JP3566346B2 - Transdermal drug delivery device - Google Patents

Description

[0001]
[Industrial applications]
The present invention relates to a transdermal administration device utilizing the action of iontophoresis.
[0002]
[Prior art]
The transdermal administration method is an excellent administration method as a means (Drug Delivery System; DDS) for delivering a drug at a predetermined concentration to a predetermined position in a living body. That is, as compared with intravenous injection or oral administration, the ratio of the drug flowing to the whole body in the blood stream is small, so that the side effect and the dose of the drug can be reduced. To this end, transdermal medication, in addition to antiphlogistic analgesia and the like, enables treatment of chronic diseases while performing daily activities depending on the type and degree of the disease. Examples of its practical use include treatment of chronic diseases of the musculoskeletal system and connective tissue, prevention of attacks of angina, calming of bronchitis, treatment of neurological diseases, and the like.
[0003]
Normally, percutaneous administration involves applying a matrix containing an active ingredient (this does not mean a lattice shape in a circuit device, but a material containing an active ingredient; the same applies hereinafter) to a plaster and apply it to a predetermined amount. This is carried out by skin contact with the site and using a concentration diffusion technique to allow a certain concentration of the drug to penetrate into the subcutaneous tissue from the skin contact site. However, penetrant drugs that are effective in treating diseases are generally high molecular compounds and have complex tertiary structures, so relying only on simple concentration diffusion phenomena does not allow the required concentration of drug to reach the affected area, In many cases, a sufficient therapeutic effect cannot be obtained. That is, since human skin has a complex multilayer structure and has a function of preventing foreign substances from penetrating from the outside, it is not easy for a polymer drug to break through a skin barrier and enter the body.
Therefore, in recent years, attention has been paid to the use of iontophorase and the combined use of absorption enhancers as means for increasing the effective penetration rate by the transdermal administration method.
[0004]
The former ionizes the active ingredient of the drug to be permeated, applies the drug under one of the electrodes (active electrodes) disposed at two places using the skin as a current path, and contacts the other electrode (an unrelated electrode). During this time, an electric power is supplied from an external power supply, and the active component ions are forcibly migrated into the skin current-carrying path by the electric repulsive force. The latter is a compound in which a substance that reduces the molecular binding force of sebum and allows the drug to easily penetrate the stratum corneum, such as limonene, is blended in the matrix together with the drug to be permeated.
Although some of these methods have been put to practical use, they can be said to be still under development. That is, the former has a problem mainly with the power supply, and the latter has a problem with effectiveness.
[0005]
As the external power source in the iontophoresis, a fixed type 100 V class DC power source is often used in hospitals and the like under the supervision of a doctor because the skin conduction path has a high resistance (10 to 100 MΩ / cm). However, in this case, since the patient cannot use it in daily life, a portable small power source (battery) is generally used. However, when a battery is used for a certain period of time, the effect of drug penetration by electrophoresis decreases due to a sudden decrease in electromotive force, or skin resistance decreases sharply due to a change in the state of skin contact, for example, perspiration. There is a problem that a large current flows and the skin surface is damaged.
[0006]
As a measure to prevent this, two kinds of metals with different ionization tendencies are conductively connected, an electromotive force is generated using an electric closed circuit formed at the time of skin contact, and a metal salt of the same type as the anode metal is used. An iontophoresis using an ionic drug applied to the skin contact surface of the anode has been proposed (JP-A-60-203270). This method is an attempt to utilize the internal reaction of the battery (oxidation-reduction reaction between the electrodes) as compared to the above-described conventional technology using an external power supply (battery). However, this method has significant disadvantages. When an electrical closed circuit is formed upon contact with the skin, first, electrons flow from the cathode, which has a high ionization tendency, to the anode, and the non-electron (oxidized) cathode becomes chemically active. Since the cathode is surrounded by water molecules, before attracting anions from inside the living skin,
Me ²⁺ + 2OH ⁻ → Me (OH) ₂ → MeO + H ₂ O
, But Me ²⁺ Is the ion of the metal constituting the cathode
It is self-evident that certain reactions occur quickly. As a result, the electromotive force of the battery changes greatly. For example, when a magnesium alloy recommended and preferred in Japanese Patent Application Laid-Open No. 60-203270 is used for the cathode, the surface of the cathode is coated with MgO within a short time. You. Mg (OH) ₂ Since the MgO-based oxide is an insulator, the electromotive force value rapidly decreases, and the iontophoresis stops.
