WO2005116123A1 - イオントフォレーシス用イオン交換膜の製造方法 - Google Patents
イオントフォレーシス用イオン交換膜の製造方法 Download PDFInfo
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- WO2005116123A1 WO2005116123A1 PCT/JP2005/010010 JP2005010010W WO2005116123A1 WO 2005116123 A1 WO2005116123 A1 WO 2005116123A1 JP 2005010010 W JP2005010010 W JP 2005010010W WO 2005116123 A1 WO2005116123 A1 WO 2005116123A1
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- ion exchange
- exchange membrane
- ion
- monomer
- polymerizable
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J47/00—Ion-exchange processes in general; Apparatus therefor
- B01J47/12—Ion-exchange processes in general; Apparatus therefor characterised by the use of ion-exchange material in the form of ribbons, filaments, fibres or sheets, e.g. membranes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/42—Electrodialysis; Electro-osmosis ; Electro-ultrafiltration; Membrane capacitive deionization
- B01D61/44—Ion-selective electrodialysis
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0002—Organic membrane manufacture
- B01D67/0006—Organic membrane manufacture by chemical reactions
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/20—Manufacture of shaped structures of ion-exchange resins
- C08J5/22—Films, membranes or diaphragms
- C08J5/2206—Films, membranes or diaphragms based on organic and/or inorganic macromolecular compounds
- C08J5/2218—Synthetic macromolecular compounds
- C08J5/2231—Synthetic macromolecular compounds based on macromolecular compounds obtained by reactions involving unsaturated carbon-to-carbon bonds
- C08J5/2243—Synthetic macromolecular compounds based on macromolecular compounds obtained by reactions involving unsaturated carbon-to-carbon bonds obtained by introduction of active groups capable of ion-exchange into compounds of the type C08J5/2231
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/30—Cross-linking
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/36—Introduction of specific chemical groups
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2325/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Derivatives of such polymers
- C08J2325/18—Homopolymers or copolymers of aromatic monomers containing elements other than carbon and hydrogen
Definitions
- the present invention relates to a method for producing an ion-exchange membrane used in iontophoresis in which an ionic drug useful for a living body is penetrated into the living body using electrophoresis.
- Iontophoresis in which an ionic drug useful for a living body is penetrated into a living body by electrophoresis, is widely known as a method for administering a desired amount of a drug to a desired affected part in a painless state.
- 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 the living body away from the drug layer.
- the ionic drug penetrates into the living body by passing a current between the working electrode and the counter electrode by the power supply.
- 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.
- the ionic drug does not always pass through the biological interface, and conversely, sodium cation, potassium cation, chloride anion, and the like may penetrate from the biological interface to the drug layer side from the biological interface.
- ionic drugs that are useful for living organisms have lower mobility than ions existing in living organisms as described above. Efficiency) was low.
- 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 that adversely affects the living body may be generated.
- the drug is usually impregnated as an aqueous solution
- the electrolysis of water proceeds at the working electrode and the counter electrode, and the pH of the drug aqueous solution changes due to H + ions and OH- ions generated by this. In addition, it can cause inflammation in the living body.
- Patent Document 1 Japanese Patent Application Laid-Open No. 3-974771
- Patent Document 2 Special Publication 3-5 0 4 3 4 3
- Patent Document 3 Japanese Patent Application Laid-Open No. Hei 4-29 7 27 7
- Patent Literature 4 Japanese Patent Application Laid-Open No. 2000-22029
- the ion exchange membrane disposed on the biological interface allows only ions having the same charge as the target drug ion to pass. Therefore, it is possible to prevent the ion having the opposite charge from the target drug from seeping out of the living body, and it is possible to obtain a higher dose of the drug than when no ion exchange membrane is provided.
- ion exchange membranes using a commercially available woven fabric used for salt production and dialysis of food compounds as a reinforcing agent (substrate) are used.
- the use of the ion-exchange membrane based on the above-mentioned woven fabric improves the use of the ion-exchange membrane as compared with the case where the ion-exchange membrane is not used, but the dose of the drug is still unsatisfactory. Was not enough.
- ascorbic acid (salt) histamine
- an object of the present invention is to provide an ion exchange membrane for iontophoresis that can efficiently administer not only an ionic drug having a small formula amount but also an ionic drug having a large formula amount of medicinal ions to a living body. It is to provide a manufacturing method.
- the present inventors have conducted various studies in order to solve the above problems. As a result, when a polymerizable monomer composition containing a non-polymerizable component is polymerized, and then the non-polymerizable component is removed to produce a ion-exchange membrane, an ionic agent having a large ionic mass is used. Of an ion-exchange membrane that can efficiently administer pharmacologically effective ions Ming completed.
- (V) a step of introducing an ion-exchange group into the polymer having a cross-linked structure when the monomer having an ion-exchange group is not contained in the monomer component.
- a working electrode, a drug-containing portion, and a working electrode structure provided with the ion exchange membrane obtained by the above-described production method; and (B) a working electrode and a counter electrode.
- An iontophoresis device for infiltrating a living body by electrophoresis is provided.
