JP4182555B2 - Iontophoresis element for transdermal administration - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an iontophoresis-type transdermal drug delivery device in which permeation drug ions are accelerated by electric field and permeated subcutaneously.
[0002]
[Prior art]
Transdermal medication has been developed as a desirable medication method because it has excellent blood concentration of the drug and local administration, and has a low patient burden. Among these, various penetration promoting methods are being studied because high molecular weight drugs are difficult to penetrate subcutaneously only by skin contact. Among them, iontophoresis is attracting attention as a promising method. Iontophoresis is a method in which soluble permeated drug ions are electrically biased and drawn into the skin, which is part of the current path, by accelerating the electric field, and mainly when pores, sweat glands, and sebaceous glands become osmotic pathways. It is considered. The case of DC electric field driving may be distinguished from iontophoresis, and the case of pulse electric field driving may be distinguished from electroporation. In electroporation, the idea is that a hole is opened in a cell membrane and a drug enters when a potential of a skin cell changes instantaneously.
[0003]
Since iontophoresis uses an electrophoretic phenomenon, application of an electric field or current is indispensable. In continuous administration, the skin under the energized electrode is often damaged. In particular, the higher the drug is, the more difficult it is to penetrate. Therefore, high electric field strength and high current density are required, and skin damage is likely to occur. In order to alleviate this, a pulse energization method has been generally used.
By the way, in order to perform these iontophoresiss, a power supply for a call is necessary, and power supply power (100V or 200V alternating current) has been often used in the past. However, miniaturization has gradually progressed in terms of convenience and safety, and in recent years, battery power drive has been performed. Necessary electric circuits are also integrated into an IC, and can be used as a portable device.
[0004]
On the other hand, so-called internal power source type iontophoresis, which attempts to penetrate the drug while generating electricity with the skin without using an external power source, has been proposed. For example, a metal salt with a high standard unipolar potential is contacted with a low metal at the same time to form an electrical closed circuit, and the difference in chemical potential is used to generate electricity. Specifically, examples of silver salts (silver electrodes) and Mg alloys are shown (Japanese Patent Application No. 59-59244). On the other hand, as a biological battery in which the redox reaction is continued by stably connecting the difference in chemical potential, a metal having a high standard monopolar potential and a metal having a low standard monopolar potential are used as electrodes, respectively. An internal power supply type iontophoresis element in which an anionic drug unrelated to the invention is arranged has been filed by the present applicant (Japanese Patent Application No. 1-150654). This method was further developed into a positive electrode / drug layer / separation layer / negative electrode laminated one-sheet disposable type (Japanese Patent Application No. 6-220193). In addition, skin power generation is achieved by improving the drug penetration efficiency by devising the shape of the skin electrode (indifferent electrode) and the appearance of a type that can be applied to both cation and anion drugs (Japanese Patent Application No. 8-310848). The application range of type iontophoresis has greatly expanded.
In this internal power supply type device, a pulse-type transdermal drug delivery device is made possible by utilizing a combination of an external capacitor and a diode (Japanese Patent Application No. 8-24245). In this pulse-type element, the pulse energization frequency band is distributed in the subcutaneous region, and the synaptic plasticity is increased by repeated micro-stimulation applied to the peripheral nerve synapse, resulting in long-term physiological activation of the skin in the region. By setting the enhancement effect inducing region, there is an advantage that the drug uptake efficiency can be further promoted.
[0005]
[Problems to be solved by the invention]
Among the iontophoretic transdermal dosing elements described above, in the external power supply method, the power supply circuit, the control circuit, the circuit part such as the pulse circuit, and the power supply part form a factor of cost increase. In addition, since the transdermal administration device having these electric circuits belongs to an electronic device, it is necessary to obtain approval for a medical device when put into practical use. On the other hand, since the drug to be loaded requires the approval of the medicine, the approval across both fields is required, which is a big obstacle to practical use.
