JP2002282371A - Low voltage drive type ionophoretic element - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a self-deflection type (inner power drive type) element which is excellent in controlling rapid infiltration of macromolecular drugs and serum concentrations. SOLUTION: A second conductive mineral 6 is layered on one surface of a drug layer 3 that contains non-infiltrating effective components. An insulation layer 2 is provided on the other surface of the drug layer 3. A hollow insulation needle 4 is formed on one surface of the insulating layer 2 opposite to the drug layer 3. On the other hand, an insulation needle with a closed end 5 covered with a first conductive mineral 1 is arranged in the neighborhood of the hollow insulation needle 4. The first conductive mineral 1 that covers the insulation needle with the closed end 5 is advanced in a stripe fashion up to an area not contacting with the skin and is conductively linked with the second conductive mineral 6 in the area not contacting with the skin. The insulation needle with the closed end 5 and the first conductive mineral 1 stripe are separated in space from the hollow insulation needle 4 on the surface of the insulation layer 2 that touches the skin. The materials constituting a free surface of the first and second conductive minerals 1 and 6 are of metals or semiconductors having mutually different electron affinities.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an iontophoresis device for permeating an active ingredient of a drug ion to be permeated into the skin by electric field acceleration.

[0002]

2. Description of the Related Art Transdermal administration has been developed as a desirable administration method because it excels in quantifying the drug concentration in blood and is excellent in local administration and less burdens patients. Iontophoresis is one of the most effective means of promoting the penetration of macromolecular drugs. Iontophoresis is a method in which a soluble ion to penetrate a drug is electrically biased to accelerate an electric field into a skin, which is a part of an electric current path, and is drawn into the skin. In the case of pulse electric current, electroporation is sometimes used. Since the iontophoresis element requires a high electric field strength and a high current density when a polymer drug is administered, the skin under the current-carrying electrode is often damaged. Further, in order to ensure the safety of energization, it is inevitable that the cost of an electric circuit such as a protection device increases. In addition, drugs that react with skin tissue
There is a problem that transdermal administration is not possible due to loss of drug efficacy during permeation and skin trouble.

The inventor of the present invention has proposed a method of using a battery which generates electricity using living skin as an electrolyte at the time of skin contact, and uses a fine needle to cut off the skin using a low-cost, high-safety method capable of administering a drug lacking skin compatibility. We applied for a minimally invasive inforess element that electrically connects the inside and the drug layer (Japanese Patent Application No. 9-32).
No. 1457). The element comprises a first conductive mineral having a metal or semiconductor A on a free surface in contact with a conductive drug layer containing a permeated drug ion, and the first conductive mineral having an electron affinity different from A. And a second conductive mineral having a free surface of a metal or semiconductor B used as a skin and insulated and insulated from the drug layer, respectively, as a positive electrode and a negative electrode, and biasing a biological battery that generates electricity using the skin as an electrolyte. Power supply. Further, hollow fine needles are provided in an insulating layer for electrically blocking the drug layer and the second conductive mineral, and the skin is punctured with the fine needles at the time of skin contact to avoid the stratum corneum and to prevent the permeated drug ions. It has the ability to penetrate into the skin. As a result, it has become possible to efficiently penetrate the polymer drug into the body even with a bias voltage that is low enough not to damage the skin without using an external power supply. Also the skin surface,
In particular, it was possible to avoid the effects of chemical changes of the drug in the stratum corneum, and it became possible to transdermally administer many drugs. However, when rapid penetration of a drug is required, for example, in the case of an acute disease, or in the case of blood concentration control, it is necessary to increase the operation margin of the bias power supply. However, the device is a biological battery using a difference in electron affinity between electrodes, and it is difficult to increase the output.

[0004]

The internal power supply type iontophoresis element using a bio-battery as a power supply has the excellent features that power generation is automatically stopped in the event of a short circuit, and that changes in pH in the skin due to electricity supply to the skin are suppressed. However, on the other hand, there is a problem that the operation margin of the power supply is small as described above. Therefore, in order to increase the operation margin of the internal power supply type iontophoresis element, it is necessary to reduce the power loss and, in particular, the internal loss of the battery. SUMMARY OF THE INVENTION An object of the present invention is to provide an iontophoresis element capable of taking a relatively large operating margin for drug ion deflection so that a high-molecular drug can be rapidly penetrated even when an internal power source (biological battery) having a relatively low electromotive force is used. It is to provide.

