HK1112725A - Iontophoresis apparatus - Google Patents

Description

Iontophoresis device

Technical Field

The present invention relates to an iontophoresis device that administers positively charged drug ions to a living body by the action of a positive voltage applied to a working electrode structure that holds the drug ions; and to an iontophoresis device in which the administration efficiency of a drug or drug ions is significantly improved.

Background

The iontophoresis device generally includes: a working electrode structure for holding a chemical solution in which a chemical component is dissociated into positive or negative ions (chemical ions); and a non-working electrode structure having a counter electrode function of the working electrode structure. In a state where these two structures are in contact with the skin of a living body (human or animal), a voltage having the same polarity as that of the drug ions is applied to the working electrode structure, thereby administering the drug ions into the living body.

Here, the charge supplied to the working electrode structure is consumed by the migration of the drug ions to the living body and the release of the biological counter ions (ions present in the living body and charged to the opposite conductivity type to the drug ions) to the working electrode structure side, but the biological counter ions (for example, Na) having a small molecular weight and a high mobility are mainly released from the living body⁺、Cl^-Etc.), there is a problem that the number of transitions (the ratio of the current contributing to the migration of the drug ions among the total current supplied to the working electrode structure) is reduced, and a sufficient amount of the drug cannot be administered.

Patent documents 1 to 10 disclose iontophoresis devices that solve such problems.

That is, in the iontophoresis devices of patent documents 1 to 10, the working electrode structure is configured as follows: an electrode; a drug holding portion disposed on a front surface side (a side in contact with the skin) of the electrode; and an ion exchange membrane which is disposed on the front surface side of the drug holding portion and selectively passes ions having the same polarity as the drug ions held in the drug holding portion. The drug ions are administered through the ion exchange membrane, thereby inhibiting the release of biological counter ions to increase the migration number and improve the drug administration efficiency.

Further, in the iontophoresis devices described in patent documents 1 to 10, the working electrode structure further includes: an electrolyte holding unit that holds an electrolyte held in contact with the electrode; and an ion exchange membrane disposed on the front surface side of the electrolyte retaining part and selectively passing ions of a conductivity type opposite to the chemical ions, wherein the chemical retaining part is disposed on the front surface side of the ion exchange membrane, thereby achieving additional effects such as isolating the electrode from the chemical ions, preventing decomposition of the chemical ions, and preventing H generated in the electrode⁺、OH^-And the movement of ions to the drug-retaining part and even to the interface of the living body skin.

Patent document 11 discloses an invention in which the iontophoresis devices disclosed in patent documents 1 to 10 are further improved, and the following are described: by using, as an ion exchange membrane, an ion exchange membrane in which an ion exchange resin (resin imparting an ion exchange function) is filled in a porous membrane formed of a raw material such as polyolefin, a vinyl chloride resin, or a fluorine resin, the dose of a drug can be significantly increased.

Patent document 1: japanese patent No. 3030517

Patent document 2: japanese patent laid-open No. 2000-229128

Patent document 3: japanese patent laid-open No. 2000-229129

Patent document 4: japanese patent laid-open No. 2000-237326

Patent document 5: japanese patent laid-open No. 2000-237327

Patent document 6: japanese patent laid-open No. 2000-237328

Patent document 7: japanese patent laid-open No. 2000-237329

Patent document 8: japanese patent laid-open publication No. 2000-288097

Patent document 9: japanese patent laid-open No. 2000-288098

Patent document 10: international publication No. 03/037425 pamphlet

Patent document 11: japanese laid-open patent publication No. 2004-188188

Disclosure of Invention

Problems to be solved by the invention

As described above, the iontophoresis device disclosed in patent document 11 is considered to be an iontophoresis device in which the administration efficiency of a drug is most excellent in a conventional known device, and the present invention provides an iontophoresis device in which the administration efficiency of a drug is significantly improved as compared with the iontophoresis device disclosed in patent document 11.

Means for solving the problems

The present invention is an iontophoresis device for administering positively charged drug ions through a cellulose-based resin film, comprising a working electrode structure having: an electrode to which a positive voltage is applied; a drug holding portion configured to hold a drug solution containing drug ions and disposed on a front surface side of the electrode; and a cellulose resin film disposed on the front surface side of the drug holding portion.

That is, the present invention is an iontophoresis device for administering a drug in which a drug component is dissociated into positive ions in a solution, and is characterized in that a cellulose-based resin film is used instead of the ion exchange membrane disposed on the front surface side of the drug holding portion in patent documents 1 to 11.

Cellulose-based resin films are known to have a function as cation exchange membranes, but since they have inferior characteristics such as ion exchange capacity compared to commonly used cation exchange membranes (for example, cation exchange membranes exemplified in patent documents 1 to 11), application of cellulose-based resin films to iontophoresis devices has not been studied.

Now, in the studies of the present inventors, the evaluation in vitro (in vitro) which has been conventionally carried out at the initial stage of development has not confirmed the characteristics superior to those of other ion exchange membranes, but as a result of the evaluation in vivo (in vivo) using a living body, it has been found that the iontophoresis device of the present invention has a very high drug administration efficiency (the amount of a drug administered per unit time under the same current condition from a membrane surface of the same surface area) as compared with the iontophoresis device using a cation exchange resin disclosed in patent document 11.

