JPH10234366A - Electrode for electroporation and its production, and pharmaceutical preparation using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an electrode for electroporation which allows very efficient introduction of medicines at low voltage and gives no electric irritation. SOLUTION: This electrode 1 for electroporation is to effect electroporation to an object to introduce a pharmaceutical preparation thereinto such as skin and mucous membrane, and an electrode part 2 to contact with the object has needle electrodes 2a, 2b, 2c, and 2d, in a density of 4-50 electrodes per cm<2> .

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an electrode for electroporation for administering a drug into a living body by electroporation (electroporation) which induces and enhances tissue permeability, for example, tissue permeability of cells, and the electroporation electrode. The present invention relates to a method for producing an electrode portion of a poration electrode and a drug administration preparation using an electroporation electrode.

[0002]

2. Description of the Related Art Electroporation is a method used for gene transfer, in which a drug such as DNA is introduced into cells by instantaneously applying a high voltage to the cells. recent years,
This electroporation technique has been applied to transdermal drug delivery for introducing a drug from the skin and transmucosal drug delivery for introducing a drug from the mucous membrane. This can be seen, for example, in Tokuheihei 3-5.
No. 02416 (Proc. Natl. Acad. Sci. USA, 90: 10504-
10508 (1933)). Electroporation is said to form a new reversible route for permeation through the skin (through holes due to reversible electrical breakdown).
In addition, the above publication discloses a method of administering a drug to skin and mucous membranes using electroporation, but distributed publications including the above publication particularly relate to shapes of electrodes for electroporation. No examples have been considered,
Usually, a wire-type electrode or a linear electrode is used by immersing it in a solution.

[0003]

However, in the above-mentioned conventional electrode for electroporation, it is necessary to supply a large amount of electricity in order to introduce a sufficient amount of a drug into a living body. In order to supply, a high voltage must be applied to a target living body (for example, skin or mucous membrane), and therefore, there has been a problem that the electroporation apparatus has a large output and a large size. In addition, since a high voltage is applied to a portion where the electrodes come into contact, there is a problem that a stimulus such as electric pain occurs in a living body (for example, skin or mucous membrane) to be introduced. Therefore, recently, there has been a demand for an electrode for electroporation that does not require a high voltage when a drug is introduced into a skin or mucous membrane to be introduced.

The present invention solves the above-mentioned conventional problems. An electroporation electrode capable of extremely efficiently introducing a drug at a low voltage and an electrode portion of the electroporation electrode are easily formed. An object of the present invention is to provide a method for producing an electrode portion of a poration electrode, and a drug administration preparation which is excellent in drug introduction efficiency and has very little electric stimulation.

[0005]

To solve this problem, an electrode for electroporation according to the present invention is an electroporation electrode for generating electroporation on an object to be introduced into a skin or mucous membrane of a mammal, especially a human. The electrode for contact is provided with a needle-shaped electrode in an electrode portion that comes into contact with the object to be introduced, and 4 to 50 needle-shaped electrodes are formed per 1 cm ² . As a result, an effect of enabling extremely efficient drug introduction at a low voltage is obtained.
Further, the method for producing an electrode for electroporation of the present invention, the surface of the electrode support made of synthetic resin or synthetic paper, carbon, platinum, gold, titanium, silver, silver chloride, copper, stainless steel, tungsten, lead, An electric wire pattern forming step of forming an electric wire pattern made of copper chloride, and four holes / c
an insulating resin layer coating step of coating the perforated insulating resin layer with m ² to 50 holes / cm ² so that the holes come into contact with the wire path pattern, and 4 holes / cm ² to 50 holes / cm ² A masking film laminating step of laminating a masking film on the insulating resin layer such that the hole communicates with the hole of the insulating resin layer, and an electric wire path on the masking film masked in the masking film laminating step. There is provided a configuration having a needle-like electrode forming step of filling a paste of a pattern forming member into each hole of the insulating resin layer and the masking film, and a masking film removing step of removing the masking film. As a result, an effect is obtained that an electrode for electroporation is easily formed, high productivity can be obtained, and mass production can be performed at low cost. In addition, the drug administration preparation of the present invention comprises an electrode support, an electric wire path formed on one surface of the electrode support, and 4 / cm ² to the electrode support.
A needle-like electrode implanted at 50 pieces / cm ² and electrically connected by the electric wire path; an insulating resin layer laminated on the electrode support to insulate between the needle-like electrodes; A hole penetrating a resin layer and formed so as not to be insulated between the needle electrodes, a backing portion formed on the other surface of the electrode support portion, and a drug sealed in the backing portion. ing. This has the effect of being able to mass-produce a drug administration preparation having excellent drug introduction efficiency and extremely low electrical stimulation with high productivity.

