JP2020179169A - Drug, etc. administration device, actuation method thereof, and supporter - Google Patents

Abstract

To provide a drug, etc. administration device penetrating a drug, etc., applied to or coming into contact with a skin surface into skin cells by applying an electric pulse to the skin.SOLUTION: A drug administration device for percutaneously administering a drug, etc., applied to a skin surface by an electroporation method, comprises a waveform generator for generating electric pulses with a prescribed waveform pattern, and electrodes for applying the electric pulses with the waveform pattern to the skin. The waveform generator generates a two-step sawtooth waveform pattern that repeats, continued from a rising slope Tu rising at a slow rate from a minimum voltage V0 to a maximum voltage Va, a falling slope part Td falling at a steep angle from the maximum voltage Va to the minimum voltage V0, the sawtooth waveform pattern having one notch part VN temporarily dropping a voltage into a V-notch shape at an intermediate part of the rising slope Tu.SELECTED DRAWING: Figure 5

Description

In the present invention, a drug or microorganism (referred to as "drug, etc.") applied or touched on the surface of the skin is brought into the cells of the skin by bringing an electrode into contact with the skin and applying an electric pulse from the electrode to the skin. The present invention relates to a drug administration device to be permeated.

As a technique for introducing a gene into an animal cell, an electroporation method (electroporation method) is known (see, for example, Non-Patent Documents 1 and 2). The electroporation method is a technique in which an electric pulse is applied to a cell to temporarily crush the cell membrane to the extent that it can be repaired immediately, increase the permeability of the membrane, and actively take up genes outside the cell membrane. .. This electroporation method is used as a technique for introducing a drug such as a hair restorer, which is applied to the skin and is difficult to penetrate subcutaneously, into the dermis layer (hereinafter referred to as "percutaneous electroporation method"). It is applied in the fields of medicine and beauty. In this percutaneous electroporation method, a current of tens to hundreds of volts is applied to the skin in microseconds to milliseconds to generate reversible pores in the intercellular lipids of the stratum corneum. This is a method for promoting the permeation of a skin-absorbing drug into the skin (see Non-Patent Documents 3 and 4). Then, a drug administration device that applies an electric pulse to the skin to carry out a percutaneous electroporation method has been put into practical use (see Non-Patent Document 5). As such a drug administration device, those described in Patent Documents 1 to 5 are known.

The drug administration device described in Patent Document 1 is a drug administration device that administers a drug through the skin by using an electric perforation method, and includes a pulse application unit (3) that generates an electric pulse and a pulse application unit (3). An electrode (41) that is electrically connected and generates an electric pulse generated by a pulse application unit (3) is provided on the user's skin (see FIGS. 1 and 3), and electricity applied by the electrode (41). pulse is a burst having a pressurized conductive portion (P _oN) and Kyutome portion (P _OFF), pressing conductive portion of the burst waveform (P _oN), so that the magnitude of the voltage draws a convex curve upward rising portions rising in the (P _U), falling portion magnitude of the voltage is lowered so as to draw a convex curve below have (P _D), the rising portion (P _U) and the trailing portion (P is continuously formed between the _D), stabilization part where the voltage becomes constant (P _S) drug administration device provided with has been disclosed (仝Document 11, see FIG. 12). The rising portion of the voltage (P _U) and the trailing portion (P _D) and the by the curved, work slowly electrical pulses to the skin, can be suppressed skin irritation, stabilizer (P _S) It is described that the voltage is applied more continuously and the drug administration / introduction efficiency is efficiently carried out by providing the above (paragraphs [0036]-[0037] in the specification of the literature).

Patent Document 2 also describes a hair restorer introduction device similar to the drug administration device described in Patent Document 1.

The iontophoresis device described in Patent Document 3 is an iontophoresis device that percutaneously introduces an ionizing component contained in an ionization solution into a living body by a pulse from a pulse output unit, and is an electrode unit (an electrode unit) that allows an electric current to flow through the affected area. 1), a pulse output unit (12) that outputs a pulse to the electrode unit (1), a power supply unit that supplies various currents to the pulse output unit (12), and a pulse output unit based on the current from the power supply unit. A control unit (9) for controlling (12) is provided, and an ionizing component contained in the ionization solution is introduced into a living body by a pulse from a pulse output unit (12). In this iontophoresis device, the control unit (9) controls the pulse output unit (12) to appropriately output a detection signal for detecting the human body to the electrode unit (1), and the electrode unit (1) and the human body Detects whether or not they are in contact. When the human body and the electrode unit (1) are in contact with each other, the pulse output unit (12) makes the shape of the rising pulse waveform curved at the time of each pulse generation and the shape of the pulse falling waveform. Make a steep linear shape, increase the pulse amplitude to a predetermined value according to the passage of time from the start of pulse output or the output pulse, make the shape of the pulse rising waveform curved, and increase the pulse amplitude to a predetermined value. Pulse control is performed so as to increase the pulse width according to the passage of time from the start of pulse output or the output pulse so as to compensate for the decrease in the amount of charge by increasing the value (Fig. 1, Fig. 2, Fig. 4,). FIG. 6, paragraphs [0016]-[0017]) of the specification.