[0005]

The living skin is composed of an epidermis region and a dermis region consisting of a stratum corneum, a granular layer, a spiny layer, and a basal layer, and a subcutaneous tissue. The stratum corneum is formed by the accumulation of dead keratinocytes, but the surface is covered with fat secreted by the sebaceous glands to provide smoothness. The conductivity of the stratum corneum is given by the moisture contained therein, but the stratum corneum has a low conductivity because it is densely layered in order to prevent invasion of foreign enemies such as bacteria. Therefore, when the electrode is brought into close contact with the skin surface, the resistance value of the sebum layer plus the stratum corneum reaches several hundred KΩ to several MΩ. On the other hand, the skin region deeper than the granular layer, which is the subepidermal layer, is composed of living cells, and its conductivity is given by body fluid ions flowing between the cells. Therefore, the conductivity of this region is high and the resistivity is several hundred Ω or less. As a result of an experimental study, it was found that about 90% of the internal loss of the above-mentioned biocell occurred in the upper epidermis region composed of the sebum layer and the stratum corneum.

Therefore, in the present invention, a drug layer containing a non-penetrable active ingredient, an insulator layer laminated on the first surface side of the drug layer and having a surface opposite to the drug layer serving as a skin contact surface, A hollow portion is provided in the body layer, and has a hollow end having a free end which can be electrically connected to or connected to the drug layer and the inside of the skin, and has a needle-like shape projecting into the skin from the skin contact surface. A hollow insulator needle, a closed end insulator needle having a closed end for electrically blocking the drug layer and the skin and having a needle-like shape projecting from the skin contact surface into the skin, It is made of a metal or semiconductor A having a structure in which a part of the insulator layer on the skin contact surface side and the closed end insulator needle are conductively and continuously provided on the closed end insulator needle and a part of which is skinned with the closed end insulator needle. A first conductive mineral having a free surface; and a first conductive mineral provided in contact with a second surface of the drug layer and the first conductive mineral. A low-voltage driven iontophoresis device, comprising: a second conductive mineral electrically connected to an object in a non-contact region and having a free surface made of a metal or semiconductor B having a different electron affinity from A. Is disclosed.

The hollow insulator needle and the closed-end insulator needle in the device of the present invention are desired to have high skin piercing ability. For example, they are formed of a hard synthetic resin or the like. The skin depth must be at least deeper than the granular layer, which is the ionic fluid circulation area. At the same time as the element is skinned, the hollow insulator needle and the closed-end insulator needle are skinned to the length of the needle. The ionic permeated active ingredient leached from the hollow insulator needle is biased by the bioelectric cell that comes into contact with the body fluid and quickly penetrates from the subcutaneous region into the blood vessel.

On the other hand, the first conductive mineral covering the closed-end insulator needle generates an electromotive force while being in contact with the body fluid in the skin. That is, at this time, a current flows through an electrically closed circuit of the first conductive mineral → the body fluid → the drug layer → the second conductive mineral → the first conductive mineral. In the device of Japanese Patent Application No. 9-32457 in which the first conductive mineral is merely insulated, the first conductive mineral generates an electrolyte using the stratum corneum, which is the upper part of the epidermis, as an electrolyte. In addition, when the generated current flows through the skin, a large internal loss is generated due to the contact resistance and the stratum corneum resistance, so that the power that can be extracted to the outside of the biological battery is small.

On the other hand, in the device of the present invention, the first conductive mineral contacts the ionic liquid to generate electricity, so that the electrolyte effect is high and the internal loss is small. That is, the power that can be extracted to the outside increases. When the first conductive mineral contacts the body fluid and undergoes a chemical change, its surface can be coated with a chemically stable conductive material such as conductive carbon or a conductive polymer. In this element, the portion of the first conductive mineral that contributes to power generation is substantially only the perforated portion that comes into contact with body fluids, and the insulated portion only exhibits a conducting wire effect. This is considered to be due to the difference in the electrolyte action between the stratum corneum surface and the body fluid. In the present invention, by spatially separating the hollow insulator needle and the closed-end insulator needle, the ionic drug component and the first conductive mineral, that is, both electrodes of the battery are short-circuited in the electrolyte to stop power generation. The danger has been significantly reduced.

