JP2010253199A - Device for electroporation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a device for highly safely allowing even the deep part of skin to be impregnated with a medicine without causing pain. <P>SOLUTION: The device 1 for electroporation includes: micro needles (anode needles) 12 serving as anodes as an electrode; and micro needles 13 (cathode needles) serving as cathodes, where the anode needles 12 and the cathode needles 13 are alternately arranged in a prescribed direction. It is favorable that the distal ends 120b of the anode needles 12 and the distal ends 130b of the cathode needles 13 are made into insertion parts long enough to penetrate the horny layer of the skin. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an electroporation device that can penetrate a drug deep into the skin.

  Electroporation has been originally used as a technique for performing transformation by applying a voltage to a cell, opening a minute hole, and then introducing a gene into the cell. In recent years, various studies have been conducted as a technique for penetrating a drug from the surface of skin, mucous membrane or the like into the body. When electroporation is performed on the surface of the skin or the like, it is considered that a path (gap part) through which the drug can pass from the surface to the inside is formed by bringing the electrode into contact with the corresponding part and applying a voltage. It is believed that the drug can penetrate into the body through this route. Therefore, since it is considered that the drug can be easily delivered directly to the target site, attempts have been made to apply electroporation to the administration of various cosmetics, drugs, and other drugs, and various devices have been proposed. (For example, refer to Patent Document 1).

International Publication No. 01/028624 Pamphlet

However, in the administration of a drug using electroporation, there is an upper limit to the voltage that can be applied from the viewpoint of safety to the living body, and the distance that can be penetrated into the body is not always sufficient. For example, although depending on the place and conditions of application, the upper limit of the standard voltage that can be normally applied is considered to be up to about 150 V, and it has been conventional to infiltrate a drug from a surface such as skin to a deep part exceeding 100 μm. It was difficult.
On the other hand, from the viewpoint of forming a path through which the drug passes from the surface of the skin or the like, there is a method of inserting the microneedle (microneedle) from the surface of the skin or the like to form the path mechanically and supplying the drug there Conceivable. However, since the insertion of the microneedle is painful, it is impossible to insert the microneedle to a depth of about 100 to 200 μm where nerve tissue exists, and the drug penetrates to such a deep portion. This has been difficult in the past.

  This invention is made | formed in view of the said situation, and makes it a subject to provide the device which can permeate | transmit a chemical | medical agent to the deep part in skin without a pain and high safety | security.

To solve the above problem,
The present invention provides an electroporation device comprising: a microneedle that also serves as an anode as an electrode; and a microneedle that also serves as a cathode.
The electroporation device of the present invention comprises at least one of the microneedle also serving as the anode and the microneedle serving as the cathode, and the microneedle serving as the anode and the microneedle serving as the cathode are alternately arranged in a predetermined direction. It is preferable.
In the electroporation device of the present invention, it is preferable that the tip of the microneedle also serving as the anode and the microneedle serving as the cathode is an insertion portion having a length penetrating the stratum corneum of the skin.

  ADVANTAGE OF THE INVENTION According to this invention, a chemical | medical agent can be osmose | permeated to the deep part in skin without pain and high safety | security. And since the permeability | transmittance of a chemical | medical agent is excellent, the medicinal effect superior to the past is acquired.

It is a schematic plan view which illustrates the device of this invention. It is a schematic sectional drawing in the II-II line of the device illustrated in FIG. FIG. 2 is a schematic plan view of the back surface of the device illustrated in FIG. 1 on the opposite side to FIG. 1. It is a schematic plan view which illustrates the other device of this invention provided with the needle which has a hollow structure. It is a schematic sectional drawing in the VV line of the device illustrated in FIG. FIG. 5 is a schematic plan view of a pressing member of the device illustrated in FIG. 4. 3 is imaging data showing a distribution state of a medicine in Example 1. It is imaging data which shows the distribution state of the chemical | medical agent in Example 2. FIG. It is an imaging data which shows the distribution state of the chemical | medical agent in the comparative example 1. It is imaging data which shows the distribution state of the chemical | medical agent in the comparative example 2. It is an imaging data which shows the distribution state of the chemical | medical agent in the comparative example 3. It is the schematic which illustrates the conventional device for electroporation used in the comparative example 3, (a) is a top view, (b) is sectional drawing in the XII-XII line of (a).