[0007]
In order to solve this drawback, the present inventor has disclosed a power supply for an iontophoresis device which is a combination of a semiconductor negative electrode and a metal positive electrode (Japanese Patent Application No. 1-150654). When this power supply is insulated with the ionic agent applied under the positive electrode to form an electrical closed circuit, when electrons flow from the semiconductor negative electrode to the metal positive electrode, holes generated in the semiconductor negative electrode are formed on the skin-contacted surface. It is deflected by the internal electric field of the Schottky barrier and drifts to the skin contact surface, and flows out to the skin as free holes or semiconductor ions, so that the electrical neutrality of the semiconductor negative electrode is maintained and the semiconductor negative electrode stably withstands long-term continuous use.
This power supply also automatically stops power generation when a short circuit occurs between the electrodes on the skin contact surface due to sweating or the like. Therefore, unlike the case where an external power supply is used, the skin is safe.
[0008]
[Problems to be solved by the invention]
When performing transdermal medication using iontophoresis, it is desirable that the medication element is set according to the size and shape of the affected part. In addition, in order for a patient to continue medication in daily life, it is desired that the medication element itself be disposable.
However, in the above-described semiconductor negative electrode utilizing skin contact power generation type iontophoresis element, the conductive matrix containing the ionic drug is disposed under the positive electrode metal, and the positive electrode is connected to the semiconductor negative electrode at a position separated by a conductive wire. In addition, it was difficult for the patient to change the shape or cut into a small area by himself.
In particular, when a drug having a large molecular weight is ion-permeated into the skin, it is often not possible to obtain a sufficient permeation concentration simply by increasing the power supply voltage or increasing the conduction current. In this case, it is effective to physiologically activate the skin cells of the living body and increase the efficiency of drug uptake.
[0009]
SUMMARY OF THE INVENTION An object of the present invention is to provide a disposable transcutaneous administration device that is relatively easy to use and economical in that the device can be reduced in area and change in shape relatively easily.
Another object of the present invention is to provide a transdermal administration device which can artificially activate the skin.
[0010]
[Means for Solving the Problems]
The present invention relates to a sticking means having a skin contacting portion, a positive metal part disposed in a sheet shape at a non-skin contacting part of the sticking means, and dispersing ions permeated onto the positive metal part. And a negative electrode having a two-layer structure in which a lower layer is a non-conductive pad and the upper layer is a semiconductor layer having a lower standard monopolar potential than the positive electrode. A sheet wherein the conductive matrix and the semiconductor layer are simultaneously used by the attaching means after the positive electrode metal part and the semiconductor layer are short-circuited by a conductor at least at the edge. Disclosed is a transdermal dosage element in the form of a pen.
The above-mentioned sheet-like positive electrode metal may be a film-like metal whose entire surface is filled with the same kind of metal without any gap, a mesh-like metal having regular mesh-like gaps, or a sheet-like metal perforated in an appropriate pattern. . The above-mentioned lattice-shaped negative electrode refers to a two-dimensional two-layer structure negative electrode having a lattice shape that is orthogonal or oblique with appropriate and regular intervals and widths.
[0011]
Further, the present invention provides a sticking means having a skin contacting part, a positive metal part arranged in a mesh or sheet shape at a non-skin contact part of the sticking means, and a coating and coating on the positive metal part. A two-layered negative electrode comprising a conductive matrix in which penetrating ions are dispersed, a non-conductive pad disposed in a grid on the conductive matrix, a lower layer having a non-conductive pad, and an upper layer having a standard monopolar potential lower than that of the positive electrode. The positive electrode metal part and the semiconductor layer are connected at least at the edge portion via a circuit, and the conductive matrix and the semiconductor layer are simultaneously used by the attaching means. In the sheet-shaped transdermal dosage element, the circuit is capable of oscillating a low frequency pulse of 50 to 500 Hz with a first circuit in which a positive electrode metal part and a semiconductor layer are short-circuited by a conductive wire, and Pulse polarity A second circuit comprising a small-voltage pulse oscillator and a drive power supply for the small-voltage pulse oscillator and a driving power supply for the low-voltage pulse oscillator, the first circuit and the second circuit being connected in such a manner that the negative electrode side has a positive potential and the positive metal side has a zero potential And a changeover switch for selectively inserting between the positive electrode metal part and the semiconductor layer.