- FIG. 1 is a schematic view showing a typical structure of an iontophoresis device using an ion-exchange membrane manufactured according to the present invention.
- FIG. 2 is a schematic view of an apparatus used for measuring a drug dose in the example.
- a polymerizable composition containing a non-polymerizable component is prepared (step (I)), and the polymerizable composition is formed into a film ( (Ii)) polymerizing the polymerizable composition in the obtained film-like material to form a film having a structure in which the non-polymerizable component is dispersed in a polymer having a cross-linked structure (step (m) )), Removing the non-polymerizable component from the obtained membrane (step (1)) and, if necessary, introducing an ion-exchange group into the polymer (step (V)) to obtain iontophoresis.
- ion exchange membranes To manufacture ion exchange membranes.
- the ion exchange membrane produced by such a method is applied to an iontophoresis device, and the ionic drug contained in the drug containing part of the device is electrophoretically transferred to a living body through the ion exchange membrane.
- ionic drugs having a small formula weight but also medicinal ions having a formula weight of about 500 to 100 can be efficiently administered to a living body. That is, in the above-mentioned ion exchange membrane, the removal of non-polymerizable components makes the membrane relatively porous as a whole. As a result, not only ionic drugs having a small formula weight but also ionic drugs having a large formula weight are obtained.
- a polymerizable composition comprising a monomer component (a) and a non-polymerizable component (b) that does not copolymerize with the monomer component is prepared.
- the monomer component (a) is for forming an ion exchange resin which is a main component of the ion exchange membrane.
- a monomer component (a) has a polymerizable functional group for forming a crosslinked structure. It is necessary to use a polyfunctional polymerizable monomer (crosslinkable monomer) having two or more groups. It is also possible to use such a crosslinkable monomer alone as the monomer component (a), but usually, an ion exchange membrane which is easy to form a membrane and has moderate flexibility is used. For this purpose, a monofunctional polymerizable monomer is used in combination with a crosslinkable monomer.
- the monofunctional polymerizable monomer is a monomer having one polymerizable functional group, and one having a functional group into which an ion exchange group can be introduced or one having an ion exchange group is used.
- hydrocarbon monomers having a functional group into which an ion exchange group can be introduced include styrene, -methylstyrene, 3-methylstyrene, 4-methylstyrene, 2,4-dimethylstyrene, and p-tert-butylstyrene. And / or aromatic vinyl compounds such as halogenated styrene and vinylnaphthalene.
- hydrocarbon monomer having a functional group into which an anion exchange group can be introduced examples include styrene, vinyl toluene, chloromethyl styrene, vinyl pyridine, vinyl imidazole, -methyl styrene, and vinyl naphthalene. These monofunctional polymerizable monomers can be used alone or in combination of two or more.
- the ion exchange group is not particularly limited as long as it is a functional group capable of having a negative or positive charge in an aqueous solution.
- the ion exchange group include a sulfonic acid group, a carboxylic acid group, and a phosphonic acid group, and a sulfonic acid group that is a strongly acidic group is particularly preferable.
- anion exchange group examples include a primary to tertiary amino group, a quaternary ammonium group, a pyridyl group, an imidazole group, a quaternary pyridinium group, and a quaternary imidazolyl group, and a quaternary ammonium group which is a strongly basic group. ⁇ A quaternary pyridinium group is preferred.
- Examples of the above-mentioned monofunctional polymerizable monomer having a cation exchange group include sulfonic acid monomers such as styrene sulfonic acid, vinyl sulfonic acid, and vinyl monosulfonic acid, methacrylic acid, and acrylic acid. Carboxylic acid monomers such as maleic anhydride; phosphonic acid monomers such as vinyl phosphoric acid; salts and esters thereof; and monofunctional polymerizable monomers having an anion exchange group. Examples of the monomer include amine monomers such as vinylbenzyltrimethylamine and vinylbenzyltriethylamine, nitrogen-containing heterocyclic monomers such as vinylpyridine and vinylimidazole, and salts and esters thereof. These monofunctional polymers having an ion exchange group can be used alone or in combination of two or more. Rukoto can also.
- the crosslinkable monomer is not particularly limited as long as it is a polyfunctional polymerizable monomer copolymerizable with the above-described monofunctional polymerizable monomer.
- examples thereof include divinylbenzenes, Polyfunctional vinyl compounds such as divinyl sulfone, butadiene, chloroprene, divinyl biphenyl, and trivinyl benzene; Functional methacrylic acid derivatives are used.
- the use ratio of each of the above polymerizable monomers used as the monomer component (a) is not particularly limited, but generally, an ion exchange group or an ion exchange group can be introduced.
- the crosslinkable monomer is used in an amount of 0.1 to 50 parts by mass, preferably 1 to 40 parts by mass, per 100 parts by mass of the monofunctional polymerizable monomer having a functional group. Is good.
- other monomers copolymerizable with these monomers in an amount of 100 parts by weight or less for example, acrylonitrile, acrolein, methylvinyl ketone, and the like can also be used.