[0010]

FIG. 1 is a sectional view showing an example of a structure in which a low voltage driving iontophoresis element of the present invention is in contact with a skin. This element was provided in contact with a drug layer 3, a second conductive mineral 6 provided thereon, a porous marine body layer 7 provided in contact with a lower portion of the drug layer 3, and a lower portion thereof. An insulator layer 2, a hollow insulator needle 4 and a closed-end insulator needle 5 formed on a part of the surface of the insulator layer 2 opposite to 7,
An electric path E connecting the first conductive mineral 1 covering the surface of No. 5 and continuing to the flat portion 2 and 1 and 6 in a non-skinned region
And consisting of

In this cross-sectional view, the fine needles provided on a part of the insulator layer 2 on the skin contact surface side are such that hollow insulator needles 4 having open ends and closed end insulator needles 5 are alternately arranged. In. The closed-end insulator needle 5 is coated with a first conductive mineral 1, which passes through a flat portion of the insulator layer 2 and in a non-skinned region via an electric path E. The connection to the second conductive mineral 6 is illustrated as an abbreviated drawing.
Typically, the diameter of the fine needles 4 and 5 is about 100 μm and the length is about 1 mm, but other values can be taken according to the purpose. In the figure, the size of the fine needle portion is relatively exaggerated more than other portions for easy understanding. The same applies to other element structure diagrams.

The insulator layer 2 has a role of electrically blocking the drug layer 3 from the skin or the skin except for the open end of the fine needle 4. On the surface of the insulator layer 2 opposite to the fine needle forming surface, a porous sponge 7 and a drug layer 3 are laminated. The hollow insulator needle 4 is connected to the drug layer 3 via a hollow portion. The drug layer 3 is often a gel containing an ionic osmotic active ingredient, but a cream base can also be used. Further, the effective component to be permeated in the drug layer is not limited to a component that does not originally exist in a living body. For example, it is also possible to use a protein or DNA of a biological constitution or a stem cell (ES cell). The porous sponge 7 in contact with the drug layer 3 can be impregnated with a conductive liquid, for example, physiological saline. As a result, the ionic drug active ingredient is leached into the conductive liquid and penetrates into the hollow insulator needle 4 together with the conductive liquid.

A second conductive mineral 6 is conductively in close contact with the drug layer 3 on the surface of the drug layer 3 opposite to the surface where the porous sponge 7 contacts. If the metal or semiconductor B forming the free surface of the second conductive mineral 6 chemically reacts with the drug layer 3, the conductive mineral contact surface of B is made of another chemically stable conductive material such as a conductive material. It can be covered with carbon or polymer of nature. As described above, the surface of the second conductive mineral 6 opposite to the drug layer contacting surface is provided with an electric path E to the first conductive mineral 1 (a conductive wire or a direct conductive mineral. (Often used). Even when the metal or semiconductor A forming the free surface of the first conductive mineral 1 formed on the surface of the closed-end insulator needle 5 chemically reacts with the bodily fluid that has come into contact with the skin by perforation, it is stable as in the case of A described above. The surface can be coated with any other conductive material.

The fine needles 4 and 5 are perforated at the tip when the element is in contact with the skin, pass through the sebum layer and the stratum corneum, and pass through the granular layer in the subepidermal region.
It must at least reach the spinous / basal layer.
Since the open end of the hollow insulator needle 4 reaches the dermis and subcutaneous tissue at a deeper part if necessary, the fine needles 4 and 5 are usually 1 mm.
Or longer needle length. Although the porous sponge body 7 is not a necessary condition for the element configuration, it can be made to be able to quickly contact the drug ions with the body fluid when the element is in contact with the skin by impregnating the conductive liquid in advance. The first and second conductive minerals 1 and 6 are selected such that the metals or semiconductors A and B constituting the respective free surfaces have different electron affinities. If the permeated drug ion (active drug component ion) contained in the drug layer 3 is negatively charged, the electron affinity of B is greater than A if the permeated drug ion is positively charged. The material is selected so that the electron affinity of A is large.

When the element is skin-contacted with a skin-contact means such as a bandage as shown in the figure, the fine needles 4 and 5 are pierced at the time of pressing, so that the patient feels slightly uncomfortable or painful. Because of the shallowness of the patient, it is instantaneous and does not cause continuous pain to the patient. The porous sponge body 7 is pressed by the pressure contact, and the conductive liquid fills the hollow portion of the fine needle, and comes into contact with the bodily fluid at the open end of the fine needle 4. After the skin contact, the pressure inside the element is lower than that at the time of the pressure contact, so that the inside of the element becomes a negative pressure. Easily contact with.

