JPWO2010061820A1 - Composite membrane and iontophoresis device including the composite membrane - Google Patents

Abstract

The composite membrane according to the present invention is a composite membrane in which a hydrophobic polymer (A) is applied to a support (B) made of a hydrophilic polymer, the hydrophobic polymer being on the surface of the support and / or Or, it is present inside. The iontophoresis device according to the present invention includes a working electrode structure, a non-working electrode structure, a working electrode of the working electrode structure, and a non-working electrode of the non-working electrode structure. An iontophoresis device for administering an ionic drug to a living body using the direct current power supply, the nonactive electrode structure being connected to the nonactive electrode The working electrode structure includes a working electrode, an electrolytic solution holding unit, a chemical solution holding unit for holding the ionic drug, and the electrolytic solution holding unit and the chemical solution. It has a diaphragm arrange | positioned between holding | maintenance parts, This diaphragm is the said composite film, It is characterized by the above-mentioned.

Description

  The present invention is a composite membrane excellent in durability and shape stability in an aqueous liquid and suitable for fractionation of a low-molecular substance in an aqueous liquid, and a living body characterized by incorporating the composite membrane. The present invention relates to an iontophoresis device used for iontophoresis in which a useful ionic drug is driven by voltage and transcutaneously transferred into a living body.

Membrane separation technology is a very useful technique as a means for separating nano-order substances such as ions and low-molecular substances in aqueous liquids. Fields where the advantages of membrane separation technology can be utilized: (1) Fields that require concentration, purification, and recovery at low temperatures (Food and biochemical industries), (2) Fields that require aseptic and dust-free (Pharmaceuticals, (Medical institutions, electronics industry field), (3) Concentration and recovery of trace amounts of expensive substances (nuclear energy, heavy metals field), (4) Special small volume separation field (pharmaceutical field), (5) High energy consumption field (distillation alternative), etc. Can be mentioned.
In these fields, separation of substances from aqueous liquids is the main, so the membrane used is hydrophilic, has a pore size and membrane structure suitable for each application, has excellent mechanical properties, and is easy to handle. Film is desired.

However, the hydrophilic polymer has a property of swelling in an aqueous liquid. Therefore, it is very suitable for microfiltration in water system and separation and purification of polymer substances, but it is difficult to apply to separation and fractionation of substances with very low molecular weight, especially those with molecular weight of 1000 or less. There is.
For example, cellulose is a typical material for hydrophilic polymers. Cellophane (registered trademark) is an example of a membrane composed of only cellulose and used for fractionation of substances having a small pore size. Although this cellophane (registered trademark) is used as a dialysis membrane in a wide range, its fractional molecular weight is about 1000 to 50000, and it does not have the fractionation properties of substances having a molecular weight of 1000 or less. This is because Cellophane (registered trademark) has a dense structure in a dry state, but when immersed in an aqueous liquid, the membrane swells and fine pores expand. As a result, it is surmised that it does not have the ability to fractionate substances having a molecular weight of 1000 or less.
As described above, in a membrane composed only of a hydrophilic polymer, the shape stability is insufficient, such as a change in pore diameter due to swelling in water, and as a result, fractionation of a substance having a molecular weight of 1000 or less is difficult.

As a method for suppressing the swelling of the membrane, there is a method in which not only a hydrophilic polymer but also a hydrophilic polymer and a hydrophobic polymer are combined.
As such an example, a cellulose composite membrane having a cellulose layer having a substantially separating ability on the surface of a polymer microporous membrane is disclosed (for example, see Patent Document 1 below). This composite membrane is a cellulose composite membrane obtained by regenerating cellulose by applying a cellulose ester solution onto a polymer porous membrane and then hydrolyzing the cellulose ester. Since this composite membrane is intended for separation of medium to low molecular weight organic substances, the cellulose ester is hydrolyzed to regenerated cellulose with the aim of suppressing the adsorption of organic substances on the membrane surface. Since regenerated cellulose is hydrophilic, hydrophobic adsorption of organic substances is suppressed, but swelling of the cellulose layer in an aqueous liquid is unavoidable, and it is difficult to fractionate a substance having a molecular weight of 5000. When the blocking property was actually evaluated using polyethylene glycol 6000 (molecular weight 6000), the blocking rate was as low as 24%.
Moreover, in order to avoid that a defect arises in a cellulose layer, the surface pore diameter of the polymeric porous membrane used as a support layer is 100 nm or less. For this reason, when the cellulose ester solution is applied, the solution does not enter the porous polymer membrane, and the resulting composite membrane is a membrane having a complete two-layer structure. Therefore, when the polymer porous membrane is made of a synthetic polymer, stress is generated in the boundary layer because the degree of swelling of the porous membrane layer and the cellulose layer differs when immersed in an aqueous liquid. In that case, since there is no bonding force to overcome the stress, as a result, a problem remains in the form stability that the porous membrane layer and the cellulose layer are peeled off.

As such a film that suppresses pore size expansion due to swelling of the cellulose layer, a composite film in which the cellulose layer is subjected to crosslinking treatment after the cellulose layer is applied is disclosed (for example, see Patent Document 2 below). In this membrane, since the cellulose layer is subjected to a crosslinking treatment, the pore size of the cellulose layer is sufficiently small, and the main use is a gas concentration separation treatment. Further, even in an aqueous liquid, the swelling of the membrane is small and the change in pore diameter is relatively small. However, since the cellulose layer is applied on the dense surface side of the anisotropic porous film, the applied cellulose-based solution does not enter the porous film, and the resulting composite film has a complete two-layer structure. Become a film. Therefore, when the porous film is immersed in an aqueous liquid, a stress is generated in the boundary layer, and there is no binding force to overcome the stress. As a result, the porous film layer and the crosslinked cellulose layer are peeled off. Stability issues remain.
Under such circumstances, proposals regarding composite membranes that are excellent in durability and form stability in aqueous liquids and suitable for fractionation of low-molecular substances in aqueous liquids are eagerly desired.

On the other hand, iontophoresis is a method in which an ionic drug useful for a living body is driven by a voltage and transcutaneously transferred into the living body, and a desired amount of drug is delivered to a desired affected area without pain. It is a method of administering a drug that has the advantage that it can be administered.
FIG. 1 shows a basic configuration of an iontophoresis apparatus that is an apparatus for performing the iontophoresis (see Patent Document 3 below).
The iontophoresis device includes a working electrode structure 110 having a chemical solution holding part 112 that holds a solution (chemical solution) of a drug that dissociates into an electrode 111 and positive or negative ions, and an electrolysis that holds an electrode 121 and an electrolytic solution. A non-working side electrode structure 120 having a liquid holding part 122, and a power source 130 connected between the electrode 111 and the electrode 121, the chemical liquid holding part and the electrolyte holding part being brought into contact with the skin In this state, by applying a voltage having the same polarity as that of the drug ion to the electrode 111 and applying a voltage having the opposite polarity to the electrode 121, the drug ion is administered to the living body.
One of the problems in such an iontophoresis device is various electrode reactions that occur in the working electrode structure 110 and the non-working electrode structure 120.
For example, when the drug is a cationic drug, water, which is a solvent for the drug, may be electrolyzed at the electrode 111 to generate hydrogen ions or oxygen gas. Further, in the electrode 121, hydroxyl ions and hydrogen gas may be generated. Furthermore, depending on the type of the drug, the drug ion may be altered by the electrode reaction, and further, chlorine gas or hypochlorous acid may be generated when the chemical liquid holding unit 112 contains chlorine ions.
On the other hand, when the drug is an anionic drug, water may be electrolyzed at the electrode 111 to generate hydroxyl ions or hydrogen gas. The electrode 121 may generate hydrogen ions or oxygen gas. In addition, depending on the type of the drug, the drug ion may be altered by the electrode reaction, and further, when the electrolyte solution holding part 122 contains chlorine ion, chlorine gas or hypochlorous acid may be generated.

  In the working-side electrode structure 110 and the non-working-side electrode structure 120, when the gas as described above is generated, energization from the electrode 111 to the chemical solution and from the electrode 121 to the electrode solution is inhibited. become. In addition, when hydrogen ions, hydroxyl ions, and hypochlorous acid are generated, they move to the living body interface, and thus have a harmful effect on the living body. In addition, when the drug is altered, an unfavorable situation may occur, for example, a desired drug effect may not be obtained or a harmful substance may be generated for a living body.

As an iontophoresis device capable of solving the above problems, Patent Document 3 proposes an iontophoresis device using a silver electrode as an anode and a silver chloride electrode as a cathode.
In this iontophoresis device, the silver at the anode is oxidized to insoluble silver chloride when energized, and the reaction at which the silver chloride is reduced to metal silver at the cathode preferentially occurs. The generation of various gases and the generation of various ions can be suppressed.
However, in this iontophoresis device, it is difficult to prevent dissolution of the silver electrode during storage of the device, and particularly when a cationic drug is administered, the types of drugs that can be applied are extremely limited. In addition, since the morphological change when silver chloride is generated from a silver electrode is large, special consideration is necessary to prevent such morphological change from affecting the characteristics of the equipment, which greatly restricts the form of the equipment. There is also a problem that causes Furthermore, in this iontophoresis device, the problem of drug alteration due to electrode reaction during energization is not necessarily solved.