Further, in the external power supply system, even if the overcurrent is prevented by the control circuit, the pH change due to the reducing action generated under the electrode on the living body skin cannot be relieved, and it is difficult to avoid skin damage. This tendency is particularly remarkable in the direct current type.
[0006]
On the other hand, even in the internal power supply system, the combination of a metal salt with a high standard unipolar potential (positive electrode) and a low metal (negative electrode) cannot prevent the hydroxylation reaction of the negative electrode, and the negative electrode deteriorates rapidly. There is a big problem that the electromotive force cannot be maintained.
In the internal power supply method, the maximum electromotive force is determined in principle by the difference in electron affinity between the two substances constituting the positive and negative electrodes. However, the electrolyte effect is small compared to the external power supply method, so naturally the maximum electromotive force that can be used is small. However, when percutaneous drugs with large molecular weights such as peptides and proteins are administered transdermally, there are many drugs that cannot obtain an effective osmotic concentration due to insufficient electromotive force in the internal power supply system.
[0007]
An object of the present invention is to provide an iontophoresis-type transdermal drug delivery device capable of effectively infiltrating a permeation drug having a large molecular weight subcutaneously even when an internal power source (biological battery) having a relatively low electromotive force is used. It is.
[0008]
[Means for Solving the Problems]
  The present inventionA drug layer in which a permeation drug is dispersed on a gel-like substrate or a plastic substrate;,
  Laminated on this drug layer, the surface opposite to the drug layer is a skin contact surface, and an insulating layer having a through-hole,
  A hollow insulator needle that is inserted through the through-hole of this insulating layer, one end of both open ends is in contact with the drug layer, and the other end protrudes outside the insulating layer;
  the aboveProvided on the skin contact surface of the insulation layer,Made of metal or semiconductor A that forms part of the skin contact surface,A first conductive mineral having a free surface;
  A second conductive mineral that is provided in contact with the drug layer and is electrically connected to the first conductive mineral and is made of a metal or semiconductor B having an electron affinity different from A, and has a free surface;
  Consisting of
  The insulating layer changes its volume when pressed against the region including the drug layer when contacting the element, whereby an iontophoresis-type transdermal drug is applied so that the hollow portion of the hollow insulator needle is at a negative pressure. An element is disclosed.
[0009]
  Furthermore, the present invention providesA drug layer in which a permeation drug is dispersed on a gel-like substrate or a substrate such as plastic,
  Laminated on this drug layer, the surface opposite to the drug layer is a skin contact surface, and an insulating layer having a through-hole,
  A hollow insulator needle that is inserted through the through-hole of this insulating layer, one end of both open ends is in contact with the drug layer, and the other end protrudes outside the insulating layer;
  the aboveProvided on the skin contact surface of the insulation layer,Made of metal or semiconductor A that forms part of the skin contact surface,A first conductive mineral having a free surface;
  A second conductive mineral that is provided in contact with the drug layer and is electrically connected to the first conductive mineral and is made of a metal or semiconductor B having an electron affinity different from A, and has a free surface;
  Consisting of
  An insulating layer is provided on the side surface of the drug layer, and the volume of the insulating layer is changed by pressing the region including the drug layer when the element is in contact with the element so that the hollow portion of the hollow insulator needle is negatively pressured. An iontophoretic transdermal dosage element is disclosed.
[0010]
  Furthermore, the present invention discloses a transdermal administration device in which a hollow portion of the hollow insulator needle is filled with a conductive liquid in advance.