On the other hand, the conductive mineral 1 covering the surface of the closed-end insulator needle 5 by perforation reaches at least the subcutaneous layer and comes into contact with the ionic conductive fluid. Body fluids are good electrolytes and have low resistance. Therefore, the electrical closed circuit E (first conductive mineral 1 → intradermal → conductive solution → porous sponge 7 → drug layer 3 → second conductive mineral 6 → first conductive mineral) When the inorganic mineral 1) is formed, a current flows through this closed circuit by an electromotive force based on the difference in electron affinity between the metal or semiconductor A and B. The perforated hollow insulator needle 4 is, as it were, an artificial pore, but unlike an organism-derived pore, the internal electrical resistance is extremely small. The conductive mineral 1 covering the perforated closed-end insulator needle 5
Since at least the distal end portion comes into contact with body fluid, only the region that comes into contact with body fluid preferentially contributes to power generation, and almost no power is generated simply at the site in contact with the stratum corneum above the epidermis. Accordingly, the circuit current selectively flows in the skin deeper than the subepidermal layer in any of the fine needles 4 and 5, and the high-resistance sebum and stratum corneum regions do not contribute to the conduction.

The electromotive force due to the difference in electron affinity between A and B is at most 1. in consideration of cost, safety and stability.
5 to 2 volts is the limit. In the case of such a low electromotive force, when an extremely high-resistance epidermis upper layer such as a sebum layer or a stratum corneum is included in the conduction path, the conduction loss is as high as 1 to 1.5 volts, so that the voltage available for iontophoresis is low. The value is as low as 1 volt or less, and the operation margin of the device is reduced.

Of course, the previous application (Japanese Patent Application No. 9-32457)
By perforating the hollow insulator needle 4 disclosed in (1), it is possible to introduce a high molecular drug ion into the skin and thus into the blood at a relatively low voltage while avoiding the sebum layer and the stratum corneum region. However, the present invention overcomes, for the first time, the instability of electromotive force and the low efficiency of drug introduction due to the weak electrolyte action of the upper epidermal layer, and also avoids a decrease in the operating margin (large internal loss of the battery) as described above. .

The needle diameter of the fine needles 4 and 5 made of a hard resin or the like is about 0.1 to 0.2 mm, and the needle length is also 1 to 2 m.
Since it is about m, if it is sterilized in advance, there is almost no pain in the patient even by perforation, and there is no concern about infection. When the element is removed from the skin, the skin at the perforated area closes immediately, so there is no risk of bleeding or bacterial infection. Therefore, this element can be applied to the skin of various parts of the body including the curved surface part, except for the special case of piercing deep into the skin.

Hereinafter, the present invention will be described in more detail with reference to specific examples. (Part 1) FIG. 2 is a view schematically showing the structure of a low-voltage iontophoresis element in a specific example. FIG. 2A is a bottom view (a bottom view as viewed from the skin contact side), and FIGS. 2B and 2C.
3A is an NN ′ cross-sectional view and an MM ′ cross-sectional view of FIG. If the section taken along the line KK 'in FIG. 2A is obtained, a structural view as shown in FIG. 1 is obtained. In FIG. 2, 1 is the first conductive mineral, 2 is the insulator layer, 3 is the drug layer, 4 is the hollow insulator needle, 5 is the closed end insulator needle, 6 is the second conductive mineral, 7 is It is a porous spongy body.

The first conductive mineral 1 is divided into six pieces 1a-1f and arranged on the insulator layer 2 in a stripe shape. Each piece includes at least one closed end insulator needle 5 therein and covers the entirety of the needle 5. Each of the striped conductive minerals 1 is directly connected to a second conductive mineral 6 on the back surface of the element as shown in FIG. Conductive material A constituting first conductive mineral 1
Is a zinc-excess zinc oxide (thickness 0.5 μm) physically deposited on a Teflon (registered trademark) resin plate (thickness 50 μm), and the stripe width is 1 mm. The zinc-excess zinc oxide is a low-resistance n-type semiconductor, and is formed on a Teflon resin plate serving as the insulator layer 2 by pattern punching and fine needle processing. In the non-contact region of each stripe, a zinc-excess zinc oxide film is formed on upper and lower side surfaces of the stripe region of the Teflon resin plate to form an electrical path.

The drug layer 3 is a conductive gel in which 0.1N KOH and human insulin are dispersed. The hollow insulator needle 4 and the closed end insulator needle 5 are formed on a Teflon resin plate (insulator layer 2) by pressing with a mold in a state where the plasticity has been increased by heating. The total length of the fine needles 4 and 5 is about 1 mm, the outer diameter is about 100 μm, and the inner diameter of the hollow part is about 50 μm.