As another iontophoresis device for solving the above-mentioned problem, Patent Literature 4 proposes an iontophoresis device shown in FIG.
This iontophoresis device is disposed on the front side of the ion exchange membrane 213, the electrolyte solution holding unit 212 that contacts the electrode 211, the second conductivity type ion exchange membrane 213 arranged on the front side of the electrolyte solution holding unit 212. A working electrode structure 210 comprising a chemical solution holding part 214 for holding a chemical solution containing the first conductive type drug ions, and a first conductive type ion exchange membrane 215 disposed on the front side of the chemical solution holding part 214, and The non-working-side electrode structure 220 including the electrode 221 and the electrolyte solution holding unit 222 and the power source 230 connected between the electrode 211 and the electrode 221 are configured. The “first conductivity type” means a positive or negative electric polarity, and the “second conductivity type” means an electric polarity (negative or positive) opposite to the first conductivity type. “Front side” means “skin side”.
In this iontophoresis device, since the electrolyte solution and the chemical solution in the working electrode structure are separated by the second conductivity type second ion exchange membrane 213, the composition of the electrolyte solution can be selected independently of the chemical solution. Therefore, it is possible to use an electrolyte solution that does not contain chlorine ions, and by selecting an electrolyte in the electrolyte solution that has an oxidation or reduction potential lower than that of water electrolysis, It is possible to suppress the generation of hydrogen gas, oxygen gas, hydroxyl ions, and hydrogen ions due to decomposition. Furthermore, in this iontophoresis device, the migration of drug ions to the electrolyte solution holding unit 212 is suppressed by the second ion exchange membrane 213, so that the alteration of drug ions due to the electrode reaction is also suppressed.

However, in the iontophoresis device described in Patent Document 4, it is difficult to completely separate the chemical solution in the chemical solution holding unit 214 from the electrolyte solution in the electrolytic solution holding unit 212.
That is, in the electrolyte solution of the electrolyte solution holding unit 212, the first conductivity type ions, the second conductivity type ions, and the undissociated electrolyte molecules, which are generated by dissociating the electrolyte, coexist, but the second conductivity type is present. Type ions and electrolyte molecules can pass through the ion exchange membrane 213 of the second conductivity type and move to the chemical solution holding unit 214. Therefore, depending on the type of drug ions and electrolytes or a combination thereof, the apparatus can be used for a certain period or more. In the meantime, these ions or molecules move to the drug solution holding part 214 and act on the drug ions, and the drug solution is discolored, the crystals are precipitated in the drug solution holding part, or the drug is deteriorated due to the alteration of the drug or harmful substances. Undesirable phenomena such as generation may occur.

As another iontophoresis device for solving the above problem, Patent Document 5 discloses an iontophoresis device shown in FIG.
This iontophoresis device includes an electrode 311, an electrolyte solution holding unit 312 that is in contact with the electrode 311 and disposed on the front surface of the electrode 311, and a first conductivity type ion exchange disposed on the front surface side of the electrolyte solution holding unit 312. The membrane 313, the second conductivity type ion exchange membrane 314 disposed on the front side of the first conductivity type ion exchange membrane 313, and the first conductivity type drug disposed on the front side of the second conductivity type ion exchange membrane 314 A working electrode structure 310 including a chemical solution holding unit 315 that holds a chemical solution containing ions, and a first conductivity type ion exchange membrane 316 disposed on the front side of the chemical solution holding unit 315, an electrode 321, and an electrode 321 On the front side of the first conductivity type ion exchange membrane 323, the electrolyte solution holding part 322 that contacts and is arranged on the front side of the electrode 321, the first conductivity type ion exchange membrane 323 arranged on the front side of the electrolyte solution 322, Arrangement Connected to the non-working side electrode structure 320 including the electrolytic solution holding unit 324 and the second conductive side ion exchange membrane 325 disposed on the front side of the electrolytic solution holding unit 324, and the electrode 311 and the electrode 321. The power supply 330 is configured. That is, this iontophoresis device is different from the device of FIG. 2 of Patent Document 2 between the electrolytic solution holding unit and the chemical solution holding unit in the working side electrode structure. In addition to 314, a first conductivity type ion exchange membrane 313 is provided.

Normally, during storage of the device, each ionic component in the electrolytic solution holding unit and the chemical solution holding unit tends to migrate to the chemical solution holding unit and the electrolytic solution holding unit, respectively, by diffusion action. Since the transfer of the conductive drug ions to the electrolytic holding part is suppressed by the second conductive ion exchange membrane, the vicinity of the electrode 311 generated when the device is energized after the device is stored for a long time and the drug is administered to the skin It is possible to suppress the degradation of the drug in Moreover, since the transfer of the second conductivity type ions in the electrolyte to the chemical solution holding unit is suppressed by the first conductivity type ion exchange membrane, the chemical solution is discolored during storage of the device, crystals are precipitated in the chemical solution holding unit, and the drug It is possible to suppress the decrease in medicinal effect and the generation of harmful substances due to the alteration of the material, and the device can be stored for a longer period.
However, for administration of drug ions, it is necessary that drug counter ions move to the electrolyte solution holding part and that the first conductivity type ions in the electrolyte solution move to the drug solution holding part. In addition, by installing two ion-exchange membranes of the second conductivity type between the electrolytic solution holding unit and the chemical solution holding unit, the above transition becomes difficult and another problem in practical use occurs.

In order to avoid such a new problem, it is possible to secure the conductivity of the drug ion by keeping the transport number of the ion exchange membrane low. It is difficult to suppress the transition of the electrolyte into the electrolytic solution and the transition of the second conductivity type ions in the electrolytic solution to the chemical solution holding portion.
In addition, even if an ion exchange membrane having a transport number that satisfies both the above-described conductivity and the degree of suppression of migration of each ion in a good balance is used, the electrolyte molecules present in an undissociated state It is difficult to suppress the migration of drug molecules, and it is not possible to completely solve the problems such as the discoloration of the drug solution, the precipitation of crystals in the drug solution holding part, the decrease in drug efficacy and the generation of harmful substances due to the drug alteration.
Therefore, Patent Document 5 proposes that a porous separation membrane be further disposed between the electrolyte solution holding unit and the drug holding unit in addition to the two ion exchange membranes. Thereby, it is suppressed that undissociated electrolyte molecules and drug molecules migrate to the chemical solution holding unit and the electrolyte solution holding unit, respectively.

  The porous separation membrane proposed in Patent Document 5 can be made of any material such as a polymer material or a ceramic material. However, for example, when the drug whose migration is to be suppressed is an extremely small molecule such as lidocaine hydrochloride (molecular weight 270), which is an anesthetic, the pores of the porous separation membrane need to be extremely small. At this time, if the porous separation membrane is composed only of a hydrophobic polymer material such as polyamide, polysulfone, polycarbonate, cellulose acetate, etc., the migration of drugs and the like can be prevented during long-term storage of the device. Therefore, it is difficult to ensure the electrical conductivity of the drug ions during subsequent use. In addition, when the porous separation membrane is composed only of a hydrophilic polymer material such as polyvinyl alcohol or cellulose, the membrane swells when contacted with water that is a solvent of a chemical solution or an electrolytic solution, and its pores Due to the increase in size, it is difficult to prevent the migration of drugs with small molecular weight and size such as lidocaine hydrochloride, and as a result, the above problems have not been solved.

JP-A-3-68430 JP-A 63-194701 U.S. Pat. No. 4,744,787 Japanese Patent No. 3040517 JP 2007-37640 A

  The problem to be solved by the present invention is to provide a composite membrane that is excellent in durability and form stability in an aqueous liquid and is suitable for use in fractionation of low-molecular substances in an aqueous liquid, and the like. In an iontophoresis device characterized by incorporating the composite membrane, when the device is stored for a certain period or longer, ions are generated by dissociation of drug molecules and drug molecules, and are generated by dissociation of electrolyte molecules and electrolyte molecules. Due to the diffusion of ions, etc., from each holding part to the electrolytic solution holding part or the chemical solution holding part due to diffusion, due to the discoloration of the chemical liquid, the precipitation of crystals in the chemical liquid holding part, the decrease in the medicinal effect, the chemical alteration It is an object of the present invention to provide an iontophoresis device capable of suppressing or suppressing generation of harmful substances, decomposition of drugs, reduction of drug administration efficiency, and the like.

  As a result of intensive studies and experiments conducted in order to solve the above-mentioned problems, the present inventors have found that a composite membrane composed of a hydrophobic polymer and a hydrophilic polymer is excellent in the fractionation performance of low-molecular substances in an aqueous liquid. And finding that the composite membrane is installed as a diaphragm between the electrolytic solution holding part and the chemical solution holding part of the working electrode side structure to suppress the alteration of the drug and the generation of harmful substances. The invention has been completed.

That is, the present invention is as follows.
[1] A composite film in which a hydrophobic polymer (A) is applied to a support (B) made of a hydrophilic polymer, the hydrophobic polymer (A) being on the surface of the support (B) and A composite membrane characterized by being present inside.

  [2] The composite film according to [1], wherein the multilayer structure of the composite film is any one of A / B type, A / B / A type, and B / A / B type.

  [3] The hydrophobic polymer (A) forms a layer on the surface of the composite membrane, and the pore diameter of the pores existing on the surface of the layer is 0.01 μm or less, and the thickness of the layer is The composite membrane according to [1] or [2], which is 0.01 to 10 μm.

  [4] The hydrophobic polymer (A) is present on the surface and inside of the support (B), and the internal permeability of the hydrophobic polymer (A) is 1 to 95 wt%. [1] -The composite film in any one of [3].

  [5] The porosity of the support (B) is 10% or more, the maximum pore diameter of the surface in contact with the hydrophobic polymer (A) is 20 nm or more, and the support (B) is The composite film according to any one of [1] to [4], wherein the surface porosity of the surface in contact with the hydrophobic polymer (A) is 10% or more.

  [6] The thickness of the composite film is 5 μm or more, and the content of the hydrophobic polymer (A) is 0.1 to 50 wt%, according to any one of the above [1] to [5]. Composite membrane.

  [7] The composite membrane according to any one of [1] to [6], wherein the hydrophobic polymer (A) is a cellulose derivative.

  [8] The composite membrane according to any one of [1] to [7], wherein the hydrophilic polymer is regenerated cellulose.

  [9] The composite membrane according to any one of [1] to [8], wherein the composite membrane has a sucrose rejection of 70% or more and a sodium chloride rejection of 40% or less.