[0011]
  According to the present invention, the bodily fluid and the permeated drug are conductively contacted by the negative pressure action in the hollow insulator needle by puncturing the hollow insulator needle to a depth below the epidermal granule layer. In use, when the first conductive mineral touches, a biological battery is formed, and the first conductive mineral → second conductive mineral → drug layer → intradermal → close of the first conductive mineral A current flows through the circuit, and drug ions dispersed in the drug layer selectively and rapidly permeate into the skin through the conductive liquid (body fluid) filled in the hollow insulator needle by the iontophoresis effect.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 is a cross-sectional view showing an example of an iontophoretic element for transdermal administration of the present invention. This element includes a drug-dispersed substrate layer 3, a second conductive mineral layer 8 provided thereon, an insulator layer 2 provided thereunder, and a part of the skin contact surface of the insulator layer 2. The first conductive mineral layer 1 provided on the substrate, the plurality of (four in the figure) hollow insulator needles 4 (4A to 4D) provided on the insulator layer 2, and the insulation that subdivides the base material layer 3 It consists of the body 20 (the end insulator in it has the function of external shielding). The first and second conductive mineral layers 1 and 8 are electrically connected (lead wires or both are in direct contact) as indicated by dotted lines.
One end of the hollow insulator needle 4 is connected to the lower part of the drug dispersion base material layer 3 and the other end protrudes to the outside. The protruding length of the needle 4 is a system length from the surface of the skin to the granule layer / spine layer / basal layer through the sebum layer and the stratum corneum, and is, for example, 1 to 2 mm. The drug dispersion base layer 3 is filled with a drug to be inserted into the body. The drug dispersion base material layer 3 is a layer having a permeation drug inside, and the drug gel itself is encapsulated or dispersed in plastic or the like. The bottom layer 2A is made of a penetrating material that can be opened or a drug gel can be taken in and out. This bottom layer 2A is connected to the inside of the hollow insulator needle 4 via a liquid.
The first and second conductive mineral layers 1 and 8 each have at least a free surface made of a metal or a semiconductor A or B, and the second conductive mineral 8 is an electron different from the first conductive mineral 1. Choose to have a good affinity.
FIG. 2 shows a state of using the device of FIG. The epidermis region is drawn larger than the actual magnification. After this element is pressed against the skin surface, the needle 4 is punctured in any layer of the subepidermal region 7 composed of a granular layer / spinned layer / basal layer. Reference numeral 6 denotes an upper skin region composed of a sebum layer and a stratum corneum. The region 7 is a region existing in the lower part (deep part) of the region 6.
[0013]
The perforated hollow insulator needle 4 penetrates at least the upper epidermis region (sebum layer / keratin layer) 6 and is deeper than the granule layer of the epidermis region 5, that is, the subepidermal region (granular layer / spinous layer / basal layer). 7 has been reached. The depth of skin penetration is at most 1 to 2 mm. Therefore, there is a feature that only a slight pain is felt at the time of skin penetration, and the patient is not sustained during use.
The hollow insulator needle 4 is pre-filled with a conductive liquid, for example, physiological saline before percutaneous, or the pressure changes at the interface 2A between the drug dispersion base material layer 3 and the insulator layer 2 at the time of percutaneous. The hollow insulator needle 4 is generated so as to have a negative pressure. As a result, as shown in the figure, the body fluid rises in the hollow insulator needle 4 by the capillary action from the region deeper than the granule layer of the epidermis. Body fluids have ionic conductivity properties. As a result, the drug-dispersed substrate layer 3 and the ion conductive body fluid come into contact with each other through the hollow insulator needle 4.
The epidermal region 5 is divided into two regions according to physical properties. The upper epidermis region (sebum layer / keratin layer) 6 is electrically extremely high resistance (several hundred KΩ to several MΩ), and the conductive component is mainly contained in the stratum corneum when sweat is not distributed on the surface. It is moisture. On the other hand, the subepidermal region (granular layer / spinous layer / basal layer) 7 has an electrically low resistance (several hundred Ω or less), and the conductive component is an ionic fluid that moistens cells. Ionic body fluids also contain water, but extravasating blood components such as leukocytes and lymph are also important components.