The conductive material B constituting the second conductive mineral 6 is gold (2 μm thick) plated on a thin copper plate (40 μm thick). The porous sponge 7 is, for example, a polyurethane plate (1 mm thick), and is impregnated with a 0.3% KOH aqueous solution. The element size is, for example, 25 × 25 mm
² This element is pressed against the skin surface of the living body so that the bottom surface shown in FIG. 2 is in skin contact, and the non-skin contact surface is fixed to the skin with a bandage or the like. As a result, the fine needles 4 and 5 are perforated, and their tips reach the dermis, and at the same time, the KOH aqueous solution impregnated in the porous spongy body 7 reaches the dermis region from the opening of the fine needle 4 by pressing. When the pressing is loosened by the end of the pressing operation, the porous sponge body 7 expands, so that the hollow portion of the hollow insulator needle 4 becomes negative pressure, and the bodily fluid in the dermis region gradually enters the hollow insulator needle 4 by capillary action. At the same time, the chemical battery using the first conductive mineral 1 and the second conductive mineral 6 as electrodes starts power generation, 1 → dermis region → hollow portion of hollow insulator needle 4 → sponge 7 → drug layer 3 → Current flows through the 6 → 1 closed circuit.

[0024] The iontophoresis device of this example was mounted on the back of a hairless rat hypertensive to which streptozocin had been administered in advance, and the glucose concentration in rat blood after 30, 60, 90, and 120 minutes. Was measured. For comparison, the element of the invention shown in FIG.
An element composed of a size and a material was prepared and mounted on the back of a hyperglycemic rat as in the present example, and the change over time in the glucose concentration in blood was measured. In the device of this comparative example, since the flat insulator layer 2 occupies the position of the closed-end insulator needle 5, the zinc-excess zinc oxide (first conductive mineral 1), which is the battery negative electrode, cleans the skin surface with an electrolyte. As a result, the closed circuit current flows inside the living body through the upper epidermis.

FIG. 3 shows data obtained by averaging three animals per group in Examples and Comparative Examples. In each case, the blood glucose concentration before insulin administration was standardized as 100. In each case, no mouse skin damage and no change in the surface of the first conductive mineral were observed after 120 minutes of skin contact. FIG. 3 shows that in each case, the blood glucose level was greatly reduced due to the iontophoretic effect of insulin. However, comparing the two element examples, the blood glucose level of the element of this example was 30 minutes after skin contact. It can be seen that the blood glucose level of the device of the comparative example has dropped to the level of the device of the present invention only after about 2 hours, while it has almost reached the minimum value. When the device of the present invention was used, the blood glucose level after 30 minutes was the same level as when 1 unit / Kg of insulin was subcutaneously injected into hyperglycemic rats. In the case of subcutaneous injection, the blood glucose level recorded the lowest value after about 30 minutes as in this example, but it was found that the blood glucose level began to increase rapidly after about 1 hour. As suggested from FIG. 3, when the device of this example is used, a low blood glucose level can be stably maintained for a long time as long as the insulin concentration in the drug layer does not decrease.

The chemical layer 3 is removed and the second conductive mineral 6 is brought into direct contact with the porous spongy body 7, so that the first conductive mineral 1 and the second conductive mineral 6 at the non-skin contact position are located between the first conductive mineral 1 and the second conductive mineral 6. A voltmeter was installed directly on the electrical path, and the voltage taken out of the chemical battery was measured by attaching it to the back of the nude mouse. It was about 0.7 volts. This result indicates that, in the device of the present embodiment in which the first conductive mineral 1 is perforated to the dermis region, the battery output increases due to the high electrolyte effect and the potential drop (internal loss of the battery) due to the upper skin layer. Reduction was achieved at the same time, indicating that the higher voltage applied to the drug layer enhanced the iontophoretic effect.

(Part 2) FIG. 4 is a diagram showing a configuration of an iontophoresis element according to another embodiment of the present invention.
4A is a bottom view of the element viewed from the skin contact side, FIG. 4B is a cross-sectional view of NN ′ of FIG. 4A, and FIG. 4C is MM ′ of FIG.
It is sectional drawing. This element does not use a porous spongy body unlike the case of the previous embodiment, but has an electric path 20 for connecting the first conductive mineral 1 and the second conductive mineral 6 in a non-skinned region. , A load in which a diode 10 and a capacitor 11 are connected in parallel is inserted. This type of element is a pulse element generated by a chemical battery as a power source at the time of skin contact, and is capable of unidirectionally pulsing an energizing current (Japanese Patent Application No. Hei 8-24245).
issue).