Examples of the drug in which the active ingredient is dissociated into cations in the present invention include morphine hydrochloride and lidocaine hydrochloride as anesthetics, carnitine chloride as a therapeutic agent for gastrointestinal diseases, and pancuronium bromide as a skeletal muscle relaxant.

The drug holding portion in the present invention may be configured as a container for holding the above-described drug in a liquid state, but may be configured to hold a substance obtained by gelling or thickening a solution of the drug with an appropriate gelling agent or the like, or may be configured to impregnate a polymer carrier or the like with a solution of the drug.

The cellulose-based resin film of the present invention is a film body composed of a cellulose-based resin such as regenerated cellulose, cellulose ester, cellulose ether, nitrocellulose or the like, and a film body composed of a cellulose-based resin mixed with and blended with other components (a resin, a plasticizer, a crosslinking agent or the like) may be used as the cellulose-based resin film of the present invention, as long as the cellulose-based resin is a cellulose-based resin as a main component and the drug administration characteristics (administration efficiency, safety and the like) to such an extent that the resin cannot be used as an iontophoresis device are not significantly impaired.

The cellulose-based resin film of the present invention is preferably a porous film having an appropriate pore size according to the molecular weight of the drug ion to be administered. The average pore diameter is typically 1 Å to several μm, more preferably 1 to 1000 Å, and particularly preferably 1 to 100 Å.

Further, since the iontophoresis device of the present invention is used in a state in which the working electrode structure is attached to the living body skin, it is desirable that the cellulose-based resin film used here has flexibility capable of following the expansion and contraction and bending of the living body skin and strength to such an extent that the cellulose-based resin film is not damaged by stress generated by such expansion and bending, but the strength is increased but the flexibility is lost when the thickness of the cellulose-based resin film is increased in general, and therefore, it is preferable to select an appropriate film thickness in accordance with the type of the cellulose-based resin film while satisfying both of the above-described characteristics.

In addition, the cellulose-based resin film of the present invention can further increase the transference number of drug ions at the time of drug administration and can further improve the drug administration efficiency by introducing a cation exchange group such as a sulfonic acid group, a carboxylic acid group, or a phosphoric acid group by reacting chlorosulfonic acid, chloroacetic acid, an inorganic cyclic triphosphate, or the like.

Alternatively, a cellulose-based resin film filled with an ion exchange resin having a cation exchange group introduced therein may be used as the cellulose-based resin film of the present invention. This also increases the number of migration of drug ions at the time of drug administration, and further improves the efficiency of drug administration.

Such a cellulose-based resin film can be obtained by: the porous film is obtained by impregnating a porous film body made of a cellulose resin with a monomer composition comprising a hydrocarbon monomer having a functional group capable of introducing a cation exchange group, a crosslinkable monomer and a polymerization initiator, and allowing chlorosulfonic acid, chloroacetic acid, an inorganic cyclic triphosphate or the like to act thereon.

Further, as the cation exchange group introduced into the cellulose-based resin membrane or the ion exchange resin, a sulfonic acid group, which is a strongly acidic group, is most preferable.

The cation exchange groups may be present as free acids, or may be present as salts with alkali metal ions such as sodium ions and potassium ions, ammonium ions, and the like.

The present invention may also be an iontophoresis device including a working electrode structure, the working electrode structure including: an electrode to which a positive voltage is applied; a drug holding unit configured to hold a drug solution containing positively charged drug ions and arranged on the front surface side of the electrode; and a composite membrane comprising a cation-exchange membrane and a cellulose-based resin membrane disposed on the front surface side of the cation-exchange membrane, the composite membrane being disposed on the front surface side of the drug-retaining portion, wherein the iontophoresis device administers the drug ions through the cellulose-based resin membrane. This increases the number of migration during drug administration, and thus provides higher drug administration efficiency.

The cellulose resin film of the present invention can be used in the same manner as described above.

In addition, the cation exchange membrane is preferably a porous membrane made of a material such as polyolefin, vinyl chloride resin, or fluorine resin, and filled with an ion exchange resin having cation exchange groups introduced therein, whereby the migration number at the time of drug administration can be further improved.

In addition, in order to prevent the air layer from being interposed between the interface between the cation exchange membrane and the cellulose-based resin membrane, the composite membrane is preferably integrated by bonding the interface between the two.

Examples of the joining method include thermal fusion bonding, ultrasonic bonding, bonding with a binder such as cyanoacrylate, and a crosslinking reaction with a crosslinking agent such as divinylbenzene, or joining of a cation exchange membrane and a cellulose-based resin membrane by forming a cellulose-based resin membrane on the cation exchange membrane, for example, regenerating cellulose by reacting sulfuric acid with a copper ammonium cellulose solution applied to the cation exchange membrane.

Here, in the case of bonding by a method such as adhesion, a crosslinking reaction, or film formation of a cellulose resin film on a cation exchange membrane, it is preferable to perform bonding treatment in a state where at least the surface of the cellulose resin film side of the cation exchange membrane is roughened by a method such as embossing, grooving, notching, mechanical polishing, chemical polishing, or the like, whereby the adhesion and the integrity between the cation exchange membrane and the cellulose resin film can be improved.