[0006]

DETAILED DESCRIPTION OF THE INVENTION An electrode for electroporation according to claim 1 of the present invention is an electrode for electroporation for generating electroporation on a skin or mucous membrane to be introduced. The electrode portion in contact with the object has a needle-like electrode, and the needle-like electrode has 4 needles / cm ^2.
５０50 electrodes are formed, whereby the electrodes for electroporation can be made small and compact, and the current supplied to the electrodes is applied to the entire contact area between each needle electrode and the skin. It has the effect of flowing widely. According to the electrode for electroporation according to claim 2 of the present invention, the needle-like electrode according to claim 1 is preferably made of carbon, platinum, gold, titanium, silver, silver chloride, stainless steel, tungsten, copper, lead or copper chloride. Any one of the forming materials, or one of platinum, gold, silver, and copper as a plating material, is formed of a forming material, thereby forming a coating film or a print pattern coat. It has the effect of being easy, having a low electric resistance, increasing the flowing current, and efficiently flowing the current to the contact portion. Here, as the material to be plated, iron, copper, chromium, tin, zinc, lead, aluminum, nickel or the like is used.

According to a third aspect of the present invention, there is provided an electrode for electroporation according to any one of the first and second aspects, wherein the electrode support is made of a sheet or film made of synthetic resin or synthetic paper. A wire path made of a material for forming a needle-shaped electrode formed on the surface of the electrode support by printing or the like, and 4 holes / cm ² which are coated on the surface of the electrode support having the wire path and contact the wire path. An insulating resin layer formed by drilling up to 50 pieces / cm ^2, and a needle-shaped electrode formed by filling a hole with a material for forming a needle-shaped electrode electrically connected to an electric wire and projecting a tip from the hole. This has the effect that the needle electrode protrudes from the insulating resin layer and accurately contacts the object to be introduced. The material for forming the needle electrode filled in the hole may be the same as or different from the material of the electric wire. The electrode for electroporation according to claim 4 of the present invention is the electrode according to claim 3, wherein the electrode support portion is a layer of a thermoplastic resin such as polyester, polyether, polyimide, polycarbonate, polyolefin and its adduct, polyamide or the like. It consists of synthetic paper impregnated with these composite laminates or these thermoplastic resins,
In addition, the insulating resin layer is made of polyester, polyolefin, or the like, and thus the electrode support portion and the insulating resin layer have excellent mechanical strength and excellent shape retention. It has the effect that it can be brought into vertical contact with an object.

According to a fifth aspect of the present invention, there is provided a method for manufacturing an electrode for electroporation, wherein carbon, platinum, gold, titanium, silver made of a sheet or a film is formed on the surface of an electrode support made of synthetic resin or synthetic paper. Line pattern forming step of forming a line pattern made of silver chloride, copper, lead or copper chloride, and an insulating resin layer having holes perforated at 4 / cm ² to 50 / cm ² by a line pattern. hole and a coating insulating resin layer coating process so as to contact, a masking film which holes are four / cm ² to 50 / cm ² or drilled hole communicates with the hole portion of the insulating resin layer Film laminating step of laminating a masking film on an insulating resin layer, and paste of a material for forming a wire path pattern on the masked film masked in the masking film laminating step A needle electrode forming step of filling each hole of the insulating resin layer and the masking film, and a masking film removing step of removing the masking film. Since it is easy to enter and projections are left in a dot-like manner, it has an effect that the electrode portion of the electrode for electroporation is easily formed. In the method for manufacturing an electrode part of an electrode for electroporation according to claim 6 of the present invention, in the method for manufacturing an electrode according to claim 5, the wire path pattern forming step is performed using iron, copper, chromium, tin, zinc, lead, aluminum,
This is a process in which any one of platinum, gold, silver, and copper is plated as a plating material on a nickel thin plate, whereby current can be stably supplied with excellent corrosion resistance. Since the plating process is performed, the film thickness and the like can be made uniform and high quality can be achieved. It has the effect of reducing the number of work steps and increasing productivity. Claim 7 of the present invention
The drug administration formulation according to the above, is a drug administration formulation using an electrode for electroporation, comprising: an electrode support, an electric wire formed on one surface of the electrode support, and four / a needle electrode implanted at a density of 50 cm / cm ² to 50 cm ² / cm ² and electrically connected to the wire path, an insulating resin layer laminated on the electrode support portion and insulating between the needle electrodes, and the electrode support portion And a hole penetrating the insulating resin layer and formed so as not to be insulated between the needle electrodes, a backing part formed on the other surface of the electrode support part, and a drug sealed in the backing part. Accordingly, since the needle-shaped electrodes are implanted in the electrode support portion having excellent mechanical strength such as rigidity, all the needle-shaped electrodes are bent to the object to be introduced. It can be brought into contact without interruption. The diameter and the number of minute holes formed in the electrode can be adjusted depending on the properties (viscosity and the like) of the drug. By arranging many needle electrodes and lowering the electrical resistance of the needle electrodes themselves,
Since the electric resistance of the object to be introduced as viewed from the electroporation device can be further reduced, the drug can be introduced into the object to be introduced by applying a lower voltage.
Since the applied voltage is low, there is an effect that the sensation of energizing the skin such as electrical stimulation can be significantly reduced. In addition, the electrode for electroporation is performed by joining the electrode support part and the backing part with heat sealing or pressure sensitive adhesive,
It is preferable that the electrode supporting portion is formed in a form that can be repeatedly used by being easily detachable, or by removably laminating an electrode supporting portion with an insulating resin layer.