[0012]
The semiconductor layer may be an oxygen-defective oxide selected from the group consisting of zinc oxide, aluminum oxide, bismuth oxide, iron oxide, lead oxide, antimony oxide, titanium oxide, and tin oxide. Further, the semiconductor layer may be the same semiconductor layer as a whole, or may have a two-layer structure of a semiconductor layer only on the skin contact surface and a lower layer of the semiconductor layer.
[0013]
[Action]
Since the transdermal drug delivery device is formed in layers of negative electrode / conductive matrix / positive electrode / adhering means and one flexible sheet, even if it is commercially available in a predetermined size, the patient cuts it by himself to obtain an appropriate size. , Can be arranged in a shape. In use, the positive electrode metal and the negative electrode semiconductor may be short-circuited at the edge of the sheet before use.
[0014]
When a conductive matrix (a conductive gel-like substance in which ions to be penetrated are dispersed; the same applies hereinafter) and a semiconductor layer are simultaneously skinned by a sticking means, a positive electrode (metal), a negative electrode (semiconductor), An external short circuit type chemical cell consisting of the electrolyte (conductive matrix and skin) is formed. In this case, the current path is a closed circuit of a semiconductor layer → a conductive wire → a positive electrode metal part → a conductive matrix → a skin → a semiconductor layer. By the electrons flowing from the negative electrode to the positive electrode, anions (penetration ions of the drug) under the sheet-shaped positive electrode are two-dimensionally electrically repelled and penetrate into the skin from the matrix. The electrons penetrating into the skin together with the anions cause a reduction reaction.
On the other hand, in the lattice-shaped semiconductor layer from which the electrons have flowed out, the excess holes are deflected by the electric field inside the Schottky barrier formed on the contact surface and penetrate into the skin to cause an oxidation reaction. The Schottky barrier prevents the inflow of electrons from the contact surface, so that a stable chemical cell electromotive force can be obtained.
[0015]
Since the negative electrode has a two-layer structure and the semiconductor layer is electrically separated from the conductive matrix by the non-conductive pad, there is no consumption due to so-called self-discharge before skin contact.
When a small voltage pulse oscillator (50-500 Hz) is connected to the transdermal administration device via the conducting wire in the direction in which the negative electrode side has a positive potential and the positive electrode metal side has a zero potential, the skin is in contact with the skin and a hole is formed in the skin when an external circuit is short-circuited. A predetermined low frequency pulse is applied to the skin from the side of the negative electrode semiconductor to be injected. The voltage has a peak value of about 0.1 to 10 (V). When this low-frequency pulse is applied to peripheral nerves distributed in the vicinity of 1 to 2 mm subcutaneously (tetanus stimulation), synaptic plasticity increases without the action of a neurotransmitter. As a result, a long-term potentiating effect (LTP effect) is exhibited over several hours to one day after application, and skin cells in the peripheral innervation region are physiologically activated. In other words, skin respiration is activated and metabolism is activated. Therefore, if ion photolysis is performed in this state, it is expected that the efficiency of absorbing permeated ions will be further enhanced.
[0016]
Since the tetanus stimulation has an accumulation effect by repeated voltage pulses, when applied to the anterior fiber of the peripheral nerve synapse, the LTP effect can be induced if the frequency is such that the nerve can be identified. In an experiment in which a pulse was directly applied to nerve fibers, an effect was observed in the range of 10 Hz to several kHz. However, when the pulse is applied from the epidermis, the effect of dispersion occurs during the propagation of the pulse, so that the frequency limit becomes more severe. According to the test result from the living body epidermis, a favorable effect was obtained in a frequency band of 50 to 500 Hz. The peak value of the voltage pulse may be about 10 mV or more at the presynaptic fiber position. However, in consideration of attenuation in a living body, a used frequency, noise potential, and the like, a magnitude of 0.1 V or more is preferable at a skin incision site.