Further, roughening of the cation exchange membrane can be performed by: an inorganic filler such as calcium carbonate or magnesium carbonate is added to a resin film constituting a cation-exchange membrane; modified polyethylene particles, modified polyacrylic resin particles and other organic fillers.

Drawings

Fig. 1 is an explanatory diagram showing a configuration of an iontophoresis device according to an embodiment of the present invention.

Fig. 2 is an explanatory diagram showing the structure of an iontophoresis device according to another embodiment of the present invention.

Fig. 3 is an explanatory view showing the time lapse (a) of the blood morphine concentration when morphine hydrochloride is administered to a mouse using the iontophoresis device of the present invention, and the pH values (b) of the drug solution and the electrolyte before and after drug administration.

Fig. 4 is an explanatory view showing the time course of the blood morphine concentration when morphine hydrochloride is administered to a mouse using a conventional iontophoresis device.

Fig. 5 is an explanatory diagram showing the configuration of a test apparatus for evaluating the in vitro morphine migration characteristics.

FIG. 6 is an explanatory view showing the evaluation results of the morphine migration characteristics in a test apparatus equivalent to the iontophoresis apparatus of the present invention.

Fig. 7 is an explanatory view showing the evaluation results of the morphine migration characteristics in a test apparatus equivalent to a conventional iontophoresis apparatus.

Detailed Description

Hereinafter, embodiments of the present invention will be described with reference to the drawings.

As shown in the drawing, the iontophoresis device X1 of the present invention includes, as large constituent elements (components), a working electrode structure 1, a non-working electrode structure 2, and a power source 3. In addition, reference numeral 4 denotes skin (or mucous membrane).

The working electrode structure 1 has: an electrode part 11 connected to a positive electrode of the power supply 3; an electrolyte holding unit 12 for holding an electrolyte held in contact with the electrode member 11; an anion exchange membrane 13 disposed in front of the electrolyte retaining portion 12; a drug holding portion 14 disposed on the front surface of the anion exchange membrane 13; and a cellulose resin film 15 disposed on the front surface of the medicine holding portion 14. The entirety of which is housed in a cover or container 16 made of a resin film, plastic, or the like.

On the other hand, the non-working electrode structure 2 has: an electrode part 21 connected to a negative electrode of the power supply 3; an electrolyte holding unit 22 for holding an electrolyte held in contact with the electrode member 21; a cation exchange membrane 23 disposed in front of the electrolyte retaining part 22; an electrolyte retaining part 24 disposed on the front surface of the cation-exchange membrane 23; and an anion exchange membrane 25 disposed in front of the electrolyte retaining portion 24. The entirety of which is housed in a cover or container 26 made of a resin film, plastic, or the like.

In this iontophoresis device X1, the electrode members 11 and 21 may be made of any conductive material without any particular limitation, and particularly, inert electrodes made of carbon, platinum, or the like may be preferably used, and particularly, carbon electrodes that do not cause elution of metal ions and migration thereof into the living body may be preferably used.

However, an active electrode such as a silver/silver chloride pair electrode (coupleelectrode) in which the electrode member 11 is made of silver and the electrode member 21 is made of silver chloride, or the like may be used.

For example, when a silver/silver chloride counter electrode is used, the electrode member 11 as the positive electrode contains a silver electrode and chlorine ions (Cl)^-) Readily react through Ag⁺Cl^-→AgCl+e^-Insoluble AgCl is generated, and chlorine ions (Cl) are generated in the electrode member 21 as the negative electrode^-) The reaction eluted from the silver chloride electrode results in suppression of the electrolytic reaction of water and prevention of H in the positive electrode⁺Sharp acidification by ions and OH at the negative electrode^-Sharp basification by ions.

On the other hand, in the working electrode structure 1 and the non-working electrode structure 2 of the iontophoresis device X1 of fig. 1, due to the action of the anion-exchange membrane 13 and the cation-exchange membrane 23, H in the electrolyte solution holding portion 12 is present⁺Rapid acidification by ions and OH in the electrolyte retaining part 22^-Since rapid alkalization by ions is suppressed, instead of an active electrode such as a silver/silver chloride counter electrode, a carbon electrode which is inexpensive and does not require a fear of elution of metal ions can be suitably used.

The electrolyte holders 12, 22, and 24 in the iontophoresis device X1 in fig. 1 hold an electrolyte for ensuring conductivity, and typically phosphoric acid-buffered saline, physiological saline, or the like is used as the electrolyte.

In addition, in order to more effectively prevent gas generation due to the electrolytic reaction of water and an increase in electrical resistance or a change in pH due to the electrolytic reaction of water, an electrolyte that is more easily oxidized or reduced than the electrolytic reaction of water (oxidation at the positive electrode and reduction at the negative electrode) may be added to the electrolyte solution holders 12 and 22, and from the viewpoint of biosafety and economy (low cost and easy availability), inorganic compounds such as ferrous sulfate and ferric sulfate may be preferably used; ascorbic acid (vitamin C), sodium ascorbate, and the like; and organic acids such as lactic acid, oxalic acid, malic acid, succinic acid, and fumaric acid, and/or salts thereof, or a combination thereof may be used, for example, a 1: 1 mixed aqueous solution of 1 mole (M) of lactic acid and 1 mole (M) of sodium fumarate.