Hereinafter, embodiments of the present invention will be described with reference to the drawings. Embodiment 1 FIG. 1A is a front view of an electrode for electroporation according to Embodiment 1 of the present invention.
FIG. 1B is a bottom view of a main part of the electrode for electroporation according to the first embodiment of the present invention. In FIG. 1, reference numeral 1 denotes an electrode portion for electroporation, and 2 denotes an electrode portion including needle-like electrodes 2a and 2c as cathodes and needle-like electrodes 2b and 2d as anodes. FIG. 2 is a bottom view of a main part of an electrode for electroporation showing a modification of the arrangement of the needle electrodes.
In FIG. 1B, the needle-shaped electrodes are a cathode 2a, an anode 2b,
Although the cathodes 2c and the anodes 2d are alternately arranged for each row, they are alternately arranged for each one in FIG. 1 and 2, the number of needle-shaped electrodes per 1 cm ² is preferably 4 to 50, and more preferably, the current easily flows uniformly over the entire contact surface, and the anode and the cathode are hardly short-circuited to each other. Preferably, 10 to 30 pieces are formed. As a material for forming the needle-shaped electrode, any one of carbon, platinum, gold, titanium, silver, silver chloride, copper, stainless steel, tungsten, lead, or copper chloride, and platinum, gold, silver A copper-plated forming material is preferably used. By setting the number of needle electrodes to the above-mentioned number, and by using the above-mentioned forming material, compared to other numbers and materials, the same amount or more of drug at a lower voltage when the same current is applied. Can be introduced.
This means that, by arranging a large number of needle-shaped electrodes, a large number of parallel circuits were arranged when viewed from the electroporation device that supplies power to the electrodes for electroporation, and the electrical resistance of the object to be introduced was reduced. In order to
Further, the electric resistance of the needle electrode itself decreases due to the use of the above-mentioned forming material.

As a voltage waveform applied to the electrode 1 for electroporation, a square pulse, a sawtooth pulse, a triangular pulse, an exponential function pulse, a sine pulse, and an exponential decrement pulse are used. The applied voltage value is 10 to 2000 V / cm
Is more preferable, and more preferably 50 to 1000 V / cm,
More preferably, 50 to 500 V / cm is suitable in view of the sensation of electricity supply to the skin and the effect of drug delivery. RC time constant when the voltage waveform applied to the electrode 1 for electroporation is an exponential decay wave (decay time due to resistance and capacitance. The output voltage value of the RC time constant circuit is 36.8% of the initial voltage value. And the pulse width when the voltage waveform is a square pulse is 10 microseconds or more.
It is preferably 100 milliseconds, and more preferably 100 microseconds to 10 milliseconds, from the viewpoint of the sense of current flowing to the skin and the like.
The number of times of energization when the electrode 1 for electroporation is used may be one or more times, but as the number of times of energization increases, the amount of drug introduced increases. When the number of times of energization is set to several times in one administration, the total amount of electricity supplied is 0.1
It is preferably from 200 to 200 millicoulombs, and more preferably from 1 to 20 millicoulombs in view of the sensation of electricity supply to the skin and the drug delivery efficiency. The total amount of electricity can be expressed by the following equation (1). Total amount of electricity = (applied voltage / resistance of object to be introduced) × pulse width × number of pulses (1)