[0014]
When the conductive mineral 1 is touched simultaneously with the perforation of the hollow insulator needle 4, an electrical closed circuit (mineral 1 → mineral 8 → drug-dispersed base material layer 3 → needle) is formed between the transdermal dosage element and the skin. 4 inside → inside skin → skin → mineral 1) is formed, an electromotive force is generated due to the difference in electron affinity between the metal or semiconductor A and B, and a circuit current flows. The perforated hollow insulator needle 4 forms an artificial pore, so to speak, unlike an organism-derived pore, the internal electrical resistance is remarkably small, so that the circuit current locally flows through this path. That is, the penetration of the drug into the skin by iontophoresis is selectively performed through the inside of the hollow insulator needle 4. The above-mentioned electromotive force due to the difference in electron affinity between A and B is limited to at most 1.5 to 2 volts in consideration of cost, safety and stability. In the case of normal percutaneous absorption, many polymer drugs that require transdermal medication such as peptides and proteins due to the potential drop due to the high resistance sebum layer and stratum corneum and the effect of blocking foreign body penetration It is difficult to ensure an effective blood concentration. However, with the apparatus of the present invention, a sufficient amount of penetration is possible.
[0015]
According to the method of the present invention, it is possible to transdermally administer some drugs that are decomposed in the epidermis region, particularly the sebum layer and the stratum corneum, such as dexamethasone and prostaglandin. The hollow insulator needle 4 can be deeply pierced to the dermis and subcutaneous tissue as necessary. The hollow insulator needle 4 made of hard resin or the like is, of course, sealed in a sterilized state before use and has an outer diameter of about 0.1 to 0.2 mmΦ. Since the puncture is usually performed only to a depth of 1 to 2 mm at most, the patient feels almost no pain, and when the transdermal dosage element is removed from the skin after use, the skin at the puncture site is again without bleeding. Since it is closed, virus infection can be prevented. Therefore, it can be affixed to the skin of various parts of the body surface except in the special case of deep puncture.
[0016]
The permeation drug comes into contact with the living body only through the conductive body fluid filling the inside of the needle 4. Since the outer portion of the needle is insulative, the separation of the conductive mineral 1 and the drug-dispersed substrate layer 3 at the skin site is much easier than the conventional laminated one-sheet type element that does not use the hollow insulator needle 4. become. Therefore, even if the device is used continuously for a long time, the conductive mineral 1 and the drug-dispersed base material layer 3 are short-circuited on the skin during use to stop power generation and prevent an accident that iontophoresis does not occur. it can. Such accidents have been observed with conventional laminated one-sheet type elements when the skin surface is significantly sweated or the gel of the drug dispersion base material softens.
[0017]
Hereinafter, the present invention will be described in more detail with reference to specific examples.
(Part 1)
FIG. 3 shows a schematic structure of a transdermal administration device according to an embodiment. FIG. 3A is a bottom view (a bottom view seen from the skin contact side), and FIG. 3B is a cross-sectional view. In the figure, 1 is a first conductive mineral, 2 is an insulator layer, 20 is a separation insulator for subdividing the substrate layer 3, 3 is a drug-dispersed substrate layer, 4 is a hollow insulator needle, Reference numeral 8 denotes a second conductive mineral. Further, in FIG. 3, a positive electrode / drug layer / separation layer / negative electrode was formed as a disposable internal power supply type transdermal administration element in a single sheet. In this embodiment, the separation between the electrodes is facilitated, and a local energization stop accident due to the contact between the electrodes on the skin surface can be suppressed, thereby enabling efficient drug delivery.