The electroporation device of the present invention (hereinafter abbreviated as “device”) includes a microneedle (hereinafter abbreviated as “anode needle”) serving as an anode as an electrode and a microneedle (hereinafter abbreviated as “cathode needle”) also serving as a cathode. It is characterized by providing. Since the microneedle also serves as an electrode, a voltage can be applied to the skin with the microneedle inserted into the skin, and the drug can easily penetrate into the deep part of the skin.
Hereinafter, the present invention will be described in detail with reference to the drawings.

(First embodiment)
1 to 3 are schematic views illustrating the device of the present invention. FIG. 1 is a plan view, FIG. 2 is a cross-sectional view taken along line II-II in FIG. 1, and FIG. It is a top view.
The device 1 comprises five anode needles 12 and four cathode needles 13. In FIG. 1, the anode needle 12 is indicated by a “+” symbol, and the cathode needle 13 is indicated by a “−” symbol. In addition, the first conductive member 14 and the second conductive member 15 are arranged on the surface 10 a of the base material 10 through the bonding layer 16 so as not to contact each other.
The first conductive member 14 and the second conductive member 15 are separately electrically connected to one end of the electric wire 19 via the connection terminal 18, and the other end of the electric wire 19 is connected to the power source 17. Yes. The power source 17 may be either an AC power source or a DC power source.

  The anode needle 12 is provided from the surface side of the first conductive member 14 through the first conductive member 14, the bonding layer 16, and the base material 10, and the tip thereof is from the back surface 10 b of the base material 10. It protrudes. The cathode needle 13 is provided from the front surface side of the second conductive member 15 so as to penetrate the second conductive member 15, the bonding layer 16 and the base material 10, and the tip thereof is the back surface of the base material 10. It protrudes from 10b.

The substrate 10 has a sheet shape or a plate shape, and has an insulating property.
Although the thickness of the base material 10 is not specifically limited, It is preferable that it is 0.2-3 mm, and it is preferable that it is 0.4-1.5 mm. By setting it to the lower limit value or more, the strength can be further increased, and by setting it to the upper limit value or less, the handleability is further improved, and the thickness of the device can be reduced.
The material of the base material 10 is not particularly limited as long as it is insulative, but various resins are suitable. Silicone resin; vinyl chloride resin; polyethylene; polypropylene; polyurethane; acrylic resin; fluorine such as polytetrafluoroethylene Resin etc. can be illustrated.

The bonding layer 16 is for adhering and fixing the first conductive member 14 and the second conductive member 15 to the base material 10 and is laminated almost entirely on the back surface of these conductive members.
The thickness of the bonding layer 16 is not particularly limited, and may be appropriately adjusted according to the material. Usually, the thickness is preferably 0.08 to 0.8 mm, more preferably 0.1 to 0.4 mm. preferable. By setting the lower limit value or more, the first conductive member 14 and the second conductive member 15 can be more stably fixed, and by setting the upper limit value or less, the handleability is further improved and the thickness of the device can be reduced. .
Note that the bonding layer 16 is not necessarily laminated on the entire back surfaces of the first conductive member 14 and the second conductive member 15.

The bonding layer 16 is not particularly limited as long as the first conductive member 14 and the second conductive member 15 can be bonded and fixed to the base material 10. For example, an adhesive may be used, or a double-sided adhesive tape in which an adhesive is applied to both surfaces of the base material or an adhesive is impregnated on the base material may be used. Examples of the base material include those made of various resins similar to the base material 10 and nonwoven fabrics. Examples of the adhesive include acrylic adhesives, rubber adhesives, silicone adhesives, and urethane adhesives.
The bonding layer 16 may be configured by combining a plurality of types, such as two or more layers. By doing in this way, according to the combination of the 1st conductive member 14 or the 2nd conductive member 15, and the base material 10, it may become possible to exhibit higher adhesive force.
The bonding layer 16 may be either conductive or insulating if the first conductive member 14 and the second conductive member 15 are not in contact with each other, but may be in contact with each other. In some cases, it is insulative. Usually, an insulating material is preferable.