The electrolyte holders 12, 22, and 24 may hold the above-mentioned electrolyte in a liquid state, but by immersing the above-mentioned electrolyte in a water-absorbing film carrier made of a polymer material or the like, the handling property and the like can be improved. The same film carrier as that used in the drug solution holding portion 14 can be used as the film carrier used here, and therefore, the detailed description thereof will be given together with the following description of the drug solution holding portion 14.

In the chemical solution holding portion 14 of the iontophoresis device X1 according to the present embodiment, at least an aqueous solution of a chemical that causes a chemical component to dissociate into positive chemical ions by dissolution is held as a chemical solution.

Here, the drug holding portion 14 may hold the drug solution in a liquid state, or may hold the drug solution by immersing it in a water-absorbing film carrier as described below, thereby improving its handling property and the like.

As a material that can be used as the water-absorbing film carrier in this case, for example, a hydrogel of an acrylic resin (an acrylate hydrogel film), a block polyurethane gel film, an ion-conductive porous sheet for forming a gel-like solid electrolyte, or the like can be used, and by immersing the aqueous solution at an impregnation rate of 20 to 60%, for example, a high transport number (high drug delivery property) of 70 to 80% can be obtained.

The impregnation rate in the present specification is defined as% by weight, and is 100 × (W-D)/D [% ] where D represents the weight during drying and W represents the weight after impregnation. In addition, the measurement of the impregnation rate should be performed immediately after the impregnation of the aqueous solution, and the influence over time should be excluded.

In addition, the transport number is a proportion of the current contributing to the movement of specific ions among the total current flowing through the electrolyte. The transport number used in the present specification refers to the transport number of the drug ions, that is, a ratio of the current contributing to the movement of the drug ions among the total current for supplying power to the working electrode structure.

Here, the above-mentioned acrylate hydrogel film (available from Sun contacts co., ltd., for example) is a gel having a three-dimensional network structure (cross-linked structure), and an electrolyte solution as a dispersion medium is added to the acrylate hydrogel film to obtain a polymer adsorbent having ion conductivity. The relationship between the impregnation rate and the migration number of the acrylate hydrogel film can be adjusted by the size of the three-dimensional network structure and the type and ratio of the monomers constituting the resin, and the acrylate hydrogel film having the impregnation rate of 30 to 40% and the migration number of 70 to 80% can be prepared by 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate (monomer ratio of 98 to 99.5: 0.5 to 2), and it was confirmed that the impregnation rate and the migration number are almost the same in the range of the normal thickness of 0.1 to 1 mm.

The block polyurethane gel film has polyethylene glycol (PEG) and polypropylene glycol (PPG) as segments, and can be prepared from a monomer constituting these and diisocyanate. The block polyurethane gel film has a three-dimensional structure crosslinked by urethane bonds, and the impregnation rate, the migration number, and the strength of the adhesive force of the substance can be easily adjusted by controlling the mesh size of the net and the kind and ratio of the monomer, as in the case of the acrylate hydrogel film. The block polyurethane gel film (porous gel film) is added with water and an electrolyte (alkali metal salt or the like) as a dispersion medium, and oxygen of an ether bond portion of polyether forming a segment forms a complex with the alkali metal salt, and when electricity is applied, ions of the metal salt move to oxygen of a next blank ether bond portion, thereby exhibiting conductivity.

An example of an ion-conductive porous sheet for forming a gel-like solid electrolyte is disclosed in Japanese patent application laid-open No. Sho 11-273452, wherein the porous sheet is based on an acrylonitrile copolymer and is based on a porous polymer having a porosity of 20 to 80%. More specifically, the acrylonitrile copolymer has a content of acrylonitrile of 50% or more (preferably 70 to 98 mol%) and a porosity of 20 to 80%. The acrylonitrile gel-like solid electrolyte sheet (solid-state battery) is soluble in a nonaqueous solvent, and is prepared by impregnating an acrylonitrile copolymer sheet having a porosity of 20 to 80% with a nonaqueous solvent containing an electrolyte and gelling the sheet, and the gel includes a gel-like to hard film-like substance.

The acrylonitrile copolymer sheet soluble in a nonaqueous solvent is preferably composed of an acrylonitrile/C1 to C4 alkyl (meth) acrylate copolymer, an acrylonitrile/vinyl acetate copolymer, an acrylonitrile/styrene copolymer, an acrylonitrile/vinylidene chloride copolymer, or the like, from the viewpoints of ionic conductivity, safety, and the like. In order to form the copolymer sheet into a porous sheet, a conventional method such as a wet (dry) papermaking method, a needle punching method (needle punching method) which is one of nonwoven fabric production methods, a water jet method (water jet method), stretching and porosification of a melt-extruded sheet, porosification by solvent extraction, or the like can be used. In the ion-conductive porous sheet of an acrylonitrile copolymer used in the solid-state battery of the present invention, a gel (gel to hard film) that retains the aqueous solution in a three-dimensional network of polymer chains and realizes the impregnation rate and the migration number is useful as a film carrier used in the drug solution retaining part 14 or the electrolyte solution retaining parts 12, 22, and 24 of the present invention.

