JP2004188188A - Equipment for iontophoresis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an iontophoresis device having a high dose of a target drug.
SOLUTION: An iontophoresis device for permeating an ionic drug into a living body through an ion exchange membrane is used. As the ion exchange membrane 6, an ion exchange membrane having a porous film as a base material is used. As such an ion exchange membrane 6, a porous film made of a thermoplastic resin having an average pore diameter of 0.005 to 5.0 μm and a porosity of 20 to 95% is used as a base material. The film is impregnated with a polymerizable monomer, and after polymerization, ion-exchange groups are introduced. The film has a thickness of 5 to 150 μm, an ion exchange capacity of 0.1 to 6.0 mmol / g, and a water content of about 5 to 90%. It is effective to obtain and use an ion exchange membrane.
[Selection diagram] Fig. 1

Description

  The present invention relates to an iontophoresis device for performing iontophoresis (ion permeation therapy) in which an ionic drug useful for a living body is penetrated into the living body using electrophoresis. The present invention relates to an iontophoresis device using an ion exchange membrane and an ion exchange membrane used in the device.

  Iontophoresis, in which an ionic drug useful for the living body is penetrated into the living body using electrophoresis, is also called iontophoresis, iontophoresis, and the like. It is widely known as a method of administering.

  Conventionally, in iontophoresis, a drug layer impregnated with an ionic drug is placed on a living body, a working electrode is arranged on the opposite side of the living body with the drug layer interposed, and a counter electrode is placed on a living body distant from the drug layer. And an electric current is passed between the working electrode and the counter electrode by the power supply to allow the ionic drug to penetrate the living body. This method aims at allowing only an ionic drug to penetrate into a living body through a biological interface such as skin or mucous membrane. However, in such a method, an ionic drug does not always pass through a biological interface, and conversely, a sodium cation, a potassium cation, a chloride anion, and the like permeate the drug layer from the living body side in many cases. In particular, ionic drugs that are useful for living organisms have a lower mobility than ions existing in living organisms as described above. ) Was low. Further, in such iontophoresis, since the drug comes into direct contact with the electrode, not only the drug is consumed by the reaction at the electrode, but also there is a possibility that a compound adversely affecting the living body may be produced. Further, since the drug is usually used in the form of an aqueous solution, the electrolysis of water proceeds at the working electrode and the counter electrode, and the H + ions and OH- ions generated thereby change the pH of the drug aqueous solution, causing inflammation in the living body. There were things.

  To solve these drawbacks, a new method of iontophoresis in which an ion exchange membrane is placed on a biological interface and drug ions penetrate into a living body through the ion exchange membrane has been proposed (for example, Patent Documents 1 to 4). reference).

  In the methods proposed in these, the ion exchange membrane disposed on the biological interface allows only ions having the same sign as the target drug ion to permeate. For this reason, it is possible to prevent ions having the opposite sign to the target drug from seeping out of the living body, and to obtain a higher dose of the drug than when no ion exchange membrane is provided. In these techniques, an ion exchange membrane using a commercially available woven fabric used for salt production or dialysis of food compounds as a reinforcing material (substrate) is used.

  In conventional iontophoresis, large-sized equipment is used, so it is possible to apply the method only in a specific place such as a hospital.However, iontophoresis can be performed at the required place at the required time. In recent years, studies on an iontophoresis device which has a simple and compact structure and is portable have been actively conducted.

  In such a portable iontophoresis device, a battery such as a button-type battery is usually used as a power source, so that the voltage value is more constant (constant voltage) than when the current value is constant (constant current). Of particular importance is the dose of the drug in the case of

  On the other hand, drug administration by iontophoresis, in particular, drug administration using a portable iontophoresis device is performed over a relatively long time unlike the method by injection or the like. It is considered that it is desirable that the patient can perform various actions and actions while wearing the device.

JP-A-3-94771 Japanese Patent Publication No. Hei 3-504343 JP-A-4-297277 JP 2000-229128 A

  However, even in the iontophoresis method using such an ion exchange membrane, the dose of the drug, particularly the dose of the drug in a constant voltage state, cannot be said to be sufficient, and further improvement in the dose is required. Was sought.

  Further, when the wearer performs various operations while wearing the iontophoresis device, the skin portion on which the iontophoresis device is mounted also expands and contracts or bends. Therefore, the ion exchange membrane used in the iontophoresis device needs to have a strength that is not destroyed by the stress generated by such expansion and contraction or bending. In general, the thicker the film, the higher the strength. However, since the film thickness is increased and the flexibility is also reduced, the followability to expansion and contraction and bending is deteriorated. Therefore, if a thick ion-exchange membrane is used with emphasis on strength, there is a problem in that the risk of the iontophoresis device being attached coming off or falling off the skin increases. Was.

  Therefore, the present invention, in iontophoresis using an ion-exchange membrane, a large dose of the target drug, and, while wearing the iontophoresis device, even if the wearer performs various actions, An object of the present invention is to provide an iontophoresis device which is hard to be detached and can be suitably used as a portable type.

  Another object of the present invention is to provide an ion exchange membrane used for the iontophoresis device as described above.

  The present inventors have conducted various studies in order to solve the above problems. As a result, they have found that the use of an ion-exchange membrane using a porous film as a base material significantly increases the dose of a drug under constant voltage conditions. Further, the present inventors have found that an ion exchange membrane using such a porous film as a substrate is much thinner and more flexible than conventional ion exchange membranes using a woven fabric, and has excellent strength. Was completed.