In the figure, reference numeral 8 denotes a flexible polyurethane insulating frame (thickness: 2 mm), which serves as a reservoir for the drug layer 3. Drug layer 3 is 0.1% Na
N ₃ containing urea cream 1% of dequalinium chloride (D
(Equalinium Chloride). Reference numeral 9 denotes an adhesive bandage for attaching this element to the skin of a living body. The first conductive mineral 1 is made of gold (thickness 0.5 μm) which is physically vapor-deposited in stripes on the hard fluororesin insulating layer 2 including closed-end insulator needles as the conductive material A. The gold stripe reaches the non-contact region of the element as shown in FIG. 4C, and is connected to the conductive wire 20A as a potential path at that position. The hollow insulator needle 4 and the closed end insulator needle 5 have an outer diameter of 100 μm and a length of 1 mm. The outer diameter of the element was 30 × 30 mm ² .

On the other hand, the second conductive material 6 has a thickness of 40 μm.
A1-Zn-Mg as conductive material B on aluminum foil
Physically vapor-deposited the alloy to a thickness of about 0.5 μm,
Is formed on the contact surface with a conductive carbon film as a protective material. A part of the non-contact surface of the drug layer 3 is connected to the conductive wire 20 and is conductively connected to the first conductive mineral 1 via the parallel load on the back surface (non-skin contact surface of the element) of the bandage 9. In this embodiment, the electron affinity of A in the first conductive mineral composition is larger than B of the second conductive mineral material, and both A and B are metal materials. The parallel load consists of a diode 10 with a reverse breakdown voltage of 1.1 volts and a capacitance 11 of 20 pF.

The element of this example was loaded on the back of a hairless rat, and the blood concentration of a drug-derived component was measured at regular intervals. In the measurement of blood concentration, three rats were regarded as one group, and the average value was taken. When the element was loaded, the peak voltage measured by installing a measuring instrument on the conductor 20A was 2.3 volts, and the frequency was 300 volts.
A sawtooth pulse current of ~ 400 Hz was observed.
For comparison, the closed-end insulator needle 5 in the device of FIG. 4 was removed, and an iontophoresis device having the same material, dimensions, and configuration as that of the present embodiment was prepared and attached to the back of a hairless rat as in the present embodiment. Then, a drug penetration experiment was performed. Also in this case, the frequency of the energizing pulse current was 300-400 Hz, but the peak voltage remained at 1.2 volts. FIG. 5 shows changes in the blood concentration of the component derived from the introduced drug at 30, 60, 90, and 120 minutes after the device was loaded. As shown in the figure, in the case of the present embodiment, the blood concentration rapidly rises, and the blood concentration reaches a saturation value about 100 minutes after loading.
However, in the comparative example, the blood concentration was still increasing 2 hours after loading, indicating that the concentration controllability was poor.

(Part 3) FIG. 6 shows a schematic structure of an iontophoresis element according to still another embodiment of the present invention. (A) of the figure is a bottom view, and (B) is a sectional view taken along the line KK '. Unlike the previous embodiment, this element has a circuit for detecting the intradermal concentration of the drug and a control circuit for the blood concentration of the drug, so that it exhibits excellent characteristics of controlling the blood concentration. That is, as shown in the figure, a pair of detection electrodes 21 and 22 are spatially separated and arranged at a place where the hollow insulator needle 4 is not arranged on the skin contact surface side of the insulator layer 2, When the signal is transmitted to the CPU 26 via the measuring circuit 25, a feedback signal from the CPU 26 is transmitted to the control circuit 27. As a result, the blood concentration higher or lower than the set value is constantly corrected non-invasively (Japanese Patent Application No. 2000-214,197).
000-103298). A pair of detection electrodes 21 and 2
Reference numeral 2 denotes a first conductive mineral 1 and a second conductive mineral 6, each of which is a conductive wire 2 whose surface is insulated on the skin contact side.
The detection signal is measured by the measurement circuit 25 on the back of the bandage
Is transmitted to

This element comprises a measuring circuit 25 and a CPU 26
(E _B ) 28 is built in as a power supply for driving the device, but the iontophoresis itself and the detection of the subcutaneous concentration of the drug are caused by the difference in electron affinity between the first conductive mineral 1 and the second conductive mineral 6. This is done by a chemical battery. Then, the portion of the element which is closer to the skin than the bandages 9 and 9 is disposable,
The back circuit portion 9 is a reused portion. The diameter of the element on the skin contact surface side is 30 mm. The first conductive mineral 1 has a thickness of 50 μm.
n-Ge _0.7 S physical vapor deposited on m Teflon sheet
i _0.3 (about 1 μm thickness), the second conductive mineral 6 has a thickness of 40
1 μm thick palladium physically deposited on a 1 μm A1 sheet. The drug layer 3 is a conductive gel in which 0.5% morphine hydrochloride is dispersed, and has a thickness of 1 mm. The porous sponge 7 is impregnated with physiological saline.