In the present invention, the conditions for impregnating the above-described membrane carrier with the chemical solution or the electrolytic solution may be selected as the most suitable conditions from the viewpoints of the impregnation amount, the impregnation rate, and the like. For example, the dipping conditions may be selected to be 40 ℃ for 30 minutes.

In addition, the anion exchange membranes (ion exchange membranes having a characteristic of selectively passing negative ions) 13 and 25 in the iontophoresis device X1 of the present embodiment may be ion exchange membranes in which an ion exchange resin having an anion exchange function is supported on a base material, and for example, NEOSEPTA (NEO SEPTA, AM-1, AM-3, AMX, AHA, ACH, ACS, ALE04-2, AIP-21) manufactured by Tokuyama Corporation, or the like; as the cation exchange membrane (ion exchange membrane having a characteristic of selectively passing positive ions) 23, an ion exchange membrane having a substrate on which an ion exchange resin having a cation exchange function is supported can be used, and for example, NEOSEPTA (NEOSEPTA, CM-1, CM-2, CMX, CMS, CMB, CLE04-2) manufactured by Tokuyama Corporation and the like can be used, and particularly, a cation exchange membrane in which an ion exchange resin having a cation exchange function is filled in a part or all of the pore part of a porous membrane or an anion exchange membrane in which an ion exchange resin having an anion exchange function is filled is preferably used.

Here, as the ion exchange resin, a fluorine-based ion exchange resin having an ion exchange group introduced into a perfluorocarbon skeleton or a hydrocarbon-based ion exchange resin having a nonfluorinated resin as a skeleton can be used, but from the viewpoint of simplicity of the production process, a hydrocarbon-based ion exchange resin is preferable, and the filling rate of the ion exchange resin is generally 5 to 95 mass%, particularly preferably 10 to 90 mass%, and further preferably 20 to 60 mass%, although it has a relationship with the porosity of the porous membrane.

The ion exchange group of the ion exchange resin is not particularly limited as long as it is a functional group that generates a group having a negative or positive charge in an aqueous solution. Specific examples of the functional group capable of serving as such an ion exchange group include a sulfonic acid group, a carboxylic acid group, and a phosphoric acid group. In addition, these acid groups may be present as free acids or in the form of salts. Examples of the counter cation in the case of the salt include alkali metal cations such as sodium ion and potassium ion, and ammonium ion. Among these cation exchange groups, a sulfonic acid group, which is a strongly acidic group, is particularly preferable in general. Examples of the anion exchange group include a primary amino group, a secondary amino group, a tertiary amino group, a quaternary ammonium group, a pyridyl group, an imidazolyl group, a quaternary pyridinium salt (quaternary pyridinium salt) group, a quaternary imidazolium salt (quaternary imidazolium) group, and the like. Examples of the counter anion of the anion exchange group include a halogen ion such as a chloride ion, a hydroxyl ion, and the like. Among these anion exchange groups, quaternary ammonium groups and quaternary pyridinium groups are generally suitably used as strongly basic groups.

The porous film may be a film or a sheet-like porous film having a plurality of communicating pores on the front and back sides without any particular limitation, and a porous film formed of a thermoplastic resin is preferable in order to achieve both high strength and flexibility.

As the thermoplastic resin constituting the porous film, polyolefin resins such as homopolymers or copolymers of α -olefins such as ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 3-methyl-1-butene, 4-methyl-1-pentene, 5-methyl-1-heptene and the like; vinyl chloride resins such as polyvinyl chloride, vinyl chloride-vinyl acetate copolymers, vinyl chloride-vinylidene chloride copolymers, vinyl chloride-olefin copolymers, etc.; fluorine-based resins such as polytetrafluoroethylene, polychlorotrifluoroethylene, polyvinylidene fluoride, tetrafluoroethylene-hexafluoropropylene copolymer, tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer, tetrafluoroethylene-ethylene copolymer and the like; polyamide resins such as nylon 6, nylon 66, and the like; polyimide resins, and the like. However, polyolefin resins are preferably used because they are excellent in mechanical strength, flexibility, chemical stability, chemical resistance, and compatibility with ion exchange resins. As the polyolefin resin, polyethylene and polypropylene are particularly preferable, and polyethylene is most preferable.

The porous membrane made of the thermoplastic resin is not particularly limited in its properties, but the average pore diameter of the pores is preferably 0.005 to 5.0 μm, more preferably 0.01 to 2.0 μm, and most preferably 0.02 to 0.2 μm, from the viewpoint of being easily made thin and excellent in strength, and also low in electric resistance. The average pore diameter in the present specification means an average flow pore diameter measured by a bubble point method (JIS K3832-1990). Similarly, the porosity of the porous membrane is preferably 20 to 95%, more preferably 30 to 90%, and most preferably 30 to 60%. The thickness of the porous film is preferably 5 to 140 μm, more preferably 10 to 120 μm, and most preferably 15 to 55 μm. In general, an anion exchange membrane or a cation exchange membrane using such a porous membrane has a thickness of about +0 to 20 μm.

As the cellulose-based resin film 15 of the iontophoresis device X1 of the present embodiment, a porous film made of regenerated cellulose produced by a cuprammonium method, a method using a tertiary amine oxide, or the like, cellulose esters such as cellulose acetate, cellulose acetate propionate, and cellulose acetate butyrate; cellulose ethers such as hydroxyethyl cellulose and hydroxypropyl cellulose; or a cellulose resin such as nitrocellulose, and has an average pore diameter of about 1 Å to several μm, more preferably 1 to 1000 Å, and particularly preferably 1 to 100 Å, and a film thickness of 10 to 200 μm, particularly preferably 20 to 50 μm.

Further, the cellulose-based resin film described above can be used as the cellulose-based resin film 15 by introducing a cation exchange group such as a sulfonic acid group, a carboxylic acid group, or a phosphoric acid group by reacting chlorosulfonic acid, chloroacetic acid, an inorganic cyclic triphosphate, or the like, and by using a cellulose-based resin film into which such a cation exchange group has been introduced, the drug administration efficiency can be further improved.

Alternatively, a film obtained by filling a cation exchange resin into the pores of a porous film made of a cellulose resin as described above may be used for the cellulose resin film 15.

Such a cellulose-based resin membrane filled with a cation exchange resin can be obtained by: a monomer composition comprising a hydrocarbon monomer having a functional group capable of introducing a cation exchange group, a crosslinkable monomer and a polymerization initiator is impregnated in a porous film made of a cellulose resin as described above, and the porous film is polymerized under appropriate reaction conditions to react with chlorosulfonic acid, chloroacetic acid, an inorganic cyclic triphosphate and the like.

Further, as the above-mentioned hydrocarbon-based monomer having a functional group into which a cation exchange group can be introduced, aromatic vinyl compounds such as styrene, α -methylstyrene, 3-methylstyrene, 4-methylstyrene, 2, 4-dimethylstyrene, p-tert-butylstyrene, α -halostyrene, vinylnaphthalene and the like can be mentioned, and 1 or 2 or more of these can be used; as the crosslinkable monomer, polyfunctional vinyl compounds such as divinylbenzene, divinylsulfone, butadiene, chloroprene, divinylbiphenyl, trivinylbenzene, polyfunctional methacrylic acid derivatives such as trimethylolmethane trimethacrylate, methylenebisacrylamide, and hexamethylenedimethylacrylamide; as the polymerization initiator, octanoyl peroxide, lauroyl peroxide, t-butyl peroxy-2-ethylhexanoate, benzoyl peroxide, t-butyl peroxyisobutyrate, t-butyl peroxylaurate, t-butyl peroxybenzoate, di-t-butyl peroxide, and the like can be used.

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

As the power source 3 in the iontophoresis device of the present invention, a battery, a constant voltage device, a constant current device (galvano device), a constant voltage/constant current device, and the like can be used, and the following constant current devices are preferably used: the current can be arbitrarily adjusted within the range of 0.01 to 1.0mA, preferably 0.01 to 0.5mA, and the device can operate under safe voltage conditions, specifically, 50V or less, preferably 30V or less.

As described in the examples described later, the iontophoresis device X1 of the present embodiment has an extremely high drug administration efficiency as compared with a conventional iontophoresis device using a cation exchange membrane instead of the cellulose-based resin membrane 15.

Fig. 2 is an explanatory diagram showing a configuration of an iontophoresis device X2 according to another embodiment of the present invention.

As shown in the drawing, the iontophoresis device X2 has the same configuration as the iontophoresis device X1 except that the iontophoresis device X1 includes a composite membrane 17 instead of the cellulose-based resin membrane 15, and the composite membrane 17 is composed of a cation exchange membrane 17a disposed on the front surface side of the drug holding portion 14 and a cellulose-based resin membrane 17b disposed on the front surface side of the cation exchange membrane 17 a.

As the cation exchange membrane 17a used in the composite membrane 17, the same cation exchange membrane as described above with respect to the cation exchange membrane 23 can be used, and as the cellulose-based resin 17b, the same cellulose-based resin membrane as described above with respect to the cellulose-based resin 15 can be used.

In order to prevent the air layer from being interposed between the cation exchange membrane 17a and the cellulose-based resin membrane 17b, the composite membrane 17 is preferably bonded at the interface between the two by a method such as thermal fusion bonding, ultrasonic bonding, bonding with an adhesive, chemical bonding with a crosslinking agent, or film formation of the cellulose-based resin membrane 17b on the cation exchange membrane 17 a. In the case of bonding by adhesion, chemical bonding, or the like, it is preferable to use a cellulose-based resin film 17b having at least a bonding-side surface roughened by a method comprising: embossing, grooving, notching, mechanical polishing, chemical polishing, or the like, or by blending an inorganic filler such as calcium carbonate or magnesium carbonate, or an organic filler such as modified polyethylene particles or modified polyacrylic resin particles with a cellulose resin.

The conditions of thermal fusion bonding and ultrasonic bonding, the type of adhesive, bonding conditions, the type of crosslinking agent, crosslinking conditions, and the like may be appropriately determined depending on the type of the cation exchange membrane 17a (mainly the type of the porous resin membrane used for the cation exchange membrane 17 a) and the type of the cellulose-based resin membrane 17b, and since bonding is performed in order to prevent the air layer from being interposed between the interface between the cation exchange membrane 17a and the cellulose-based resin membrane 17b and thereby preventing the drug administration efficiency from being lowered, bonding is sufficient with such a strength that interfacial peeling is not caused by the expansion and contraction or bending of the skin when the iontophoresis device is mounted.

In the iontophoresis device X2 of the present embodiment, since the ion exchange capacity of the composite membrane 17 is improved by the cation exchange membrane 17a, the number of drug administrations can be increased, and the drug administration efficiency can be equal to or higher than that of the iontophoresis device X1.

Example 1 (in vivo test 1)

The administration test of morphine hydrochloride by the iontophoresis device X1 was carried out using 20 to 24-week-old C57BL/6 mice (females) as test animals.

In the iontophoresis device X1, neosepa ALE04-2 manufactured by Tokuyama Corporation was used as the anion exchange membranes 13 and 25, neosepa CLE04-2 manufactured by Tokuyama Corporation was used as the cation exchange membrane 23, a dialysis membrane UC8-32-25 (average pore diameter: 50 Å, permeation Molecular Weight (MWCO): about 14000, film thickness: 50 μm) made of a-cellulose 99% regenerated cellulose available from viskease Companies, Inc., of 50, was used as the cellulose-based resin membrane 15, morphine hydrochloride of 50mg/mL was used as the drug solution of the drug holding portion 14, and a 7: 1 mixed solution of 0.7mol/L sodium fumarate aqueous solution and 0.7mol/L lactic acid aqueous solution was used as the electrolyte solutions of the electrolyte holding portions 12, 22, and 24. The effective area of the working electrode structure 1 (the area of the film surface of the cellulose-based resin film 15 to which the chemical is applied, see symbol S in FIG. 1) was 2.23cm²。

In addition, the administration of the agent is carried out as follows: the working electrode structure 1 and the non-working electrode structure 2 were brought into contact with different parts of the shaved abdomen of the mouse, and the applied current was 0.45mA/cm²Was continuously energized for 120 minutes under a constant current condition.

The transition of the blood morphine concentration of the mouse under the current under the above conditions is shown in fig. 3(a), and the pH values of the electrolytes in the electrolyte retaining parts 12, 22, 24 and the drug solution in the drug retaining part 14 before and after the start and end of the energization are shown in fig. 3 (b).

Comparative example 1 (in vivo test 2)

An iontophoresis device having the same structure as the iontophoresis device X1 of example 1 was used in place of the cellulose-based resin film 15, except that a cation-exchange membrane (neosepa CLE04-2 manufactured by Tokuyama Corporation) was used, and morphine hydrochloride was administered to mice under the same conditions as in example 1.

The NEO SEPTA ALE04-2 as an anion exchange membrane and CLE04-2 as a cation exchange membrane are ion exchange membranes having a structure in which an ion exchange resin is filled in the pores of a porous membrane, and the iontophoresis device used in comparative example 1 has the same structure as the iontophoresis device of patent document 11, which has been known in the art and can achieve the highest drug administration efficiency.

Fig. 4 shows the transition of the blood morphine concentration of the mouse in the comparative example 1 during the energization.

Reference example 1 (in vitro test 1)

A test apparatus having a structure equivalent to that of the iontophoresis apparatus X1 used in example 1 was prepared and set at 0.45mA/cm²Was continuously energized for 120 minutes under a constant current condition.

Fig. 5 is an explanatory view showing the structure of the test apparatus, in which 11 and 21 are electrode plates, 13 and 25 are anion-exchange membranes (neosepa ALE04-2 manufactured by Tokuyama Corporation), 23 is a cation-exchange membrane (neosepa CLE04-2 manufactured by Tokuyama Corporation), 15 is a cellulose-based resin membrane (dialysis membrane UC8-32-25 manufactured by viskease Companies, inc.), and 4 is skin collected from a mouse. In addition, a 7: 1 mixed solution of 0.7mol/L sodium fumarate aqueous solution and 0.7mol/L lactic acid aqueous solution was used as an electrolyte solution in the A, D and E compartments defined by the membranes 13, 15, 4, 25 and 23, morphine hydrochloride of 50mg/mL was used as a drug solution in the B compartment, and physiological saline was used in the C compartment.

Fig. 6 shows the transition of morphine concentration in the C chamber during energization in reference example 1.

Comparative reference example 1 (in vitro test 2)

The same test apparatus as in reference example 1 was used at 0.45mA/cm except that a test apparatus having a structure equivalent to that of the iontophoresis apparatus used in comparative example 1, that is, a cation exchange membrane (NEOSEPTA CLE04-2 manufactured by Tokuyama Corporation) was used in place of the cellulose-based resin film 15 in FIG. 5²Was continuously energized for 120 minutes under a constant current condition.

Fig. 7 shows the transition of morphine concentration in the C chamber during energization in comparative reference example 1.

As is clear from a comparison between fig. 3(a) and fig. 4, the iontophoresis device of the present invention can administer morphine with an efficiency 5 to 10 times or more higher than that of the iontophoresis device having the structure of comparative example 1, which has the highest drug administration efficiency at present.

As shown in fig. 3(b), the electrolytes in the electrolyte retaining portions 12, 22, and 24 and the drug solution in the drug retaining portion 14 of the iontophoresis device of the present invention hardly change in pH before and after the entire energization, and thus the safety and stability of drug administration are ensured.