That is, according to the present invention, (A) a working electrode structure including a working electrode, a drug-containing portion and an ion exchange membrane, (B) a counter electrode structure including the working electrode and a counter electrode, and (C) A power supply unit electrically connected to the working electrode structure and the counter electrode structure, and an ion for infiltrating the ionic drug contained in the drug-containing portion into a living body by electrophoresis through an ion exchange membrane. In the tophoresis device,
An iontophoresis device is provided, wherein the ion exchange membrane has a structure in which a void portion of a porous film is filled with an ion exchange resin.

  Further, according to the present invention, there is provided a working electrode structure for iontophoresis in which an electrode, an ionic drug-containing layer, and an ion-exchange membrane are arranged in this order, wherein the ion-exchange membrane is a void portion of a porous film. A working electrode structure for iontophoresis, characterized in that the working electrode structure has a structure filled with an ion exchange resin.

  According to the present invention, there is further provided an ion exchange membrane for iontophoresis, wherein the ion exchange membrane has a structure in which a void portion of a porous film is filled with an ion exchange resin.

  The iontophoresis device of the present invention achieves a higher dose of a drug by using an ion-exchange membrane based on a porous film as compared with an ion-exchange membrane that has been used in iontophoresis. it can.

  In addition, the ion exchange membrane for iontophoresis of the present invention can be a flexible membrane while maintaining the required strength, so that the unevenness of the skin, and expansion and contraction, a thing excellent in followability to bending. Become. This is presumed to be due to the fact that the use of a porous film as the base material enables the thinning to be achieved while maintaining the strength, and the relatively low resin filling amount in the base material.

  Therefore, the iontophoresis device of the present invention exerts an excellent effect in all applications where iontophoresis has been considered up to now, such as beauty use, medical use, and health promotion use for administering supplements. In addition, in order to make the device portable, the device has extremely high practicality in a wider range of applications.

  The iontophoresis device of the present invention is used for administration of an ionic drug to a living body using electrophoresis, and is characterized by using an ion exchange membrane based on a porous film, An ionic drug is administered in vivo through such an ion exchange membrane. As shown in FIG. 1, the iontophoresis device includes a working electrode structure 1, a counter electrode structure 2, and a power supply unit 3 electrically connected to these structures.

  The working electrode structure 1 includes an electrode (working electrode) 4 serving as a working electrode, a drug containing portion 5 containing an ionic drug, and an ion exchange membrane 6 having a porous film as a base material. The ion exchange membrane 6 selectively allows ions of the same polarity as the medicinal ions of the ionic drug to be administered to permeate. As shown in FIG. 1, in the working electrode structure 1, a working electrode 4, a drug containing part 5, and an ion exchange membrane 6 are arranged in this order. Normally, these members are laminated in one exterior material (not shown) to constitute the working electrode structure 1, and the ion exchange membrane 6 is arranged in a direction in which the ion exchange membrane 6 is located on a biological interface (skin). Used.

  Note that an ion exchange membrane 8 may be further included between the electrode and the drug-containing layer in order to prevent the decomposition of the drug to be administered and to prevent the pH of the drug-containing portion 5 from changing due to the electrode reaction. It is preferable that the ion exchange membrane 8 selectively permeate ions of the opposite polarity to the medicinal ions.

  If necessary, an ion-conductive sheet, such as an ion-conductive gel, a porous film, or a woven cloth, can be provided between the ion exchange membrane 6 and the biological interface. These gels and sheets can have a structure integrated with the working electrode structure 1, and can be sandwiched between the gel and the sheet and the biological interface only during use. Further, in the working electrode structure 1, although not shown, a porous material impregnated between the working electrode 4 and the ion exchange membrane 8 with an ionic conductive gel, an ionic electrolyte solution, or an ionic electrolyte solution. Films and cloths can also be placed.

  As the working electrode 4 in the working electrode structure 1, an electrode used in a normal electrochemical process can be used without any limitation. Examples thereof include electrodes made of electronic conductors such as gold, platinum, silver, copper, nickel, zinc, and carbon; semiconductor electrodes; and self-sacrifice electrodes such as silver / silver chloride. These may be used alone or in combination. can do. Preferably, gold, platinum, silver, carbon and the like are mentioned. These electrodes can be used as they are formed into a paper-like material in which plates, sheets, meshes, and fibers are laminated in an irregular shape, and the electrode members are formed on the ion exchange membrane by plating or vapor deposition. It can also be provided and used.

  As the drug-containing portion 5 in the working electrode structure 1, a drug-containing layer used in normal iontophoresis can be used without any limitation. That is, water, a solution of an ionic drug dissolved in a solvent such as ethanol, a gel obtained by mixing the solution with polyvinyl alcohol or polyvinylpyrrolidone, or a porous film, gauze or the like impregnated with the solution. Can be used. The ionic drug used in the drug-containing portion 5 is not particularly limited, and is composed of a positive ion and a negative ion. When the positive ion or the negative ion enters the living body, The substance is not particularly limited as long as it has a pharmacological effect.

  As such ionic drugs, ionic drugs having an effect of positive ions include anesthetics such as procaine hydrochloride, lidocaine hydrochloride, dibucaine hydrochloride, antineoplastic drugs such as mitomycin and bleomycin hydrochloride, and analgesic drugs such as morphine hydrochloride Drugs, steroids such as medroxyprogesterone acetate, histamine, insulin and the like. On the other hand, ionic drugs exerted by negative ions include vitamin B2, vitamin B12, vitamin C, vitamin E and vitamins such as folic acid. Agents, anti-inflammatory agents such as aspirin and ibuprofen, corticosteroids such as dexamethasone-based water-soluble preparations, and antibiotics such as benzylpenicillin potassium.