When electroporation is caused by using the electrode 1 for electroporation shown in FIGS. 1 and 2 and an iontophoresis or ultrasonic introduction method is applied to the site, the drug is synergistically produced. It is more effective because the delivery is increased. In particular, in the case of the introduction method using iontophoresis, it is useful because it can be easily used together with an electroporation apparatus. The energization voltage in the iontophoresis used in combination may be any of a DC voltage, a pulse voltage, and a pulse depolarization voltage that depolarizes a polarization voltage by a short circuit at each pulse output. This is particularly excellent because it does not substantially provide electrical stimulation to the patient. When used in combination with iontophoresis, the current flowing in iontophoresis is preferably 0.01 to 10 mA, and more preferably 0.01 to 5 mA. Also,
The energization voltage is preferably 0.1 to 50 V, more preferably 1 to 30 V, and still more preferably 3 to 15 V. When the energizing voltage is a pulse depolarizing voltage, the pulse frequency is preferably 100 Hz to 1000 kHz, more preferably 1 kHz to 500 kHz, and still more preferably 10 kHz to 300 kHz. ON / O
The FF ratio (duty ratio) is preferably 1 to 99%, more preferably 10 to 80%, and still more preferably 1 to 99%.
5% to 50%. As the electrode used for iontophoresis, either a polarizable electrode or a non-polarizable electrode may be used, but it is more preferable to use a non-polarizable electrode with less pH fluctuation. Avoid applying electrical stimulation to the patient,
This is for improving the drug delivery efficiency.

The drugs used in this embodiment include, for example, morphine, fentanyl, pethidine, codeine,
Buprenorphine, butorphanol, eptazocine,
Central analgesics such as pentazocine, insulin, calcitonin, calcitonin-related gene peptide, vasopressin, desmopressin, protirelin (TRH), corticotropin (ACTH), luteinizing hormone-releasing factor (LH-RH), growth hormone-releasing hormone (G
RH), nerve growth factor (NGF) and other release factors, angiotensin (angiotensin), parathyroid hormone (PTH), thyroid stimulating hormone (TSH, thyrotropin), follicle stimulating hormone (FSH), luteinizing hormone (LH) , Prolactin, serum gonadotropin, placental gonadotropin (HCG), pituitary gonadotropin (HMG), growth hormone, somatostatin, somatomedin, glucagon, oxytocin, gastrin, secretin, endorphin, enkephalin, cholestkinin, endothelin , Neurotensin, interferon, interleukin, transferrin, erythropoietin, superoxide desmutase (SOD), granulocyte stimulating factor (G-CSF), intestinal vasodilator peptide ( IP), muramyl dipeptide,
Peptides such as corticotropin, urogastron, human atrial diuretic peptide (h-ANP), tranquilizers such as carmazepine, chlorpromazine, diazepam, nitrazepam, pleomycin, adreamycin, 5-
Antineoplastic drugs such as fluorouracil and mitomycin,
Cardiotonic drugs such as digitalis, digoxin, digitoxin,
There are antihypertensive agents such as reserpine and clonidine, and sex hormones such as estradiol and testosterone, but the drug used is not limited thereto, and may be any drug that can be introduced transdermally or transmucosally.

As described above, according to the present embodiment, a large number of needle electrodes are arranged and the electrical resistance of the needle electrodes themselves is reduced, so that the electrical resistance of the object to be introduced as viewed from the electroporation apparatus is reduced. Since the drug can be lowered, the drug can be introduced into the introduction target by applying a low voltage.

(Embodiment 2) Next, a method of manufacturing an electrode portion of an electrode for electroporation according to Embodiment 2 of the present invention will be described with reference to the drawings. FIG.
4 (e) and FIGS. 4 (a) to 4 (c) are process diagrams showing a method for manufacturing an electrode portion. First, as shown in FIG. 3A, a silver paste (DB6022 made by Acheson) is placed on an electrode support portion 3 made of a polyethylene terephthalate film (for example, Teijin Tetron type S, a film having a thickness of 75 μm) or the like.
The screen printing of the pattern of the electric wire lines 4 and 5 for supplying electric power from the power supply unit of the electroporation apparatus was performed by using (Pattern forming step). Next, FIG.
As shown in FIG. 3B, an insulating resin film 6 having holes (diameter: 50 μm) formed in a dotted pattern on the printed patterns of the electric wire paths 4 and 5 made of silver is coated, and shown in FIG. 3C. The exposure of the silver 7 was made dotted (insulating resin layer coating step). In the state shown in FIG. 3C, the silver 7 is lower than the insulating resin film 6, and the electrode cannot be brought into contact with the skin. Therefore, the masking film 8 having holes (diameter: 50 μm) formed in a dotted pattern as shown in FIG. 3D is overlaid as shown in FIG. 3E (masking film laminating step), and then masking is performed. A silver paste 9 as shown in FIG. 4A is coated from above the film 8 (needle electrode forming step). Next, FIG.
As shown in (b) and (c), after the silver paste 9 is cured,
The masking film 8 and a part of the silver paste 9 coated on the film 8 were removed so that the remainder of the silver paste 9 remained on the insulating resin film 6 in a dotted manner (masking film removing step). In this way, four or more needle-like electrodes 9a protruding to come into contact with the skin can be obtained.