- the non-polymerizable component (b) is used together with the monomer component (a), and the non-polymerizable component (b) is formed by polymerization of the monomer component (a). Therefore, it is necessary to be compatible with the above monomer component (a) and not copolymerized with the monomer component (a). That is, when the non-polymerized component (b) is not compatible with the monomer component (a), a porous portion is unevenly formed in the finally obtained ion exchange membrane, and the ion The permeability becomes unstable, and the non-polymerized component (a) is a monomer component.
- the non-polymerizable component (b) cannot be removed from the polymer.
- the non-polymerized component (b) being compatible with the monomer component (a) means that when both are mixed, there is a quantitative ratio capable of forming a uniform solution without separation into two phases. It is not necessary that a completely homogeneous solution be formed at every mixing ratio.
- the non-polymerizable component (b) is not particularly limited as long as it satisfies the above conditions, and may be any of various organic solvents and polymers that do not copolymerize with the monomer.
- non-copolymerizable polymer (Hereinafter, referred to as a non-copolymerizable polymer).
- organic solvent examples include alcohols such as methanol, ethanol, 1-butanol, and 2-ethoxyethanol; aliphatic hydrocarbons such as hexane, cyclohexane, heptane, and 1-octane; fatty acids such as octanoic acid; Amines such as dimethyloctylamine; aromatic hydrocarbons such as toluene, xylene and naphthalene; ketones such as acetone, cyclohexanone and methylethylketone: ethers such as dibenzyl ether and diethylene glycol dimethyl ether; Halogenated hydrocarbons such as methylene chloride, chloroform form, ethylene bromide, etc .; dimethyl phthalate, octyl phthalate, dimethyl isophthalate, dibutyl adipate, triethyl citrate, acetyl butyl butyl citrate, dibutyl sebague
- Alcohol esters of aromatic acids and aliphatic acids; alkyl phosphate esters; and the like One type can be used alone, or two or more types can be used in combination. These are appropriately selected according to the type and composition of the monomer component (a) in consideration of the compatibility with the monomer component (a), the polymerization temperature (do not volatilize at the polymerization temperature), and the like. Of these, 1-butanol, 2-ethoxyethanol, dibenzyl ether, octyl phthalate, acetyl-triptyl citrate and the like are particularly preferred.
- non-copolymerizable polymer examples include styrene-butadiene copolymer, acrylonitrile-butadiene copolymer, polybutadiene, and polypropylene glycol. These are also appropriately selected according to the type and composition of the monomer component (a) in consideration of the compatibility with the monomer component (a), etc., but polybutadiene and polypropylene glycol are particularly preferable. .
- the average molecular weight of such a non-copolymerizable polymer is generally from 500 to 10,000, preferably from 500 to 6,000.
- the average molecular weight is less than 500, the dose of a large medicinal ion is low, but if the average molecular weight exceeds 10,000, the sign is opposite to that of the medicinal ion. It is not preferred that the effect of eliminating ions in the living body having a low level is low.
- non-polymerizable component (b) it is possible to use only one of the above-mentioned organic solvents and non-copolymerizable polymers, but generally, a mixture of both is used.
- a mixture of both is used.
- the dosing amount of a large amount of medicinal ion cannot be sufficiently exhibited unless the amount of addition is large, so that the effect of eliminating the opposite sign ion becomes insufficient and the non-copolymerization
- the non-copolymer component (b) is preferably used in an amount of 5 to 200 parts by mass, more preferably 10 to 150 parts by mass, per 100 parts by mass of the monomer component (a).
- the organic solvent and the non-copolymerizable polymer are preferably used together in a mass ratio of 100: 20 to 100: 500, particularly preferably 100: 50 to 100: 300.
- the amount of the organic solvent or the non-copolymerizable polymer is less than the above range, the administration of a medicinal ion having a large formula amount is not sufficient, and when the amount is more than the above range, the effect of eliminating the opposite sign ion is obtained. Tends to decrease.
- the polymerizable composition is easily prepared by mixing the monomer component (a) and the non-polymerizable component (b).
- a polymerization initiator is blended therein for efficiently proceeding the polymerization.
- a polymerization initiator is not particularly limited, but is generally octanoyl peroxide, lauroyl peroxide, t-butyl vinyloxy 2-ethylhexanoate, benzoyl peroxide, or t Organic peroxides such as butylperoxyisobutyrate, t-butylperoxylaurate, t-hexyloxybenzoate, and di-t-butylperoxide are used.
- Such a polymerization initiator is used in an amount of 0.1 to 20 parts by mass, particularly 0.5 to 10 parts by mass, per 100 parts by mass of the monofunctional polymerizable monomer in the monomer component (a). It is compounded in an amount.
- the polymerizable composition may contain additives known per se, such as a plasticizer, if necessary.
- the above polymerizable composition is formed into a film.
- the film-like material can be formed by any known method.However, the polymerizable composition is formed into a sheet or film because of its simple production and excellent mechanical strength of the finally obtained ion exchange membrane. It is preferable to form a film by bringing the polymerizable composition into contact with the porous substrate and allowing the polymerizable composition to penetrate into the voids of the porous substrate.