A transdermal drug administration experiment was carried out in which this element was loaded on the back of a NWY hairless rat and the blood concentration was controlled. When measured immediately after loading, the perforated closed-end insulator needle 5 and the second
Of the chemical battery using the conductive minerals 6 as the electrodes respectively (that is, the drug layer applied voltage) was about 1.2 volts. In addition, a pair of detection electrodes 2 measured simultaneously.
The voltage between 1 and 22 was 0.35 volts. First, in order to prepare a biocalibration curve of a drug concentration, several kinds of the above-mentioned elements having different concentrations of morphine hydrochloride dispersed in the drug layer 3 were prepared, attached to the back of a HWY type hairless rat, and passed for a certain period of time. The measurement was performed every time. The measurement is performed by operating the CPU 26 after a predetermined time has elapsed, switching the two standard resistances of the measurement circuit 25, and calculating the resistance value R _d in the skin between the detection electrodes 21 and 22 from the potential drop across the standard resistance read. The blood is collected at each time, and compared with the blood concentration [M] of morphine obtained by chemical analysis (Japanese Patent Application No. 2000-103298). At this time, the control circuit 27 is not driven, and is short-circuited in a state of zero resistance. R _d vs. thus obtained. [M] Using the calibration curve, an experiment on blood concentration control was performed next.

The device shown in FIG. 6 using the drug layer 3 having a morphine hydrochloride concentration of 0.5% was attached to an HWY hairless rat, and
_Rd was measured every 0 minutes. The morphine blood concentration [M] at that time was determined using the above-mentioned calibration curve (not shown), and the set blood concentration [M] was obtained. Concentration control was performed in contrast to the above. That is, the blood concentration [M] measured at that time is the set value [M]. If it is lower, the load resistance of the control circuit 27 is reduced to increase the voltage applied to the drug layer, and conversely, [M] is the set value [M]. If it is higher, the load resistance of 27 is increased, and the voltage applied to the drug layer 3 is reduced. FIG. 7 shows the obtained control results together with the case of the comparative example. In the comparative example, only the closed-end insulator needle 5 in the stripe of the first conductive mineral 1 was removed from the device shown in FIG. This is a control experiment.

In this embodiment, the blood concentration is approximately [M] after about 30 minutes. And excellent density controllability is shown, but it can be seen that the density control takes about 3 hours in the comparative example. This is because, in the case of the comparative example, the external take-out voltage of the chemical battery using the first conductive mineral 1 and the second conductive mineral 6 as electrodes, respectively, is such that the contact resistance and the sebum just below the first conductive mineral 1 The set value [M] because the resistance greatly decreased due to the resistance of the stratum corneum and the stratum corneum (approximately 0.3 volts measured immediately after mounting), iontophoresis did not sufficiently occur, and the operating margin for control was small. This is considered to be due to the increase in deviation from the distance.

Although the present invention has been described in detail with reference to specific embodiments, the present invention is not limited to the above embodiments. For example, the material of the insulator needles 4 and 5 to be perforated may be metal, and a composite material whose surface is covered with an insulating film may be used. The length of the perforation may be such that the stratum corneum is avoided in principle, and may be about 0.5 mm. However, it goes without saying that the delivery efficiency of the drug is improved by reaching the deep part of the skin. The element of the present invention has a needle diameter as small as an acupuncture treatment needle, so it is not suitable for injecting a drug such as injection, etc., but maintains a required concentration of the drug without causing pain to the patient by iontophoresis. Can be administered in a controlled manner. It is obvious that the first and second conductive mineral materials used as the electrodes for the chemical battery can be selected from many metals and semiconductor groups according to the purpose without being limited to the examples.