The first conductive member 14 is a substantially W-shaped conductive sheet having a bent portion and a branched portion, and electrically connects the five anode needles 12.
The second conductive member 15 is a substantially U-shaped conductive sheet having a bent portion, and electrically connects the four cathode needles 13.
In FIG. 2, the portions of the first conductive member 14 and the second conductive member 15 that are not displayed in cross section (indicated by diagonal lines) are located on the back side of the paper surface than the portions that are displayed in cross section. It is also clear from the plan view shown in FIG. 1 that the one conductive member 14 and the second conductive member 15 are spaced apart from each other without contacting each other.
The first conductive member 14 and the second conductive member 15 are not limited to those shown here, and may have other shapes.

The thicknesses of the first conductive member 14 and the second conductive member 15 are not particularly limited, but are preferably the same as the thickness of the bonding layer 16. By setting it to the lower limit value or more, the strength can be further increased, and by setting it to the upper limit value or less, the handleability is further improved, and the thickness of the device can be reduced.
The material of the first conductive member 14 and the second conductive member 15 is not particularly limited as long as it has conductivity. Specific examples of preferable ones include metals such as gold, silver, copper, platinum, aluminum, and titanium; alloys such as stainless steel, and metal salts such as silver chloride.

  The anode needle 12 has a needle-like shape including a substantially disc-shaped head portion 12a and a body portion 12b erected from one flat surface of the head portion 12a. Similarly, the cathode needle 13 has a needle shape having a substantially disc-shaped head portion 13a and a body portion 13b.

In the anode needle 12, the front end portion 120b of the body portion 12b protruding from the back surface 10b of the base material is an insertion portion into the skin. Central axial length L ₁ of the distal end portion 120b may be adjusted in accordance with the site of the skin surface for attaching the device 1, but usually is preferably a length to penetrate the stratum corneum, stratum corneum It is more preferable that the length stays in the epidermis below the layer, and it is particularly preferable that the length is about (thickness of stratum corneum) + (5 to 10 μm). This is because the electroporation effect is more easily obtained in the epidermis below the stratum corneum. Further, if the L ₁ is too long, the tip portion 120b has reached deep within the skin, sometimes painful.
In the cathode needle 13, the distal end portion 130 b of the body portion 13 b protruding from the back surface 10 b of the base material is also an insertion site into the skin, similar to the distal end portion 120 b, and its length L ₂ in the central axis direction is L ₁ is the same as that.

For example, in the case of humans, the thickness of the stratum corneum varies from part to part of the body and varies from person to person. It is about 122 μm. Therefore, L ₁ and L ₂ may be appropriately adjusted to desired values in consideration of these numerical values.

The angles θ ₁ and θ ₂ of the tip portions 120b and 130b are not particularly limited as long as they do not hinder insertion into the skin, but are preferably 15 to 35 °. By setting it to the lower limit value or more, the strength of the tip portions 120b and 130b can be further increased, and by setting the value to the upper limit value or less, the tip portions 120b and 130b can be more easily inserted into the skin. Here, θ ₁ and θ ₂ are angles formed by the tip portions 120b and 130b in the longitudinal section including the central axis of the body portion 12b of the anode needle 12 and the body portion 13b of the cathode needle 13. is there.

  The material of the anode needle 12 and the cathode needle 13 is not particularly limited as long as it can be used as an electrode, but a material having high safety to the human body is preferable. Specific examples of preferable materials include metals such as gold, silver and platinum; alloys such as stainless steel.

  The distance D between the central axes of the adjacent anode needle 12 and cathode needle 13 may be appropriately adjusted within a range in which a voltage can be applied. Usually, it is preferably 2 to 20 mm. A voltage can be applied satisfactorily by setting it to the lower limit value or more, and the device can be miniaturized by setting it to the upper limit value or less, and the number of anode needles 12 and cathode needles 13 can be easily increased.

  In the device 1, the anode needle 12 and the cathode needle 13 are alternately arranged in two directions orthogonal to each other (a direction forming an angle of about 45 ° with the longitudinal direction and the lateral direction of the base material 10 in plan view). The distance D between the central axes of the anode needle 12 and the cathode needle 13 adjacent to each other in these two directions is substantially constant. By arranging the anode needle and the cathode needle in this way, a voltage can be applied uniformly over a wide range in the skin surface direction in the device 1 mounting portion. As a result, a higher effect of uniformly infiltrating the drug deep into the skin over a wide range can be obtained. Such an effect can be obtained even in the device 1 in which the arrangement positions of the anode needle 12 and the cathode needle 13 are interchanged with each other.