  In the present invention, the ion exchange membrane 6 having the porous film as a base material is such that an ion exchange resin having a cation exchange function or an anion exchange function is filled in part or all of the voids of the porous film. It is.

  The ion-exchange resin may be a fluorine-based ion-exchange resin in which an ion-exchange group is introduced into a perfluorocarbon skeleton, or a so-called hydrocarbon-based ion-exchange resin having a non-fluorinated resin as a skeleton. It is preferable to use a hydrocarbon-based ion-exchange resin for simplicity of the process. Although the filling rate of the ion exchange resin in the ion exchange membrane 6 is also related to the porosity of the porous film described later, it is generally 5 to 95% by mass to facilitate the permeation of drug ions, In order to increase the strength of the exchange membrane, it is preferably from 10 to 90% by mass, particularly preferably from 20 to 60% by mass.

  Further, the ion exchange group of the ion exchange resin is not particularly limited as long as it is a functional group that generates a group having a negative or positive charge in an aqueous solution. Specific examples of such a functional group that can be an ion exchange group include a sulfonic acid group, a carboxylic acid group, and a phosphonic acid group as the cation exchange group. These acid groups may be present as free acids or in the form of salts. Examples of the counter cation in the case of a salt include an alkali metal cation such as a sodium ion and a potassium ion, and an ammonium ion. Of these cation exchange groups, sulfonic acid groups, which are generally strongly acidic groups, are particularly preferred. Examples of the anion exchange group include a primary to tertiary amino group, a quaternary ammonium group, a pyridyl group, an imidazole group, a quaternary pyridinium group, and a quaternary imidazolium group. Examples of the counter anion in these anion exchange groups include a halogen ion such as a chloride ion and a hydroxy ion. Among these anion exchange groups, generally, quaternary ammonium groups and quaternary pyridinium groups, which are strong basic groups, are preferably used.

  In addition, it is preferable that such an ion-exchange resin is a cross-linking type, since it is excellent in strength and also excellent in stability against various solvents.

  The most characteristic feature of the ion-exchange membrane 6 used in the present invention is that the above-mentioned ion-exchange resin is formed in a film shape using a porous film as a base material. A conventional ion exchange membrane using a woven fabric as the base material does not have both sufficient strength and flexibility, and further has low drug administration efficiency. Further, even in an ion exchange membrane such as a cast type formed without using a base material, both sufficient strength and flexibility cannot be satisfied. The solvent or the like contained in the containing layer dissolves or swells, and the iontophoresis device cannot be used substantially.

  In the present invention, as the porous film used as the base material of the ion exchange membrane, a film having a large number of pores communicating between the front and back or a sheet-like film is used without particular limitation. In order to achieve both the properties, it is preferable that the resin is made of a thermoplastic resin.

  As the thermoplastic resin constituting the porous film, ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 3-methyl-1-butene, 4-methyl-1-pentene, 5-methyl-1- Polyolefin resins such as homo- or copolymers of α-olefins such as heptene; polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, vinyl chloride-vinylidene chloride copolymer, vinyl chloride-olefin copolymer, etc. Vinyl chloride resin; polytetrafluoroethylene, polychlorotrifluoroethylene, polyvinylidene fluoride, tetrafluoroethylene-hexafluoropropylene copolymer, tetrafluoroethylene-perfluoroalkylvinyl ether copolymer, tetrafluoroethylene-ethylene copolymer Fluorinated resin such as nylon 6, nylon Polyamide resins, such as polyamide 66; polyimide resins and the like can be used without limitation, but polyolefins are excellent in mechanical strength, flexibility, chemical stability, and chemical resistance, and have good compatibility with ion exchange resins. It is preferable to use a resin. As the polyolefin resin, polyethylene and polypropylene are particularly preferred, and polyethylene is most preferred.

The properties of the porous film made of the thermoplastic resin are not particularly limited, but the average pore size of the pores is preferably 0.005 to 5 in that it is thin and excellent in strength, and is easily formed into an ion exchange membrane having low electric resistance. 0.0 μm, more preferably 0.01 to
The thickness is preferably 2.0 μm, most preferably 0.02 to 0.2 μm. The average pore size means an average flow pore size measured according to the bubble point method (JIS K 3832-1990). Similarly, the porosity of the porous film is preferably 20 to 95%, more preferably 30 to 90%, and most preferably 30 to 60%. Further, the thickness of the porous film is preferably 5 to 140 μm, more preferably 10 to 120 μm, and most preferably 15 to 55 μm so that the ion exchange membrane has a thickness as described below. Usually, the thickness of the ion exchange membrane manufactured by the manufacturing method described later is about the thickness of the porous film used as the base material plus about 0 to 20 μm.

  Such a porous film can be obtained by the methods described in JP-A-9-212964 and JP-A-2002-338721. Specifically, the organic liquid is mixed with the thermoplastic resin and formed into a sheet or film, and then the organic liquid is extracted with a solvent, or the thermoplastic resin is filled with an inorganic filler and / or an organic filler. It can be obtained by stretching a sheet made of the resin composition. In addition, it can be obtained as a commercial product (for example, Asahi Kasei "Hipore", Ube Industries "Yupore", Tonen Tapils "Cetella", Nitto Denko "Exepol", Mitsui Chemicals "Hillette", etc.).