  [10] Working-side electrode structure, non-working-side electrode structure, and DC power source connected with different polarities between the working-side electrode of the working-side electrode structure and the non-working-side electrode of the non-working-side electrode structure An iontophoresis device for administering an ionic drug to a living body using the DC power source, wherein the non-working side electrode structure includes the non-working side electrode and a non-working side electrolyte solution holding unit. On the other hand, the working electrode structure is disposed between the working electrode, the electrolytic solution holding unit, the chemical solution holding unit for holding the ionic drug, and between the electrolytic solution holding unit and the chemical solution holding unit. The iontophoresis device comprising a diaphragm, wherein the diaphragm is the composite film according to any one of [1] to [9].

[11] The amount of lidocaine hydrochloride permeated from the aqueous lidocaine hydrochloride solution at 25 ° C. and 0.4 mol / L through the diaphragm is 5.0 × 10 ⁻⁷ mol / L · hr · cm ² or less, and The iontophoresis device according to [10] above, wherein a potential difference between both surfaces of the diaphragm is 10 V or less in a membrane resistance measurement measured at a current density of 0.5 mA / cm ² .

  Since the composite membrane of the present invention is excellent in durability and form stability in an aqueous liquid, it can be suitably used for fractionation of low molecular weight substances in an aqueous liquid. In addition, an iontophoresis device utilizing the characteristics of the composite membrane can be provided.

1 is a schematic diagram of a conventional iontophoresis device disclosed in Patent Document 3. FIG. 1 is a schematic diagram of a conventional iontophoresis device disclosed in Patent Document 4. FIG. 1 is a schematic diagram of a conventional iontophoresis device disclosed in Patent Document 5. FIG. It is the schematic of the iontophoresis apparatus of one Embodiment of this invention.

Hereinafter, the present invention will be described in detail.
The composite membrane of the present invention is a composite membrane in which a hydrophobic polymer (A) is applied to a support (B) made of a hydrophilic polymer, and the hydrophobic polymer (A) is a surface of the support. And / or present inside.
The presence of polymers having different properties in part of the membrane makes it possible to supplement the problems of hydrophilic polymers with hydrophobic polymers and hydrophobic polymers with hydrophilic polymers.
That is, with only a hydrophilic polymer, no matter how dense the membrane is, it swells in an aqueous liquid and the pore size of the membrane expands. For this reason, there is no problem in the separation and fractionation of polymers, but the separation and fractionation of low molecules having a molecular weight of 1000 or less becomes difficult.
However, in a composite membrane in which a hydrophobic polymer is applied to a support made of a hydrophilic polymer, the hydrophobic polymer layer does not swell even in an aqueous liquid, and as a result, the composite membrane is durable in an aqueous liquid. It becomes a film excellent in property and form stability. At this time, if the hydrophobic polymer layer is controlled to have a pore size suitable for the size of the fractionated molecule, the presence of this layer enables fractionation of low molecules.

  On the other hand, when a membrane composed only of a hydrophobic polymer is used when fractionating a low molecular weight molecular weight of 1000 or less, or when used as a diaphragm for preventing or suppressing the migration of a low molecular weight molecular weight of 1000 or less, Since the pore size is very small and dense, it is very difficult to permeate water-based liquids, or when it is incorporated as a diaphragm of an iontophoresis device, it ensures electrical conductivity when transferring drug ions into the living body. It becomes difficult to do. Therefore, it is desirable that the hydrophobic polymer layer is as thin as possible. However, as the hydrophobic polymer layer becomes thinner, the strength of the layer decreases, and handling becomes difficult. Therefore, in order to support such a thin hydrophobic polymer layer, the permeation performance of various ions that are conductive sources Therefore, a support membrane made of a hydrophilic polymer that is excellent in resistance is required.

Further, in the composite membrane, when the hydrophobic polymer layer is not provided, the above-described effects cannot be expressed. However, in the composite membrane in which the hydrophobic polymer is coated on the support made of the hydrophilic polymer, Since the hydrophobic polymer layer is formed at least on the surface on the application side, the above effect is exhibited.
In addition, a state in which a part of the hydrophobic polymer enters the inside of the hydrophilic support membrane and a layer (C layer) in which the hydrophobic polymer and the hydrophilic polymer are mixed exists in the aqueous liquid of the composite membrane. This is one of the preferred embodiments from the viewpoint of durability and form stability.
The C layer is, for example, a hydrophilic polymer when a hydrophobic polymer solution forming the A layer is applied to the surface of the hydrophilic polymer film forming the B layer to form a composite film. A hydrophobic polymer solution enters from the pores on the surface of the membrane and solidifies inside the membrane, which means a layer in a state where the hydrophilic polymer and the hydrophobic polymer are firmly bonded, This state is similar to a state generally called an anchor effect.
When such a film having no C layer is immersed in an aqueous liquid, when the stress is generated at the interface between the A layer and the B layer because the swelling property of the polymer is different between the A layer and the B layer. In addition, it may be difficult to overcome the stress and maintain the bonded state of the two layers. On the other hand, in the film having the C layer, the A layer and the B layer are strongly bonded due to the presence of the C layer, and the A layer and the B layer are difficult to peel off. As a result, durability and form stability are excellent. A composite film is preferable.

  In order to form the C layer, as described above, it is necessary that the hydrophobic polymer forming the A layer penetrates into the hydrophilic polymer film forming the B layer. The internal permeability of the molecule is preferably 1 to 95 wt%. If it is less than 1 wt%, shape stability due to the anchor effect cannot be expected, and if it is more than 95 wt%, pinholes may be formed in the A layer in the composite film. From the viewpoint of low molecular fractionation It is not preferable. More preferably, it is 10-90 wt%, More preferably, it is 20-90%, Most preferably, it is 30-90 wt%.

It is also a preferred embodiment that the composite film of the present invention has a multilayer structure, and the multilayer structure is any one of A / B type, A / B / A type, and B / A / B type. In the expression of these multilayer structures, for example, a part of A may exist inside B if it is an A / B type. Moreover, if it is A / B / A type, if A is a hydrophobic polymer, there will be no other restriction | limiting, A may be the same kind or different. The same applies to B of B / A / B type. In addition, as long as the A / B / A type is used, both the A layer and the B layer are not limited to one layer, and may be a multilayer. Similarly to the above, in the case of a multi-layer structure, a multi-layer structure of the same polymer or different polymers may be used.
If it is A / B type, it is as above-mentioned that it is one of the preferable aspects that A exists in B inside. However, even when there is little or almost no amount present, it is one of the preferred embodiments that the structure is such that the hydrophilic polymer layer is sandwiched between the hydrophobic polymer layers, for example, A / B / A type. One. Thereby, the shape change of a composite film by the difference in swelling characteristic at the time of aqueous liquid immersion is suppressed. That is, in the case of the A / B type, although depending on the thickness of the A layer and the B layer, the A layer does not stretch due to the difference in the swelling characteristics of each layer, but the B layer tends to stretch. On the inner side, there is a case where the composite film is rounded with the B layer on the outer side. In this case, stress is generated at the interface between the A layer and the B layer, and the layer may be peeled off. However, in the case of a structure such as A / B / A type, for example, the above-described phenomenon that the film is rounded is not observed, and the layer does not peel off, depending on the thickness of the A layer on both surfaces. It is a composite film with excellent durability and dimensional stability.

In order to prevent or control the migration of a substance having a molecular weight of 1000 or less as described above, that is, to prevent or control the migration of a substance having a molecular weight of 1000 or less, the hydrophobic polymer layer (A layer) is formed on the surface of the composite membrane. The pore diameter of pores present on at least one of the surfaces facing the outside of the A layer is 0.01 μm or less, and the thickness of the A layer is 0.01 to 10 μm. Is one of the preferred embodiments.
The surface pore diameter should be appropriately set depending on the size and shape of the substance to be fractionated, but is more preferably 0.005 μm or less, further preferably 0.003 μm or less, and most preferably 0.001 μm. It is as follows. The surface pore diameter can be controlled by the polymer concentration of the hydrophobic polymer solution to be applied and the drying speed after the application.
The thickness of the layer A should also be set appropriately depending on the substance to be separated, and the permeability of the aqueous liquid, the chemical counter ions inside the iontophoresis device, and the permeability of the first conductivity type electrolyte ions. From the viewpoint, it is more preferably 0.01 to 5 μm, further preferably 0.01 to 3 μm, particularly preferably 0.01 to 1 μm, and most preferably 0.01 to 0.5 μm.

  Further, it is preferable that the porosity of B is 10% or more, the maximum pore diameter of the pores existing on the surface in contact with A is 20 nm or more, and the surface porosity is 10% or more. One. With such a structure, for example, when forming the composite film by applying the hydrophobic polymer solution forming the A layer to the surface of the hydrophilic polymer film forming the B layer, the above-mentioned C This is desirable because a layer can be easily formed, and as a result, a composite film excellent in durability and form stability can be easily obtained.

Here, the maximum pore diameter is a pore diameter showing the structural characteristics of the film-like material obtained by a method based on the bubble point method. In other words, the maximum pore diameter in the bubble point method refers to the diameter of the largest hole in the layer having the densest structure (layer having the smallest pore diameter) existing in a part of the membrane. This is an important characteristic that determines the separation characteristics, fractionation performance of a membrane, i.e. whether a certain size of substance passes through the membrane.
Here, in the support (B), when this dense layer is present on the surface in contact with A in the support, the measurement result (maximum pore diameter) itself can be said to be the maximum pore diameter of the surface in contact with A. When the dense layer does not exist on the surface in contact with A, the measurement result does not match the maximum pore diameter of the surface in contact with A. In this case, the structure of the surface in contact with A is not the most dense layer in B ( Therefore, it can be said that the hole diameter of the surface in contact with A is larger than the maximum hole diameter of the measurement result.
Therefore, by measuring the maximum pore size of the membrane by the bubble point method, it can be said that the maximum pore size of the surface in contact with A is equal to or larger than the measurement result. If the result is 20 nm or more, it can be said that the maximum pore diameter of the surface in contact with A of B is 20 nm or more.

The porosity of the support composed of the hydrophilic polymer constituting the support (B) is more preferably 20% or more, still more preferably 30% or more, and even more preferably 40% or more. The maximum pore diameter of the surface of the membrane in contact with the hydrophobic polymer is more preferably 30 nm or more, still more preferably 50 nm or more, and particularly preferably 100 nm or more. The surface porosity is more preferably 20% or more, still more preferably 30% or more, still more preferably 40% or more, and particularly preferably 50% or more. The upper limit of the porosity and the surface porosity is preferably 90% or less, more preferably 80% or less, from the viewpoint of mechanical strength.
The composite membrane of the present invention preferably has a thickness of 5 μm or more from the viewpoint of mechanical strength and handleability. The lower limit is preferably 1 mm or less, depending on the application. The content of the hydrophobic polymer is preferably 0.1 to 50 wt%. Hydrophobic polymers mainly exhibit improved durability and shape stability of composite membranes, low molecular fractionation performance, etc., but if their content is high, the permeability of aqueous liquids decreases, Because the permeability of drug counter ions and electrolyte ions when using an iontophoresis device is reduced, it is necessary to apply a large voltage to administer the drug ions in a desired amount in vivo. Considering the influence on a living body, it is not preferable. Moreover, since it will become difficult to express the said performance if there is little content, 0.1-50% of content of hydrophobic polymer is preferable, More preferably, it is 0.1-30 wt%, More preferably It is 0.1-20 wt%, Especially preferably, it is 0.1-10 wt%, Most preferably, it is 0.1-5%.

  The hydrophobic polymer constituting the composite membrane of the present invention means a polymer exhibiting poor solvent resistance to water. It is not particularly limited as long as it exhibits poor solvent properties with respect to water. For example, cellulose derivatives such as cellulose acetate, methyl cellulose, ethyl cellulose, nitrocellulose; polyvinyl chloride, polyvinylidene chloride, polystyrene, poly -Vinyl polymers such as N-vinylcarbazole, polyvinyl acetate, polyacrylonitrile, polymethacrylonitrile, polymethyl vinyl ether; acrylic polymers such as polymethyl acrylate, polyethyl acrylate, polymethyl methacrylate, polyethyl methacrylate; polycaprolactone, polyethylene Polyester such as terephthalate, polybutylene terephthalate, polycyclohexyldimethylene terephthalate, polyethylene naphthalate, polybutylene naphthalate Polycarbonate obtained by interfacial polycondensation of bisphenol A and phosgene or transesterification of bisphenol A and diphenyl carbonate; polyarylate obtained by polycondensation of bisphenol A and aromatic dicarboxylic acid; pyromellitic anhydride and aromatic diamine Polyimide obtained by polycondensation of polymethylene, polyamideimide obtained by polycondensation of trimellitic acid and aromatic diamine, 4,4 ′-[isopropylidenebis (p-phenyleneoxy)] diphthalic dianhydride and aromatic diamine Polyimides such as polyetherimide obtained by polycondensation of polysulfone; polysulfone obtained by polycondensation of dichlorodiphenylsulfone and bisphenol A, and polycondensation obtained by polycondensation of dichlorodiphenylsulfone and dihydroxydiphenylsulfone. Ether sulfones, polyethers such as polyphenylene ether obtained by oxidative polymerization of 2,6-dimethylphenol, polyether ether ketone obtained by polycondensation of dihalogenobenzophenone and hydroquinone; polydimethylsiloxane, polydipropylsiloxane, polydiphenylsiloxane And the like.

  Here, unless otherwise specified, the “polymer” is not only a single polymer, but also an alternating copolymer, a random copolymer, or a block copolymer obtained by copolymerizing 50 mol% or less of another copolymerizable monomer. A graft copolymer may be included. Moreover, these polymers may be used independently or may use 2 or more types together. In the hydrophobic polymer, a highly substituted cellulose derivative exhibiting hydrophobicity is particularly preferred from the viewpoints of solubility in a solvent, handleability when the solution is dissolved, low molecular fractionation performance, and the like. Specific examples of the highly substituted cellulose derivative exhibiting hydrophobicity include cellulose acetate having a substitution degree of 2.2 or more, ethyl cellulose having a substitution degree of 1.5 or more, and nitrocellulose having a substitution degree of 1.5 or more. Cellulose acetate having a substitution degree of 2.2 or more is particularly preferred.

The hydrophilic polymer constituting the composite membrane of the present invention means a polymer that does not dissolve in water but has water in the polymer and has a two-dimensional or three-dimensional support structure throughout the system. . Note that “not soluble in water” means that the substantial solubility in water at a neutral pH at 25 ° C. is 0.5 g / 100 g or less of water.
The hydrophilic polymer is not particularly limited as long as it has the characteristics as described above. Examples thereof include celluloses such as natural cellulose, regenerated cellulose, and microbially produced cellulose; carboxymethyl cellulose ethyl cellulose having a low degree of substitution, and the like. Cellulose derivatives; Polyalkylene oxides such as polyethylene glycol and polypropylene glycol; Polymerization of acrylic acid or methacrylic acid esters such as 2-hydroxypropyl acrylate, 2-hydroxyethyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate And a polymer.
Of the above, from the viewpoints of the degree of hydrophilicity, the ease of operation for complexation, and the affinity with a high-substituted cellulose derivative which is a preferred example of a hydrophobic polymer, regenerated cellulose and natural cellulose are preferred, and regenerated cellulose is preferred. More preferred.

Among them, the combination of A as a highly substituted cellulose derivative and B as a regenerated cellulose is most preferable because it exhibits high affinity not found in other polymer combinations. As a result, it is needless to say that the thickness of the C layer is thick, but even when the thickness of the C layer is thin or almost absent, the joining surfaces of A and B are firmly joined, particularly in an aqueous liquid. Durability and form stability are manifested.
In the composite membrane of the present invention, the rejection of an aqueous sucrose solution (MW: 340, concentration: 500 ppm, 25 ° C.) is preferably 70 wt% or more, more preferably 80 wt% or more, and further preferably 90 wt% or more. Further, the rejection of sodium chloride (MW: 58.5 (chlorine ions: 35.5, sodium ions: 23), concentration: 500 ppm, 25 ° C.) is preferably 40 wt% or less, more preferably 30 wt% or less. More preferably, it is 20 wt% or less. In view of this numerical value, it can be used as a permselective membrane having a fractionation property that does not prevent the permeation of ions having a molecular weight of 100 or less while fractionating low molecular weights of about 300 to 1000.

Next, the manufacturing method of a composite film is demonstrated.
As one method, first, a support (B) made of a hydrophilic polymer is prepared. In the production method, a liquid containing a hydrophilic polymer is cast into a flat film using a film die, a doctor blade or the like. At this time, the casting method is not limited to the above method, and the shape of the die to be used is not particularly limited, and a known one can be applied.
The solvent or the like is removed from the cast hydrophilic polymer solution by various methods, and then a support (B) made of the hydrophilic polymer is obtained through a washing step, a solvent replacement step, and a drying step. This support (B) has a porosity of 10% or more, the maximum pore diameter of the surface in contact with the hydrophobic polymer (A) is 20 nm or more, and the support (B) is a hydrophobic polymer ( It is preferable that the surface porosity of the surface in contact with A) is 10% or more.

Next, the hydrophobic polymer (A) is applied to the support (B) made of the hydrophilic polymer. Here, the application may be any known method such as application and impregnation, and is not particularly limited. Thereafter, the solvent in the liquid containing the hydrophobic polymer was removed by various methods, and the hydrophobic polymer and the hydrophilic polymer were combined through a washing step and a drying step as necessary. A composite membrane is obtained.
In the above method, the operation of first forming the hydrophilic polymer support (B) and then forming the hydrophobic polymer (A) layer on the hydrophilic polymer support (B) has been described. Conversely, first, the hydrophobic polymer membrane is prepared. Then, an operation for forming a hydrophilic polymer layer may be performed.
Further, in order to produce a composite film having a plurality of hydrophobic polymer layers and hydrophilic polymer layers, the above-described operation may be carried out a plurality of times, and it is necessary as appropriate depending on the desired laminated structure. What is necessary is just to implement operation and it does not restrict | limit at all.

  Here, in order to explain more specifically, in the case of using cellulose acetate (substitution degree: about 2.5) which is a suitable example as a hydrophobic polymer and regenerated cellulose which is a suitable example as a hydrophilic polymer However, the respective polymers are not limited to those described above. As a composite method, a regenerated cellulose support is first prepared and then a cellulose acetate solution is applied to the surface to form a cellulose acetate layer, but this is not limited.

First, in preparing the regenerated cellulose support, the cellulose raw material is not particularly limited, and examples thereof include cotton linter, pulp, waste paper, bacterially produced cellulose, regenerated cellulose and the like.
As for the solvent, for example, a solvent having a solubility in cellulose, such as copper ammonia, caustic soda, sulfuric acid, liquid ammonia / ammonium thiocyanate, N-methylmorpholine N-oxide, DMAc / LiCl, and the like. Among these solvents, a copper ammonia solution is preferable from the viewpoint of dissolution stability as a cellulose solution.
The cellulose concentration in the dope prepared by dissolving cellulose in the solvent as described above is preferably in the range of 2 to 20 wt%, more preferably 3 to 15 wt%, and further preferably 4 to 12 wt%. When the cellulose concentration is in the above range, the cellulose is uniformly dissolved in the solvent, and it is easy to control the casting thickness in the flat film casting process described later, and is excellent in strength. A regenerated cellulose support is obtained. Next, this cellulose solution is cast into a film using a film die, a doctor blade or the like.

The subsequent steps will be described using a copper ammonia cellulose solution, which is a preferred cellulose solution in the present invention, as an example.
After casting the cellulose solution, the film-like cellulose solution is introduced into a coagulation medium to form a film structure (hereinafter also referred to as a coagulation step). The coagulating liquid to be used may be any liquid that dissolves ammonia, and water, an alkaline aqueous solution such as an aqueous sodium hydroxide solution, an acidic aqueous solution such as dilute sulfuric acid, and an aqueous solution containing an organic solvent such as acetone are particularly suitable. Subsequently, a solvent or the like dissolving cellulose is extracted or removed, or its dissolving ability is lowered to obtain a solidified cellulose porous membrane (hereinafter also referred to as a regeneration step).
The regeneration solution used in this regeneration step may be any acid that can elute copper that is complexed with cellulose, such as inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, odorous acid, hydrofluoric acid, and the like. And organic acids such as acetic acid, succinic acid and tartaric acid can be used. Sulfuric acid is preferred. The concentration may be a minimum concentration at which regeneration is completed, and is preferably 15 wt% or less in consideration of economy. The regenerating method is performed by immersing in a tank filled with an acid or spraying using a device such as a shower.

  After the regeneration step, it is washed with water or other cleaning agents. Thereafter, the regenerated cellulose support may replace moisture retained by the porous membrane with an appropriate organic solvent, if necessary. By carrying out like this, when drying is implemented while heating in the drying process mentioned later, the degree to which a film contracts by drying can be controlled. As a result, a slightly porous regenerated cellulose support in which the internal permeability of the hydrophobic polymer (A) is 1 to 95 wt% is obtained.

Finally, the regenerated cellulose support that has undergone the above steps is dried. This condition is not particularly limited, and for example, it is possible to arbitrarily select conditions according to the purpose and use of the film, such as natural drying at room temperature, heat drying (40 to 200 ° C.), freeze drying, and the like. it can.
A cellulose acetate layer is combined with the regenerated cellulose support obtained by the above method.
The cellulose acetate used here is required to have a degree of substitution having hydrophobic performance, and for example, cellulose acetate manufactured by Wako Pure Chemical (substitution degree: about 2.5) may be used.
The solvent should just be a solvent which has favorable solubility with respect to the said cellulose acetate, and an acetone solvent is preferable from a viewpoint of dissolution stability and a handleability.
The polymer concentration of the cellulose acetate solution prepared by dissolving using the above solvent is preferably in the range of 0.1 to 20 wt%, more preferably 3 to 15 wt%, and still more preferably 5 to 15 wt%. It is preferable for the concentration of cellulose acetate to be in the above-mentioned range since the operation for compositing to the regenerated cellulose support described later becomes easy.

  The cellulose acetate solution is applied to the surface of the regenerated cellulose support and combined. At this time, a known method such as a doctor blade can be used for coating. At this time, the surface of the regenerated cellulose support has a porosity of 10% or more, the maximum pore diameter of the surface in contact with the hydrophobic polymer (A) is 20 nm or more, and the cellulose support is highly hydrophobic. If the surface porosity of the surface in contact with the molecule (A) is 10% or more, the cellulose acetate solution penetrates into the inside of the regenerated cellulose support, and the multilayer structure of the diaphragm is A / B type, A / B / A layer in which regenerated cellulose and cellulose acetate are mixed, such as A-type and B / A / B-type, is formed. Then, the durability and shape stability of the composite film are improved by the anchor effect described above, which is preferable. The application may be on one surface or on both surfaces.

Thereafter, solvent removal and drying may be performed as necessary. About the method of solvent removal and drying, a suitable method may be used among well-known methods, for example, if it is a drying method, natural drying at room temperature, heat drying (40-200 degreeC) etc. will be mentioned.
The composite membrane produced as described above is installed as a diaphragm between the electrolytic solution holding unit and the chemical solution holding unit to produce an iontophoresis device. The members described later can be used as members used in apparatuses other than the composite membrane. In the iontophoresis device thus produced, ions generated by dissociation of drug molecules and drug molecules, ions generated by dissociation of electrolyte molecules and electrolyte molecules, etc. are stored from the respective holding parts while the device is being stored. By the diffusion, the transition to the electrolytic solution holding unit or the chemical solution holding unit is suppressed or suppressed. As a result, an iontophoresis device that has no problems such as discoloration of chemicals, precipitation of crystals in the chemicals holding part, reduction of medicinal effects, generation of harmful substances due to alteration of drugs, degradation of drugs, and reduction of drug administration efficiency, etc. Since it can be produced, it can be said that the composite membrane can be used very suitably in iontophoresis.

Hereinafter, an iontophoresis device incorporating the composite membrane will be described in detail.
FIG. 4 shows an example of the configuration of the iontophoresis device of the present invention.
In the following description, for the sake of convenience, an iontophoresis device for administering a drug that dissociates into positive ions (for example, lidocaine hydrochloride as an anesthetic, morphine hydrochloride as an anesthetic, etc.) will be described as an example. In the case of a device for administering a drug that dissociates into negative ions (for example, ascorbic acid that is a vitamin drug), the polarity of the power source, each electrode member, and each ion-exchange membrane in the following description Vice versa.

As shown in FIG. 4, the iontophoresis device of the present invention includes, as components, a working electrode structure 410, a non-working electrode structure 420, a working electrode of the working electrode structure, and a non-working electrode. A DC power source 430 is connected between the non-working side electrodes of the working side electrode structure with different polarities.
The DC power source 430 may be a power source used in a normal iontophoresis device. In addition, when the power source, the working side electrode structure, and the non-working side electrode structure are used by being incorporated into one exterior material, a battery can be used for the power source unit. A coin-type silver oxide battery, an air zinc battery, a lithium ion battery, or the like can be used.
The working-side electrode structure 410 is disposed on the front side of the electrolyte solution holding unit 412, the electrode 411 connected to the positive electrode of the power source 430, the electrolyte solution holding unit 412 disposed on the front surface side so as to be in contact with the positive electrode 411. And a cation exchange membrane 415 disposed on the front side of the chemical solution holding unit 414, the entirety of which is made of a resin film or a plastic material. In a cover or container 416.
On the other hand, the non-working-side structure 420 includes an electrode 421 connected to the negative electrode of the power source 430, an electrolyte solution holding unit 422 disposed on the front surface side so as to contact the negative electrode 421, and a front surface side of the electrolyte solution holding unit 422. A cation exchange membrane 423 disposed on the front surface of the cation exchange membrane 413, an electrolyte solution holding unit 424 disposed on the front side of the cation exchange membrane 413, and an anion exchange membrane 425 disposed on the front side of the electrolyte solution holding unit 424. It is accommodated in a cover or container 426 made of a resin film or a plastic material.

As the electrode 411 and the electrode 421, an electrode used in a normal electrochemical process can be used without any limitation. Examples include electronic conductors such as gold, platinum, silver, copper, nickel, zinc, and carbon, semiconductor electrodes, self-sacrificial electrodes such as silver / silver chloride, and the like, which can be used alone or in combination. .
Electrolyte holding parts 412, 422, and 424 are for holding an electrolytic solution for ensuring electrical conductivity, and phosphate buffered saline, physiological saline, and the like are usually used as this electrolytic solution. In addition, an electrolyte that is more easily oxidized or reduced than the water electrolysis reaction is added to this electrolyte solution in order to more effectively prevent the generation of gas due to the water electrolysis reaction, the increase in electrical resistance due to this, or the pH change. From the viewpoint of economy and biosafety, for example, inorganic compounds such as ferrous sulfate and ferric sulfate, pharmaceutical agents such as ascorbic acid and sodium ascorbate, lactic acid, oxalic acid and apple Organic acids such as acids, succinic acid and fumaric acid and / or their salts can be preferably used, and the above can also be used as a mixture.

The chemical solution holding unit 414 holds an aqueous solution of a drug that dissociates into a positive drug ion that has a medicinal effect and a negative drug counter ion that is a counter ion. Positive ionic drugs include anesthetics such as procaine hydrochloride, lidocaine hydrochloride, dibucaine hydrochloride, antineoplastic agents such as mitomycin and bleomycin hydrochloride, analgesics such as morphine hydrochloride, steroids such as medroxyprogesterone acetate, histamine, etc. Is mentioned. On the other hand, as negative ionic drugs, 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, benzylpenicillin Antibiotics such as potassium are included.
The electrolytic solution holding unit and the chemical solution holding unit may hold the respective liquids in a liquid state, but they can be handled by impregnating and holding the electrolytic solution and the chemical solution in the following absorbent thin film carrier. It is also possible to improve the performance.
As a material that can be used as a water-absorbing thin film carrier in this case, in addition to gauze and filter paper, gel membranes such as acrylic hydrogel and segmented polyurethane gel can be used. By impregnating at an impregnation rate, a high drug delivery property can be obtained.

The diaphragm installed between the electrolyte solution holding part and the chemical solution holding part in the working electrode structure is a composite film in which the hydrophobic polymer (A) is applied to the support (B) made of the hydrophilic polymer. The hydrophobic polymer (A) is present on the surface and / or inside of a support composed of the hydrophilic polymer. The presence of polymers with different properties in part of the membrane makes it possible for hydrophilic polymers to complement the problems of hydrophobic polymers, and hydrophobic polymers to complement the problems of hydrophilic polymers. be able to.
That is, when the membrane is composed only of a hydrophilic polymer, no matter how dense the membrane is, it swells in an aqueous liquid and the pore size of the membrane increases. Therefore, there is no problem in suppressing the migration of the polymer, but it is difficult to inhibit the migration of a low molecule having a molecular weight of 1000 or less, such as lidocaine hydrochloride (molecular weight 270).
In contrast, in a membrane in which a hydrophobic polymer is applied to a support made of a hydrophilic polymer, the hydrophobic polymer layer does not swell even in an aqueous liquid. Even if it is in contact with an aqueous liquid, the film has excellent durability and form stability. At this time, if the pore size of the pores existing in the hydrophobic polymer layer is controlled to a pore size suitable for the size of the molecule for which migration is to be prevented or suppressed, the presence of this layer prevents or inhibits the migration of low molecules. Is also possible.

  In the present specification, “inhibition of migration of molecules or ions” does not necessarily mean complete inhibition. For example, even when migration of electrolyte molecules or drug molecules occurs at a certain rate, Including the case where the migration of electrolyte molecules or drug molecules is restricted to the extent that the working structure can be retained without causing a decrease in drug administration efficiency or decomposition of the drug in the electrolyte solution holding unit over the required period . In addition, an electrolytic solution in which two or more types of electrolytes are dissolved may be used in the electrolytic solution holding unit, and similarly, a chemical solution in which two or more types of drugs are dissolved may be used in the chemical solution holding unit. Depending on the type of electrolyte held in the liquid holding part, there is an electrolyte that does not affect the administration efficiency of the drug even when transferred to the drug holding part, and similarly, depending on the type of drug held in the drug holding part In addition, there may be a drug that does not produce a harmful substance due to decomposition even when transferred to the electrolyte holding part, in such a case, an electrolyte molecule that reduces the administration efficiency of the drug when transferred to the drug holding part, It is sufficient to use a diaphragm that can prevent the migration of only drug molecules that decompose upon energization to produce harmful substances.

Further, the amount of lidocaine hydrochloride permeated from a 0.4 mol / L aqueous lidocaine hydrochloride solution through the composite membrane used as the diaphragm of the present invention is 5.0 × 10 ⁻⁷ mol / L · hr · cm ² or less. In addition, in the film resistance measurement, it is one of preferred embodiments that the potential difference between both surfaces of the film measured at a current density of 0.5 mA / cm 2 is 10 V or less. The permeation amount of the lidocaine hydrochloride is more preferably 4.0 × 10 ⁻⁷ mol / L · hr · cm ² or less, and further preferably 3.0 × 10 ⁻⁷ mol / L · hr · cm ² or less. About membrane resistance, More preferably, it is 5 V or less, More preferably, it is 3 V or less. Satisfying the above numerical values means that even if the drug used is a small molecule such as lidocaine hydrochloride (molecular weight 270), the migration of drug ions to the electrolytic solution holding part or the chemical liquid holding part of the electrolyte molecule during device storage This is suitable because it can highly inhibit or suppress the transition to, and does not hinder the efficient transfer of drug ions into the living body when energized.

In addition, the iontophoresis device of the present invention includes, in addition to the composite diaphragm composed of a hydrophilic polymer and a hydrophobic polymer, between the electrolyte solution holding unit and the chemical solution holding unit of the working electrode structure. An ion exchange membrane of one ion conductivity type and / or second ion conductivity type may be disposed (not shown). By arranging an ion exchange membrane with an appropriate transport number, it is possible to supplement the function of the composite diaphragm.
Regarding the ion exchange membranes 415, 423, and 425, commercially available ion exchange membranes can be used without any limitation.
Here, as the ion exchange membrane, in addition to the one in which the ion exchange resin is formed into a film shape, the heterogeneous ion exchange membrane obtained by dispersing the ion exchange resin in a binder polymer and forming the membrane by heat molding or the like. Alternatively, a resin having a functional group capable of introducing an ion exchange group dissolved in a solvent is impregnated and filled in a substrate such as a porous film, and after the polymerization or solvent removal, the ion exchange group is introduced. Various things, such as a homogeneous ion exchange membrane obtained by performing, are known, and these can be used without any limitation.

EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further, this invention is not limited to these Examples etc. In addition, each measuring method etc. are as follows.
(1) Confirmation of internal structure and laminated structure of composite film After immersing the composite film in liquid nitrogen, freezing and cleaving, adjusting the cross section of the film, a scanning electron microscope (SEM: manufactured by JEOL Ltd.) : JSM-6380), the internal structure and laminated structure of the film were confirmed.
(2) Surface pore size of the hydrophobic polymer (A) layer of the composite membrane The surface of the A layer was observed with an SEM, and the pore size was evaluated. If the pores are 0.01 μm or less, observation with an SEM is impossible. Therefore, when pores cannot be observed, the surface pore diameter is assumed to be 0.01 μm or less.
(3) Thickness of the hydrophobic polymer (A) layer of the composite membrane As in the confirmation of the layer structure of (1) above, cross-sectional observation of the composite membrane by SEM was performed, and the thickness was measured. When A penetrates into B and the boundary layer between A and B is not clear, measure the film thickness of the entire composite film, and subtract the film thickness of B obtained in advance by the method of (5) below. It was set as the thickness of A layer. As for the film thickness of the composite film, five cross-sectional sections were adjusted for one film, five points were measured for one section, and an average value of a total of 25 measurement results was used.
(4) The internal permeability of the hydrophobic polymer (A) of the composite membrane to the hydrophilic polymer support (B) From the above (3), the thickness of the layer A is determined, and the specific gravity of each substance and the membrane From the area, the weight of the A layer existing on the surface was calculated.
Further, the weight of A in the composite membrane was determined by the following (9). From this and the weight of the A layer, the internal permeability of A was calculated.
Internal permeability (%) = {1- (weight of surface A layer) / (weight of A in composite film)} × 100

(5) Film thickness of hydrophilic polymer support (B) of composite membrane A cross section of the membrane was prepared in the same manner as in (1) above, and observed with SEM to measure the film thickness. Five cross-sectional sections were prepared for one membrane, and five points were measured for one section. The average value of the measurement results of a total of 25 points was defined as the film thickness d (μm).
(6) Porosity of hydrophilic polymer support (B) of composite membrane The hydrophilic polymer support (B) is dried in a vacuum so that the moisture content is 0.5% or less. The weight W (g) and the volume V (cm 3) of the hydrophilic polymer support (B) after drying were measured, and the porosity ε (%) was calculated using the following formula. Ρ in the formula means the density (g / cm ³ ) of the hydrophilic polymer.
Porosity ε (%) = {1-W / (ρ × V)} × 100
(7) Maximum pore diameter of the surface of the composite membrane in contact with A of the hydrophilic polymer support (B) In accordance with the bubble point method, fluorocarbon or alcohol having a surface tension γ of 9 to 24 mN / m is used as the wetting liquid. It was measured. For the wetting curve, the applied pressure and the air permeation amount are measured in the pressure increase mode, and the maximum pore diameter D _BP (nm) is obtained from the pressure P _BP (Pa) at which the first bubble is generated in the obtained wetting curve by the following equation. It was.
Maximum pore diameter D _BP (nm) = 10 ⁶ × 2.860 × γ / P _BP
However, measurement was not possible when the maximum pore diameter was 15 nm or less due to restrictions on the measuring apparatus.
(8) Surface porosity of the surface of the composite membrane in contact with A of the hydrophilic polymer support (B) The surface of B on the side to which A was applied was observed with SEM, and a photograph thereof was obtained. When it was difficult to determine whether the hole was on the surface, all the holes observed on the photograph were regarded as holes on the surface. Next, the holes on the surface were analyzed by an image processing apparatus (for example, IP1000-PC manufactured by Asahi Kasei Co., Ltd.) to determine the area of each hole. The surface porosity was determined from the value obtained by combining the areas of the respective holes (S _p ) and the observed area of the film (S _t ) by the following equation.
Surface porosity (%) = (S _p / S _t ) × 100

(9) Content ratio of hydrophobic polymer in composite membrane When a hydrophilic polymer membrane is composited by applying a hydrophobic polymer or the like, the weight of the hydrophilic polymer membrane is measured in advance, and then the hydrophobic polymer After the composite film is produced by applying a functional polymer solution, the weight of the entire composite film is measured again. From this weight change, the content of each polymer was determined by calculation.
In addition, the same method was used to produce a composite membrane by, for example, applying a hydrophilic polymer solution after producing a hydrophobic polymer membrane.
In addition, when multiple layers of each polymer layer are laminated, the weight and content before lamination are ascertained and the weight after lamination is measured. The content rate was determined.
(10) Morphological stability evaluation of the composite membrane in contact with aqueous liquid After immersing the composite membrane in distilled water at 25 ° C. for 24 hours, the state of the membrane is observed, and it is visually checked whether there is any morphological change such as layer peeling. It was evaluated and evaluated.
○: No peeling ×: Peeling (11) Evaluation of fractionation of composite film (low molecular block rate)
A sucrose aqueous solution and a sodium chloride aqueous solution having a concentration of 500 ppm were prepared, a permeation experiment was conducted at a temperature of 25 ° C. and a filtration pressure of 0.15 MPa, and a rejection rate was calculated from the result and the following equation.
Blocking rate (%) = {1− (solute concentration of permeate / solute concentration of feed solution)} × 100

(12) Evaluation of the drug permeation amount of the composite membrane (diaphragm) The composite membrane (previously immersed in distilled water for 24 hours) is sandwiched between two-chamber glass cells (KH-55P manufactured by Beadrex / membrane area: 5 cm ² ) Were filled with an aqueous lidocaine hydrochloride solution (0.4 mol / L) and an electrolytic solution (disodium fumarate: 0.4 mol / L, sodium ascorbate: 0.02 mol / L) and allowed to stand at 25 ° C. After 30 days, the liquid was extracted from the electrolyte side, and the amount of lidocaine hydrochloride permeated to the electrolyte side was measured by liquid chromatography.
The measurement results were evaluated as the lidocaine permeation amount (mol / L) per unit area (1 cm ² ) and unit time (1 hr) of the membrane.
(13) Measurement of electrical resistance of composite membrane (diaphragm) As in (11) above, a glass cell, composite membrane, and each solution were set, and an auxiliary electrode (silver) and a reference electrode (salt chloride) were placed on the lidocaine hydrochloride solution side. Silver) is immersed in the working electrode (silver) on the electrolyte side, and a current of ^2.5 mA is passed through a galvanostat (HAL-3001 manufactured by Hokuto Denko) connected to the electrode (current density: 0.5 mA / cm ² ). At 25 ° C., the potential difference between the electrodes was measured. In addition to this, the potential difference between the electrodes when the composite membrane is not installed is also obtained, and the value when the membrane is not installed is subtracted from the value when the membrane is installed to obtain the electrical resistance of the composite membrane to be measured. .

