbon atoms which may have a substituent, an aryloxy group having from 6 to 20 carbon atoms which may have a substituent, an aralkyl group having from 7 to 30 carbon atoms which may have a substituent, a halogen atom, or an alkyl ester group having from 5 to 19 carbon atoms which may have a substituent.

4. the substituent of the alkyl group is selected from the group consisting of an alkoxy group having from 1 to 4 carbon atoms, an alkylcarbonyl group having from 2 to 5 carbon atoms, an alkyloxycarbonyl group having from 2 to 5 carbon atoms, an alkylcarbonyloxy group having from 2 to 5 carbon atoms, an aryl group having from 6 to 20 carbon atoms, a cyano group, and a halogen atom; a substituent of the alkoxy group, the alkylcarbonyl group, the aryl group, the aryloxy group, and the aralkyl group is selected from the group consisting of a saturated or unsaturated alkyl group having from 1 to 20 carbon atoms, an alkoxy group having from 1 to 20 carbon atoms, an alkylcarbonyl group having from 2 to 20 carbon atoms, an alkyloxycarbonyl group having from 2 to 20 carbon atoms, an alkylcarbonyloxy group having from 2 to 20 carbon atoms, an aryl group having from 6 to 20 carbon atoms, a cyano group, and a halogen atom; 4. The ion-selective membrane according to claim 3, wherein the substituent of the alkyl ester group having from 5 to 19 carbon atoms, which may have a substituent, is selected from the group consisting of an alkoxy group having from 1 to 4 carbon atoms, an alkylcarbonyl group having from 2 to 5 carbon atoms, an alkyloxycarbonyl group having from 2 to 5 carbon atoms, an alkylcarbonyloxy group having from 2 to 5 carbon atoms, an aryl group having from 6 to 20 carbon atoms, a cyano group, and a halogen atom.

5. The membrane solvent contains a compound represented by any one of the following general formulas (2), (3), and (4): 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 In the general formulas (2), (3), and (4), X ７ From X １６ are each independently a hydrogen atom or an aromatic substituent having a hydrophobicity constant π of 0 or more, R １ From R ８ each independently represents an alkyl group having 4 to 18 carbon atoms which may have a substituent, R １ From R ８ 2. The ion-selective membrane according to claim 1, wherein the substituents in each of the following are independently a substituent of the alkyl ester group.

6. The ion-selective membrane according to claim 1, characterized in that the compound represented by the general formula (1) is bis(2-ethylhexyl) isophthalate (DOIP), bis(2-ethylhexyl) terephthalate (DOTP), tetra(2-ethylhexyl) pyromellitic acid (TOP), or a mixture of two or more thereof.

7. 2. The ion-selective membrane according to claim 1, wherein the polymer is a polymer having a cross-linked structure.

8. 2. The ion selective membrane of claim 1, wherein the ion selective membrane is a chloride ion selective membrane.

9. The ion-selective membrane of claim 1 , further comprising an ionic additive.

10. 10. The ion-selective membrane according to claim 9, wherein the ionic additive comprises a hydrophilic cation and a hydrophobic anion.

11. 11. An ion-selective electrode comprising an electrode made of at least one type of conductor and the ion-selective membrane according to claim 1 applied to the electrode.

12. An ion sensor comprising the ion selective electrode according to claim 11, a reference electrode, and a measuring device for measuring the potential difference between the ion selective electrode and the reference electrode.

13. A specimen testing device comprising: the ion selective electrode according to claim 11; and a supply mechanism for supplying a specimen to the ion selective electrode.

14. The ion-selective membrane described in claim 1, characterized in that the polymer is at least one selected from the group consisting of polymers of ethylene which may have a substituent, polymers of diene compounds, polymers having urethane bonds, polymers having siloxane bonds, cellulose derivatives, and polymers of organosilicon compounds.

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