  In the present invention, as the ion exchange membrane 6 based on the porous film, the amount of the ion exchange groups is 0.1 to 6.0 mmol / g, particularly 0.3 to 4.0 mmol in terms of ion exchange capacity. / G. The higher the ion exchange capacity, the lower the electrical resistance of the ion exchange membrane and the larger the drug dose at a constant voltage. However, when the ion exchange capacity exceeds 4.0 mmol / g, production becomes difficult, and when the ion exchange capacity exceeds 6.0 mmol / g, production is substantially impossible.

The ion exchange membrane 6 preferably has a water content of 5% or more, preferably 10% or more, so that the electric resistance does not increase by drying. Generally, the water content is maintained at about 5 to 90%. In order to obtain a water content in such a range, it can be controlled by the type of ion exchange group, ion exchange capacity, degree of crosslinking, and the like. In order to further obtain a high dose of the target drug, the fixed ion concentration of the ion exchange membrane 6 should be 6.0 to 6.0.
It is preferably 15.0 mmol / g-water.

Further, the thickness of the ion exchange membrane 6 is preferably 5 to 150 μm, more preferably 10 to 130 μm, and particularly preferably 15 to 60 μm. The thicker the ion exchange membrane 6 is, the higher the physical strength is, while the thinner the ion exchange membrane 6 is, the better the followability to the living body surface and the lower the electrical resistance of the ion exchange membrane 6 is. In order to make the iontophoresis device of the present invention portable, the strength of the ion-exchange membrane 6 is preferably 0.1 MPa or more, especially 0.2 MPa or more in burst strength, and its flexibility is , 15cm ^3/100 or less in Clark stiffness, in particular 10 cm ^3/100 or less, and most preferably be not less ^{5 cm} 3/100 or less.

  In the iontophoresis device of the present invention, when the ion exchange membrane 6 is used so as to be in direct contact with the surface of a living body such as skin, the smoother the ion exchange membrane 6 is, the better the adhesion to the surface of the living body is. It is preferable. For example, the ten-point average surface roughness Rz (JIS B 0601-1994) of the ion exchange membrane 6 is preferably 10 μm or less, particularly preferably 5 μm or less. The ion-exchange membrane 6 having such a smooth surface and excellent in both strength and flexibility is obtained only by using a porous film as a base material. You can't get it with what you say.

  The production method of the ion exchange membrane 6 used in the present invention is not particularly limited as long as the above-described porous film is used as a substrate, but from the viewpoint that a high-performance membrane can be efficiently produced, the following method is used. It is particularly preferred to produce by a production method.

  That is, a monomer having a functional group capable of introducing an ion-exchange group, a monomer composition comprising a crosslinkable monomer and a polymerization initiator is impregnated into the pores of the porous film, and then a monomer A method of polymerizing a body composition and introducing a cation exchange group or an anion exchange group into the polymer.

  In this production method, as the monomer having a functional group into which an ion exchange group can be introduced, a conventionally known hydrocarbon monomer used in the production of an ion exchange resin is used without any particular limitation. You.

  For example, examples of the hydrocarbon monomer having a functional group into which a cation exchange group can be introduced include styrene, α-methylstyrene, 3-methylstyrene, 4-methylstyrene, 2,4-dimethylstyrene, and p-tert. And aromatic vinyl compounds such as -butylstyrene, α-halogenated styrene, and vinylnaphthalene, and one or more of these can be used.

  On the other hand, examples of the monomer having a functional group into which an anion exchange group can be introduced include styrene, vinyltoluene, chloromethylstyrene, vinylpyridine, vinylimidazole, α-methylstyrene, and vinylnaphthalene.

  The crosslinkable monomer is not particularly limited, and examples thereof include polyfunctional vinyl compounds such as divinylbenzenes, divinylsulfone, butadiene, chloroprene, divinylbiphenyl, and trivinylbenzene, and trimethylolmethanetrile. Polyfunctional methacrylic acid derivatives such as methacrylic acid ester, methylenebisacrylamide, and hexamethylenedimethacrylamide are used.

  In addition to the above components, other hydrocarbon monomers copolymerizable with the above monomers and the crosslinkable monomer, and plasticizers may be added as necessary. As such other monomers, for example, acrylonitrile, acrolein, methyl vinyl ketone and the like are used. As the plasticizer, dibutyl phthalate, dioctyl phthalate, dimethyl isophthalate, dibutyl adipate, triethyl citrate, acetyl tributyl citrate, dibutyl sebacate, dibenzyl ether and the like are used.

  As the polymerization initiator, a conventionally known one is used without any particular limitation. Specific examples of such a polymerization initiator include octanoyl peroxide, lauroyl peroxide, t-butylperoxy-2-ethylhexanoate, benzoyl peroxide, t-butylperoxyisobutyrate, and t-butylperoxy. Organic peroxides such as laurate, t-hexylperoxybenzoate and di-t-butyl peroxide are used.

  In addition, a known additive used for producing an ion exchange membrane may be blended.

  In such a monomer composition, the crosslinkable monomer is used in an amount of 0.1 to 50 parts by mass, preferably 1 to 100 parts by mass of the monomer having a functional group into which an ion exchange group can be introduced. It is preferable to mix in an amount of ４０40 parts by mass, and it is preferable to use 0 to 100 parts by mass of another monomer copolymerizable with these monomers. Depending on the type of the crosslinkable monomer, the greater the amount of the crosslinkable monomer, the better the strength of the resulting ion exchange membrane, while if too large, the flexibility is reduced, and The tendency for the electrical resistance of the ion exchange membrane to increase increases. The polymerization initiator is used in an amount of 0.1 to 20 parts by mass, preferably 0.5 part by mass, based on 100 parts by mass of the total of the monomer having a functional group capable of introducing an ion exchange group and the crosslinkable monomer. It is preferable to mix 10 to 10 parts by mass.