[0037]

As described above, according to the present invention, the self-biasing type (in the iontophoresis device, not only can the drug be efficiently delivered into the skin by applying a very low voltage drug layer, By greatly reducing the internal loss in the power region, it is possible to increase the operation margin of the device, thereby significantly improving the controllability of the drug blood concentration and damaging the skin. In addition, it is possible to administer the drug at a high concentration and to rapidly penetrate the drug, and to widen the selection range of the electrode material (metal or semiconductor) constituting the internal power supply battery for iontophoresis bias. Of the two electrodes, the non-drug side electrode is perforated and only the perforated part that comes into contact with body fluids contributes to power generation, and the skin contacted part shows almost only a function as a conductive path, so sweating It is possible to prevent the inter-electrode short circuit due to etc., the power generation stop accident.

[Brief description of the drawings]

FIG. 1 is a diagram showing the iontophoresis element of the present invention when worn on the skin.

FIG. 2 is a diagram showing an element configuration in an embodiment.

FIG. 3 is a diagram showing a drug blood penetration effect according to an example in comparison with a comparative example.

FIG. 4 is a diagram showing an element configuration according to another embodiment.

5 is a diagram showing a drug permeation effect by the iontophoresis device of FIG. 4 in comparison with a comparative example.

FIG. 6 is a diagram showing an element configuration according to still another embodiment.

FIG. 7 is a diagram showing controllability of a drug blood concentration by the iontophoresis element of FIG. 6 in comparison with a comparative example.

[Explanation of symbols]

 REFERENCE SIGNS LIST 1 First conductive mineral 2 Insulating pair layer 3 Drug layer 4 Hollow insulator needle 5 Closed-end insulator needle 6 Second conductive mineral 7 Porous sponge body 8 Insulator frame 9 Adhesive plaster 10 Diode 11 Capacity 20, 23 , 24 Conducting wires 21, 22 A pair of detecting electrodes 25 Measurement circuit 26 CPU 27 Control circuit 28 Battery A, B Metal or semiconductor

Claims (8)

[Claims] 1. A drug layer containing an active ingredient to be permeated, an insulator layer laminated on a first surface side of the drug layer, and a surface opposite to the drug layer serving as a skin contact surface, and the insulator layer The hollow portion has an open end that can be electrically connected to or connected to the drug layer and the inside of the skin, and has a needle-like shape protruding into the skin from the skin contacting surface. A hollow insulator needle, a needle-like closed end insulator needle whose shape protrudes into the skin from the skin contact surface, a part of the insulator layer on the skin contact surface side, and the closed end insulator needle. A first conductive mineral having a free surface made of metal or semiconductor A having a structure in which a part thereof is perforated with a closed-end insulator needle, the conductive mineral being provided continuously in a conductive manner; 2 and is electrically connected to the first conductive mineral in a non-contact region, and is different from A A second conductive minerals made of a metal or semiconductor B has a force, more made low voltage drive type iontophoresis device. 2. The hollow portion of the hollow insulator needle is filled with a conductive liquid in advance, and / or the drug layer side can be set to a negative pressure as compared with the open end side.
The low voltage drive type iontophoresis device according to the above. 3. When the active ingredient to be permeated is anionic or electronegative with respect to the skin, the A is the B
A metal or a semiconductor having a lower electron affinity, wherein the A has a higher electron affinity than the B if the permeated active ingredient is cationic or electrically positive with respect to the skin The low voltage drive type iontophoresis device according to claim 1 or 2, wherein 4. The method according to claim 1, wherein said hollow insulator needle and said closed-end insulator needle have a length such that they reach a position deeper than a granular layer in an epidermis region during perforation. The low voltage drive type iontophoresis device according to the above. 5. The insulator layer comprises a laminate of a water-permeable flexible insulator layer having a predetermined thickness and a non-water-permeable insulator layer having the hollow insulator needle and the closed end insulator needle. Item 5. The low voltage drive type iontophoresis device according to any one of Items 1 to 4. 6. The first conductive mineral is disposed on the insulator layer as a plurality of striped films electrically separated from each other, and each of the striped films is a non-skinned region. 2. A conductive connection to the second conductive mineral.
6. The low-voltage driven iontophoresis device according to any one of claims 1 to 5. 7. An electric circuit for intermittently pulsing an electric current on an electric path connecting the first and second conductive minerals in a non-contact region. 7. The low voltage drive type iontophoresis element according to any one of 6. 8. A sensor for measuring the intradermal or blood concentration of the effective ingredient to be permeated is provided on the surface of the insulator layer on the skin contacting surface, and the output of the sensor is measured and 8. A device for controlling the concentration of a drug to be penetrated by returning to an electric path connecting the first and second conductive minerals in a non-skin contact area, and incorporating a device on the electric path. The low voltage drive type iontophoresis device according to any one of the above.