The conductive mineral 1 is composed of six substantially L-shaped stripe pieces 1A to 1F provided on the insulator 2, and each stripe piece 1A to 1F is connected to the conductive mineral 8 on the back surface. The four insulating layers 21 to 24 surrounded by the stripe pieces 1A to 1F and divided by the insulating layer 20 have six hollow insulator needles 4 regularly arranged vertically and horizontally. The cross section is as shown in FIG. The conductive mineral 1 is obtained by oxidizing the surface of a galvanized iron film having a thickness of 30 μm to form an oxygen-deficient zinc oxide semiconductor A on the surface. The separating insulator 20 is a foamed polyethylene having a thickness of 2 mm, the insulating layer 2 is a fluororesin plate having a thickness of 100 μm, and the drug-dispersing base layer 3 is a conductive gel in which 0.01 N KOH and human insulin are dispersed. The hollow insulator needle 4 is made of the same material as that of the insulator layer 2. For example, the hollow insulator needle 4 is formed by pressing a fluororesin in a thermoplastic state to finish the hollow needle, and is integrated with the insulator layer 2. The length of the hollow needle protruding outside the element is about 1 mm, the outer diameter is about 150 μm, and the inner diameter is about 80 μm. The conductive mineral 8 is a gold-plated iron film having a thickness of 30 μm. The thickness of the plating layer (gold) is about 3 μm.
[0018]
The size of the device for transdermal administration of this example is, for example, 25 × 25 mm.²It is. When this element is compressed once before being attached to the skin, the foamed polyethylene insulator 2 bends, and at the same time, the conductive gel oozes from the drug-dispersed substrate layer 3 to the hollow portion of the hollow insulator needle 4.
Next, when the element is attached with an adhesive bandage after contact with the pressure skin, the foamed polyethylene is released from the compressed state, so that the inside of the hollow insulator needle 4 which has been stabbed is in a negative pressure state and reaches deeper than the grain layer. The body fluid rises in the needle from the tip opening portion of the hollow insulator needle 4 and comes into contact with the conductive drug gel that has penetrated to the upper part of the needle due to capillary action. As a result, a closed circuit of conductive mineral 1 → conductive mineral 8 → drug dispersed base material layer 3 → hollow insulator needle 4 inside → skin (including the inside) → conductive mineral 1 is formed, and gold and zinc oxide Power generation by a chemical battery having positive and negative electrodes, respectively, causes a circuit current to flow.
[0019]
The transdermal dosing element of this example was attached to the back of a hairless rat that had been hyperglycemic in advance by administering streptozotocin, and the glucose concentration in the rat blood was measured 60 minutes, 120 minutes, 180 minutes, and 240 minutes later.
For comparison, an element obtained by removing the insulator 2 and the hollow insulator needle 4 from the element shown in FIG. 3 (other elements for transdermal administration composed of exactly the same pattern, size, and material) was prepared. A change in blood glucose concentration was examined by wearing it on the back of hairless rats with high blood sugar.
The data which took the average value as 3 animals in each group are shown in FIG. In either case, the blood glucose concentration before insulin administration is normalized to 100. After 240 minutes, no skin damage was observed in this example or the comparative example.
[0020]
FIG. 4 shows that percutaneous absorption of insulin occurs in any case, but it can be seen that a significant decrease in glucose blood concentration can be obtained in a shorter time than in the comparative example. In the case of the comparative example, the relative blood glucose concentration tends to saturate at 50 to 55% before administration, and a sufficient healing effect cannot always be obtained even by prolonged insulin transdermal administration. Suggests. On the other hand, in the case of the Example, it turned out that the effect equivalent to subcutaneous injection is acquired.
That is, it was found that a polymer drug such as human insulin having a main component of hexamer and a molecular weight of 15,000 or more can also be effectively iontophoresed at a low voltage according to the present invention.
[0021]
(Part 2)
A beaker was filled with 0.05% NaCl (pH 7.2), and an ICR nude mouse dorsal skin was placed on the beaker for in vitro iontophoresis. The lower surface of the skin membrane was in contact with the aqueous solution, and the transdermal dosing element of the present invention was loaded on the upper surface. In this embodiment, the element having the pattern and dimensions shown in FIG. 1 was used. The conductive mineral 1 was a 30 μm-thick gold-plated copper film, and the drug-dispersed substrate layer 3 was 1% Decalinium Chloride C.₃₀H₄₀Cl₂N_FourThe agar gel and the conductive mineral 8 in which the surface of the tin-plated iron film having a thickness of 30 μm is oxidized to form SnO on the surface layer.₂The difference from the previous embodiment is that the n-type semiconductor is formed.