  The above-mentioned porous film is filled with a monomer composition comprising a monomer having a functional group into which such an ion exchange group can be introduced, a crosslinkable monomer, a polymerization initiator and other components. Then, the polymerization may be carried out. The method for filling the monomer composition into the porous film is not particularly limited. For example, the monomer composition may be applied to the porous film, sprayed, or the porous film may be used as the monomer composition. It can be suitably carried out by immersion in or the like. When applying the monomer composition, for example, the two may be contacted under reduced pressure such that the monomer composition is favorably filled into the voids of the porous film, or a pressure treatment may be performed after the contact. A method may be adopted. Further, when polymerizing the monomer composition filled in the porous film, a method in which the temperature is raised from room temperature while applying pressure while sandwiching the surface of a polyester or the like with a smooth film, and the polymerization is preferably adopted. . By performing polymerization while sandwiching such a film, polymerization inhibition due to the influence of oxygen in the environment can be prevented, and the surface after polymerization can have the smoothness as described above. The polymerization conditions may be appropriately determined according to the type of the polymerization initiator used, the composition of the monomer composition, and the like. Generally, the state of heating to about 80 to 120 ° C. for 5 minutes to 10 hours The degree may be maintained.

  Next, the polymer filled and polymerized in the porous film is subjected to a known ion exchange group introduction treatment to obtain an ion exchange membrane. The method of ion-exchange group introduction treatment may be appropriately selected and adopted from known methods.For example, when a cation exchange membrane is obtained, sulfonation, chlorosulfonation, phosphoniumation, hydrolysis and the like may be performed. In order to obtain an anion exchange membrane, treatments such as amination and alkylation may be performed.

  Further, the ion exchange membrane used in the present invention can be produced by a known ion exchange membrane production method other than the above method without any problem. For example, styrene sulfonic acid, vinyl sulfonic acid, α-halogenated vinyl sulfonic acid can be used. Such as sulfonic acid monomers such as methacrylic acid, acrylic acid, and maleic anhydride; phosphonic acid monomers such as vinyl phosphoric acid; and salts thereof having a cation exchange group. Hydrogen monomers, amine monomers such as vinylbenzyltrimethylamine, vinylbenzyltriethylamine and trimethylaminoethyl methacrylate, nitrogen-containing heterocyclic monomers such as vinylpyridine and vinylimidazole, salts and esters thereof, etc. Using a monomer having an anion exchange group, a crosslinkable monomer, a polymerization initiator and other components. Using Ranaru monomer composition, after similarly filled in the porous film, it is possible to obtain also by polymerizing.

  Further, instead of such a monomer composition, a solvent or a resin-soluble ion-exchange resin or a resin having a functional group capable of introducing an ion-exchange group is mixed with a solvent to form a solution or paste-like composition. It is also possible to adopt a method of obtaining a product, impregnating the product with a porous film, and then removing the solvent. When an ion exchange resin is used, the solvent can be removed to form an ion exchange membrane as it is, or when a resin having a functional group capable of introducing an ion exchange group is used, after removing the solvent, The ion exchange group may be introduced by the method described above.

  The counter electrode structure 2 includes an electrode (counter electrode) 4 ′ that is a counter electrode of the working electrode 4 in the working electrode structure 1, and is used for a portion including the electrode that is a counter electrode in a normal iontophoresis device. The structure can be taken without any restrictions. That is, the counter electrode structure 2 may be the electrode (counter electrode 4 ′) itself, or a structure in which the electrode (counter electrode 4 ′) is arranged on a sheet made of an ion-conductive gel, a porous film, a woven fabric, or the like. Further, a structure in which an electrode (counter electrode 4 ′) is arranged on an ion exchange membrane using a porous film as a base material or another ion exchange membrane may be used. Preferably, as shown in FIG. 1, the counter electrode 4 ', the electrolyte containing portion 9 containing an ionic electrolyte, and the ion exchange membrane 10 are laminated in this order, and the ion exchange membrane 10 is arranged on the biological interface. Preferably, the structure is such that In this case, the ion exchange membrane 10 may be an ion exchange membrane having the above-described porous film as a base material, or may be another ion exchange membrane. In addition, the ion exchange membrane 10 may be any of those that selectively transmit ions of the same polarity or opposite polarity to the medicinal ions of the target drug. In order to prevent permeation into the drug, it is preferable to selectively permeate ions of the opposite polarity to the medicinal ions of the target drug.

  As the electrolyte-containing portion 9 in the counter electrode structure 2, a solution itself obtained by dissolving an ionic electrolyte in a solvent such as water or ethanol, a gel obtained by mixing the solution with polyvinyl alcohol or polyvinyl pyrrolidone, or A solution obtained by impregnating the solution with a porous film, gauze, or the like can be used. The ionic electrolyte can be used without any limitation as long as it is ionic when dissolved in a solvent such as water or ethanol such as sodium chloride or potassium chloride.

  Further, in the counter electrode structure 2, as in the case of the working electrode structure 1, an ion exchange membrane may be further provided between the counter electrode 4 'and the ion exchange membrane 10, or the ion exchange membrane 10 An ion-conductive gel, a porous film, a sheet made of a woven cloth, or the like, through which ions can pass, may be provided between the interface and the ion-exchange membrane that is closest to the counter electrode 4 ′. A porous film or woven fabric impregnated with an ionic conductive gel or an ionic electrolyte solution or an ionic electrolyte solution can be provided between them.

  As the power supply unit 3 in the iontophoresis device of the present invention, a power supply unit used in a normal iontophoresis device can be used without any limitation. When the working electrode structure 1, the counter electrode structure 2, and the power supply unit 3 are independent, an external power supply that can be connected to a battery or a system power supply can be used. In this case, a voltage or current stabilization system, It is preferable to have a power supply control system such as a system for applying a pulse current.

  When the iontophoresis device of the present invention is portable, it is preferable to use a battery as a power source. Examples of the battery include a coin-type silver oxide battery, an air zinc battery, and a lithium ion battery. By using such a small battery as a power supply, for example, as shown in FIG. 3, the working electrode structure 1, the counter electrode structure 2, and the power supply unit 3 are incorporated in a single exterior material, so that it is small and easy to carry. It can be an iontophoresis device. In addition, when such a portable iontophoresis device is used, it is more preferable to use a highly flexible resin or rubber as an exterior material, since a high followability to the skin shape can be obtained.

  The method of using the apparatus for iontophoresis of the present invention is not particularly limited, and may be used according to a known method. Generally, the working electrode structure 1 and the counter electrode structure 2 are used for drug penetration. What is necessary is just to make it adhere to the surface of a certain living body, and then apply a voltage from the power supply unit 3 to flow a current. In this case, by disposing the ion-exchange membrane 6 in the working electrode structure 1 so as to be located between the drug-containing portion 5 and the surface of the living body, the pharmacological effect generated from the ionic drug present in the drug-containing portion 6 can be reduced. The ions have permeate the living body through the ion exchange membrane 6.

  The iontophoresis device of the present invention using the ion-exchange membrane 6 having such a porous film as a base material has various effects of the conventional iontophoresis device using the ion-exchange membrane, The dosage of the drug can be very high. Further, the ion exchange membrane of the present invention can be made into a membrane having extremely low resistance by thinning, and thus has a feature that the dosage can be particularly increased when a battery is used as a power source. Further, since the dose is large, it is easy to reduce the size, and it is unlikely that the ion-exchange membrane is broken or the ion-exchange membrane is broken even when the apparatus is moved with the apparatus mounted. Therefore, the iontophoresis device of the present invention is particularly effective as a portable ontophoresis device.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples. The characteristics of the ion exchange membranes shown in the examples and comparative examples are values measured by the following methods.

(1) ion exchange capacity and water content;
The ion exchange membrane is immersed in a 1 (mol / l) HCl aqueous solution for 10 hours or more.

  Thereafter, in the case of a cation exchange membrane, the hydrogen ion type is replaced with a sodium ion type with a 1 (mol / l) NaCl aqueous solution, and the released hydrogen ions are replaced with a potentiometric titrator (COMMITE-900) using an aqueous sodium hydroxide solution. , Hiranuma Sangyo Co., Ltd.) (Amol). On the other hand, in the case of an anion exchange membrane, the chloride ion exchange resin is replaced by a nitrate ion exchange resin with a 1 (mol / l) NaNO3 aqueous solution, and the released chloride ion is subjected to a potentiometric titration using an aqueous silver nitrate solution. (COMTITE-900, manufactured by Hiranuma Sangyo Co., Ltd.) (Amol).

Next, the same ion-exchange membrane was immersed in a 1 (mol / l) NaCl aqueous solution for 4 hours or more, washed sufficiently with ion-exchanged water, taken out of the membrane, wiped off surface moisture with tissue paper or the like, and weighed when wet ( Wg) was measured. Next, the film was dried under reduced pressure at 60 ° C. for 5 hours, and its mass was measured (Dg). Based on the above measured values, the ion exchange capacity was determined by the following equation.
Ion exchange capacity = A × 1000 / W [mmol / g-dry mass]
Water content = 100 × (WD) / D [%]
Fixed ion concentration = ion exchange capacity / water content × 100 [mmol / g-water]
(2) Membrane resistance An ion-exchange membrane was sandwiched in a two-chamber cell provided with a platinum black electrode, and both sides of the ion-exchange membrane were filled with a 3 (mol / l) sulfuric acid aqueous solution. The resistance between the electrodes at ° C. was measured, and the resistance was determined from the difference between the resistance between the electrodes and the resistance between the electrodes when no ion exchange membrane was provided. The membrane used for the above measurement was one that had been equilibrated in a 3 (mol / l) sulfuric acid aqueous solution in advance.

(3) Surface roughness Rz
The surface roughness of the surface of the ion-exchange membrane was measured using a three-dimensional roughness measuring device (TDF-3A, manufactured by Kosaka Laboratory). In the obtained roughness curve, the ten-point average roughness (Rz) measured by setting the evaluation length to 11 mm was defined as the surface roughness Ra of the ion exchange membrane.

(4) Flexibility The dried ion-exchange membrane was placed in an atmosphere at 25 ° C. and a relative humidity of 60% for one night or more to adjust the humidity. From this, a sample having a width of 30 mm and a length of 20 cm was cut out, and then the Clark rigidity was measured in accordance with JIS-P8143. The smaller the value is, the more flexible the ion exchange membrane is.

(5) Burst strength After the ion exchange membrane was immersed in a 1 mol / L-HCl aqueous solution for 4 hours or more, it was sufficiently washed with ion exchange water. Next, the burst strength of the ion exchange membrane was measured using a Mullen-type burst strength meter (manufactured by Toyo Seiki Seisaku-sho, Ltd.).