In the electrode for electroporation having a needle-like electrode shown in FIG. 4 (c), the number of needle-like electrodes, the material of the needle-like electrode, the energization voltage of electroporation, and R
The C time constant, the pulse width, the number of times of energization, the total amount of electricity to be applied, the combined use of iontophoresis, and the exemplified drug are the same as those in Embodiment 1, and the description thereof is omitted. In FIGS. 3 and 4, the electrode support 3 is made of one layer of thermoplastic resin such as polyester, polyether, polyimide, polycarbonate, polyolefin and its adduct, polyamide or the like, a composite laminate thereof, or these thermoplastic resins. It is made of impregnated synthetic paper, and the insulating resin film 6 is made of polyester, polyolefin or the like.

(Embodiment 3) Next, a method for producing a drug administration preparation using an electrode for electroporation according to Embodiment 3 of the present invention will be described with reference to the drawings. FIGS. 5A to 5C are process diagrams showing a method for producing a drug administration preparation using the electrode for electroporation according to the present embodiment. In the figure, 2 is an electrode portion, 3 is an electrode support portion, 4 and 5 are electric wire paths, 6 is an insulating resin layer, 9a is a needle electrode, and these are the same as the electrode portion of the second embodiment. The same reference numerals are given and the description is omitted. Reference numeral 20 denotes a hole formed through the electrode support portion 3 and the insulating resin layer 6 of the needle-shaped electrode 9a so as not to be insulated.
A backing portion having a depression and a flange portion 21a formed around the depression by a thermoplastic resin sheet or film such as a polyester such as polyethylene terephthalate, polyamide, polyolefin, polycarbonate or the like or a laminate thereof;
Reference numeral 2 denotes a drug filled in the depression of the backing portion 21.
Here, the hole 20 is formed in a circle, an oval, or a rectangle. In the case of a circular shape, the diameter is 1 μm to 1000 μm, preferably 5 μm to 500 μm. As the particle size becomes smaller than 5 μm, the leaching rate becomes slower depending on the properties of the drug, and a longer time is required for the introduction. It is not preferable because a tendency is observed.
In the case of an oval or rectangular shape, it is preferable that the minor axis is formed in a range of 5 μm to 500 μm. First, the hole 2 is inserted between the needle-shaped electrodes 9a of the electrode 2 obtained in the second embodiment so as not to be insulated.
0 is opened (FIGS. 5A and 5B). Next, a backing portion 21 having a depression and a flange portion 21a formed around the depression is prepared in a polyethylene terephthalate film and a polyethylene sheet or film or a laminated film in which these are laminated. Next, a drug 22 such as sodium carboxycellulose containing 6-carboxyfluoroserine is filled in the depression of the backing portion 21 according to the application conditions. Next, the electrode portion 2 is overlapped with the flange portion 2.
1a is bonded via a heat seal or a pressure-sensitive adhesive (FIG. 5C). As a result, a preparation for drug administration is obtained.

The method of using the present embodiment configured as described above will be described below with reference to the drawings. FIG.
FIG. 9 is a schematic diagram showing a use state of the drug administration preparation of the third embodiment. In the figure, 23 is an object to be introduced into the skin or mucous membrane,
Reference numeral 24 denotes a drug that oozes out of the hole 20 and stays between the introduction target 23 and the insulating resin layer 6 and is electroporated. When the needle-shaped electrode 9a of the electrode portion 2 comes into contact with the introduction target 23, the drug 22 stored in the backing portion 21 exudes from the hole portion 20. Then, electroporation can be performed by applying a current to the wire paths 4 and 5 of the electrode unit 2.