In the transdermal drug delivery device of this example, when the hollow insulator needle 4 was punctured, special care was taken not to penetrate the skin membrane and directly contact the NaCl aqueous solution.
[0022]
As a comparative example, an element for transdermal administration having the same material, pattern, and size as those in the above-described embodiment except for the insulator layer 2 and the hollow insulator needle 4 was prepared, and another nude mouse was removed. Affixed to the skin membrane.
In either case, the aqueous solution in the beaker was sampled over time after the start of the experiment, and the concentration of decalinium chloride in the aqueous NaCl solution was measured. Data measured every hour is shown in FIG. Compared with the comparative example, this example showed a very high (about 5.5 times) iontophoresis effect. In the case of in vitro, there is no physiological activation of the skin due to energization, and therefore iontophoresis in a situation where the effect of opening pores and sweat glands, which are the main pathways of percutaneous penetration, cannot be expected. When applied on the stratum corneum, the penetration efficiency of drug ions is lower than in vivo. However, in the case of the present invention, iontophoresis is induced in the drug layer via a body fluid (or a simulated body fluid such as physiological saline) in the ion conduction region below the stratum corneum, so that high penetration efficiency is maintained. . This high penetration efficiency can be obtained not only because the barrier of the drug permeation path is lowered, but also because the substantially higher electric field is applied to the drug ions due to the lower internal loss of the electromotive force generated thereby, and the drift velocity is increased. Conceivable.
As described above, according to the present invention, iontophoresis can be performed by substantially excluding the influence of the sebum layer and the stratum corneum having a very high electrical resistance and a large capacitance. Not only can skin damage be avoided by driving and high penetration efficiency can be obtained, but also the influence of electrical polarization, which is said to be caused by application of a unidirectional voltage, can be minimized.
[0023]
(Part 3)
6A and 6B are views showing the structure of a transdermal drug delivery device in still another embodiment of the present invention, FIG. 6A is a bottom view, and FIG. 6B is a cross-sectional view taken along line MM ′. In this element, a parallel load of a capacitor 9 and a diode 10 is inserted in an electrical path for short-circuiting the conductive mineral 1 and the conductive mineral 8 of the element shown in FIG. This type of element uses a chemical battery generated at the time of skin contact as a power source, and the energization current can be converted into a unipolar pulse (Japanese Patent Application No. 8-24245). Element size is 30x30mm²It was.
The conductive mineral 1 is an iron film having a thickness of 30 μm, which is metallic zinc formed by plating the free surface. The conductive mineral 8 is an iron film having a thickness of 30 μm and having a surface plated with platinum. The insulator 20 for separation is a foamed polyurethane with a thickness of 3 mm, and the insulator layer 2 and the hollow insulator needle 4 are made of polycarbonate. The needle length is about 1.5 mm. The drug-dispersed substrate layer 3 is 0.1% NaN_Three2% L-ascorbic acid is dispersed in the contained hard urea cream. The capacitor 9 is 20 pF, and the reverse breakdown voltage of the diode 10 is 0.6V.
[0024]
The conductive mineral 1 was pressed against the back of the HWY hairless rat, the hollow insulator needle 4 was perforated and fixed with a bandage, and the blood concentration of vitamin C was examined at regular intervals. The blood concentration was 3 per group, and the average value was taken. When the element was loaded, the peak value of the electromotive voltage measured between the conductive mineral 1 and the conductive mineral 8 was 0.85 V, and a sawtooth wave pulse current having a frequency of 300 to 360 Hg was observed.