(6) Permeation of drug through virtual skin system Filter paper (Advantech) using an aqueous solution of 10% by mass of polyvinyl alcohol (NH-20 manufactured by Nihon Gosei) so that the applied amount of polyvinyl alcohol after removing the solvent is 2 mg / cm 2. It was applied on a filter paper for chemical analysis 5C), and then left at room temperature for 24 hours or more to remove water to obtain virtual skin. Next, the virtual skin, an ion-exchange membrane to be measured, and a protective ion-exchange membrane for preventing the drug from reaching the electrode are installed in the cell shown in FIG. 2, and the drug solution chamber is filled with an aqueous solution of the drug at a predetermined concentration. In the skin room,
A 0.9 mass% aqueous sodium chloride solution and two electrode chambers were filled with a 0.1 (mol / l) aqueous sodium lactate solution. In the case where the ion exchange membrane to be measured is a cation exchange membrane, the anion exchange membrane obtained in Production Example 1 described later is used as the protective ion exchange membrane. The cation exchange membrane obtained in Production Example 7 described below was used. Next, while the cell was kept at 25 ° C., the drug solution chamber and the virtual skin chamber were stirred, and a current was supplied for one hour at a predetermined constant current density or constant voltage. Immediately after the energization was completed, the liquid in the virtual skin chamber was withdrawn, and the amount of the drug was measured by liquid chromatography. The same operation was performed without energization, the blank value was measured, and the difference from the amount of drug when energized was calculated to obtain the drug permeation amount.

(7) Permeation amount of drug in living skin system As living skin, shaved back skin of rabbit (male), shaved back skin of rat (6 weeks old, male), or mini pig (Yucatan Micropig, 5 months old) , Female), the amount of drug permeation through the living skin system was measured in the same manner as in the virtual skin system.

Production Example 1:
A monomer composition consisting of 380 g of chloromethylstyrene, 20 g of divinylbenzene, and 20 g of t-butylperoxyethylhexanoate was prepared, and 420 g of this monomer composition was placed in a 500 ml glass container, and each of them was 20 cm × A 20 cm porous film (made of polyethylene having a mass average molecular weight of 250,000, a film thickness of 25 μm, an average pore diameter of 0.03 μm, and a porosity of 37%) is immersed under atmospheric pressure at 25 ° C. for 10 minutes, and is immersed in the porous film. The monomer composition was impregnated. Subsequently, the porous film was taken out of the monomer composition, coated on both sides of the porous film with a 100 μm polyester film, and then heated and polymerized at 80 ° C. for 5 hours under a nitrogen pressure of 3 kg / cm 2. . Then, the obtained film was reacted at room temperature for 5 hours in an amination bath consisting of 10 parts by mass of 30% by mass of trimethylamine, 5 parts by mass of water and 5 parts by mass of acetone to obtain a quaternary ammonium type anion exchange membrane. .

  The ion exchange capacity, water content, fixed ion concentration, membrane resistance, film thickness, surface roughness, burst strength, and flexibility of the obtained anion exchange membrane were measured. Table 1 shows the results.

Production Examples 2 to 5:
An anion exchange membrane was produced in the same manner as in Production Example 1 except that the monomer composition and the porous film were changed to the compositions shown in Table 1. Table 1 shows the physical properties of the obtained film.

Production Example 6:
Using the monomer composition shown in Table 1, the porous film was impregnated in the same manner as in Production Example 1. Subsequently, the porous film was taken out of the monomer composition, and a 100 μm polyester film was used as the porous film. After coating on both sides, the mixture was heated and polymerized at 45 ° C. for 3 hours and at −75 ° C. for 5 hours under a nitrogen pressure of 3 kg / cm 2. Next, the obtained membrane was immersed in a mixture of methyl iodide and n-hexane at a ratio of 1: 3 (mass ratio) at 30 ° C. for 24 hours to obtain a quaternary pyridinium-type anion exchange membrane.

  Table 1 shows the results of measuring the ion exchange capacity, water content, fixed ion concentration, membrane resistance, film thickness, surface roughness, and flexibility of the obtained anion exchange membrane.

Production Examples 7 and 8:
The monomer composition shown in Table 1 was filled in a porous film in the same manner as in Production Example 1. Subsequently, the porous film was taken out of the monomer composition, coated on both sides of the porous film with a 100 μm polyester film, and polymerized by heating at 80 ° C. for 5 hours under a nitrogen pressure of 3 kg / cm 2. Next, the obtained membrane was immersed in a 1: 1 mixture of 98% concentrated sulfuric acid and chlorosulfonic acid having a purity of 90% or more at 40 ° C. for 45 minutes to obtain a sulfonic acid type cation exchange membrane.

  The ion exchange capacity, water content, fixed ion concentration, membrane resistance, film thickness, surface roughness and flexibility of the obtained cation exchange membrane were measured. The results are shown in Table 1.

Examples 1 to 7
Using a 10 mmol / L solution of magnesium ascorbic acid phosphate, which is an anionic drug, the drug permeation amount was measured using virtual skin under a constant current condition of a current density of 0.5 mA / cm ² . Table 2 shows the results of the ion exchange membrane used and the amount of drug permeation.

Comparative Example 1
Examples were as follows except that Neosepta AMX, an anion exchange membrane (manufactured by Tokuyama; membrane properties are described in Table 1) was used as an ion exchange membrane based on a woven fabric used for conventional iontophoresis. The drug permeation amount in the virtual skin system was measured in the same manner as in Example 1. Table 2 shows the results.

Comparative Example 2
The drug permeation amount was measured in the same manner as in Example 1 using only the virtual skin without using the ion exchange membrane to be measured. The results are shown in Table 2.