The solutions and supports used in the following examples and comparative examples were as follows.
[Hydrophobic polymer solution 1]
Cellulose acetate (manufactured by Wako Pure Chemical Industries, Ltd.) was prepared by dissolving in acetone to a concentration of 10 wt%.
[Hydrophobic polymer solution 2]
Wako Pure Chemical Industries ethyl cellulose (ethoxyl group content: about 49 wt%) was prepared by dissolving in a mixed solution of chloroform (90 wt%) / toluene (10 wt%) to a concentration of 5 wt%.
[Hydrophobic polymer solution 3]
A nitrocellulose solution (trade name: Collodion, concentration: 5 wt%) manufactured by Wako Pure Chemical Industries, Ltd. was used.
[Hydrophilic polymer solution 1]
According to a known method, cotton linter is used as a cellulose source and dissolved in a copper ammonia solution to prepare a copper ammonia cellulose solution having a composition (cellulose: 8 wt%, ammonia: 6 wt%, copper: 3 wt%, and most others are water). did.

[Hydrophilic polymer support 1]
The copper ammonia cellulose solution produced by the preparation of the hydrophilic polymer solution 1 was cast on a glass plate with a thickness of 250 μm using a doctor blade. Next, the film-like solution was immersed in a coagulation bath (water: 30 ° C.) for 20 minutes together with a glass plate to coagulate. Next, it was immersed in a sulfuric acid bath (3 wt% / 25 ° C.) for 20 minutes to remove the solvent, and then washed with water.
The membrane after washing with water was immersed in isopropyl alcohol (IPA: 100 wt% / 25 ° C.) for 2 hours to replace the moisture retained by the membrane with IPA. Thereafter, heat drying (150 ° C./10 minutes) was performed to obtain a thin, translucent regenerated cellulose film having a white tint.
This film had a porosity of 42%, the maximum pore diameter of the surface on which A was applied was 200 nm or more, a surface porosity of 68%, and a thickness of 32 μm.

[Hydrophilic polymer support 2]
The hydrophilic polymer support 1 was the same as the hydrophilic polymer support 1 except that the coagulation bath was (caustic soda (11 wt%): 25 ° C.) and the water was not replaced with IPA after washing with water. In the same manner as above, a transparent regenerated cellulose film having a thickness of 15 μm was obtained.
This film had a porosity of 3%, there were no holes observable on both sides with an electron microscope, and the surface porosity could not be calculated.

[Hydrophilic polymer support 3]
A commercially available hydrophilic polyethersulfone membrane (manufactured by Pall Corp., trade name: Supor, nominal pore size: 0.1 μm) was used. This film had a porosity of 60%, the maximum pore diameter of the surface on which A was applied was 200 nm or more, a surface porosity of 48%, and a thickness of 132 μm.

[Hydrophilic polymer support 4]
A thin film obtained by calendering (linear pressure: 4000 kg / cm) of a recycled cellulose non-woven fabric (Asahi Kasei Fibers, product name: SE103) was used. This film had a porosity of 25%, the maximum pore diameter of the surface on which A was applied was 1 μm or more, a surface porosity of 22%, and a thickness of 150 μm.
[Hydrophobic polymer support 1]
A thin film obtained by calendering a polyethylene terephthalate nonwoven fabric (linear pressure: 4000 kg / cm) was used. This film had a porosity of 22%, the maximum pore diameter of the surface on which A was applied was 1 μm or more, a surface porosity of 24%, and a thickness of 140 μm.

[Example 1]
The cellulose acetate solution (10 wt%) obtained in [Hydrophobic polymer solution 1] is applied to one surface of the regenerated cellulose support obtained in [Hydrophilic polymer support 1] using a doctor blade. Then, the set thickness of the doctor blade was set to 50 μm and coating was performed. Then, it was made to dry at 25 degreeC for 24 hours, and the composite film was obtained.
When the cross section of this film was observed with an SEM, the boundary between the cellulose acetate layer and the cellulose layer was not clear, and the cellulose acetate component was present on the surface and inside of the cellulose film.
Further, when the composite membrane was immersed in distilled water at 25 ° C. for 24 hours, there was no change in the form of the membrane, and no separation between the cellulose acetate layer and the cellulose layer was observed.
Thereafter, the amount of lidocaine hydrochloride permeated and the electrical resistance of the membrane were measured. The amount of lidocaine hydrochloride permeated after 30 days was 1.0 × 10 ⁻⁷ mol / L · hr · cm ² and the electrical resistance was 0.5V. .
Other measured values are shown in Table 1 below.

[Example 2]
A composite membrane was obtained in the same manner as in Example 1 except that the ethyl cellulose solution (5 wt%) obtained in [Hydrophobic polymer solution 2] was used as the hydrophobic polymer solution.
When the cross section of this film was observed with an SEM, the boundary between the ethyl cellulose layer and the cellulose layer was not clear, and the ethyl cellulose component was present on the surface and inside of the cellulose film.
When this composite membrane was immersed in distilled water at 25 ° C. for 24 hours, there was no change in the form of the membrane, and no peeling between the ethylcellulose layer and the cellulose layer was observed.
Thereafter, the amount of lidocaine hydrochloride permeated and the electrical resistance of the membrane were measured. The amount of lidocaine hydrochloride permeated after 30 days was 2.0 × 10 ⁻⁷ mol / L · hr · cm ² , and the electrical resistance was 3.1V. .
Other measured values are shown in Table 1 below.

[Example 3]
A composite membrane was obtained in the same manner as in Example 1 except that the cellulose nitrate solution (5 wt%) obtained in [Hydrophobic Polymer Solution 3] was used as the hydrophobic polymer solution.
When the cross section of this film was observed with an SEM, the boundary between the cellulose nitrate layer and the cellulose layer was not clear, and the cellulose nitrate component was present on the surface and inside of the cellulose film.
When this composite membrane was immersed in distilled water at 25 ° C. for 24 hours, there was no change in the form of the membrane, and no peeling between the cellulose nitrate layer and the cellulose layer was observed.
Thereafter, the amount of lidocaine hydrochloride permeated and the electrical resistance of the membrane were measured. As a result, the amount of lidocaine hydrochloride permeated after 30 days was 2.5 × 10 ⁻⁷ mol / L · hr · cm ² , and the electrical resistance was 4.3V. .
Other measured values are shown in Table 1 below.

[Comparative Example 1]
A composite membrane was obtained in the same manner as in Example 1 except that the hydrophilic polymer membrane was changed to a membrane obtained with the hydrophilic polymer support 2.
When the cross section of this film was observed by SEM, it was a two-layer structure in which an ethyl cellulose layer was present in contact with the cellulose layer.
When this composite membrane was immersed in distilled water at 25 ° C. for 1 hour, the membrane became round with the ethyl cellulose layer inside, and the ethyl cellulose layer and the cellulose layer were completely peeled off, and could not exist as a composite membrane.
Other measured values are shown in Table 1 below.

[Example 4]
On both surfaces of the regenerated cellulose membrane obtained with the hydrophilic polymer support 2, the ethylcellulose solution (5 wt%) obtained with the hydrophobic polymer solution 1 is applied to the doctor blade with a set thickness of the doctor blade. The coating was carried out at 50 μm. Then, it was made to dry at 25 degreeC for 24 hours, and the composite film was obtained.
When the cross section of this film was observed by SEM, it was a three-layer structure in which the cellulose layer was sandwiched between the ethyl cellulose layers.
When this composite membrane was immersed in distilled water at 25 ° C. for 24 hours, there was no change in the form of the membrane, and no peeling between the ethylcellulose layer and the cellulose layer was observed.
Other measured values are shown in Table 1 below.

[Example 5]
A doctor blade is used to apply a cellulose acetate solution (10 wt%) obtained in [hydrophobic polymer solution 1] to both surfaces of the regenerated cellulose membrane as the hydrophilic polymer support 2. Coating was performed with the thickness set to 50 μm. Then, it was made to dry at 25 degreeC for 24 hours, and the composite film was obtained.
When the cross section of this film was observed by SEM, it was a three-layer structure in which the cellulose layer was sandwiched between cellulose acetate layers.
When this composite membrane was immersed in distilled water at 25 ° C. for 24 hours, there was no change in the form of the membrane, and no separation of the cellulose acetate layer and the cellulose layer was observed.
Thereafter, the amount of lidocaine hydrochloride permeated through the membrane and the electrical resistance were measured. As a result, the amount of lidocaine hydrochloride permeated after 30 days was not confirmed, and the electrical resistance was 3.5V.
Other measured values are shown in Table 1 below.

[Example 6]
A composite membrane was obtained in the same manner as in Example 1 except that [Hydrophilic polymer support 3] was used as the hydrophilic polymer support.
When the cross section of this membrane was observed by SEM, the boundary between the cellulose acetate layer and the polyethersulfone layer was not clear, and the cellulose acetate component was present on the surface and inside of the polyethersulfone support membrane.
When this composite membrane was immersed in distilled water at 25 ° C. for 24 hours, there was no change in the form of the membrane, and no separation of the cellulose acetate layer and the polyethersulfone layer was observed.
Thereafter, the amount of lidocaine hydrochloride permeated and the electrical resistance of the membrane were measured. The amount of lidocaine hydrochloride permeated after 30 days was 1.5 × 10 ⁻⁷ mol / L · hr · cm ² and the electrical resistance was 2.4V. .
Other measured values are shown in Table 1 below.