The electrically transport drug benefit device (20) described in Patent Document 4 sends a signal of the occurrence of an event or condition related to the operation of the benefit device (20) to a patient wearing the benefit device (20), and sends the event or condition. At least one sensor (28,48) to detect, a tactile signal generator (36) that generates a tactile signal in response to the sensor (28,48) and sends it to the patient, and an event or condition is the sensor (28,48). ), The controller (56) communicates with the sensor (28, 48) and the tactile signal generator (36) to control the tactile signal generator (36) to generate the tactile signal (Sr). The tactile signal generator (36) generates a tactile signal in the form of a current having a predetermined magnitude and waveform and transmits it to the patient so that the tactile current passing through the skin can be felt by the patient ( (See Fig. 1-Fig. 8).

Japanese Unexamined Patent Publication No. 2009-213585 Japanese Unexamined Patent Publication No. 2009-247526 Japanese Unexamined Patent Publication No. 2005-237545 Special Table 2000-507472 U.S. Pat. No. 4,919,139

Atsushi Sugimura, Shin Shimizu, "Electroporation", Chemistry and Biology, Vol.29, No.1, Japan Society for Bioscience and Biotechnology, January 1991, pp.54-60. Taku Yamamoto, "Basic Principles and Applications of Genome Editing", 1st Edition, Shokabo Co., Ltd., June 1, 2018, p.52. Keiichi Kawai, "Transdermal delivery method (mesoporation method) of drugs using iontophoresis and electroporation and its dermatological application", Drug Delivery System Vol. 27, No. 3, Japan DDS Society, 2012 , Pp.164-175. David A. Edwards, et al., "Analysis of enhanced transdermal transport by skin electroporation", Journal of Controlled Release, Vol. 34, DDS Society of Japan, June 1995, pp.211-221. Toyohisa Ueda, "Study of substance delivery efficiency by percutaneous electroporation method", Journal of Japanese Dermatological Association, No. 118, Japanese Dermatological Association, March 25, 2008, p. .4. Mitsuyoshi Miyata et al., "Anti-inflammatory effect of Beppu hot spring-derived microbial alga Mucidosphaerium sp. RG92 strain", Hot spring science, Vol. 68, No. 3, Japan Hot Spring Science Society, December 2018, pp.204-215 ..

The techniques described in the above patent documents are all drug administration devices used for carrying out percutaneous electroporation, and are an electrode that gives an electric pulse to the skin and a control that controls an electric pulse flowing through the electrode. It is equipped with a device. Then, in Patent Documents 1-3, the waveform of the electric pulse flowing through the electrode is adjusted so that the rise of the pulse is gradually increased in a saturation curve so as to suppress irritation to the skin. In Patent Document 4, a square wave having a pulse width of 1 μs to 2 ms is used for the electric pulse (see FIGS. 2 to 4), and the waveform of the electric pulse is the amount and ratio of the drug delivered through the skin. It is stated that it is selected so as not to have a significant effect on the pulse (Pulse 12 pp. 12-16). Further, as another example of the waveform of the electric pulse, Fig. 6, Fig. 9, Fig. As described in No. 10, a trapezoidal pulse waveform in which the rising portion has a gentle slope and the falling portion has a steep slope is also disclosed. As described above, conventionally, the pulse shape of the electric pulse has been devised so as to suppress the irritation to the skin of the user.

However, in the conventional technology related to drug administration devices, what shape of electric pulse further promotes the penetration effect of the drug into the skin, that is, what kind of pulse-shaped electric pulse is applied to the drug. There are no examples of studies being conducted from the perspective of maximizing transdermal transport efficiency.

Therefore, an object of the present invention is to provide a drug administration device capable of enhancing the permeation effect of a drug into the skin and a control method thereof in carrying out the percutaneous electroporation method. ..

The first configuration of the drug administration device according to the present invention is that the drug or microorganism applied to the skin surface, or a sheet coated or infiltrated with the drug or microorganism is attached to the skin surface to be in contact with the skin surface. It is a drug administration device that percutaneously administers a drug or microorganism by the electroporation method.
A waveform generation means that generates an electric pulse of a predetermined waveform pattern,
An electrode that applies an electric pulse of the waveform pattern generated by the waveform generation means to the skin is provided.
The waveform generating means is a serrated waveform pattern in which a rising slope portion that rises from the minimum voltage to the maximum voltage with a gentle slope is followed by a falling slope portion that falls from the maximum voltage to the minimum voltage with a steep slope. Therefore, it is characterized in that it generates the two-stage serrated waveform pattern having one notch portion in which the voltage temporarily drops in a V-notch shape in the middle of the rising inclined portion.

As described above, by changing the waveform pattern of the electric pulse to a two-step serrated waveform pattern, it is possible to enhance the effect of permeating the drug into the skin as compared with the conventional case. This has been proved by actually conducting a test, and the details will be described later.

Here, the "V-notch shape" refers to a V-shaped mouth shape (for example, refer to "Shape of V-notch test piece" of JIS Z 2242: 2018).

The second configuration of the drug administration device according to the present invention has a plurality of shapes in the first configuration, depending on the combination of the drug or microorganism (HLB value, electrical conductivity) to be applied. A waveform pattern storage means for storing waveform shape parameters that specify the shape of the step serrated waveform pattern, and
Input means and
A parameter setting means for acquiring the specified information of the combination of the drug or microorganism (HLB value, electric conductivity) to be applied, which is input from the input means, and
A waveform pattern selection means for reading out the waveform shape parameter from the waveform pattern storage means according to the combination information of (HLB value, electric conductivity) acquired by the parameter setting means is provided.
The waveform generating means is characterized in that it generates an electric pulse of the waveform pattern in a two-stage sawtooth shape according to the waveform shape parameter read by the waveform pattern selecting means.