In the present invention, not only the device 1 shown in FIG. 1, but when at least one of the anode needle and the cathode needle is plural, the anode needle and the cathode needle are alternately arranged in one direction, thereby In the arrangement direction, a voltage can be applied uniformly over a wide range. And the range which can apply a voltage uniformly can be expanded by performing such an alternating arrangement with respect to several directions. For example, the range in which the voltage can be applied uniformly can be expanded as the alternate arrangement is performed in two directions and the angle formed by the two directions at this time approaches 90 °. Furthermore, a higher effect can be obtained by providing a plurality of units alternately arranged in such a plurality of directions.
The distance between the central axes of the adjacent anode needles and the distance between the central axes of the adjacent cathode needles are preferably larger than the distance between the central axes of the adjacent anode needle and the cathode needle. By doing in this way, the range which can apply a voltage uniformly can be expanded further.

  Although FIG. 1 shows a device in which the difference in the number of anode needles and cathode needles is 1, the present invention is not limited to this. However, in order to apply a voltage uniformly over a wide range depending on the surface direction of the skin, the difference in the number of needles is preferably 3 or less, more preferably 2 or less, and 1 or 0. It is particularly preferred.

  The device 1 is mounted on the skin surface, the tip 120b of the anode needle 12 and the tip 130b of the cathode needle 13 are respectively inserted into the skin, and voltage is applied from the power source 17 to the first conductive member 14 and the second conductive member 15. By applying, voltage can be applied to all of the plurality of anode needles 12 and cathode needles 13, and electroporation can be performed. At this time, since the voltage can be applied to the skin with the microneedle inserted into the skin, a gap is formed between the cells from the insertion portion of the tip portions 120b and 130b toward the deep portion in the skin. The drug can be easily penetrated deep into the skin. The drug needs to be supplied to the target site on the skin, and the timing may be either before or after electroporation.

(Second embodiment)
In the present invention, as the anode needle and the cathode needle, those having a hollow structure and capable of injecting a drug from the tip may be used. By using such a device, it is possible to perform both electroporation and supply of a drug to a target site. Therefore, such a device is suitable when performing electroporation at the supply site after supplying the drug, or when supplying the drug to the target site while performing electroporation. 4 to 6 are schematic views illustrating a device including such a needle and a pressing member for injecting a medicine, FIG. 4 is a plan view in a state where the pressing member is removed, and FIG. 4 is a cross-sectional view taken along line VV, and FIG. 6 is a plan view of the pressing member. 4 to 6, the same components as those shown in FIGS. 1 to 3 are denoted by the same reference numerals as those in FIGS. 1 to 3, and detailed description thereof is omitted. The same applies to the following drawings.

  The device 2 shown here comprises an anode needle 22 and a cathode needle 23. The anode needle 22 is the same as the anode needle 12 in FIGS. 1 to 3 except that it includes a hollow portion 22c that consistently penetrates the head portion 22a and the body portion 22b. The cathode needle 23 is the same as the cathode needle 13 in FIGS. 1 to 3 except that it includes a hollow portion 23c that consistently penetrates the head portion 23a and the body portion 23b.

  In the anode needle 22 and the cathode needle 23, the hollow portions 22c and 23c are injection paths for injecting the drug from the tip portions 220b and 230b to the skin insertion site. The inner diameters of the hollow portions 22c and 23c may be the same as or different from each other, and are not particularly limited as long as the injection of the medicine is not hindered. In general, the size is preferably 25 to 75% with respect to the maximum outer diameters of the body portion 12b of the anode needle 12 and the body portion 13b of the cathode needle 13.

  On the surface 10a of the base material 10, a first partition wall 101 having a predetermined height is erected along the peripheral edge of the first conductive member 14 so as to surround the first conductive member 14, A second partition wall 102 having a predetermined height is erected along the peripheral edge portion of the second conductive member 15 so as to surround the second conductive member 15.

  The device 2 further includes a drug layer 202 in contact with the head 22a of the anode needle 22 and the head 23a of the cathode needle 23 inside the first partition 101 and the second partition 102, respectively. A pressing member 201 that presses 202 is provided.

The drug layer 202 is a layer that contains a drug to be administered, and may be the drug itself or may be one in which the drug is held on a base material. Preferred examples of the drug layer 202 include a drug-containing liquid, a material containing a drug-containing liquid in a base material such as a woven fabric or a non-woven cloth, and a gel containing a drug.
The thickness of the drug layer 202 when not pressed is not particularly limited, and can be arbitrarily adjusted according to the amount of drug used.