[Example 7]
A composite membrane was obtained in the same manner as in Example 1 except that [Hydrophilic polymer support 4] was used as the hydrophilic polymer support.
When the cross section of this membrane was observed by SEM, the boundary between the cellulose acetate layer and the regenerated cellulose layer was not clear, and the cellulose acetate component was present on the surface and inside of the polyethersulfone support membrane.
When this composite membrane was immersed in distilled water at 25 ° C. for 24 hours, there was no change in the form of the membrane, and no separation of the cellulose acetate layer and the regenerated cellulose layer was observed.
Thereafter, the amount of lidocaine hydrochloride permeated and the electrical resistance of the membrane were measured. As a result, the amount of lidocaine hydrochloride permeated after 30 days was not confirmed, and the electrical resistance was 0.7V.
Other measured values are shown in Table 1 below.

[Comparative Example 2]
The membrane of the hydrophilic polymer support 2 was used as it was without applying a hydrophobic polymer.
When this composite membrane was immersed in distilled water at 25 ° C. for 24 hours, the membrane swelled and spread about 100% in the film thickness direction and about 10% in the area direction. When this membrane was used to evaluate the fractionation properties of low molecules, the blocking ability of sucrose was about 15% and there was no fractionation performance of low molecules.
Thereafter, the lidocaine hydrochloride permeation amount and electric resistance of the membrane were measured, and the lidocaine hydrochloride permeation amount after 30 days was 2.5 × 10 ⁻⁶ mol / L · hr · cm ² , and the electric resistance was 0.4V. .
The membrane had a large amount of lidocaine hydrochloride permeated and was unsuitable as a membrane for an iontophoresis device.
Other measured values are shown in Table 1 below.

[Comparative Example 3]
[Hydrophobic polymer solution 1] was applied onto a glass substrate, and the film obtained after drying was peeled off from the glass substrate to obtain a film consisting only of the hydrophobic polymer. When this composite membrane was immersed in distilled water at 25 ° C. for 24 hours, almost no deformation of the membrane was observed.
Thereafter, the lidocaine hydrochloride permeation amount and electric resistance of the membrane were measured, and no lidocaine permeation after 30 days was observed, and the electric resistance was 10 V or more (because the measurement upper limit of the apparatus is 10 V, the accurate value is Unknown.) The membrane had high electrical resistance and was unsuitable as a diaphragm for an iontophoresis device.
Other measured values are shown in Table 1 below.

[Comparative Example 4]
A composite membrane was obtained in the same manner as in Example 1 except that the hydrophobic polymer support 1 was used as the support membrane. When this composite membrane was immersed in distilled water at 25 ° C. for 24 hours, almost no deformation of the membrane was observed.
Thereafter, the amount of lidocaine hydrochloride permeated and the electrical resistance of the membrane were measured. As a result, no lidocaine permeation was observed after 30 days, and the electrical resistance was 10 V or more. The membrane had high electrical resistance and was unsuitable as a diaphragm for an iontophoresis device.
Other measured values are shown in Table 1 below.

  Since the composite membrane of the present invention is excellent in durability and form stability in an aqueous liquid, it is a composite membrane suitable for use in fractionation of low molecular weight substances in an aqueous liquid. Such a composite membrane can be used as a membrane composed of a composite of a hydrophobic polymer and a hydrophilic polymer, which is installed between the electrolyte holding part and the drug holding part in the working electrode structure of the iontophoresis device. For example, when the apparatus is stored for a certain period or longer, ions generated by dissociation of drug molecules and drug molecules, ions generated by dissociation of electrolyte molecules and electrolyte molecules, and the like are diffused from the respective holding units by the diffusion. Transition to the holding unit or the chemical solution holding unit is suppressed or suppressed. As described above, the composite membrane of the present invention has problems such as discoloration of the chemical solution, precipitation of crystals in the chemical solution holding portion, decrease in drug efficacy, generation of harmful substances due to drug alteration, decomposition of the drug, decrease in drug administration efficiency, etc. Therefore, the present invention can be suitably used for an iontophoresis device that does not have any.

110 Working Side Electrode Structure of Patent Literature 3 111 Electrode of Working Side Electrode Structure of Patent Literature 3 112 Chemical Solution Holding Unit of Patent Literature 3 120 Non-Working Side Electrode Structure of Patent Literature 3 121 Non Working Side Electrode of Patent Literature 3 Electrode solution holding part of non-working side electrode structure of Patent Literature 3 130 Power source of Patent Literature 3 210 Working side electrode structure of Patent Literature 4 211 Electrode of working side electrode structure of Patent Literature 212 Patent Electrolytic solution holding part 213 of working side electrode structure of document 4 Second conductive ion exchange membrane of working side electrode structure of patent document 4 214 Chemical solution holding part 215 of working side electrode structure of patent document 4 First-conductivity-type ion-exchange membrane of working side electrode structure 220 Non-working side electrode structure of Patent Document 4 221 Electrode of non-working side electrode structure of Patent Document 4 222 Non-working side electrode structure of Patent Document 4 Structure Electrolyte Holding Unit 230 Power Supply of Patent Document 4

310 Working Electrode Structure of Patent Document 5 311 Electrode of Working Electrode Structure of Patent Document 5 312 Electrolyte Holding Unit of Working Electrode Structure of Patent Document 5 313 First Working Electrode Structure of Patent Document 5 Conductive Ion Exchange Membrane 314 Second Conductive Ion Exchange Membrane of Working Electrode Structure of Patent Document 5 315 Chemical Solution Holding Unit of Working Electrode Structure of Patent Document 5 316 First Working Electrode Structure of Patent Document 5 Conductive Ion Exchange Membrane 320 Non-Working Electrode Structure of Patent Document 5 321 Electrode of Non-Working Electrode Structure of Patent Document 5 322 Electrolyte Holding Unit of Non-Working Electrode Structure of Patent Document 5 323 Patent Document 5 First Conductive Ion Exchange Membrane of Non-Working Side Electrode Structure 324 Electrolytic Solution Holding Part 325 of Non-working Side Electrode Structure of Patent Document 5 330 Second Conducting Type Ion Exchange Membrane of Non-working Side Electrode Structure of Patent Document 5 330 Special Power of literature 5

410 Working electrode structure of apparatus according to the present invention 411 Electrode of working electrode structure of the apparatus according to the present invention 412 Electrolyte holding part of the working electrode structure of the apparatus according to the present invention 413 of the apparatus according to the present invention Separation membrane of working electrode structure 414 Chemical solution holding portion of working electrode structure of device according to the present invention 415 Cation exchange membrane of working electrode structure of device according to the present invention 416 Working electrode structure of device according to the present invention Body cover or container 420 Non-working side electrode structure of the device according to the present invention 421 Electrode of the non-working side electrode structure of the device according to the present invention 422 Electrolyte holding of the non-working side electrode structure of the device according to the present invention Part 423 Cation exchange membrane of non-working side electrode structure of device according to the present invention 424 Electrolyte holding part 425 of non-working side electrode structure of device according to the present invention 425 An anion exchange membrane of the non-working side electrode structure of the device according to the present invention 426 Cover or container of the non-working side electrode structure of the device according to the present invention 430 Power source of the device according to the present invention

Claims (11)

  A composite film obtained by applying a hydrophobic polymer (A) to a support (B) made of a hydrophilic polymer, wherein the hydrophobic polymer (A) is on the surface and / or inside of the support (B). A composite membrane characterized by being present in   The composite film according to claim 1, wherein a multilayer structure of the composite film is any one of A / B type, A / B / A type, and B / A / B type.   The hydrophobic polymer (A) forms a layer on the surface of the composite membrane, and the pore diameter of the pores existing on the surface of the layer is 0.01 μm or less, and the thickness of the layer is 0.01 The composite film according to claim 1, wherein the composite film is 10 μm to 10 μm.   The hydrophobic polymer (A) is present on the surface and inside of the support (B), and the internal permeability of the hydrophobic polymer (A) is 1 to 95 wt%. 2. The composite membrane according to item 1.   The porosity of the support (B) is 10% or more, the maximum pore diameter of the surface in contact with the hydrophobic polymer (A) is 20 nm or more, and the support (B) is highly hydrophobic. The composite membrane according to any one of claims 1 to 4, wherein the surface porosity of the surface in contact with the molecule (A) is 10% or more.   The composite membrane according to any one of claims 1 to 5, wherein the thickness of the composite membrane is 5 µm or more and the content of the hydrophobic polymer (A) is 0.1 to 50 wt%.   The composite membrane according to any one of claims 1 to 6, wherein the hydrophobic polymer (A) is a cellulose derivative.   The composite membrane according to claim 1, wherein the hydrophilic polymer is regenerated cellulose.   The composite membrane according to any one of claims 1 to 8, wherein the composite membrane has a sucrose rejection of 70% or higher and a sodium chloride rejection of 40% or lower.   A working-side electrode structure, a non-working-side electrode structure, and a DC power source connected with different polarities between the working-side electrode of the working-side electrode structure and the non-working-side electrode of the non-working-side electrode structure An iontophoresis device for administering an ionic drug to a living body by the DC power source, wherein the non-working side electrode structure includes the non-working side electrode and a non-working side electrolyte solution holding unit, The working electrode structure has a working electrode, an electrolytic solution holding unit, a chemical solution holding unit for holding the ionic drug, and a diaphragm disposed between the electrolytic solution holding unit and the chemical solution holding unit. The iontophoresis device is characterized in that the diaphragm is the composite membrane according to any one of claims 1 to 9. The amount of lidocaine hydrochloride permeated from a 0.4 mol / L aqueous lidocaine hydrochloride solution at 25 ° C. through the diaphragm is 5.0 × 10 ⁻⁷ mol / L · hr · cm ² or less, and the current density potential difference between both surfaces of the membrane in the membrane resistance measurement measured at 0.5 mA / cm ² is less than 10V, iontophoresis device according to claim 10.

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