According to this configuration, it is possible to further enhance the penetrating effect of the drug into the skin by selecting the optimum waveform shape parameter according to the (HLB value, electric conductivity) of the drug to be used.

Here, the "HLB value" is a hydrophilic-lipophilic balance, which is a measure of the degree of hydrophilicity and lipophilicity (hydrophobicity) (for example, JIS K 3211: 1990). reference). The stronger the hydrophilicity, the higher the HLB value.

The third configuration of the drug administration device according to the present invention is a rectangular wave having a frequency higher than the frequency of the two-step serrated waveform pattern generated by the waveform pattern generator in the first or second configuration. A carrier generation means for generating a carrier wave that is
The waveform generating means is characterized in that the carrier wave generated by the carrier wave generating means is amplitude-modulated by the two-stage sawtooth-shaped waveform pattern to generate an electric pulse.

The method for controlling the drug administration device according to the present invention is a drug or microorganism applied to the skin surface, or a drug touched to the skin surface by attaching a sheet coated or infiltrated with the drug or microorganism to the skin surface. Alternatively, it is a control method for controlling a drug or the like administration device that percutaneously administers a microorganism by an electroporation method.
The rising slope that rises from the minimum voltage to the maximum voltage with a gentle slope, followed by the falling slope that falls from the maximum voltage to the minimum voltage with a steep slope, is a serrated waveform pattern in which the rising slope is repeated. A two-stage sawtooth-shaped electric pulse of the waveform pattern having one notch portion in which the voltage temporarily drops in a V-notch shape is output to the electrode so as to be applied to the electrode. It is characterized by controlling the voltage.

The supporter according to the present invention includes a supporter cloth made of an elastic fiber member formed in a shape that can be wound and fixed to a wearing portion of a wearer.
A conductive pulse application layer formed in a layer on the side of the supporter cloth in contact with the wearer's mounting portion (hereinafter referred to as "back surface side").
A drug diffusion layer formed in a layered manner on the back surface side of the pulse application layer and formed of a member capable of permeating the drug or microorganism to be administered.
A drug or the like administration device having any one of the first to third configurations, which is attached to the surface side of the supporter cloth and applies an electric pulse to the pulse application layer.
A drug supply unit that is attached to the surface side of the supporter cloth, stores a drug or microorganism that is transdermally administered to the wearer's wearing site, and sequentially supplies the drug or microorganism to the drug diffusion layer by permeation diffusion. It is characterized by being prepared.

According to this configuration, the user who receives the drug or the like attaches the supporter to the site where the drug or the like is administered. At this time, the entire mounting site is covered with the supporter's drug diffusion layer. In this state, the drug administration device is activated. As a result, the drug or the like permeated and diffused from the drug or the like supply unit into the drug or the like diffusion layer is administered to the wearing site by the percutaneous electroporation method. In this case, the user does not need to hold the drug or the like administration device by hand during the period of administration of the drug or the like, and simply wears the supporter. Therefore, it is possible to easily administer a drug or the like. In addition, even if the administration time of the drug or the like is long, the user can freely perform another action during the administration, so that the drug or the like is administered for a long time. It can be done without difficulty.

As described above, according to the drug administration device and the drug administration method of the present invention, the waveform pattern of the electric pulse is changed from the minimum voltage to the maximum voltage following the rising slope portion that rises to the maximum voltage with a relatively gentle inclination. It is a serrated waveform pattern in which the falling slope that falls to the lowest voltage with a relatively steep slope repeats, and the notch where the voltage temporarily drops in a V notch shape is 1 in the middle of the rising slope. By adopting a two-step serrated corrugated pattern, it is possible to enhance the effect of permeation of the drug or microorganism into the skin as compared with the conventional case.

In addition, by selecting the optimum waveform shape parameter according to the drug or microorganism (HLB value, electrical conductivity) used, it is possible to further enhance the effect of the drug penetrating into the skin.

Further, according to the supporter of the present invention, the user only needs to wear the supporter during the period of administration of the drug or the like, and does not need to hold the drug or the like administration device by hand. Therefore, it is possible to easily administer a drug or the like. In addition, even if the administration time of the drug or the like is long, the user can freely perform another action during that time, and the drug or the like can be administered for a long time without difficulty. It becomes.

It is a block diagram which shows the structure of the drug administration apparatus which concerns on Example 1 of this invention. It is a figure which shows an example of the probe for electroporation. It is a figure which shows the basic structure of the waveform generator 16 of FIG. It is a figure which shows the basic structure of the probe driver 17 (probe driver 17a, 17b, 17c) for EP of FIG. It is a figure which shows the waveform of the electric pulse output by a waveform generator 16. It is a figure which shows the voltage pulse pattern of the electric pulse used in the percutaneous electroporation method in the effect verification test. It is a figure which shows the measurement result of the permeation amount of the RG component with respect to the voltage pulse pattern of each electric pulse of FIG. It is a scatter diagram which shows the distribution of the HLB value and the electric conductivity of each test MC A to J of Table 1. It is a figure which shows the measurement result of the permeation amount for each voltage pulse pattern of the test MC A to C. It is a figure which shows the measurement result of the permeation amount for each voltage pulse pattern of the test MC D to G. It is a figure which shows the measurement result of the permeation amount for each voltage pulse pattern of the test MC H to J. It is an enlarged perspective view of the main part of the supporter which concerns on Example 2. FIG. It is sectional drawing of the main part of the supporter of FIG. It is a figure which shows the example which attaches the supporter which concerns on Example 2.