As described above, according to the present embodiment, since the needle-shaped electrodes are implanted in the electrode support portion having excellent mechanical strength such as rigidity, all the needle-shaped electrodes are bent to the object to be introduced. Can be brought into contact without contact. The diameter and the number of minute holes formed in the electrode can be adjusted depending on the properties (viscosity and the like) of the drug. By arranging a large number of needle-shaped electrodes and lowering the electrical resistance of the needle-shaped electrodes themselves, the electrical resistance of the object to be introduced as viewed from the electroporation apparatus can be further reduced. The drug can be introduced into the introduction target. Since the applied voltage is low, the sensation of energizing the skin such as electrical stimulation can be significantly reduced. Also,
The electrode for electroporation is a disposable type that can be easily removed by bonding the electrode support part and the backing part with heat sealing or pressure-sensitive adhesive, so it can be peelably laminated with the insulating resin layer. Can be used repeatedly. Note that the electrode support portion and the insulating resin layer may be peelably joined. Also in this case, the electrode supporting portion can be used repeatedly, and an expensive needle-like electrode can be effectively used, and resource saving can be improved.

[0019]

【Example】

(Example 1) Next, using the electrode for electroporation of FIG. 1, the cumulative permeation amount of the drug was confirmed. A Franz cell for permeation experiments was used as an experimental device. FIG. 7 is a configuration diagram showing a Franz cell for transmission experiments. In FIG. 7, 1 is an electrode for electroporation, 30 is a sampling port, 31 is skin, 32 is a donor cell, 3
Reference numeral 3 denotes a receiver-side cell. First, the skin of the 8-week-old Wistar rat was removed after removing the abdomen thereof, and the stratum corneum side was placed upward (donor side) and the dermis side was placed downward (receiver side) in a Franz cell for permeation experiments in FIG. The skin 31 was set, a 6-carboxyfluoroserine solution (0.1 mg / ml) was added to the stratum corneum (upper side), and a phosphate buffer was added to the dermis side (lower side). The electrode 1 for electroporation shown in FIG. 1 is brought into contact with the skin 31, and 27.5 volts and a pulse width of 1
A millisecond square pulse was applied 10 times. The dermis-side solution of the receiver-side cell 33 was sampled from the sampling port 30 every predetermined time, and 6-carboxyfluoroserine contained in the solution was quantified to determine the permeation amount (introduction amount).
The results are shown by open circles in FIG. FIG. 8 is a graph showing the accumulated amount of 6-carboxyfluoroserine per unit time (cumulative introduction amount). Line segments extending up and down from the white circle indicate variations in characteristics.

(Comparative Example) Next, a comparative example will be described.
The electrode of FIG. 9 was used as an electrode for electroporation to be compared. FIG. 9A is a front view showing a conventional electrode for electroporation, and FIG. 9B is a bottom view showing a conventional electrode for electroporation. 9, reference numeral 40a denotes a needle electrode serving as an anode, 40b denotes a ring electrode serving as a cathode, 41 denotes a needle electrode 40a and a ring electrode 4
0b is an electrode for electroporation. 8
After removing the hair from the abdomen of aged Wistar rats, the skin was excised, the skin 31 was set in a Franz cell for permeation experiments shown in FIG. 7, and a 6-carboxyfluoroserine solution (0. 1 mg / ml), and a phosphate buffer was added to the dermis side (lower side). The electrode 41 for electroporation shown in FIG. 9 was brought into contact with the skin 31, and a square pulse having a voltage of 100 volts and a pulse width of 1 millisecond was applied 10 times from an electroporation power supply (BTX) (not shown). The dermis solution was collected every predetermined time, and 6-carboxyfluoroserine contained in the solution was quantified to determine the permeation amount (introduction amount). The results are shown by black circles in FIG.

The voltage applied to the electrode was 1 in the comparative example.
The current was 1.27 amperes in both cases, even though the voltage was 00 volts and the voltage in the case of the embodiment was 27.5 volts. In addition, as is apparent from FIG. 8, it was found that the cumulative permeation amount of 6-carboxyfluoroserine was about twice as large in the example than in the comparative example. That is, by using the electrode 1 for electroporation of the present embodiment, a lower voltage (1/1 /
In 4), it was found that a higher transmission amount was obtained. Although the present embodiment has been described with reference to the skin, it is apparent that the same effect can be obtained in the case of the mucous membrane.

[0022]