For comparison, except for the insulator layer 2 and the hollow insulator needle 4 except for the insulator layer 2 and the hollow insulator needle 4, an element for transdermal administration composed of exactly the same material, design and size was prepared, and the HWY hairless rat Vitamin C iontophoresis was carried out. In this case as well, a sawtooth wave pulse current having a frequency of 300 to 360 Hz flowed through the circuit as described above.
[0025]
FIG. 7 shows the subcutaneous penetration concentration of vitamin C obtained in this example and the comparative example over time. The pulse frequency used in this example and the comparative example belongs to a frequency band that enhances the plasticity of peripheral nerve synapses and exhibits a long-term potentiating effect (LTP effect), thereby causing physiological activation of the skin. Although not shown in the figure, vitamin C can be obtained using a direct current type transdermal medication device (conventional device without a hollow insulator needle 4 with a parallel load consisting of a capacitor 9 and a diode 10) of the same material, design and size. When administered, it was found that only about 60% of the comparative example penetrated when loaded for 3 hours.
It can be seen from FIG. 7 that the device of this example exhibits a penetration capability that is at least twice as high as that of the device of the comparative example. In the comparative example, the blood concentration saturated with time. This is also considered to be the effect that the pH of the skin surface changed during transdermal administration, and the difference from the isoelectric point of the drug became smaller. However, in this example, no saturation was observed even after 5 hours, indicating the possibility of avoiding the influence of pH change on the skin surface.
[0026]
Although the present invention has been described in detail using the above embodiments, the present invention is not limited to the above embodiments. For example, the hollow insulator needle to be punctured may be made of metal and the outside thereof may be coated with an organic or inorganic insulating film. Further, in principle, the depth to be punctured should be punctured up to the stratum corneum, so that the minimum purpose can be achieved by entering about 0.5 mm from the surface. However, it is also true that the penetration rate of the drug increases as the skin is deeply penetrated. When it is desired to administer locally to the deep part of the body, for example, when a pressure injection (instillation drip) is used, the diameter of the needle to puncture is painful to the patient, but according to the method of the present invention, the needle diameter is Because only the outer diameter used is sufficient, the patient's pain is greatly reduced.
The magnitude of the bioelectromotive force is basically determined by the difference in electron affinity between A that forms the free surface of the first conductive mineral and B that forms the free surface of the second conductive mineral. However, according to the present invention, even when a combination of A and B that causes only a lower electromotive force than in the above-described embodiments is used, it is possible to penetrate the polymer drug. For example, in the case of human insulin, it has been confirmed that transdermal administration can be performed even when a transdermal administration element having a voltage as low as 0.1 V as measured by an external circuit of a biological battery is used.
In the above embodiment, the biological battery is used as the power source for pulsing the energization current. However, it is of course possible to use an external power source together with the control circuit. In this case, it goes without saying that various shaped pulses such as a rectangular wave and a triangular wave can be used in addition to the sawtooth wave pulse. Further, although the number of needles 4 is plural, there may be one example. There are also structures such that only the needle 4 can be removed, or the insulating layer and the needle can be removed. Further, there is a method in which an insulator layer with needles for a small region (21 to 24 in FIG. 3) with the needles 4 is made and this is adhered to the lower part of the dispersion base material layer 3. Further, the separating insulator 20 may be eliminated to form a uniform base material layer 3. However, in that case, only the insulator on the side portion from which the drug does not escape from the base material layer 3 to the outside of the side portion is left.
[0027]
【The invention's effect】
As described above, according to the present invention, a polymer drug can be efficiently permeabilized subcutaneously even when an internal power-source iontophoresis element with low electromotive force that does not damage the skin is used. In addition, the drug can be effectively percutaneously absorbed while minimizing the influence of the physical and chemical action on the skin surface, for example, the influence of pH change and the chemical change of the drug in the sebum layer and stratum corneum. Furthermore, in a disposable internal power supply type transdermal drug delivery device that has a positive electrode / drug layer / separation layer / negative electrode layered into a single sheet, separation between the electrodes is facilitated, and local energization interruption due to contact between the electrodes on the skin surface is suppressed. There is an advantage that efficient drug delivery is possible.
[Brief description of the drawings]
FIG. 1 is a diagram showing an element for transdermal administration of the present invention.
FIG. 2 is a diagram showing a use state of a transdermal administration element.
FIG. 3 is a diagram showing an embodiment of the present invention.
FIG. 4 is a diagram showing the effect of penetration into a drug skin according to an example as compared with the case of a comparative example.
FIG. 5 is a graph showing the drug penetration rate according to another example in comparison with the comparative example.
FIG. 6 is a diagram showing an element for transdermal administration in still another embodiment.
7 is a graph showing the drug penetration rate by the transdermal administration device of FIG. 6 in comparison with the comparative example.
[Explanation of symbols]
1 Conductive mineral
2 Insulator layer
3 Drug dispersion base material layer
4 Hollow insulator needle
5 Epidermis area
6 Sebum layer / stratum corneum
7 Granule layer / spiny layer / basal layer region
8 Conductive minerals
9 capacity
10 Diode
11 Bandage
20 Insulator
A, B Metal or semiconductor

Claims (6)

A drug layer in which a permeation drug is dispersed on a gel-like base material or a base material such as plastic ,
Laminated on this drug layer, the surface opposite to the drug layer is a skin contact surface, and an insulating layer having a through-hole,
A hollow insulator needle that is inserted through the through-hole of this insulating layer, one end of both open ends is in contact with the drug layer, and the other end protrudes outside the insulating layer;
Provided in the skin contact surface of the insulating layer, made of a metal or semiconductor A forms part of skin contact surface, a first conductive mineral having a free surface,
A second conductive mineral that is provided in contact with the drug layer and is electrically connected to the first conductive mineral and is made of a metal or semiconductor B having an electron affinity different from A, and has a free surface;
Consisting of
The insulating layer changes its volume when pressed against the region including the drug layer when contacting the element, whereby an iontophoresis-type transdermal drug is applied so that the hollow portion of the hollow insulator needle is at a negative pressure. element. A drug layer in which a permeation drug is dispersed on a gel-like substrate or a substrate such as plastic,
Laminated on this drug layer, the surface opposite to the drug layer is a skin contact surface, and an insulating layer having a through-hole,
A hollow insulator needle that is inserted through the through-hole of this insulating layer, one end of both open ends is in contact with the drug layer, and the other end protrudes outside the insulating layer;
Provided in the skin contact surface of the insulating layer, made of a metal or semiconductor A forms part of skin contact surface, a first conductive mineral having a free surface,
A second conductive mineral that is provided in contact with the drug layer and is electrically connected to the first conductive mineral and is made of a metal or semiconductor B having an electron affinity different from A, and has a free surface;
Consisting of
An insulating layer is provided on the side surface of the drug layer, and the volume of the insulating layer is changed by pressing the region including the drug layer when the element is in contact with the element so that the hollow portion of the hollow insulator needle is negatively pressured. Iontophoresis type transdermal dosage element.   The transdermal administration element according to claim 1 or 2, wherein the hollow portion of the hollow insulator needle is filled with a conductive liquid in advance.   When the permeation agent has an active ingredient composed of an anion, the first conductive mineral is a metal or semiconductor having a lower electron affinity than the second conductive mineral, and the permeation agent is composed of a cation. 4. The transdermal dosage element according to claim 1, wherein the first conductive mineral is a metal or semiconductor having an electron affinity higher than that of the second conductive mineral when having an active ingredient.   5. The transdermal dosage element according to claim 1, 2 or 3 or 4, wherein the hollow body needle has a length enough to reach beyond the granular layer or basal layer of the epidermis region at the time of puncturing.   4. An electric means for pulsing an energizing current is additionally provided on an electric system path connecting the first conductive mineral and the second conductive mineral in a non-contact area. Transdermal dosing element.

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