[0017]
If the semiconductor layer of the negative electrode has an oxide semiconductor layer on the skin contact surface and a lower layer formed of a double structure of a cation metal forming the oxide semiconductor layer, the conductivity of the semiconductor layer increases, and the conductivity of this region increases. It is preferable because the loss can be reduced. The cationic metal is gradually oxidized by receiving the moisture at the skin contact portion, and a stable oxide semiconductor film thickness is formed.
[0018]
【Example】
Hereinafter, the present invention will be described in more detail based on examples.
(1) FIG. 1 is a view showing a configuration of a transdermal administration device according to an embodiment of the present invention. FIG. 1A is a top view, and FIG. 2B is a cross-sectional view along AA '. In the figure, 1 is a bandage of the sticking means, 2 is a sheet-like positive electrode metal part (for example, a metal layer), 3 is a conductive matrix in which permeated drug ions are dispersed, 4 is a grid-like negative electrode, and 5 and 5 ′ are This is a conductive sheet that short-circuits the positive and negative electrodes. The negative electrode 4 includes a lower non-conductive pad 42 in contact with the conductive matrix 3 and a semiconductor layer 41 disposed on the lower non-conductive pad 42. Although the height of the negative electrode 4 is not negligible in the drawing, it is actually extremely small. The above-mentioned sheet-like positive electrode metal may be a film-like metal whose entire surface is filled with the same kind of metal without any gap, a mesh-like metal having regular mesh-like gaps, or a sheet-like metal perforated in an appropriate pattern. . The above-mentioned lattice-shaped negative electrode refers to a two-dimensional two-layer structure negative electrode having a lattice shape that is orthogonal or oblique with appropriate and regular intervals and widths.
[0019]
At the edge portions L and M, the conductive sheet 5 electrically connects the positive electrode metal portion 2 and the semiconductor layer 41 as shown in FIG. The conductive sheet 5 and the conductive matrix 3 are separated by non-conductive pads 42 so as not to be electrically connected. The conductive sheet 5 may be a bonded lead wire.
In use, the skin contact surfaces a, b, and c are used in contact with the skin. At the time of this skin contact, it is as follows. When a conductive matrix (a conductive gel-like substance in which permeating ions are dispersed; the same applies hereinafter) and a semiconductor layer are simultaneously insulated with an adhesive bandage, a positive electrode (metal), a negative electrode (semiconductor), and an electrolyte ( An external short circuit type chemical cell composed of a conductive matrix and skin) is formed. In this case, the current path is a closed circuit consisting of the semiconductor layer 41 → the conducting wire 5 → the positive electrode metal part 2 → the conductive matrix 3 → the skin → the semiconductor layer 41.
The conductive sheets 5, 5 'have a role of short-circuiting the external circuit of the chemical battery formed when the chemical battery is in contact with the skin, but the chemical battery is consumed because a closed circuit including the positive electrode and the negative electrode is not formed before the skin contact. There is no.
[0020]
The positive electrode metal part 2 is in two-dimensional contact with the conductive matrix 3. Impregnated ion M generated by dissociation of ionic drug salt contained in conductive matrix 3 ⁻ As the pH of the conductive matrix 3 changes with the infiltration of the living body, or the alkali ions constituting the drug salt are precipitated as a metal, use a metal that is resistant to corrosion, such as a noble metal, when used for a long time. Is desirable. However, since the use of inexpensive materials is required for the disposable type, it is more preferable to use inexpensive copper-based metal for the positive electrode metal part 2 by making contact with the conductive matrix 3 before use.
[0021]
The conductive matrix 3 is made of a gel-like conductive polymer such as polyvinylpyrrolidone gel. However, in order to avoid a problem such as a change in the pH of the matrix caused by skin contact for a long period of time and a rash on the skin surface of a living body. In addition, it is necessary to take into consideration the mitigation of the pH change by a well-known technique, for example, the use of an insoluble salt generation reaction by blending an acidic base material such as uric acid, or the blending of a material that causes a neutralization reaction such as the use of an ester by blending an alcohol. preferable.
[0022]
The semiconductor layer 41 constituting the negative electrode 4 is usually formed using an oxygen-defective oxide semiconductor. These semiconductors can reduce the specific resistance to 1 Ω · cm or less by thinning and improving the oxygen vacancy rate, and an n-type low-resistance semiconductor thin film is formed. Such oxygen-defective oxide semiconductors include zinc oxide (ZnO) and aluminum oxide (Al ₂ O _3-x ), Tin oxide (SnO), bismuth oxide (Bi) ₂ O ₃ ), Antimony oxide (Sb ₂ O ₃ ), Iron oxide (Fe ₃ O _4-x ), Chromium oxide (CrO) _2-x ), Molybdenum oxide (MoO) _2-x ), Niobium oxide (NbO) _2-x ), Titanium oxide (Ti ₂ O _3-x ) To form a kind of non-stoichiometric compound.
[0023]
These n-type oxide semiconductors can be formed on a base by using a known thin film forming method such as sputtering, vapor deposition, or CVD. Therefore, if a polyimide or PTFE resin film is used for the base, the negative electrode 4 can be formed once. Can be formed. That is, the n-type oxide becomes the semiconductor layer 41 and the underlying polymer becomes the non-conductive pad 42.
On the other hand, since an n-type oxide can be formed over a metal, the semiconductor layer 41 can have a double structure by using an element constituting a cation of an n-type oxide semiconductor as a base. For example, zinc oxide is formed on zinc, and aluminum oxide is formed on aluminum. In this case, the n-type oxide semiconductor can be formed on the base metal by the thin film deposition method or by oxidation of the metal surface by acid treatment or the like. When the semiconductor layer 41 has a double structure of an oxide and a metal, the non-conductive pad 42 under the negative electrode 4 is formed by attaching a flexible sheet such as a woolen fabric or a polymer to the semiconductor layer 41. Can be.
[0024]
The semiconductor layer 41 constituting the negative electrode 4 is made of n-type germanium or an alloy thereof, n-type silicon or an alloy thereof, n-type silicon or an alloy thereof, a rare earth compound or a mixture thereof, which induces physiological activation by inducing interferon or the like when penetrated into a living body. Can be configured. In general, in an oxide semiconductor, even if electrons flow to the positive electrode side by skin contact, the oxidation reaction is prioritized. Therefore, the possibility that the semiconductor is ionized from the skin contact surface and penetrates into a living body is small. Conversely, when a non-oxide semiconductor having a covalent bond that is relatively stable against oxidation is used for the negative electrode, when electrons flow out to the positive electrode side by skin contact, holes flow to the skin contact surface and become positively charged, It becomes unstable and is separated from the crystal by the internal electric field due to the Schottky barrier, and penetrates into the living body as cations. Therefore, in the semiconductor layer 41 made of germanium or the like, a cytokine-inducing effect in a living body can be expected.
[0025]
The conductive sheets 5, 5 'in FIG. 1 may be formed of, for example, metal foil. Ready-made aluminum foil, tin foil and the like can be used.
In the one-sheet transdermal administration device of FIG. 1, the positive electrode metal part 2 is made of pure copper, the width of the lattice negative electrode 4 is 2 mm, the height is 2 mm, the lattice interval (the exposed width of the conductive matrix 3) is 12 mm, The matrix 3 was used as a base material having a thickness of about 2 mm in which 0.5 mol of sodium citrate was dispersed in a gelatin gel. That is, a group of three male SD rats were shaved and the skin was brought into contact with the conductive matrix 3 and the negative electrode 4 simultaneously. The mean blood levels of the rats were measured after 2, 4, 6, and 8 hours. For comparison, a group of rats was loaded with a dummy transdermal element of the same area in which only a gelatin matrix in which 0.5 mol of sodium citrate was dispersed was applied to a bandage 1, and the blood concentrations were compared. .
[0026]
FIG. 2 shows a change in citrated blood concentration when the type of the semiconductor layer 41 of the negative electrode 4 is changed, in comparison with a dummy. Regardless of which semiconductor layer 41 was used, a blood concentration higher than that of the dummy was observed, indicating that the iontophorase of the present invention was more effective for drug permeation by several to ten times than a simple concentration diffusion. In the case of iontophoresis, it is shown that the blood concentration becomes constant approximately 4 hours after skin contact. Although not shown, when the blood concentration after 6 hours was compared with that of the dummy, an effect of about 10 times that of the dummy with the aluminum oxide negative electrode and about 4 times that of the dummy with the germanium negative electrode was observed.
[0027]
Further, apart from FIG. 2, the effect on the effect of iontophoresis was compared between the case where the semiconductor layer 41 is a single layer and the case where the semiconductor layer 41 has a two-layer structure of an oxide semiconductor / metal. After attaching an insulating film of 1 mm thickness to the lower surface of each base film of 0.5 μm thick ZnO deposited on the PTFE polymer film and 0.1 μm thick ZnO deposited on the zinc film, as shown in FIG. It was shaped like a lattice. These negative electrodes 4 were disposed on the surface of a gelatin gel layer in which 0.5 mol of sodium citrate was dispersed, to constitute a transdermal administration device for iontophoresis. The sizes of the positive electrode metal and the grid-shaped negative electrode are the same as described above. This was loaded on SD male rats and the effect of iontophoresis was examined, but no significant difference was found. However, in the case of the oxide semiconductor / metal two-layer structure, the blood concentration after the elapse of 4 hours from the skin contact was maximized, and the blood concentration tended to slightly decrease thereafter.
[0028]
(2) A gold thin film sheet is adhered to the bandage 1 as the positive electrode metal part 2, and a polyvinylpyrrolidone gel in which 0.8 mol of α-tocopherol derivative salt is dispersed is applied thereon as a conductive matrix 3 in a layered manner. did. Next, a grid-shaped negative electrode 4 having a width of 2 mm, a height of 1.5 mm, and a grid interval of 10 mm is closely attached to the conductive matrix 3. The negative electrode 4 is a semiconductor layer 41 whose upper layer is made of n-ZnO / Zn with a thickness of 0.6 mm, and whose lower layer is a nylon sheet with a thickness of 0.9 mm. The layer of the conductive matrix 3 is 40 × 40 mm ² A lead wire 51 is pulled out from the edge of the positive electrode metal 2 at one edge of the sheet-shaped element having the size of and connected to the changeover switch 6. On the other hand, the conductive sheet 5 connected to the grid-like negative electrode at the edge of the sheet-like element has a short circuit (A circuit) with the positive metal 2 and a low voltage (10 V or less) oscillating within a frequency range of 50 to 500 Hz. Tetanus stimulating circuits (B circuits) to which a low-frequency pulse oscillator 8 and an oscillator power supply 7 are connected are connected in parallel with each other. The changeover switch 6 switches between the A circuit and the B circuit. Tetanus stimulation refers to voltage stimulation repeatedly applied to a synapse.
[0029]
FIG. 3 shows this in a side view. The polarity of the pulses is connected such that the polarity is positive on the negative electrode 4 side and zero on the positive electrode 2 side. The A and B circuits and the changeover switch can be freely attached and detached, and the seat can be exchanged freely. The small voltage pulse from the low-frequency pulse oscillator 8 increases the plasticity of the synapse of the peripheral nervous system distributed in the dermis region when the transdermal administration device is in skin contact, and activates the cells in the application region. This activation lasts several hours or more after the pulse application (after the application of the tetanus stimulus), and is called a long-term potentiation effect (LTP effect). Tetanus stimulation by a low-frequency pulse is used to increase the efficiency of drug uptake by activating the biological skin surface. Therefore, after the percutaneous administration element is in contact with the skin, the circuit B is first selected by the changeover switch 6 to activate the physiological condition, and then the circuit A is selected by the changeover switch 6 to maintain the iontophoresis. As described above, the LTP effect gradually decreases after several hours, and therefore, when performing iontophoresis after long hours of contact, it is possible to automatically switch once every few hours to give the tetanus stimulation. preferable. The application time of the tetanus stimulus is about 1 minute for the first time and about 30 seconds for the additional time. The pulse frequency and the peak voltage are selected according to the depth of the affected area and the activity of the peripheral nerves of the living skin. Generally, when the affected part is deep, the frequency is lowered and the peak voltage is raised. If the frequency is 50 Hz or less, the degree of induction of the LTP effect is small due to weak stimulation accumulation, and if it exceeds 500 Hz, the pulse separation recognition effect at the synapse is reduced and the expression of the LTP effect is reduced. Therefore, it is desirable to use pulses of an appropriate frequency in a frequency band of 50 to 500 Hz.
[0030]
The transdermal administration device shown in FIG. 3 was in skin contact with the back of a white rabbit that had been shaved and depilated, and the effect of iontophoresis was examined. The frequency of the low-frequency pulse oscillator 8 was 200 Hz, and the peak voltage was 3 V. A group of two white rabbits was loaded with a transdermal administration element of the same standard at the same location, and the average blood concentration of α-tocopherol was measured every two hours. One group used only the A circuit, that is, only the iontophoresis as in the previous example. The other group is a case where the tetanus stimulus is first applied using the B circuit for 1 minute, the circuit is immediately switched to the A circuit, and the B circuit is activated for 5 minutes every 5 hours to apply the tetanus stimulus.
[0031]
FIG. 4 illustrates the obtained result. It can be seen that, compared to the case where only the A-circuit is used, the LTP effect of the synapse is induced by the tetanus stimulation, and the drug uptake efficiency when the physiological activation is measured is increased by two to three times. Since the tetanus stimulus has an addition (memory) effect, further improvement in the capturing efficiency can be expected by optimizing the size and frequency of the stimulus.
[0032]
(3) The pulse frequency and the peak voltage were changed in order to examine the tetanus stimulating effect of the one-sheet transdermal administration device shown in FIG. 3 in more detail. In this example, the permeating ionic drug dispersed in the conductive matrix 3 was 0.3 mol of sodium ascorbate. The positive electrode metal 2 was a silver mesh, and the semiconductor layer 41 of the negative electrode 4 was 1.5 μm thick n-Ge0.7Si0.3 deposited on an Al thin film. The size of the conductive matrix 3 is 20 × 40 mm ² And Other materials and dimensions were the same as in the previous example.
[0033]
The transdermal administration device was loaded on the back of a shaved SD male rat. The rats were grouped in groups of two, and the average blood concentration of ascorbic acid was examined every hour for each group. FIG. 5 shows the obtained results.
FIG. 5 shows data obtained when a low-frequency pulse having a peak voltage of 3 V or 6 V was immediately applied by the circuit B for 1 minute after the transdermal administration device was loaded on the rat, and the circuit was switched to the circuit A for iontophoresis. Is shown. In the case of the figure, it can be seen that the Tetanus effect at 300 Hz is the largest, but the most preferable frequency in combination with the peak voltage is not selected. Note that the pulse duty ratio was 50%. Also, in the data comparing the effect of the peak voltage at 200 Hz, the effect of 6V is slightly higher than that of 3V, but the time decay is slightly larger at 6V than at 3V. Although not shown, the frequency of 50 Hz or less was not shown. However, when a part of the test was performed at 25 Hz, no significant difference was observed from that before the application of the tetanus stimulation.
From the above, it is considered that the preferable frequency of the tetanus stimulation is 50 Hz or more and 500 Hz or less. Although the peak voltage was set to several volts in the illustrated experiment, the effect was also observed when a 200 Hz stimulus was applied at 0.1 V for 5 minutes, so that about 0.1 V to 10 V is considered appropriate.
[0034]
In addition, in the blood test of the rat, germanium and silicon were detected together with ascorbic acid from the blood, regardless of the frequency and voltage pulse applied. In the previous examples (1) and (2), the blood concentration of the cation (metal ion) constituting the semiconductor of the negative electrode 4 was not so high as to show a significant difference. This is considered to be a phenomenon peculiar to a non-oxide semiconductor having a strong characteristic.
[0035]
Although the present invention has been described with reference to the embodiments, the iontophoresis effect is also observed when bismuth oxide, lead oxide, antimony oxide, titanium oxide, or the like is used as the semiconductor layer of the negative electrode 4 in addition to the above. Was done. The penetrating drug dispersed in the conductive pad can be selected from many drugs such as an antibiotic, an antiepileptic drug, an antiarrhythmic drug, a hormonal drug, and insulin, in addition to the examples described above.
[0036]
【The invention's effect】
As described above, according to the present invention, a one-sheet disposable transdermal administration device can be obtained without using an external power supply. Therefore, transdermal medication can be safely, economically, and effectively performed in daily life without worrying about an excessive current failure (skin damage) due to a change in skin resistance caused when a portable external power supply is used. .
In addition, by using tetanus stimulation to enhance plasticity of nerve synapses, physiological activation of the skin can be induced and the efficiency of drug uptake by iontophorase can be improved. For this reason, it is considered that the use range of transdermal administration can be expanded more than before.
[Brief description of the drawings]
FIG. 1 is a diagram showing a structural example of a one-sheet transdermal administration device according to an embodiment.
FIG. 2 is data showing the effect of iontophoresis using the device of FIG.
FIG. 3 is a view showing a structural example of a one-sheet transdermal administration device according to another embodiment.
FIG. 4 is data showing the effect of iontophoresis using the device of FIG.
FIG. 5 is data showing the tetanus stimulating effect using the device of FIG. 3;
[Explanation of symbols]
1 bandage
2 Positive metal part
3 Conductive matrix
4 Negative electrode
5, 5 'conductive sheet
6 Changeover switch
7 Oscillator power supply
8 Low frequency pulse oscillator
41 Semiconductor Layer
42 Non-conductive pad
51 conductor
A short circuit
B Tetanus stimulation circuit

Claims (3)

Attachment means having a skin contact portion, a positive metal part disposed in a sheet shape at a non-skin contact part of the sticking means, and a conductive matrix applied on the positive metal part and dispersed with permeation ions And a negative electrode having a two-layer structure in which the lower layer is a non-conductive pad and the upper layer is a semiconductor layer having a lower standard monopolar potential than the positive electrode, and the lower layer is disposed in a grid on the conductive matrix.
A sheet-shaped transdermal skin, wherein the conductive matrix and the semiconductor layer are simultaneously used by the bonding means after the positive electrode metal part and the semiconductor layer are short-circuited by a conductor at least at the edge. Dosing element. An attaching means having a skin contacting part, a positive metal part arranged in a mesh or sheet shape at a non-skin contact part of the sticking means, and the permeation ions dispersed on the positive metal part are dispersed. A conductive matrix and a negative electrode having a two-layer structure in which a lower layer is a non-conductive pad and the upper layer is a semiconductor layer having a lower standard monopolar potential than the positive electrode are arranged in a grid on the conductive matrix. Consisting of
A sheet-shaped member in which the positive electrode metal part and the semiconductor layer are connected via a circuit at least at an edge portion, and the conductive matrix and the semiconductor layer are simultaneously used by the attaching means. Wherein the circuit comprises a first circuit in which a positive electrode metal part and a semiconductor layer are short-circuited by a conductive wire;
A second pulse generator comprising a small voltage pulse oscillator and a drive power source for the low voltage pulse oscillator, which are capable of oscillating a low frequency pulse of 50 to 500 Hz and are connected in such a manner that the pulse polarity is positive potential on the negative electrode side and zero potential on the positive electrode metal side. Circuit and
A transdermal administration device comprising: a changeover switch for selectively inserting one of the first circuit and the second circuit between the positive electrode metal part and the semiconductor layer. The semiconductor layer is one type selected from the group consisting of oxygen-deficient oxides consisting of zinc oxide, aluminum oxide, bismuth oxide, iron oxide, lead oxide, antimony oxide, titanium oxide, and tin oxide; 2. The semiconductor device according to claim 1, wherein the whole is formed of the same oxide semiconductor layer, or the surface in contact with the oxide semiconductor layer is the oxide, and the lower layer is formed of a two-layer structure of a metal constituting the oxide semiconductor layer. 3. The transdermal administration element according to 2.

Images