The pressing member 201 is detachably provided in the device 2.
In the pressing member 201, a protrusion 2011, which is a pressing force application site, is provided at a substantially central portion of the upper surface 201a facing the outside of the device 2 when the pressing member 201 is mounted. When the device 2 is attached, the first pressing portion 2012 having a shape that can be inserted into the first partition wall 101 and the second partition wall 102 are inserted into the lower surface 201 b that is disposed opposite to the drug layer 202. Each of the possible second pressing portions 2013 is protruded.

  The pressing member 201 is capable of moving up and down (moving in the direction of the arrow in FIG. 5) while being attached to the device 2, and presses the pressing member 201 (forces downward in the arrow in FIG. 5). The first pressing part 2012 and the second pressing part 2013 apply a pressing force to the drug layer 202 in the first partition wall 101 and the second partition wall 102. Thereby, the chemical | medical agent in the chemical | medical agent layer 202 is supplied from the front-end | tip parts 220b and 230b via the hollow part 22c of the anode needle 22, and the hollow part 23c of the cathode needle 23. FIG.

The first partition wall 101 and the second partition wall 102 separate the drug layer 202 between the first conductive member 14 and the second conductive member 15 on the base material 10. A short circuit (short circuit) of the cathode needle 23 is prevented.
The heights of the first partition 101 and the second partition 102 are not particularly limited, and may be adjusted as appropriate according to the thickness of the drug layer 202, and may be the same or different from each other.
When the first partition wall 101 and the second partition wall 102 are provided without being in contact with the first conductive member 14 and the second conductive member 15, respectively, as shown here, the material of these partition walls As long as it has the intensity | strength which can isolate | separate the chemical | medical agent layer 202, any of electroconductivity and insulation may be sufficient. The first partition 101 and the second partition 102 may be in contact with each other or may not be in contact with each other.
On the other hand, at least when the first partition 101 is in contact with the first conductive member 14 or when the second partition 102 is in contact with the second conductive member 15 and these partitions are in contact with each other ( The material of these partition walls needs to be insulative (not shown), and when these partition walls are not in contact with each other, the material of these partition walls may be either conductive or insulating.
And the material of the 1st partition 101 and the 2nd partition 102 should just be suitably selected from various resins, metals, etc. according to the objective.
The first partition 101 and the second partition 102 may be fixed to the substrate surface 10a using an adhesive or the like so that the anode needle 22 and the cathode needle 23 are not short-circuited. It may be integrally molded.

The pressing member 201 needs to be configured to prevent the anode needle 22 and the cathode needle 23 from being short-circuited, and the material of at least the portion excluding the first pressing portion 2012 and the second pressing portion 2013 is insulative. It is preferable that the whole material is insulative. And the material which has the intensity | strength which can press the chemical | medical agent layer 202 stably should just be selected, and the thing similar to the material of the base material 10 can be illustrated as a preferable thing.
The height of the convex part 2011, the 1st press part 2012, and the 2nd press part 2013, and the thickness of the press member 201 of the site | part in which these are not provided are not specifically limited.
The convex portion 2011, the first pressing portion 2012, and the second pressing portion 2013 may be fixed to the upper surface 201a or the lower surface 201b of the pressing member using an adhesive or the like, or are integrally formed with the pressing member 201. May be.
Although the convex part 2011 is not essential, by providing this, the chemical | medical agent layer 202 can be uniformly pressed over the whole region.

The device 2 is the same as the device 1 shown in FIGS.
The device 2 is attached to the skin surface, the tip 220b of the anode needle 22 and the tip 230b of the cathode needle 23 are respectively inserted into the skin, and voltage is applied from the power source 17 to the first conductive member 14 and the second conductive member 15. By applying, electroporation can be performed. And like the case where the device 1 is used, a chemical | medical agent can be osmose | permeated deeply in the skin. The supply timing of the drug may be before, after or after electroporation.

  The device of the present invention is not limited to what has been described so far, and a part of the configuration may be changed, added, or deleted within a range not impeding the effects of the present invention. For example, the number, arrangement form, shape, and the like of the anode needle, the cathode needle, the first conductive member, the second conductive member, and the like may be appropriately adjusted according to the purpose.

  Since the device of the present invention can be reduced in size and thickness, it is suitable for constituting a kit by combining with a drug according to the application.

Using the device of the present invention, an anode needle and a cathode needle can be inserted into the skin to apply a voltage, and the drug can penetrate into the skin from the insertion site.
At this time, it is considered that a gap is formed between cells toward the deep part in the skin by electroporation, and the drug can easily penetrate into the deep part in the skin through this gap.
The device of the present invention can be applied not only to humans but to all animals.

  The voltage to be applied is not particularly limited as long as it is within a safe range for the living body. Usually, it is preferably 30 to 150V. By setting the lower limit value or more, a higher effect of penetrating the drug into the deep part in the skin can be obtained, and by setting the upper limit value or less, safety to the living body can be improved.

  The number of pulses at the time of applying the voltage may be adjusted as appropriate according to the mounting site and purpose of the device. The voltage application time may be appropriately adjusted according to the application conditions such as the number of pulses.

In order for the drug to penetrate into the skin, it is necessary to supply the drug to the target site of the skin.
The timing of supplying the drug may be before, during or after electroporation.
Specifically, when a drug is supplied and then electroporation is performed by attaching the device to the supply site, or while the device is attached to the target site of the skin and performing electroporation, the target site When a drug is supplied to a cell, it is considered that the formation of a gap between cells and the penetration of the drug through the gap proceed in parallel. When supplying a drug to the target site while performing electroporation, it is preferable to use a device that can also supply a drug, such as the device 2 shown in FIG.
In addition, when the drug is supplied to the target site after the device is attached to the target site on the skin and electroporation is performed, the drug penetrates through the gap between the cells that have been formed in advance. Conceivable.

  When the device is not used, the medicine may be supplied by a known method such as coating, rubbing, or dropping.

  The drug is not particularly limited as long as it is administered into the skin and exhibits activity. Specifically, what can be used as active ingredients, such as a pharmaceutical, cosmetics, or a quasi-drug, can be illustrated. And any of a low molecular weight compound and a high molecular weight compound may be sufficient, and the one where molecular weight is small usually has the high penetration effect in skin. In addition, it is preferable to appropriately select whether the drug is preferably hydrophilic or hydrophobic depending on the electroporation conditions and cannot be generally described. Usually, when a voltage is applied in the stratum corneum, a highly hydrophobic drug is preferable.

The drug may be administered in combination with other components as long as the effects of the present invention are not hindered.
Examples of other components include pH adjusters, humectants, preservatives, fragrances, and pigments.
As for a chemical | medical agent and another component, all may be used individually by 1 type, and may use 2 or more types together. When two or more kinds are used in combination, the combination and ratio may be appropriately selected according to the purpose.

As a method for efficiently administering a drug into the skin, for example, a method using iontophoresis is known. However, in iontophoresis, a DC voltage is applied and the drug is infiltrated by passing charges between the electrode and the drug. Therefore, the usable drug is a compound having an ionic property as a whole and a small molecular weight. It is limited to.
On the other hand, the administration method using the device of the present invention uses electroporation, and an AC voltage or a DC voltage is applied to form a gap between cells, and the gap is passed through the gap. Therefore, the penetration mode of the drug is completely different from the case of using iontophoresis. A compound having a large molecular weight or a nonionic compound can be suitably used as a drug, and the application range of the drug is wide.

In addition, as a method of administering a drug into the skin, a hollow structure or a non-hollow structure microneedle is used alone to insert into the skin, and a drug is supplied to the insertion site, or electroporation is used alone. A method is known in which a voltage is applied to the skin surface to allow the drug to penetrate from the skin surface into the skin. However, in the method of using the microneedle alone, when the medicine pressing means such as the piston portion is not used, the penetration distance of the medicine into the skin is generally determined by the depth at which the microneedle is inserted into the skin. Considering the pain associated with the insertion of the needle, for example, there is no problem in inserting it to a depth of about 50 μm, but it is difficult to insert it to a depth of about 100 μm. Therefore, the penetration distance of the drug becomes limited. On the other hand, in the method using electroporation alone, the penetration distance of the drug is generally determined by the applied voltage. In consideration of safety to a living body, for example, it is not problematic to apply a voltage of about 100 V, but it is difficult to apply a voltage of about 200 V.
On the other hand, the administration method using the device of the present invention uses a microneedle inserted into the skin as an electrode and performs electroporation, thereby greatly increasing the penetration distance of the drug into the skin. It has an effect and allows the drug to penetrate deeper into the skin than before.

Hereinafter, the present invention will be described in more detail with reference to specific examples. However, the present invention is not limited to the following examples.
The drug was administered by the method described below, and the distribution state of the drug in the skin was compared (Examples 1 to 3 and Comparative Examples 1 to 3).

[Example 1]
(device)
The drug was administered using the device 1 shown in FIGS. Details of the device are as follows. The anode needle 12 and the cathode needle 13 are both made of stainless steel, the angles θ ₁ and θ ₂ are both 28 °, and the outside of the non-tapered portions of the body portions 12b and 13b (the outer diameter is constant except for the tip side). The diameter is 0.23 mm, the maximum outer diameter of the tip portions 120 b and 130 b is 0.2 mm, the lengths L ₁ and L ₂ of the tip portions are both 0.4 mm, the anode needle 12 and the cathode needle 13 The distance L between the central axes was set to 4 mm. As the base material 10, a material made of silicone resin, 15 mm long, 15 mm wide, and 0.7 mm thick was used. As the bonding layer 16, a double-sided adhesive tape having a thickness of 0.1 mm (Nystack ( (Registered trademark) manufactured by Nichiban Co., Ltd.) was used, and the vinyl chloride resin double-sided tape was placed on the substrate 10 side. The first conductive member 14 and the second conductive member 15 were both made of silver and having a thickness of 0.1 mm.

(Drug administration)
The abdominal skin was removed from the hairless rat, the device was attached, and a voltage of 100 V was applied for 10 seconds under the condition of 100 milliseconds and 100 pulses (plug electroporation).
Next, after removing the device, 1 mL of an aqueous solution containing dextran labeled with FITC as a drug (molecular weight: about 4000, hereinafter abbreviated as FITC-labeled dextran) at a concentration of 1 mg / mL at the site where the device was mounted It was applied and allowed to stand for 8 hours. Then, using a confocal laser scanning microscope (CSM), the FITC-labeled dextran was detected, and the distribution state in the skin was observed. FIG. 7 shows the imaging data obtained at this time and at the stage of 8 hours after the drug application. In FIG. 7, the upper side of the paper corresponds to the skin surface side. The white portion is a drug detection unit. The same applies to subsequent imaging data.
From FIG. 7, it was confirmed that the drug had penetrated from the skin surface to a distance of 128 μm at the deepest point.

[Example 2]
The drug was administered in the same manner as in Example 1 except that the applied voltage was 150V. FIG. 8 shows the imaging data obtained at this time and at the stage of 8 hours after the application of the medicine.
From FIG. 8, it was confirmed that the drug penetrated deeper than in the case of Example 1.

[Example 3]
The drug was administered in the same manner as in Example 1 except that the drug was applied to the skin removed from the abdomen of the hairless rat, a device was attached to the application site, and a voltage was applied. When the imaging data at the stage of 8 hours after the drug application was acquired, the penetration distance of the drug was almost the same as in the case of Example 1.

[Comparative Example 1]
The skin of the abdomen was removed from the hairless rat in the same manner as in Example 1, applied with a drug, and allowed to stand for 8 hours. And the chemical | medical agent was detected similarly to Example 1. FIG. FIG. 9 shows the imaging data obtained at this time and at the stage of 8 hours after the application of the medicine.
From FIG. 9, it was confirmed that the drug penetrated to a distance of 50 μm from the skin surface at the deepest point.

[Comparative Example 2]
The drug was administered and detected in the same manner as in Example 1 except that no voltage was applied. FIG. 10 shows the imaging data obtained at this time in the stage of 8 hours after the application of the medicine.
From FIG. 10, it was confirmed that the drug penetrated to the distance of 53 μm from the skin surface at the deepest point.

[Comparative Example 3]
The drug was administered and detected in the same manner as in Example 1 except that the conventional electroporation device shown in FIG. 12 was used. That is, electroporation was performed by a conventional method.

12A and 12B are schematic views illustrating the electroporation device used in this comparative example, where FIG. 12A is a plan view and FIG. 12B is a cross-sectional view taken along line XII-XII in FIG.
The device 9 shown here is not a microneedle as an electrode for applying a voltage, but a substantially W-shaped first conductive sheet 94 having a bent portion and a branched portion, and a substantially U-shaped second electrode having a bent portion. 1 is different from the device 1 shown in FIG.
In the device 9, the first conductive sheet 94 is woven into the base material 90 through the groove 90c formed so as to penetrate from the front surface 90a to the back surface 90b of the base material 90, and the exposed surface on the front surface 90a side is An anode sheet 92 is formed. Similarly, the second conductive sheet 95 is woven into the base material 90 through the groove 90c, and the exposed surface on the surface 90a side forms a cathode sheet 93 (not shown). The distance S between the centers of the adjacent anode sheet 92 and the cathode sheet 93 is the same as the distance D between the central axes of the adjacent anode needle 12 and the cathode needle 13 in the device 1. Therefore, the arrangement form of the anode sheet 92 and the cathode sheet 93 viewed from the surface 90a side of the substrate 90 is the same as the anode needle 12 and the cathode needle 13 of the device shown in FIG. 1 except that the shapes of these electrodes are different. .
The first conductive sheet 94 and the second conductive sheet 95 are separately connected to one end of the electric wire 19 via the connection terminal 18, and the other end of the electric wire 19 is connected to the power source 17. . Then, on the back surface 90b side of the base material 90, an insulating bonding sheet 96 is laminated on the back surface 90b, the first conductive sheet 94, or the second conductive sheet 95, and the first conductive The conductive sheet 94 and the second conductive sheet 95 are fixed to the base material 90.
In the device 9, the base material 90 is the same material as the base material 10 of the device 1, and here, a vinyl chloride resin having a thickness of 0.2 mm was used. The first conductive sheet 94 (anode sheet 92) and the second conductive sheet 95 (cathode sheet 93) are made of the same material as the anode needle 12 and the cathode needle 13 of the device 1, both of which are silver here. Then, a thickness of 0.1 mm was used. Further, the bonding sheet 96 is made of the same material as that of the bonding layer 16 of the device 1, and the same material as in Example 1 was used here. The distance S between the centers of the adjacent anode sheet 92 and the cathode sheet 93 is 4 mm, and both the anode sheet 92 and the cathode sheet 93 have a substantially square shape with a side of 2 mm in plan view.

FIG. 11 shows imaging data obtained in this comparative example at the stage of 8 hours after drug application.
From FIG. 11, it was confirmed that the drug had penetrated from the skin surface to a distance of 58 μm at the deepest point.

  Table 1 shows drug administration methods and maximum penetration distances in Examples 1 to 3 and Comparative Examples 1 to 3.

As is clear from the above results, when the penetration distances of the drugs were compared, Examples 1 to 3 were much longer than Comparative Examples 2 to 3. Compared to Comparative Example 1, Comparative Example 2 was 3 μm and Comparative Example 3 was 8 μm longer, whereas Examples 1 and 2 were 78 μm longer and Example 2 was longer. As described above, Examples 1 to 3 have an effect larger than that obtained by adding the effects of Comparative Example 3 and Comparative Example 4, and a synergistic effect exceeding the level expected from the results of Comparative Example 3 and Comparative Example 4. Had. Further, as is clear from the results of Examples 1 and 3, even when the order of electroporation and drug application was switched, no great difference was found in the penetration distance of the drug, and the same excellent effect was shown.
Thus, by using the microneedle that also serves as an electrode and performing electroporation in the skin, a drug penetration effect much greater than that of the prior art was obtained.

  The present invention can be used in the medical field, the beauty field, and the like using pharmaceuticals, cosmetics, quasi drugs, and the like.

  1, 2 ... electroporation device, 12, 22 ... anode needle, 13, 23 ... cathode needle, 120b, 220b ... tip of anode needle, 130b, 230b ... cathode needle Tip of

Claims (3)

  An electroporation device comprising: a microneedle that also serves as an anode as an electrode; and a microneedle that also serves as a cathode.   2. The microneedle also serving as an anode and the microneedle serving as a cathode are provided in plural, and the microneedle serving as an anode and the microneedle serving as a cathode are alternately arranged in a predetermined direction. A device for electroporation as described in 1.   The electroporation according to claim 1 or 2, wherein a tip portion of the microneedle also serving as the anode and a microneedle serving as the cathode is an insertion portion having a length penetrating the stratum corneum of the skin. Device.