- This porous substrate functions as a shape-imparting material for forming a film. By using such a porous substrate, a high strength for preventing breakage during storage, use, and the like can be obtained. In addition, a film having both flexibility and good flexibility to follow the skin shape during use can be obtained.
- the porous substrate is not particularly limited, but generally, paper, woven fabric, non-woven fabric, porous film and the like are used.
- a nonwoven fabric or a porous film can be obtained in that a thin ion exchange membrane having a high mechanical strength can be obtained (that is, a drug can be efficiently administered and breakage can be effectively prevented).
- the porous film has a large number of pores communicating between the front and back, and is generally made of a thermoplastic resin.
- thermoplastics include ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 3-methyl-1-butene, 4- Polyolefin resin consisting of homopolymer or copolymer of olefin such as methyl-11-pentene, 5-methyl-11-heptene; polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, vinyl chloride-vinylidene chloride copolymer, Vinyl chloride resins such as vinyl chloride-refin copolymers; polytetrafluoroethylene, polychlorotrifluoroethylene, polyvinylidene fluoride, tetrafluoroethylene-hexafluoropropylene copolymer, tetrafluoro Fluorinated resins such as ethylene-perfluoroalkyl vinyl ether copolymer and t
- the properties of the porous film made of a thermoplastic resin as described above are not particularly limited, but an ion exchange membrane having low electric resistance can be obtained, and a membrane having high physical strength can be obtained.
- the average pore size of the pores is in the range of 0.05 to 5.0 m, preferably in the range of 0.01 to 2.0 m, most preferably in the range of 0.02 to 0.2 m Is good.
- the average pore diameter is a value measured by the bubble point method. From a similar point of view, the porosity of the porous film should be in the range of 20 to 95 ⁇ 1 ⁇ 2, preferably 30 to 90%, and most preferably 30 to 60%.
- the thickness of the porous film to be used is preferably in the range of 5 to "50 m, especially 10 to 120 m.
- the porous film composed of the thermoplastic resin as described above can be obtained by a method described in, for example, JP-A-9-212964, JP-A2002-338871, and the like.
- an organic liquid is mixed with a thermoplastic resin, formed into a sheet or film, and then the organic liquid is extracted with a solvent, or an inorganic filler and Z or Z are added to the thermoplastic resin. It can be obtained by stretching a sheet filled with an organic filler.
- Such porous stretched films are commercially available products (for example, Asahi Kasei “Hipore”, Ube Industries “Yupore”, Pils "Cetella”, Mitsubishi Chemical Dexepol, Mitsui Chemicals "Hilet”, etc.) are also available.
- nonwoven fabric used as the porous substrate those manufactured by a dry method and a wet method can be used without any particular limitation.
- the material of the nonwoven fabric for example, polyester fiber, polypropylene fiber, polyamide fiber, nylon fiber, acrylic fiber, rayon fiber, vinylon fiber, polyurethane fiber and the like can be used.
- the properties of such a nonwoven fabric are not particularly limited, but in terms of obtaining an ion-exchange membrane that is thin, has excellent strength, and has a low electric resistance, the basis weight is 20 to 100 g / m 2 , The thickness is preferably from 30 to 250 m.
- the method for infiltrating the polymerizable composition into the porous substrate described above is not particularly limited, but generally, application, spraying, immersion, or the like is employed.
- application, spraying, immersion, or the like is employed.
- both are contacted under reduced pressure, or pressure treatment is performed after the contact so that the solution can be filled well in the voids of the porous substrate.
- pressure treatment is performed after the contact so that the solution can be filled well in the voids of the porous substrate.
- the polymerizable composition in the film obtained in the above step (ii) is polymerized.
- the polymerization means, for example, a method in which a film-like material of the polymerizable composition is polymerized by raising the temperature from room temperature while pressurizing the film between polyester or other smooth films. In other words, by performing polymerization while sandwiching the film, polymerization inhibition due to the influence of oxygen in the environment can be prevented, and the surface after polymerization can be made smooth.
- 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. What is necessary is just to hold for about 10 to 10 hours. This polymerization is carried out under conditions where the used non-polymerizable component (b) is not volatilized or decomposed.
- the non-polymerizable component (b) contained in the polymerizable composition does not copolymerize with the monomer component (b) and is compatible with the monomer component (b).
- a film having a structure in which a polymer having a cross-linked structure is used as a matrix and a non-polymerizable component (b) is uniformly dispersed in the polymer as it is (hereinafter, simply referred to as a cured product film) is formed. It is formed
- the non-polymerizable component (b) is removed from the cured product film obtained above, whereby the intended ion exchange membrane is obtained. That is, by removing the non-polymerizable component (b) dispersed in the cured product, the obtained ion-exchange membrane becomes porous as a whole. It is possible to move inside the membrane.
- the method for removing the non-polymerizable component (b) is not particularly limited, and may be appropriately performed according to the type and amount of the component (b) used.
- a non-copolymerizable polymer or a non-volatile (or non-volatile) organic solvent is used as the component (b) (or when both are used in combination)
- the non-copolymer component (b) may be immersed and eluted in a soluble solvent capable of dissolving, and then the volatile solvent may be removed by volatilization.
- the solvent may be one that has wettability to the cured film and dissolves the non-polymerizable component (b).
- the solvent can be used without any limitation, and specific examples thereof include organic solvents having high volatility among those exemplified as the organic solvent usable as the component (b). These are appropriately selected depending on the wettability to the cured product film and the solubility of the non-polymerizable component (b) used. Specifically, methanol, ethanol, acetone, methyl ethyl ketone, toluene, Xylene, methylene chloride, black form and the like can be suitably used.
- the above-mentioned ion is contained in the polymer formed by the monomer component (a). It is necessary to introduce an exchange group.
- a known method may be appropriately selected and adopted as a method of the ion-exchange group introduction treatment.
- the method of introducing the ion-exchange group in a general method for producing a hydrocarbon-based ion-exchange membrane is used. What is necessary is just to follow the introduction method. For example, when a cation exchange membrane is obtained, treatments such as sulfonation, cation sulfonation, phosphonization, and hydrolysis may be performed. When anion exchange membranes are obtained, amination, alkylation, etc. May be performed.
- the introduction of such an ion-exchange group can be performed before or after the step (IV) of removing the non-copolymerizable component (b), or in parallel with the step (IV).
- a non-copolymerizable polymer or a non-volatile (or non-volatile) organic solvent is used as the non-polymerizable component (b).
- the ion-exchange group should be introduced after the step (IV). Is preferred.
- the component (b) When such a non-polymerizable component (b) is used, the component (b) is converted into a volatile solvent or an ion exchange group prior to the ion exchange treatment. It may be replaced with a solvent that is miscible with the reagent used.
- the ion-exchange membrane obtained by the above manufacturing method has, for example, a structure in which a porous base material is filled with a porous ion-exchange resin. It is easily applied to iontophoresis devices.
- the filling rate of the ion-exchange resin in the membrane is related to the porosity of the porous substrate / the blending amount of the component (b). It is preferably 5% by mass, and more preferably 10% by mass to 90% by mass in order to facilitate the permeation of drug ions and increase the strength of the ion exchange membrane.
- the content of the ion-exchange group is 0.1 to 6.0 mmol in terms of ion-exchange capacity from the viewpoint of lowering the electric resistance of the ion-exchange membrane and lowering the voltage required for administration of the ionic drug.
- Z g, especially 0. 3 to 4. 0 mm o I g a is preferably.
- the water content is preferably at least 100 / 0.In general, the water content is maintained at about 5 to 90 ⁇ 1 ⁇ 2. Control by known methods based on the type of group, ion exchange capacity, degree of crosslinking, etc. Can do.
- the fixed ion concentration of the ion exchange membrane is preferably 3.0 to 15.0 mmo Ig-water.
- the thickness of the above-mentioned ion exchange membrane is generally 5 to 150 ⁇ m, particularly 10 to 130 ⁇ m by using the porous substrate having the above thickness. It exhibits well-balanced properties in terms of physical strength, electrical resistance of the membrane, and its ability to follow living body surfaces.
- the ion exchange membrane obtained by the above-described manufacturing method is an iontophoresis device used for administration of an ionic drug to a living body using electrophoresis, including a step of passing an ionic drug through the ion exchange membrane.
- Fig. 1 shows a typical structure of such an iontophoresis device.
- this 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 ion exchange membrane obtained by the above-described manufacturing method is suitably used for the working electrode structure 1.
- 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 manufactured by the method described above.
- the ion exchange membrane 6 selectively permeates ions having the same polarity as the medicinal ions of the ionic drug to be administered.
- the working electrode 4 the drug-containing portion 5, and the ion exchange membrane 6 are arranged in this order.
- these members are laminated in one exterior material (not shown) to form the working electrode structure 1, and the ion exchange membrane 6 is oriented in a direction in which the ion exchange membrane 6 is located on the biological interface (skin) 7. It is used by being arranged.
- 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, a sheet or the like through which ions formed of an ion-conductive gel, a porous film, a woven cloth, or the like can pass can be provided between the ion exchange membrane 6 and the biological interface 7. These gels and sheets can have a structure integrated with the working electrode structure 1, and can be sandwiched between the living body interface 7 and the gel or sheet only when used.
- a woven fabric can also be arranged.
- an electrode used in a normal electrochemical process can be used without any limitation.
- an electrode made of an electronic conductor such as gold, platinum, silver, copper, nickel, zinc, and carbon, a semiconductor electrode, and a self-sacrifice electrode such as silver-silver chloride are exemplified. These may be used alone or in combination. be able to.
- gold, platinum, silver, carbon and the like are mentioned.
- these electrodes those formed into a paper-like material obtained by laminating plates, sheets, meshes, and fibers in an irregular shape can be used as they are. It can be used by being provided by vapor deposition.
- the drug-containing layer used in ordinary iontophoresis can be used without any limitation. That is, a solution itself in which an ionic drug is dissolved in a solvent such as water or ethanol, a gel obtained by mixing the solution with polyvinyl alcohol, polyvinylpyrrolidone, or the like, or impregnation of a porous film, gauze, or the like with the solution. Those that have been used can be used.
- the ionic drug used in the drug-containing portion 5 is not particularly limited, and is composed of a cation and an anion. When the cation or the anion enters the living body, The substance is not particularly limited as long as it has a pharmacological effect.
- ionic drugs examples include cations that have an effect, such as anesthetics such as proforce hydrochloride, lidocaine hydrochloride, and dibuforce hydrochloride; and antineoplastic drugs such as mitomycin and bleomycin hydrochloride.
- Analgesics such as morphine hydrochloride, steroids such as medroxyprogesterone acetate, histamine, and insulin.
- ionic drugs that anions exert an effect include Vitamin B2, Vitamin B12, Vitamin C, Vitamin E, vitamins such as folic acid, anti-inflammatory agents such as aspirin and ibuprofen, corticosteroids such as dexamethasone-based water-soluble preparations, and antibiotics such as potassium benzylpenicillin And so on.
- the ion-exchange membrane 6 is obtained by the above-described manufacturing method.
- a large amount of medicinal ions having a large ion formula for example, a formula having a formula mass of 300 to 150, In particular, even a medicinal ion in the range of 400 to 1000 can be efficiently administered to a living body. That is, when an ion exchange membrane manufactured by a conventionally known method is used, since the membrane is formed densely, it is not possible to efficiently administer a large amount of medicinal ions in the ionic form. .
- the ion exchange membrane 6 When the ion exchange membrane 6 is used in such an iontophoresis device so as to be in direct contact with the surface of a living body such as the skin, the ion exchange membrane 6 is smooth in order to ensure good adhesion. Is preferred.
- the counter electrode structure 2 is provided with an electrode (counter electrode) 4 ′ serving as a counter electrode of the working electrode 4 in the working electrode structure 1, and is used in a portion including the electrode serving as a counter electrode in an ordinary iontophoresis device.
- the counter electrode structure 2 may be the electrode (counter electrode 4 ′) itself, or the electrode (counter electrode 4 ′) is arranged on a sheet made of ion-conductive gel, porous film or woven fabric.
- the structure may be such that an electrode (counter electrode 4 ') is arranged on an ion exchange membrane based on a porous film or another ion exchange membrane.
- a counter electrode 4 ′, an electrolyte-containing portion 9 containing an electrolyte and a ion exchange membrane 10 are laminated in this order, and the ion exchange membrane 10 is It is preferable that the structure is arranged on the upper side.
- the ion exchange membrane 10 may be an ion exchange membrane formed by the above-described method or an ion exchange membrane manufactured by other methods. It is preferable that the ion-exchange membrane is formed using a porous film as a porous base material.
- the ion exchange membrane 10 may be any of those which selectively transmit ions of the same polarity or opposite polarity to the medicinal ions of the target drug. In order to prevent the permeation from the body to the counter electrode structure, it is preferable that the permeant ion selectively permeate ions having the opposite polarity to the medicinal ions of the target drug.
- the electrolyte-containing portion 9 in the counter electrode structure 2 may be a solution itself in which an electrolyte is dissolved in a solvent such as water or ethanol, a gel obtained by mixing the solution with polyvinyl alcohol or polyvinylpyrrolidone, or a gel obtained by mixing the solution.
- a solution in which a solution is impregnated 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.
- an ion exchange membrane may be further provided between the counter electrode 4 ′ and the ion exchange membrane 10.
- an ion-conductive gel between the membrane 10 and the biological interface, there may be provided an ion-conductive gel, a sheet made of a porous film, woven cloth, or the like, through which ions can pass.
- a porous film or woven fabric impregnated with an ion-conductive gel, an electrolyte solution, or even an electrolyte solution can be provided between the ion-exchange membrane and the closest ion exchange membrane.
- a power supply unit used in a normal iontophoresis device can be used without any limitation. If 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 grid power supply can be used. In this case, a voltage or current stabilization system or It is preferable to have a power supply control system such as a system for applying a pulse current.
- the iontophoresis device of the present invention When the iontophoresis device of the present invention is portable, it is preferable to use a battery as a power source.
- the battery include a coin-type silver oxide battery, an air zinc battery, and a lithium ion battery.
- a small battery By using such a small battery as a power source, a small and easy-to-carry iontophoresis device that incorporates the working electrode structure 1, the counter electrode structure 2, and the power supply unit 3 in one external material is provided.
- Can be Examples In order to more specifically describe the present invention, examples and comparative examples will be described below, but the present invention is not limited to these examples.
- the characteristics of the ion exchange membranes shown in the examples and comparative examples indicate values measured by the following methods.
- the same ion-exchange membrane is immersed in 1 (mo IZI) HCI aqueous solution for 4 hours or more, washed thoroughly with ion-exchanged water, taken out of the membrane, wiped off surface moisture with tissue paper, etc., and weighed (Wg) Was measured.
- the membrane was dried under reduced pressure at 60 ° C. for 5 hours, and its weight was measured (D g). Based on the above measured values, the ion exchange capacity, the water content, and the fixed ion concentration were calculated by the following equations.
- Ion exchange capacity A X 100 OXD [mmo I Zg—dry weight]
- An ion-exchange membrane is sandwiched in a two-chamber cell equipped with a platinum black electrode, and both sides of the ion-exchange membrane are filled with 0.5 (mo 1 1) aqueous sodium chloride solution.
- An AC bridge (frequency: 1 000 cycles Z seconds) 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 is prepared in advance with 0.5 (mo IZ sodium chloride aqueous solution). Used in equilibrium
- the surface roughness of the surface of the ion-exchange membrane was measured using a three-dimensional roughness measuring instrument (Kosaka Laboratory TDF-3A type).
- the height difference between the peak portion and the deepest portion adjacent thereto was measured, and the average value of the height difference measured over a length of 11 mm was defined as the surface roughness of the ion exchange membrane.
- the chamber was filled with an aqueous solution of the drug at a predetermined concentration
- the virtual skin chamber was filled with a 0.9% by weight aqueous sodium chloride solution
- the two electrode chambers were filled with a 0.1 (mol / sodium lactate aqueous solution.
- the ion exchange membrane to be measured is a cation exchange membrane
- the anion exchange membrane obtained in Comparative Production Example 1 is used, and when the measurement target is an anion exchange membrane, the comparison is made.
- the positive ion exchange membrane obtained in Production Example 2 was used.
- the drug solution chamber and the virtual skin chamber were agitated, and electricity was supplied at a predetermined constant current density or constant voltage for 3 hours.
- 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 conducting electricity, the blank value was measured, and the difference from the amount of drug when electricity was supplied was calculated to be the drug permeation amount.
- Chloromethylstyrene (polymerizable monomer) 380 g
- non-polymerizable component (b) 200 g of dibenzyl ether, an organic solvent, was added to the monomer mixture to prepare a polymerizable composition.
- this polymerizable composition was placed in a glass container of 1 OOOm I, and a 20 cm ⁇ 2 Ocm porous film (made of polyethylene having a weight average molecular weight of 250,000, a film thickness of 25 m, an average pore 0.03 / m N porosity (370 / o) was immersed under atmospheric pressure at 25 ° C. for 10 minutes, and the porous film was impregnated with the polymerizable composition.
- a 20 cm ⁇ 2 Ocm porous film made of polyethylene having a weight average molecular weight of 250,000, a film thickness of 25 m, an average pore 0.03 / m N porosity (370 / o) was immersed under atmospheric pressure at 25 ° C. for 10 minutes, and the porous film was impregnated with the polymerizable composition.
- the porous film was taken out of the polymerizable composition, and both sides of the porous film were covered with a 100- ⁇ m polyester film. Then, under a nitrogen pressure of 3 kg, cm 2 at 80 ° C. for 5 hours. Heat polymerization was performed to obtain a film. Then, the obtained film was immersed in methanol for 24 hours to extract and remove dibenzyl ether. Then, in a amination bath consisting of 10 parts by weight of 30% by weight trimethylamine, 5 parts by weight of water and 5 parts by weight of acetone. The mixture was reacted at room temperature for 5 hours to obtain a quaternary ammonium-type anion-exchange compound.
- a monomer mixture composition having the 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 from the mixture, 1 was coated on both sides of the porous film in Poriesu ether film 00 ⁇ M, 3 k gZ cm 2 of nitrogen pressure,
- Polymerization was conducted by heating at 80 ° C for 5 hours. The obtained film is immersed in acetone for 24 hours and then dried. Subsequently, the mixture was immersed in a 1: 1 mixture of 98% concentrated sulfuric acid and chlorosulfonic acid having a purity of 9 Oo / o or more at 40 ° C. for 45 minutes to obtain a sulfonic acid type cation exchange.
- A Made of polyethylene with a weight average molecular weight of 250,000, thickness 25 m, average pore size 0.03 Um, porosity 37%
- B Made of polyethylene with a weight average molecular weight 200,000, film thickness 27 um, average pore size 0. 2 m, porosity 50%
- PPG polypropylene glycol (diol type, average molecular weight 3000)
- Neosepta AM X manufactured by Tokuyama; B properties are listed in Table 1) as ion exchange system based on woven fabric used for conventional iontophoresis The amount of permeated drug was measured in the same manner as in Example 1. Table 2 shows the results.
- the amount of the drug was measured in the same manner as in Example 1 except that the anion exchange membrane of Comparative Production Example 1 produced without using the non-polymerizable component (b) was used. Table 2 shows the results.
- 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. Table 2 shows the results.
- the drug permeation amount was measured in the same manner as in Example 1 except that the ion-exchange membrane shown in Table 3 was used and a 10 mmO IZL solution of dexamethasone phosphate sodium salt was used. The results are shown in Table 3.
- the drug permeation amount was measured in the same manner as in Example 6, except that the anion exchanger of Comparative Production Example 1 produced without adding the component (b) was used. Table 3 shows the results.
- the drug permeability was measured in the same manner as in Example 6, using only the virtual skin without using the ion exchange membrane to be measured. Table 3 shows the results.
- the drug permeation amount was measured in the same manner as in Example "I, except that a 1 Ommo I ZL solution of the cationic drug lidocaine hydrochloride was used. Is shown in Table 5.
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- Chemical Kinetics & Catalysis (AREA)
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- Water Supply & Treatment (AREA)
- Medicinal Chemistry (AREA)
- Radiology & Medical Imaging (AREA)
- Materials Engineering (AREA)
- Urology & Nephrology (AREA)
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Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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US11/597,610 US20090124957A1 (en) | 2004-05-27 | 2005-05-25 | Method of Producing an Ion-Exchange for Iontophoresis |
EP05745929A EP1752487A4 (en) | 2004-05-27 | 2005-05-25 | PROCESS FOR PREPARING AN ION EXCHANGE MEMBRANE FOR IONTOPHORESIS |
Applications Claiming Priority (2)
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JP2004157683A JP2005334339A (ja) | 2004-05-27 | 2004-05-27 | イオントフォレーシス用イオン交換膜の製造方法 |
JP2004-157683 | 2004-05-27 |
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WO2005116123A1 true WO2005116123A1 (ja) | 2005-12-08 |
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PCT/JP2005/010010 WO2005116123A1 (ja) | 2004-05-27 | 2005-05-25 | イオントフォレーシス用イオン交換膜の製造方法 |
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US (1) | US20090124957A1 (ja) |
EP (1) | EP1752487A4 (ja) |
JP (1) | JP2005334339A (ja) |
WO (1) | WO2005116123A1 (ja) |
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CN105126633B (zh) * | 2015-09-18 | 2017-04-26 | 东南大学 | 一种高压静电纺丝法制备阴离子交换膜的方法 |
JP6999110B2 (ja) * | 2017-10-10 | 2022-01-18 | 国立大学法人 東京大学 | 浸透圧調整物質定着用アニオン性イオン交換膜、浸透圧調整物質検出方法、および浸透圧調整物質検出キット |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS51128390A (en) * | 1975-05-01 | 1976-11-09 | Asahi Chem Ind Co Ltd | Preparation of prrous resins |
JPS5382867A (en) * | 1976-12-29 | 1978-07-21 | Mitsubishi Chem Ind | Production of porous crosslinked copolymer |
JPH02251230A (ja) * | 1989-03-23 | 1990-10-09 | Tokuyama Soda Co Ltd | 高分子多孔膜の製造方法 |
JPH10158416A (ja) * | 1996-11-27 | 1998-06-16 | Tokuyama Corp | 微多孔性荷電膜およびその製法 |
JP2000229128A (ja) * | 1999-02-10 | 2000-08-22 | R & R Ventures Kk | イオントフォレーゼ装置 |
JP2004188188A (ja) * | 2002-11-27 | 2004-07-08 | Tokuyama Corp | イオントフォレーシス用装置 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4093570A (en) * | 1975-05-01 | 1978-06-06 | Asahi Kasei Kogyo Kabushiki Kaisha | Production of porous polymers |
US4154917A (en) * | 1975-05-01 | 1979-05-15 | Asahi Chemical Ind | Production of porous polymers |
US7734339B2 (en) * | 2002-11-27 | 2010-06-08 | Tokuyama Corporation | Iontophoresis apparatus |
-
2004
- 2004-05-27 JP JP2004157683A patent/JP2005334339A/ja active Pending
-
2005
- 2005-05-25 US US11/597,610 patent/US20090124957A1/en not_active Abandoned
- 2005-05-25 EP EP05745929A patent/EP1752487A4/en not_active Withdrawn
- 2005-05-25 WO PCT/JP2005/010010 patent/WO2005116123A1/ja active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS51128390A (en) * | 1975-05-01 | 1976-11-09 | Asahi Chem Ind Co Ltd | Preparation of prrous resins |
JPS5382867A (en) * | 1976-12-29 | 1978-07-21 | Mitsubishi Chem Ind | Production of porous crosslinked copolymer |
JPH02251230A (ja) * | 1989-03-23 | 1990-10-09 | Tokuyama Soda Co Ltd | 高分子多孔膜の製造方法 |
JPH10158416A (ja) * | 1996-11-27 | 1998-06-16 | Tokuyama Corp | 微多孔性荷電膜およびその製法 |
JP2000229128A (ja) * | 1999-02-10 | 2000-08-22 | R & R Ventures Kk | イオントフォレーゼ装置 |
JP2004188188A (ja) * | 2002-11-27 | 2004-07-08 | Tokuyama Corp | イオントフォレーシス用装置 |
Non-Patent Citations (1)
Title |
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See also references of EP1752487A4 * |
Also Published As
Publication number | Publication date |
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EP1752487A4 (en) | 2011-07-27 |
US20090124957A1 (en) | 2009-05-14 |
EP1752487A1 (en) | 2007-02-14 |
JP2005334339A (ja) | 2005-12-08 |
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