Hereinafter, embodiments for carrying out the present invention will be described with reference to the drawings.

(1) Configuration of Drug Administration Device FIG. 1 is a block diagram showing a configuration of a drug administration device according to Example 1 of the present invention. The drug or the like administration device according to Example 1 includes a main body 1, a face probe 2, a point probe 3, a scalp probe 4, and a cooling probe 5. The face probe 2, the point probe 3, the scalp probe 4, and the cooling probe 5 are each connected to the main body 1 by a connection cord. The three probes, the face probe 2, the point probe 3, and the scalp probe 4, are electroporation probes (hereinafter referred to as “EP probes”) used for applying an electric pulse to the skin. These three probes include electrodes 6 that come into contact with the skin where the drug is administered. The cooling probe 5 is a probe used for cooling the skin. The cooling probe 5 includes a cooling element 7 (heat pump or Peltier element).

FIG. 2 shows an example of EP probes (face probe 2, point probe 3, scalp probe 4). In the EP probe shown in FIG. 2, a columnar contact protrusion 8b is formed on one side surface of the probe body 8a, and the tip surface of the contact protrusion 8b comes into contact with the skin where a drug or microorganism is administered. The contact surface is 8c. Five thick disk-shaped electrodes 6 are arranged on the abutting surface 8c in the shape of five dice, and a groove portion 8d having a cross-shaped outer shape is formed so as to partition between the electrodes 6. Are formed in a series. A switch 8e for inputting a start / stop instruction of an electric pulse is provided on the front end side side surface of the probe main body 8a. Further, one end of the cord 9 is connected to the side surface on the base end side of the EP probe, and the other end of the cord 9 is connected to the main body 1.

In FIG. 1, the main body 1 includes a waveform pattern memory 10, a main controller 11, a clock generator 12, an input device 13, a display device 14, a buzzer 15, a waveform generator 16, and probe drivers 17a, 17b, 17c, and 17d. There is. The waveform pattern memory 10 (waveform pattern storage means) is a memory for storing parameter information for generating a waveform pattern of an electric pulse. The main controller 11 is a module that controls a drug or the like administration device, and is configured by using a microcomputer in this embodiment. The clock generator 12 is an oscillator that generates a clock. The input device 13 is a device for the user to input various instructions to the main controller 11, and is configured by using various button switches and a touch panel display. The display device 14 is a device that displays a message output to the user by the main controller 11, and is configured by using a normal display, a touch panel display, an LED lamp, or the like. The buzzer 15 is a device that outputs an electronic sound message output by the main controller 11 to the user. The waveform generator 16 (waveform generating means) is a module that generates an electric pulse waveform for electroporation. The probe drivers 17a, 17b, 17c, and 17d are electronic circuit devices that drive the face probe 2, the point probe 3, the scalp probe 4, and the cooling probe 5, respectively. Hereinafter, the probe drivers 17a, 17b, and 17c for driving the EP probe will be collectively referred to as "EP probe driver 17".

Further, the main controller 11 includes a parameter setting unit 11a, a waveform selection unit 11b, a level setting unit 11c, and a time setting unit 11d as functional modules. These functional modules are functionally configured in the main controller 11 by loading and executing programming in the main controller 11.

The parameter setting unit 11a (parameter setting means) is a module that performs a process of acquiring information on a combination of drugs or microorganisms (HLB value, electrical conductivity) to be applied, which is input from the input device 13 by the user. The waveform selection unit 11b (waveform pattern selection means) reads out the waveform shape parameter from the waveform pattern memory 10 according to the combination information (HLB value, electrical conductivity) acquired by the parameter setting unit 11a, and is a waveform generator. It is a module that performs the process of setting to 16. The level setting unit 11c is a module that performs a process of setting the magnitude (amplitude) of the electric pulse to be output to each EP probe driver 17 based on the level information of the electric pulse input from the input device 13 by the user. The time setting unit 11d is a module that performs a process of setting the duration of the electric pulse to be output to the waveform generator 16 based on the information of the output duration of the electric pulse input from the input device 13 by the user.

FIG. 3 is a diagram showing a basic configuration of the waveform generator 16 of FIG. The waveform generator 16 includes a sine wave generator 16a, a pulse wave generator 16b, and a coupling transformer 16c. The sine wave generator 16a generates the sine wave X shown in the upper part of FIG. 3B. The pulse wave generator 16b generates the rectangular pulse wave Y shown in the lower part of FIG. 3B. The square pulse wave Y is a series of rectangular pulses generated periodically, and its period is the same as that of the sine wave X. Further, the pulse width of the square pulse wave Y is shorter than the quarter period of the sine wave X. A sine wave X output by the sine wave generator 16a and a rectangular pulse wave Y output by the pulse wave generator 16b are input to both ends of the primary coil of the coupling transformer 16c. A composite pulse wave L, which is a composite wave of a sine wave X and a square pulse wave Y, is output from both ends of the secondary coil of the coupling transformer 16c.

FIG. 4 is a diagram showing a basic configuration of the EP probe driver 17 (probe drivers 17a, 17b, 17c) of FIG. The EP probe driver 17 includes an amplifier 17p, a duty cycle pulse generator 17q, a pulse amplitude controller 17r, and a modulator 17s. The amplifier 17p amplifies and outputs the combined pulse wave L input from the waveform generator 16. The duty cycle pulse generator 17q generates and outputs a carrier wave L / M, which is a rectangular wave for modulation synchronized with the combined pulse wave L. The pulse amplitude controller 17r controls the amplitude of the carrier wave L / M output by the duty cycle pulse generator 17q based on the level setting value (LEVEL) of the level setting unit 11c. The modulator 17s generates an electric pulse in which the carrier wave output by the duty cycle pulse generator 17q is amplitude-modulated by the amplified combined pulse wave L output by the amplifier 17p, and outputs the electric pulse to the EP probe.