As shown in fig. 6 and 7, the morphine migration speed in the test device of the present invention (reference example 1) was about ten percent different from that in the test device of the conventional structure (comparative reference example 1) in the in vitro test.

In the technical field to which the present invention pertains, it is common practice to perform in vitro evaluation and study without using a living body in the stage of selecting the material of the device component, and as described above, the fact that the effect obtained by using the cellulose-based resin film is confirmed after in vivo evaluation but is not confirmed in vitro evaluation proves difficult to constitute the present invention.

The present invention has been described above based on the embodiments, but the present invention is not limited to these embodiments, and various changes can be made within the scope described in the claims.

For example, in the above-described embodiment, the case where the working electrode structure includes the electrode member 11, the drug holding portion 14, the cellulose-based resin film 15 (or the composite film 17), the electrolyte holding portion 12, and the anion exchange membrane 13 has been described, but the electrolyte holding portion 12 and the ion exchange membrane 13 may be omitted. At this time, the function of suppressing decomposition of the chemical in the vicinity of the electrode member 11, H⁺The function of inhibiting the migration of ions to the skin interface and the pH fluctuation at the skin interface caused by the migration of ions is inferior to that of the above embodiment, but the basic operational effect of the present invention, that is, the efficiency of administration of medicinal ions to living bodies can be similarly achieved, and such an iontophoresis device is also included in the scope of the present invention.

Similarly, in the non-working electrode structure, the cation exchange membrane 23 and the electrolyte solution holding portion 24 may be omitted, or in addition, the anion exchange membrane 25 may be omitted, and in this case, the performance of suppressing the pH change on the surface of the non-working electrode structure 2 in contact with the skin 4 is inferior to the above-described embodiment, but the basic operational effect of the present invention, that is, the efficiency of administration of the drug ions to the living body is also achieved, and such an iontophoresis device is included in the scope of the present invention.

Alternatively, the iontophoresis device may be provided without providing the non-working electrode structure 2 itself, and the iontophoresis device may be provided with a configuration in which, for example, a voltage is applied to the working electrode structure in a state in which a part of the living body is in contact with a ground member while the working electrode structure is in contact with the skin of the living body, thereby administering the drug.

In the above-described embodiment, the case where the working electrode structure, the non-working electrode structure, and the power supply are individually configured was described, but the iontophoresis device may be configured such that these elements are incorporated into a single housing or the device in which these elements are incorporated is integrally formed into a sheet or a pad to improve the handleability thereof, and such iontophoresis device is included in the scope of the present invention.

Claims (9)

1. An iontophoresis device comprising a working electrode structure, the working electrode structure including:

an electrode to which a positive voltage is applied;

a drug holding unit configured to hold a drug solution containing positively charged drug ions and arranged on the front surface side of the electrode;

a cellulose resin film disposed on the front surface side of the drug holding portion,

the device administers the drug ions through the cellulose-based resin film.

2. An iontophoresis device comprising a working electrode structure, the working electrode structure including:

an electrode to which a positive voltage is applied;

a drug holding unit configured to hold a drug solution containing positively charged drug ions and arranged on the front surface side of the electrode;

a composite membrane comprising a cation-exchange membrane and a cellulose-based resin membrane disposed on the front surface side of the cation-exchange membrane, the composite membrane being disposed on the front surface side of the drug-retaining portion,

the iontophoresis device administers the drug ions through the cellulose-based resin film.

3. The iontophoresis device according to claim 2, wherein the cation exchange membrane and the cellulose-based resin membrane are integrated by bonding an interface between the cation exchange membrane and the cellulose-based resin membrane.

4. The iontophoresis device according to claim 3, wherein a surface of the cation exchange membrane on the cellulose-based resin membrane side is roughened,

the interface is bonded by any method such as adhesion with a binder, crosslinking reaction with a crosslinking agent, or film formation of the cellulose-based resin film on the cation exchange membrane.

5. The iontophoresis device according to any one of claims 2 to 4, wherein the cation exchange membrane has a structure in which an ion exchange resin is filled in pores of a porous membrane.

6. The iontophoresis device according to any one of claims 1 to 5, wherein a cation exchange group is introduced into the cellulose-based resin membrane.

7. The iontophoresis device according to any one of claims 1 to 6, wherein an ion exchange resin having a cation exchange group introduced therein is filled in the cellulose-based resin membrane.

8. The iontophoresis device according to any one of claims 1 to 7,

the working electrode structure further includes:

an electrolyte holding unit that holds an electrolyte held in contact with the electrode;

an anion exchange membrane provided on the front surface side of the electrolyte retaining part,

the drug retaining portion is disposed on the front surface side of the anion exchange membrane.

9. The iontophoresis device according to any one of claims 1 to 8, further comprising a non-working electrode structure body having:

a second electrode to which a negative voltage is applied;

a second electrolyte holding portion that holds an electrolyte held in contact with the second electrode;

a second cation exchange membrane disposed on the front surface side of the second electrolyte solution holding portion;

a third electrolyte solution holding unit that is disposed on the front surface side of the second cation exchange membrane and holds an electrolyte solution;

and a second anion exchange membrane disposed on the front surface side of the third electrolyte solution holding portion.