Example 7
A 1 mmol / L solution of dexamethasone phosphate sodium salt was used in place of the 10 mmol / L solution of magnesium ascorbate phosphate, and was obtained in Production Example 1 under a constant current condition of a current density of 0.05 mA / cm ² . The amount of drug permeated through the virtual skin system of the membrane was measured. Table 3 shows the results.

Comparative Example 3
Examples were as follows except that Neosepta AMX, an anion exchange membrane (manufactured by Tokuyama; membrane properties are described in Table 1) was used as an ion exchange membrane based on a woven fabric used for conventional iontophoresis. The amount of drug permeated through the virtual skin system was measured in the same manner as in 7. The results are shown in Table 3.

Comparative Example 4
The drug permeation amount was measured in the same manner as in Example 7 using only the virtual skin without using the ion exchange membrane to be measured. The results are shown in Table 3.

Examples 8, 9 and Comparative Examples 5, 6
Using a 10 mmol / L solution of histamine dihydrochloride, which is a cationic drug, a drug permeation amount was measured using virtual skin under a constant current condition of a current density of 0.5 mA / cm ² . Table 4 shows the results of the ion exchange membrane used and the drug permeation amount.

Example 10, Comparative Examples 7 and 8
Using a 10 mmol / L solution of lidocaine hydrochloride, which is a cationic drug, the drug permeation amount was measured using virtual skin under a constant current condition of a current density of 0.5 mA / cm ² . Table 5 shows the results of the ion exchange membrane used and the amount of drug permeation.

Examples 11 and 12, Comparative Example 9
Using a 10 mmol / L solution of sodium ascorbate as an anionic drug, the drug permeation amount through the virtual skin system was measured under a constant voltage condition of an applied voltage of 10 V. Table 6 shows the results of the ion exchange membrane used and the amount of drug permeation.

Example 13 and Comparative Example 10
Using a 10 mmol / L solution of magnesium ascorbic acid phosphate, the drug permeation amount in the living skin system was measured under a constant current condition of a current density of 0.5 mA / cm ² . For the living skin, shaved rat skin (male) was used. Table 7 shows the results of the ion exchange membrane used and the amount of drug permeation.

Example 14, Comparative Example 11
Using a 10 mmol / L solution of histamine dihydrochloride, the drug permeation amount in the living skin system was measured under a constant current condition of a current density of 0.5 mA / cm ² . Shaved rabbit skin (male) was used as the living skin. Table 8 shows the results of the ion exchange membrane used and the drug permeation amount.

Example 15 and Comparative Example 12
Using a 10 mmol / L solution of magnesium ascorbic acid phosphate, the drug permeation amount through the living skin system was measured under a constant voltage condition of an applied voltage of 15 V. For the living skin, shaved rat skin (male) was used. Table 9 shows the results of the ion exchange membrane used and the amount of drug permeated.

Example 16 and Comparative Example 13
The drug permeation amount in the living skin system was measured in the same manner as in Example 13, except that the back skin of a miniature pig (Yucatan Micropig, 5 months old, female) was used as the living skin. Table 10 shows the results of the ion exchange membrane used and the amount of drug permeation.

FIG. 1 is a schematic diagram showing a typical configuration of an iontophoresis device of the present invention. FIG. 2 is a schematic view of an apparatus used for measuring a drug permeation amount in the embodiment. FIG. 2 is a schematic cross-sectional view of a portable iontophoresis device in which all components are incorporated in one exterior material.

Explanation of reference numerals

1: Working electrode structure 2: Counter electrode structure 3: Power supply parts 4, 4 ': Electrode 5: Ionic drug containing part 6: Ion exchange membrane based on porous film 7: Biological surface (interface)
8: Ion exchange membrane 9: Electrolyte containing part 10: Ion exchange membrane 11: Coin cell battery 12: Exterior material

Claims (9)

(A) a working electrode, a working electrode structure including a drug-containing portion and an ion exchange membrane; (B) a counter electrode structure including the working electrode and the counter electrode; and (C) a working electrode structure and the counter electrode structure. An iontophoresis device for infiltrating a living body by electrophoresis through an ion-exchange membrane, comprising an ionic drug contained in the drug-containing portion, comprising a power supply unit electrically connected to
The iontophoresis device, wherein the ion-exchange membrane has a structure in which voids of a porous film are filled with an ion-exchange resin. 2. The iontophoresis device according to claim 1, wherein the porous film is made of a thermoplastic resin. The iontophoresis device according to claim 1, wherein the porous film has an average pore size of 0.005 to 5.0 μm and a porosity of 20 to 95%. 4. The iontophoresis device according to claim 1, wherein the ion exchange membrane has a thickness of 5 to 150 [mu] m. 5. The iontophoresis device according to claim 1, wherein the ion exchange membrane contains the ion exchange resin in an amount ranging from 5 to 95% by mass. An electrode, an ionic drug-containing layer, and an ion exchange membrane are arranged in this order to provide a working electrode structure for iontophoresis, wherein the ion exchange membrane is filled with an ion exchange resin in a porous film. A working electrode structure for iontophoresis, characterized by having a bent structure. An ion exchange membrane for iontophoresis, having a structure in which an ion exchange resin is filled in voids of a porous film. The ion exchange membrane for iontophoresis according to claim 7, wherein the porous film has an average pore diameter of 0.005 to 5.0 µm and a porosity of 20 to 95%. 9. The ion exchange membrane for iontophoresis according to claim 7, having a thickness of 5 to 150 [mu] m.

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