For example, it is assumed that the combined pulse wave L is a sine wave as shown in the upper part of FIG. 4B. At this time, the duty cycle pulse generator 17q generates a carrier wave L / M, which is a rectangular wave for modulation synchronized with the combined pulse wave L, as shown in the middle stage of FIG. 4B. At this time, the period of the carrier wave L / M is set to be sufficiently shorter than the period of the combined pulse wave L, and the amplitude of the carrier wave L / M is based on the level setting value (LEVEL) of the level setting unit 11c, and the pulse amplitude controller 17r. Set by. The modulator 17s amplitude-modulates the carrier wave L / M with the combined pulse wave L, and outputs an electric pulse O to the EP probe as shown in the lower part of FIG. 4B.

(2) Operation of the drug administration device The operation of the drug administration device of the present embodiment configured as described above will be described below. When using the drug administration device, the user first applies the drug or microorganism to be used (hereinafter referred to as "drug used") or the drug to be used on the skin surface to which the drug or microorganism is administered. Alternatively, attach the infiltrated sheet to the skin surface. Next, the (HLB value, electrical conductivity) of the drug to be used is input by the input device 13 of the main body 1 of the drug or the like administration device. Here, the HLB value refers to a hydrophilic-lipophilic balance, and is a measure of the degree of hydrophilicity and lipophilicity (hydrophobicity) of the drug or the like used. The HLB value takes a value of 0 to 20. When the HLB value is in the middle value (about 10), the transdermal transport efficiency of the drug is the highest. The electric conductivity σ is a measure of the ease of conducting an electric pulse of a drug or the like used. When σ ≈ 0, it is difficult for the electric pulse to be transmitted into the skin, and the transdermal transport efficiency of the drug or the like is lowered. Therefore, it is necessary to apply a large electric pulse. On the contrary, when σ is large, the electric pulse reaches the dermis layer in the skin too much, and therefore, when an excessively large electric pulse is applied, the pain becomes large. The parameter setting unit 11a acquires the (HLB value, electrical conductivity) input from the input device 13, and the waveform selection unit 11b corresponds to the acquired (HLB value, electrical conductivity) combination thereof. The waveform shape parameters suitable for the combination are read from the waveform pattern memory 10 and set in the waveform generator 16. This is realized by storing in the waveform pattern memory 10 a correspondence table between the combination of (HLB value, electric conductivity) and the waveform shape parameter in advance. Here, the "waveform shape parameter" is a parameter that specifies the shape of the waveform pattern used when the waveform generator 16 generates the waveform pattern. In addition, the user inputs the intensity and duration of the electric pulse (time for applying the electroporation method) by the input device 13. Based on this input, the level setting unit 11c sets the intensity (amplitude) of the electric pulse, and the time setting unit 11d sets the duration of the electric pulse in the waveform generator 16. Then, the user applies the electrode 6 of the face probe 2, the point probe 3, or the scalp probe 4 connected to the main body 1 to the skin at the place where the drug or the like is applied (or the sheet to which the drug or the like is applied or infiltrated is attached). (Or the surface of the sheet), the start instruction of the electric pulse is input from the input device 13 or the switch 8e of the probe main body 8a. As a result, the waveform generator 16 generates an electric pulse having a specified waveform pattern, intensity, and duration, and any of the probe drivers 17a, 17b, and 17c is connected to the main body 1 of the face probe 2, point. An electric pulse is output to the probe 3 or the scalp probe 4. Here, the probe drivers 17a, 17b, and 17c pulse-modulate the waveform of the electric pulse output by the waveform generator 16 with a square wave having a frequency higher than the waveform of the electric pulse, and pulse-modulate the waveform of the electric pulse. Is output to the face probe 2, the point probe 3, or the scalp probe 4. This electrical pulse is conducted from the electrode 6 to the skin surface, and a percutaneous electroporation method is performed.

Here, the waveform of the electric pulse output by the waveform generator 16 is shown in FIG. In FIG. 5, the period of the waveform of the electric pulse is T ₀ . Waveform generator 16, following the rising slope portion which rises up to the voltage V _a at a gradual slope from the minimum voltage V ₀ (part of the section T _u), falls to the lowest voltage V ₀ steeply from the maximum voltage V _a It is a serrated corrugated pattern in which the falling slope portion (the portion of the section T _d ) repeats, and has one notch portion VN in which the voltage temporarily drops in a V notch shape in the middle of the rising slope portion. Outputs a two-step serrated waveform pattern. The waveform pattern memory 10 stores parameters for determining the amplitude, frequency, V-notch position, depth, and the like of the two-stage serrated waveform pattern.

(3) Test results of percutaneous electroporation using a drug administration device (3.1) Evaluation test 1
Finally, the test results of the percutaneous electroporation method using the drug administration device according to the present invention will be described. It is necessary to actually carry out a permeation test of a drug or the like to confirm what kind of shape of the electric pulse further promotes the permeation effect of the drug or the like into the skin. Therefore, a drug penetration test was conducted using electric pulses of various shapes.

In this test, a gel containing an RG component (hereinafter referred to as "RG component-containing gel") was used as a drug. Here, the "RG component" refers to an ethanol extract of the Beppu hot spring-derived microbial alga Mucidosphaerium sp. RG92 strain (see Non-Patent Document 6), and is a drug whose anti-inflammatory effect on skin cells has been confirmed. Further, it has been confirmed that the RG component contains a light emitting component in ultraviolet irradiation.

The following method was used as the test method.
(1) First, an RG component-containing gel is applied to a test site on the skin of a subject.
(2) Percutaneous electroporation is performed by applying an EP probe electrode to the skin test site and energizing an electric pulse for 10 minutes.
(3) By the tape stripping method (a method of exfoliating the stratum corneum on the skin surface with an adhesive tape), the stratum corneum at the test site of the skin is exfoliated in order of 2 to 3 layers, and each exfoliated layer. In the stratum corneum of the above, the amount of the fluorescent component peculiar to the RG component is measured by irradiation with ultraviolet rays, and the permeation amount of the RG component is quantified.

FIG. 6 shows the voltage pulse pattern of the electric pulse used in this test. In the percutaneous electroporation method, 10 types of electric pulses as shown in FIGS. 6 (a) to (e) and (a / 2) to (e / 2) were used. (A) to (e) have a frequency of 12 kHz, and (a / 2) to (e / 2) have a frequency of 6 kHz. Further, (a) and (a / 2), (b) and (b / 2), (c) and (c / 2), (d) and (d / 2), (e) and (e / 2). ) Are similar to each other. (A), (a / 2) is a sine wave, (b), (b / 2) is a sawtooth wave, and (c), (c / 2) is a trapezoidal shape as shown in Patent Documents 1 and 2. Waves, (d), (d / 2) and (e), (e / 2) are two-stage sawtooth waves used in the drug administration device of the present invention. In (d) and (d / 2), the position of the V notch is behind the center of the rising inclined portion, and in (e) and (e / 2), the position of the V notch is located on the rising inclined portion. It is said to be on the front side of the center.

FIG. 7 shows the measurement results of the permeation amount of the RG component with respect to the voltage pulse pattern of each electric pulse of FIG. In FIG. 7, the horizontal axis represents the voltage pulse pattern of each electric pulse, and the vertical axis represents the permeation amount (relative value) of the RG component. From FIG. 7, the permeation amount of the RG component was larger as a whole when the frequency was 6 kHz than when the electric pulse had a frequency of 12 kHz. Further, even at the same frequency, the permeation amount of the RG component greatly differs depending on the voltage pulse pattern of the electric pulse, and the two-stage sawtooth wave (e / 2) has the largest permeation amount, followed by the trapezoidal wave (c /). 2) and the two-stage sawtooth wave (d / 2) were about the same. From the above results, it can be seen that in the percutaneous electroporation method, a high drug penetration effect can be obtained by using a two-step sawtooth wave as the voltage pulse pattern of the electric pulse. In particular, the maximum drug penetration effect can be obtained by using a voltage pulse pattern in which the position of the V notch in the two-stage sawtooth wave is set to the front side of the center of the rising inclined portion as in (e / 2). I understand.

(3.2) Evaluation test 2
Next, the test results conducted on various microbial cocktails will be described. Here, the "microorganism cocktail" (MC) refers to a mixture of a plurality of microorganisms having medicinal properties. As the test microbial cocktail, the test MCs A to J whose HLB value and electric conductivity are as shown in Table 1 were used. In addition, FIG. 8 shows the distribution of HLB values and electrical conductivity of each of the test MCs A to J in Table 1.

The test method is the same as in the evaluation test 1, and the voltage pulse patterns of the electric pulses used in the test are (a) to (e) and (a / 2) to (e / 2) shown in FIG. It was used. 9 to 11 show the measurement results of the permeation amount for each voltage pulse pattern of each of the test MCs A to J. The method for measuring the permeation amount is the same as that in the evaluation test 1. Further, the unit of the permeation amount on the vertical axis of each graph of FIGS. 9 to 11 is common to each graph. There are five types of voltage pulse patterns to be compared, (a) and (a / 2), (b) and (b / 2), (c) and (c / 2), (d) and (d / 2). ), (E) and (e / 2) are similar patterns, respectively. (A) to (e) have a frequency of 12 kHz, and (a / 2) to (e / 2) have a frequency of 6 kHz. In order to evaluate the permeation amount for each of the five types of voltage pulse patterns, the deviation value of the permeation amount for each of the five voltage pulse patterns was obtained for each test MC and each frequency, and two for each voltage pulse pattern. The larger deviation value of the deviation values with respect to the frequency (6 kHz, 12 kHz) is used as the deviation value of the voltage pulse pattern with respect to the test MC. Then, for each voltage pulse pattern, the average of the deviation values for each test MC was obtained, and the average deviation values were compared to evaluate the superiority of each voltage pulse pattern in the permeation amount.

Table 2 shows the deviation values of the permeation amount for each of the test MCs and the five voltage pulse patterns for each frequency. Table 3 shows the deviation value of each voltage pulse pattern for each test MC and the average deviation value of each voltage pulse pattern.

From Tables 2 and 3, the average deviation values of the voltage pulse patterns (e) and (e / 2) are the largest with respect to the permeation amount, followed by the patterns (c), (c / 2), the patterns (d), ( The order is d / 2). Therefore, it can be seen that the largest MC penetration effect can be obtained by using the voltage pulse patterns (e) and (e / 2).

In this embodiment, the supporter according to the present invention will be described. FIG. 12 is an enlarged perspective view of a main part of the supporter according to the second embodiment. FIG. 13 is a cross-sectional view of a main part of the supporter of FIG. The supporter 20 according to this embodiment includes a supporter cloth 21, a pulse application layer 22, a drug diffusion layer 23, a flooded fit cloth 24, a drug supply unit 25, and a drug administration device 26.

The supporter cloth 21 is composed of an elastic fiber member formed in a shape that can be wound and fixed to the wearing portion of the wearer. The overall shape of the supporter cloth 21 differs depending on the part of the body where the supporter 20 is supposed to be attached. For example, when it is assumed that the supporter cloth 21 is attached to the limbs, the overall shape may be tubular or the end may be stopped by a hook-and-loop fastener. It has a possible surface shape, and when it is supposed to be worn on the shoulder or back, it has a surface shape that can be stopped at the end with a sash or a hook-and-loop fastener. The pulse application layer 22 is a sheet-like layer formed of a conductive stretchable flexible member formed in a layer on the back surface side (the side in contact with the wearer's mounting portion) of the supporter cloth 21. The pulse application layer 22 has a multi-layer structure in which the insulating layer 22c, the electrode layer 22a, the insulating layer 22d, the electrode layer 22b, and the insulating layer 22e are laminated in this order from the top. The insulating layers 22c, 22d, and 22e are layers of an insulator. The electrode layer 22a and the electrode layer 22b are insulated from each other by an insulating layer 22c, and the electrode layer 22a and the electrode layer 22b are provided with two output electrode terminals (HT1, HT2) of the waveform generator 16 of the drug administration device 26. They are connected to each other (see FIG. 3). As the electrode layer 22a and the electrode layer 22b, a thin flat or mesh-like conductor sheet or a conductor sheet on which printed wiring is formed can be used. The drug diffusion layer 23 is a sheet-like layer formed in a layer on the back surface side of the pulse application layer and formed by a water-impregnated member (sponge-like member) through which the administered drug or microorganism can permeate. The flooded fit cloth 24 is a hydrogel sheet that is detachably provided on the back surface side of the drug diffusion layer 23 and allows the drug or the like to permeate. The flooded fit cloth 24 is a replaceable disposable sheet.

Further, a plurality of electrodes 27 are provided on the back surface side of the drug diffusion layer 23, and the upper side of each electrode 27 penetrates the drug diffusion layer 23 and is connected to either of the electrode layers 22a and 22b. Has been done. The voltage pulse output by the waveform generator 16 of the drug administration device 26 is applied from these electrodes 27 to the supporter mounting site of the body via the flooded fit cloth 24.

The drug supply unit 25 is attached to the surface side of the supporter cloth 21, stores the drug or microorganism to be transdermally administered to the wearer's wearing site, and sequentially permeates and diffuses the drug diffusion layer. It is a device to supply. The drug supply unit 25 is composed of a cartridge adapter 25a and a cartridge ampoule 25b. The cartridge ampoule 25b is a replaceable cartridge ampoule containing a drug or microorganism. The cartridge adapter 25a is a relay / fixing device to which the cartridge ampoule 25b can be attached / detached. Inside the cartridge adapter 25a, a tubular injection lumen 25c having one end (drainage end) connected to the drug diffusion layer 23 is formed.

FIG. 12B illustrates the operation of attaching / detaching the cartridge ampoule 25b of the drug supply unit 25. A connector 25e to which the connection cap 25d of the cartridge ampoule 25b can be connected is rotatably provided at the liquid inlet end of the liquid injection lumen 25c. When mounting the cartridge amble 25b on the cartridge adapter 25a, insert the tip of the connection cap 25d of the cartridge amble 25b into the connector 25e from directly above the upper surface of the cartridge adapter 25a, and then insert the main body of the cartridge amble 25b. The main body of the cartridge amble 25b is fitted into the fitting groove 25f provided on the upper surface of the cartridge adapter 25a by rotating the connector 25e by 90 degrees around the rotation shaft 25g of the connector 25e so as to be parallel to the upper surface of the cartridge adapter 25a. Let me. By fitting the tip of the connection cap 25d to the connector 25e, the inner chamber of the cartridge amble 25b is in a state of communicating with the liquid injection lumen 25c, and the chemicals and the like in the cartridge amble 25b are poured into the liquid injection lumen 25c and injected. It leaches into the drug diffusion layer 23 through the liquid lumen 25c. The drug solution or the like diffused in the drug or the like diffusion layer 23 permeates into the flooded fit cloth 24 and infiltrates the surface of the supporter mounting portion of the body. When the cartridge amble 25b is removed from the cartridge adapter 25a, the reverse operation of the operation shown in FIG. 12B may be performed.

The drug administration device 26 is a device that outputs an electric pulse having a waveform pattern as described with reference to FIG. 5 in Example 1 to the pulse application layer 22. The drug administration device 26 is attached to the surface side of the supporter cloth 21. On the surface of the drug administration device 26, a power button 26a for inputting an instruction to turn on / off the power and voltage intensity adjusting buttons 26b and 26c for inputting an instruction for adjusting the intensity of the output electric pulse are provided. The internal configuration of the drug administration device 26 is the same as that in FIG. 1, but in the drug administration device 26 of this embodiment, the electrode layer 22a of the pulse application layer 22 is used instead of the probes 6 and 7 in FIG. , 22b are connected.