As described above, according to the electrode for electroporation of the present invention, by arranging a large number of needle-like electrodes, the electric resistance of the object to be introduced as viewed from the electroporation apparatus can be reduced. Therefore, there is obtained an advantageous effect that it is possible to efficiently introduce a drug into an introduction target by applying a low voltage. Further, the needle-shaped electrode is formed of any one of carbon, platinum, gold, titanium, silver, silver chloride, copper, stainless steel, tungsten, lead or copper chloride, or any one of platinum, gold, silver and copper Since the electric resistance of the object to be introduced as viewed from the electroporation apparatus can be further reduced by being formed of one type of plating material as a plating material, the object to be introduced can be applied by applying a lower voltage. An advantageous effect is obtained that a drug can be introduced into the drug. Further, since the needle-shaped electrodes are densely implanted, there is an effect that the device can be made compact and small while having a large amount of drug delivery. Furthermore, an electric wire path comprising a sheet-shaped or film-shaped electrode support made of synthetic resin or synthetic paper, a needle-shaped electrode forming member formed by printing or the like on the surface of the electrode support, and an electrode having an electric wire path the electric line is coated on the surface of the support portion and abuts four holes / cm ² to 50 / cm ² or drilled insulating resin layer, the electric line to an electric connection acicular formation of the electrode member hole By providing a needle-shaped electrode that is filled in the portion and the tip protrudes from the hole, the advantageous effect that the needle-shaped electrode can be made to protrude from the insulating resin layer and accurately contact the object to be introduced can be obtained. can get. Further, the electrode support portion is made of synthetic paper impregnated with one layer of thermoplastic resin such as polyester, polyether, polyimide, polycarbonate, polyolefin and adduct thereof, polyamide or a composite laminate thereof or these thermoplastic resins, And, since the insulating resin layer is formed of polyester, polyolefin, etc., the pattern is efficiently printed,
The advantageous effect that the insulating resin layer can be efficiently formed can be obtained.

According to the method for producing an electrode for electroporation of the present invention, carbon, platinum, which is made of a sheet or a film, is formed on the surface of an electrode support made of synthetic resin or synthetic paper.
An electric wire pattern forming step for forming an electric wire pattern composed of gold, titanium, silver, silver chloride, copper, stainless steel, tungsten, and lead, and insulation with holes perforated from 4 / cm ² to 50 / cm ² and a coating insulating resin layer coating step to the hole of the resin layer to the electric line pattern abuts, hole four / cm ² to 50 / cm ² or drilled masking film a hole insulating resin layer A masking film laminating step of laminating a masking film on an insulating resin layer so as to communicate with the holes of the insulating resin layer and a paste of a material for forming a wire path pattern on the masking film masked in the masking film laminating step. And a masking film removing step of removing the masking film to fill each hole of the needle electrode. This has an advantageous effect that the electrode portion of the electrode for electroporation is easily formed. In addition, the wire path pattern forming step,
Iron, copper, chromium, tin, zinc, lead, aluminum, nickel, by plating any one of platinum, gold, silver, copper as a plating material on a thin plate,
Electrodes with excellent corrosion resistance can be mass-produced at low cost. Since the plating thickness is constant, a stable current can be passed, and an advantageous effect that a high quality electrode can be manufactured with high productivity can be obtained.

According to the drug administration preparation of the present invention, an electrode support, an electric wire formed on one surface of the electrode support,
A needle electrode which is electrically connected with the electric line is implanted with four / cm ² to 50 pieces / cm ² to the electrode support portion, insulation is laminated to the electrode supporting portion for insulating between said needle electrode A resin layer and a hole penetrating the electrode support portion and the insulating resin layer and formed so as not to be insulated between the needle electrodes;
By providing the backing portion formed on the other surface of the electrode support portion and the drug sealed in the backing portion, the needle-like electrodes are densely implanted, so that the size and size can be reduced. By changing the diameter and the number of holes formed according to the properties of the drug, an optimal formulation for the drug can be obtained, and the drug can be delivered according to the properties of the drug. The excellent effect that the needle-shaped electrode and the hole can combine to deliver a large amount of drug at a low voltage very efficiently can be realized.

[Brief description of the drawings]

FIG. 1A is a front view of an electrode for electroporation according to a first embodiment of the present invention. FIG. 1B is a bottom view of a main part of the electrode for electroporation according to the first embodiment of the present invention.

FIG. 2 is a main part bottom view showing a modified example of the arrangement of the needle-like electrodes constituting the electrode for electroporation according to the first embodiment of the present invention.

FIG. 3A is a process chart showing a method for manufacturing an electrode part according to a second embodiment of the present invention. FIG. 3B is a process chart showing a method for manufacturing an electrode part according to a second embodiment of the present invention. (D) Process diagram showing a method for manufacturing an electrode unit according to a second embodiment of the present invention (e) Process diagram showing a method for manufacturing an electrode unit according to a second embodiment of the present invention Showing process chart

FIG. 4 (a) is a process diagram showing a method for manufacturing an electrode portion in Embodiment 2 of the present invention. (B) is a process diagram showing a method for manufacturing an electrode portion in Embodiment 2 of the present invention. Process chart showing a method for manufacturing an electrode part in Embodiment 2.