FIG. 14 is a diagram showing an example in which the supporter 20 according to the second embodiment is attached. FIG. 14 shows an example in which the supporter 20 is attached to the wrist, elbow, shoulder, knee, and ankle, respectively. The overall shape of the supporter cloth 21 is a shape suitable for mounting according to each mounting portion. As described above, when the supporter 20 of the present embodiment is used, the user only needs to attach the supporter 20 to the administration site during the period of administration of the drug or the like, and the drug or the like administration device 26 itself. You don't have to hold it in your hand. Therefore, the user can easily administer the drug or the like. In addition, even if the administration time of the drug or the like is long, the user can freely perform another action during that time, and the drug or the like can be administered for a long time without difficulty. It becomes.

1 Main body 2 Face probe 3 Point probe 4 Head skin probe 5 Cooling probe 6 Electrode 7 Cooling element 8a Probe main body 8b Abutment protrusion 8c Abutment surface 8d Groove 8e Switch 9 Code 10 Waveform pattern memory 11 Main controller 11a Parameter setting part 11b Waveform selection Part 11c Level setting part 11d Time setting part 12 Clock generator 13 Input device 14 Display device 15 Buzzer 16 Waveform generator 16a Sine wave generator 16b Pulse wave generator 16c Coupled transformer 17 EP probe driver 17p Amplifier 17q Duty cycle pulse generation Instrument 17r Pulse amplitude controller 17s Modulator 17a, 17b, 17c, 17d Probe driver 20 Supporter 21 Supporter cloth 22 Pulse application layer 22a, 22b Electrode layer 22c, 22d, 22e Insulation layer 23 Drug diffusion layer 24 Flooded fit cloth 25 Drugs Supply part 25a Cartridge adapter 25b Cartridge amble 25c Injection lumen 25d Connection cap 25e Connector 25f Fitting groove 26 Drug administration device 26a Power button 26b, 26c Voltage strength adjustment button 27 Electrode

Claims (5)

A drug or microorganism applied to the skin surface, or a drug or microorganism touched to the skin surface by attaching a sheet coated or infiltrated with the drug or microorganism to the skin surface is transdermally applied by an electroporation method. It is a drug administration device to be administered,
A waveform generation means that generates an electric pulse of a predetermined waveform pattern,
An electrode that applies an electric pulse of the waveform pattern generated by the waveform generation means to the skin is provided.
The waveform generating means is a serrated waveform pattern in which a rising slope portion that rises from the minimum voltage to the maximum voltage with a gentle slope is followed by a falling slope portion that falls from the maximum voltage to the minimum voltage with a steep slope. The drug or the like is characterized in that it generates the two-stage serrated waveform pattern having one notch portion in which the voltage temporarily drops in a V-notch shape in the middle of the rising inclined portion. Dosing device. A waveform pattern storage means for storing waveform shape parameters that specify the shape of the two-stage serrated waveform pattern having a plurality of shapes according to the combination of the drug or microorganism to be applied (HLB value, electric conductivity).
Input means and
A parameter setting means for acquiring the specified information of the combination of the drug or microorganism (HLB value, electric conductivity) to be applied, which is input from the input means, and
A waveform pattern selection means for reading out the waveform shape parameter from the waveform pattern storage means according to the combination information of (HLB value, electric conductivity) acquired by the parameter setting means is provided.
The administration of a drug or the like according to claim 1, wherein the waveform generating means generates an electric pulse of the waveform pattern in a two-stage sawtooth shape according to the waveform shape parameter read out by the waveform pattern selecting means. apparatus. A carrier wave generating means for generating a carrier wave which is a rectangular wave having a frequency higher than the frequency of the two-stage sawtooth-shaped waveform pattern generated by the waveform pattern generating unit is provided.
The drug or the like according to claim 1 or 2, wherein the waveform generating means generates an electric pulse in which the carrier wave generated by the carrier wave generating means is amplitude-modulated by the waveform pattern having a two-stage sawtooth shape. Dosing device. A drug or microorganism applied to the skin surface, or a drug or microorganism touched to the skin surface by attaching a sheet coated or infiltrated with the drug or microorganism to the skin surface, transdermally by the electroporation method. It is a control method for controlling an administration device such as a drug to be administered.
The rising slope that rises from the lowest voltage to the maximum voltage with a gentle slope, followed by the falling slope that falls from the maximum voltage to the lowest voltage with a steep slope, is a serrated waveform pattern in which the rising slope is repeated. A two-stage sawtooth-shaped electric pulse of the waveform pattern having one notch portion in which the voltage temporarily drops in a V-notch shape is output to the electrode so as to be applied to the electrode. A method for controlling a drug administration device, which comprises controlling a voltage. A supporter cloth made of elastic fiber members formed in a shape that can be wound and fixed to the wearer's wearing part,
A conductive pulse application layer formed in a layer on the side of the supporter cloth in contact with the wearer's mounting portion (hereinafter referred to as "back surface side").
A drug diffusion layer formed in a layered manner on the back surface side of the pulse application layer and formed of a member capable of permeating the drug or microorganism to be administered.
The drug or the like administration device according to any one of claims 1 to 3, which is attached to the surface side of the supporter cloth and applies an electric pulse to the pulse application layer.
A drug supply unit that is attached to the surface side of the supporter cloth, stores a drug or microorganism that is transdermally administered to the wearer's wearing site, and sequentially supplies the drug or microorganism to the drug diffusion layer by permeation diffusion. A supporter characterized by being prepared.