FIG. 5 (a) A process chart showing a method for producing a drug administration preparation according to Embodiment 3 of the present invention. (B) A process chart showing a method for producing a drug administration preparation according to Embodiment 3 of the present invention. 3) A process chart showing a method for producing a drug administration preparation according to Embodiment 3 of the present invention.

FIG. 6 is a schematic diagram showing a use state of the drug administration preparation according to the third embodiment of the present invention.

FIG. 7 is a configuration diagram showing a Franz cell for transmission experiments.

FIG. 8 is a graph showing the cumulative permeation amount (cumulative introduction amount) of 6-carboxyfluoroserine with respect to elapsed time.

FIG. 9A is a front view showing a conventional electrode for electroporation. FIG. 9B is a bottom view of a main part showing a conventional electrode for electroporation.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Electroporation electrode 2 Electrode part 2a, 2b, 2c, 2d Needle electrode 3 Electrode support part 4, 5 Electric wire 6 Insulating resin film (insulating resin layer) 7 Silver 8 Masking film 9 Silver paste 9a Needle electrode 16 Hole 17 Porous electrode 18 Drug-containing gel 19 Backing 20 Hole 21 Backing 21a Flange 22, 24 Drug 23 Introduction target 30 Sampling port 31 Skin 32 Donor cell 33 Receiver cell 40a Needle electrode 40b Ring electrode 41 Conventional Electroporation electrodes

Claims (7)

[Claims] 1. An electrode for electroporation for causing electroporation on an object to be introduced into the skin or mucous membrane, wherein the electrode portion in contact with the object to be introduced comprises a needle electrode, Electrodes 4 to 50 per cm ²
An electrode for electroporation, wherein a plurality of electrodes are formed. 2. The method according to claim 1, wherein the needle-shaped electrode is formed of any one of carbon, platinum, gold, titanium, silver, silver chloride, copper, stainless steel, tungsten, lead or copper chloride, platinum, gold,
The electrode for electroporation according to claim 1, wherein the electrode is formed of a forming material obtained by plating one of silver and copper as a plating material. 3. A sheet-like or film-like electrode support made of synthetic resin or synthetic paper, and an electric wire path made of a material for forming the needle-like electrode formed on the surface of the electrode support by printing or the like. Holes coated on the surface of the electrode support portion having the wire path and contacting the wire path are 4 holes / cm ^2-
An insulating resin layer perforated at 50 pieces / cm ^2, and a material for forming the needle-like electrode electrically connected to the electric wire path is filled in the hole, and the needle-like shape is formed by projecting a tip from the hole. The electrode for electroporation according to claim 1, further comprising: an electrode. 4. A synthetic material in which the electrode support portion is impregnated with one layer of thermoplastic resin such as polyester, polyether, polyimide, polycarbonate, polyolefin and its adduct, polyamide or the like, a composite laminate thereof, or these thermoplastic resins. The electrode for electroporation according to claim 3, wherein the electrode is made of paper, and the insulating resin layer is formed of polyester, polyolefin, or the like. 5. An electric wire made of any one of carbon, platinum, gold, titanium, silver, silver chloride, copper, stainless steel, tungsten, lead and copper chloride on the surface of an electrode support made of synthetic resin or synthetic paper. a wire path pattern forming step of forming a road pattern and coated such hole portion 4 / cm ² to 50 pieces / cm ² drilled the hole insulating resin layer on the conductive line pattern abuts insulation A resin layer coating step and a masking film having holes perforated at 4 / cm ² to 50 / cm ² , wherein the masking film is connected to the insulating resin such that the holes communicate with the holes of the insulating resin layer. A masking film laminating step of laminating the layers, and a paste of a forming material of the electric wire path pattern on the masking film masked in the masking film laminating step. A method for producing an electrode for electroporation, comprising: a step of forming a needle-like electrode for filling a layer and each hole of the masking film; and a step of removing a masking film for removing the masking film. 6. The method according to claim 1, wherein the electric wire path pattern forming step comprises:
The step of forming a thin plate of chromium, tin, zinc, lead, aluminum and nickel by plating any one of platinum, gold, silver and copper as a plating material. A method for producing an electrode for electroporation. 7. An electrode support, an electric wire path formed on one surface of the electrode support, and 4 / cm ^{2 to} 5
A needle electrode implanted at 0 / cm ² and electrically connected by the electric wire path, an insulating resin layer laminated on the electrode support portion and insulating between the needle electrodes, the electrode support portion and the insulation A hole penetrating a resin layer and formed so as not to be insulated between the needle electrodes, a backing portion formed on the other surface of the electrode support portion, and a drug sealed in the backing portion. A preparation for drug administration, characterized in that: