KR20220121010A - Highly Efficient device of Transdermal Drug Delivery via Skin by Bipolar Arc Plasma and Dual Pulse Electroporation - Google Patents

Abstract

The present invention relates to a high-efficiency device for transdermal-administration drug delivery using bipolar arc plasma and dual pulse electroporation. The high-efficiency device for transdermal-administration drug delivery, according to the present invention, comprises: a control unit (MCU); a voltage varying unit; a plasma processing unit; an EP pulse generator, photoMOS1, and photoMOS2; and an electrode. According to the present invention, transdermal drug delivery (TDD) can be effectively introduced to increase an absorption rate.

Description

Highly Efficient device of Transdermal Drug Delivery via Skin by Bipolar Arc Plasma and Dual Pulse Electroporation

The present invention is a skin care device using BAP-DPEP technology, bipolar arc plasma (BAP) and dual pulse electroporation (DPEP) (electroporation method, for making micropores in the cell membrane) It relates to a device that provides a high-efficiency effect of transdermal drug delivery (TDD), which provides systemic action by administering a drug through the skin by using a double electric pulse (gene introduction method).

I. Introduction

People generally lose skin elasticity as they age, resulting in skin wrinkles and sagging. Therefore, there is a tendency to use various functional cosmetics (functional cosmetics) to maintain skin elasticity. However, since the skin protects the human body from external stimuli or substances, it is opaque to water-soluble ingredients and cannot be effectively managed only by applying functional cosmetics. In particular, transdermal drug delivery (TDD) is a method of providing systemic action by administering drugs through the skin. Drugs for use in TDD are abundant and limited to small drugs with molecular weights ≤500 Da [1, 2]. In addition, since the skin protects the human body from external stimuli or chemicals, most substances outside the body cannot penetrate inside [3, 4]. Therefore, microneedle (MN) arrays, electrophoresis and iontophoresis are used to solve this problem [5-8]. In this study, the formation of microchannels was analyzed for percutaneous drug delivery using bipolar arc plasma (BAP).

Skin-care systems remove skin wastes through electricity, vibrations, low frequency, galvanic currents, heat and ozone to care for the skin. devices are included [9-12]. [13] Recently, by supplying hydrogen water to the skin, it contributes to the removal of free radicals that age blood, blood vessels, and cells. proposed management device.

When a drug is introduced into cells, an electric field (or high voltage) is applied to the cells to increase membrane permeability, and DNA enters the cells. However, conventional electronic devices or ionic injectors promote absorption by simply printing a frequency without considering the dryness of the skin. High-voltage electrophoresis uses high voltages of several hundred kilovolts or more, but can be used continuously because of its short pulse width, which induces instantaneous electrical perforation between the cell membranes of the skin. It is not possible, and when applied to the face area, pain appears.

Existing high-voltage electroporation techniques involve applying a high voltage to the skin. Long-term use increases skin irritation, so it is only possible for a short period of time. Techniques using bipolar arc plasma (BAP) and dual pulse electroporation (DPEP) help to effectively create microchannels in the skin and introduce transdermal drug delivery (TDD) deep into the skin.

As the related prior art 1, Patent Registration No. 10-11173110000 registers "a transdermal drug delivery skin massager capable of helping the skin penetration of a drug by means of an ultrasonic wave conductor and maximizing the massage effect".

The transdermal drug delivery skin massager includes a main body, a head member formed on one side of the main body to massage the skin in contact with the skin, and installed in the main body, for cell stimulation of skin or skin cells through the head member A vibration oscillator for generating vibration, a power supply for supplying power to the vibration oscillator, and a coating agent guide that is formed on the head member and can move the coating agent applied to the skin during massage according to the movement direction of the head member .

The coating agent guide is formed to protrude continuously or discontinuously along the edge of the head member, and further includes a sensor unit installed on the head member to diagnose a user's skin condition, and the sensor unit includes a temperature sensor and a protein sensor. , including any one or two or more selected from an acidity sensor and an optical biosensor.

As a related prior art 2, Patent Publication No. 10-2019-0105272 discloses "a cosmetic composition for enhancing transdermal drug delivery of wrinkle-improving peptides (Acetyl Hexapeptide-8, Acetyl Tetrapeptide-5, Cu-Peptide) using skin-absorbing peptides" It relates to a cell membrane-penetrating peptide to increase the transdermal drug absorption of Acetyl Hexapeptide-8. It contains Tat-Peptide together with Acetyl Hexapeptide-8 to increase the transdermal drug absorption. Acetyl Hexapeptide-8 and Tat-Peptide are used. Disclosed is a cosmetic composition that contains at the same time to excellently increase the amount of percutaneous skin absorption.

Patent Registration No. 10-11173110000 (Registration Date: Feb. 09, 2012), "A transdermal drug delivery skin massager that can help the drug penetrate the skin by ultrasound and maximize the massage effect", Kim Hee-gu Patent Publication No. 10-2019-0105272 (Publication date March 05, 2018), "Cosmetic composition for enhancing transdermal drug delivery of wrinkle-improving peptides (Acetyl Hexapeptide-8, Acetyl Tetrapeptide-5, Cu-Peptide) using skin-absorbing peptides ", Eulji University Industry-University Cooperation Foundation

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An object of the present invention to solve the above problems is the skin by bipolar arc plasma (BAP) and dual pulse electroporation (DPEP) (electroporation method, a gene transfer method using double electric pulses to make a thin hole in the cell membrane) Provided is a device for providing high-efficiency effects of transdermal drug delivery (TDD), which provides systemic action by administering a drug through the

In order to achieve the object of the present invention, an apparatus for providing a high-efficiency effect of transdermal drug delivery to the skin by bipolar arc plasma and dual pulse electroporation includes: a power supply; a control unit (MCU) for controlling plasma output to the skin through a plasma processing unit and an electrode by selectively using a bipolar arc plasma (BAP) technology or a double pulse electroporation (DPEP) technology; It is connected to the control unit (MCU) and has an oscillation circuit connected by two TR switching elements (photoMOS1, photoMOS2), a resistor (R), a capacitor (C) and a transformer, and the bipolar arc plasma (BAP) technology is a voltage variable unit boosting the voltage of the primary coil of the transformer to the secondary coil to be used; a plasma processing unit connected to the voltage variable unit and generating plasma by applying a bipolar arc plasma (BAP) technique or a double pulse electroporation (DPEP) technique under the control of the control unit (MCU); an EP pulse generator connected to the control unit (MCU); (+) and (-) electrodes are respectively connected to one side and the other side of the secondary coil of the transformer of the plasma processing unit, an insulator or dielectric is provided between the secondary coils of the transformer, and an electrode in contact with the skin includes

The present invention provides an apparatus for providing a highly efficient effect of transdermal drug delivery (TDD) by bipolar arc plasma (BAP) and double pulse electroporation (DPEP). Using bipolar arc plasma (BAP) and dual pulse electroporation (DPEP) technologies to form microchannels and highly efficient transformation drug delivery (TDD) to the skin The impact was analyzed. The BAP technique was applied to pig skin to form microchannels with biological samples, and plasma was measured and observed with micropores. During BAP, an output voltage of 1 kVpp at 40 kHz was applied at duty rates of 20%, 40% and 60%. The BAP technique was applied to the stratum corneum, and microchannels with an average size of 30 μm x 30 μm and 77 μm x 55 μm were formed only in the keratin layer without damage to the dermal layer. Next, double pulse electroporation (DPEP) was stimulated to increase the permeability of the endothelial membrane in structures with microchannels. The proposed technique of bipolar arc plasma stimulation (BAP) and double pulse electroporation (DPEP) was developed as a skin test in 20 female subjects with an average age of 44 years to effectively achieve deeper transdermal drug delivery (TDD). introduced to increase the absorption rate by 418%.

Figure 1 (a and b) the function of the arc plasma (arc plasma). Compared to normal plasma, arc plasma can stimulate sparks and has no ozone. (c) An enlarged view of the arc plasma concept.
2 is a conceptual diagram of bipolar arc plasma (BAP) technology.
3 is (a) a pig skin sample (size: 4 x 4 cm, thickness: 2.0-3.8 mm); (b) Observation of pig skin using light microscopy.
Figure 4 is sample 1. showing the stratum corneum (a) before and after stimulation (b).
5 is sample 2 showing the stratum corneum (a) before and after stimulation (b).
6 is sample 3 showing the stratum corneum (a) before and after stimulation (b).
7 is an electroporation technique used in this study. (a) a device using the proposed electroporation technique, (b) before and during electroporation, (c) absorption of sweat and skin pores, and (d) electroporation.
8 is an implemented circuit diagram of a BAP-DPEP technique according to the present invention;
Fig. 9 shows (a) voltage shape of DPEP technology at 5°, AC (waveform) formed by photoMOS control, and (b) DC waveform display. PhotoMOS is a combination of high voltage and low voltage controlled by a control unit. Through this, it is possible to output the same type of voltage as in 5ㅀ, and this electronic voltage is transmitted to both ends of the electrode and outputted to the user's skin.
Figure 10 (a) Voltage obtained using the BAP-DPEP technique. (b) Voltages obtained when BAP and DPEP techniques are used separately and simultaneously at different time periods.
11 is an absorption depth effect result of Raman spectroscopy.
12 shows skin absorption when not in use (blue) and when using BAP and DPEP (orange).
13 is a photograph of cosmetic absorption experiments by BAP and DPEP;
S4. Steps in a technology to create transient pores in cell membranes using electroporation (see: Two sequential electroporation using the MedPulser DNA Delivery System (DDS) in healthy adults) Tolerance of electroporation therapy, Moleculare Therapy, DOI: 10.1038 / mt. 27. 2009. Source: PubMed)
14 is a skin absorption measurement result (* p<0.05 by Paired t-test, # p<0.05 by Wilcoxon signed rank test).
15 shows that the skin absorption rate of S6: BAP + DPEP was about 96 times higher than that of the skin coated with only the sample.
As a result of checking the skin absorption depth using the test product, a significant difference (p <0.05) was found in the ampoule + device simultaneous use group compared to the ampoule alone group.
S7: Skin absorption depth (comparison of groups)
16 is a 3D Raman microscopy result for skin absorption of Ampoule and Device + Ampoule in 4 patients (RS1-17 to 20): (a) Before Device + Ampoule; (b) after Device + Ampoule; (c) before ampoule; and (d) after Ampoule.
17 is a calibration peak (calibration peak) (a) ferulic acid sample (b) sample collected after plasma stimulation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. In the description of the present invention, if it is determined that a detailed description of a related known function or a known configuration may unnecessarily obscure the gist of the present invention, the detailed description thereof will be omitted. In addition, the accompanying drawing numbers are assigned the same reference numbers in different drawings when indicating the same configuration.

The present invention relates to skin by bipolar arc plasma (BAP) and dual pulse electroporation (DPEP) (electroporation, a gene transfer method using double electric pulses to make micropores in the cell membrane) It provides a high-efficiency effect of transdermal drug delivery (TDD), which provides systemic action by administering the drug through the

In this study, using bipolar arc plasma (BAP) and dual pulse electroporation (DPEP) techniques, microchannels were formed and high-efficiency transformation drug delivery was conducted. TDD) effect on the skin was analyzed. The BAP technique was applied to pig skin to form microchannels with biological samples, and plasma was measured and observed with micropores. During BAP, an output voltage of 1 kVpp at 40 kHz was applied at duty rates of 20%, 40% and 60%. The BAP technique was applied to the keratin layer, and microchannels with an average size of 30 μm×30 μm and 77 μm×55 μm were formed only in the keratin layer without damage to the dermal layer.

Next, the skin was stimulated using double pulse electroporation (DPEP) to increase the permeability of the endothelial membrane in structures with microchannels. The technique of BAP and DPEP effectively introduced deeper transdermal drug delivery (TDD) by developing a skin test on 20 female subjects with an average age of 44 years, increasing the absorption rate of the skin by 418%. .

II. BAP technology

To use both bipolar arc plasma (BAP) and double pulse electroporation (DPEP) technologies, a hybrid skin-care system that sequentially applies these technologies according to the skin condition was used.

Figure 1 (a and b) the function of the arc plasma (arc plasma). Compared to normal plasma, arc plasma can stimulate sparks and has no ozone. (c) It is a diagram showing an enlarged view of the arc plasma concept.

As can be seen in Figure 1, Bipolar Arc Plasma (BAP) is used as the first technology, and when applied it creates an arc-based plasma without generating more ozone than human safety allowable levels, thus lifting household plasma. It is convenient and safe to use in household plasma lifting devices. To reduce ozone emission from plasma stimulation systems on the skin and avoid effects on the human body, bipolar arc plasma (BAP) technology has been studied in direct contact with the skin. A general dielectric barrier discharge (DBD) technique provides a concept of distributing a voltage over a large area and contacting the skin with a low voltage [14, 15]. Therefore, the dielectric barrier discharge (DBD) method is less irritating to the skin. However, DBD technology can be harmful to the human body due to the emission of significant amounts of ozone. In contrast, bipolar arc plasma (BAP) technology induces a relatively low output voltage directly into a narrow skin area without ozone emission. Arc plasma energy is concentrated at a point and reacts with the skin to form fine holes in the stratum corneum. As a result of the experiment, the ozone concentration emitted by the proposed device was maintained below the human safety limit of 0.05 ~ 0.06ppm.

BAP technology consists of three stages at 1 kVpp output at 40 kHz voltage, i.e. 20%, 40% and 60% duty rates (see Figure 2). The electrodes use a leaf-shaped trivalent chromium plating injection with a titanium coating on the surface. BAP uses an arc plasma that does not emit ozone from the skin layer. The output current has an output power high enough to turn on 567 LEDs simultaneously. In addition to its tremendous power, it pierces less and damages the skin less than other cosmetic devices (eg, ionic devices) as shown in FIG. 2 .

2 is a conceptual diagram of bipolar arc plasma (BAP) technology.

The experiment was started by preparing 8 pieces of 4cm x 4cm size of pig skin with a thickness of 2.0 to 3.8mm as shown in FIG. 3 . After thawing, the pork skins stored in the freezer were prepared in a size of 50 mm x 50 mm.

3 is (a) a pig skin sample (size: 4 cm x 4 cm, thickness: 2.0-3.8 mm); (b) A photograph of pig skin observation using an optical microscope.

See Figure 3 (a). Thereafter, after being hydrated in 0.1M NaCl solution for 5 to 10 minutes, moisture was removed and bipolar plasma was applied. The thickness of the pig skin (2.0 ~ 3.8 mm) was measured in a Petri dish (Petri dish), and the pig skin was stored. Pig skin thicker than 3.0 mm was discarded because it was difficult to observe with a light microscope. Those with a thickness of 2.0-3.0 mm were used for the BAP experiment. Pig skin is thawed at room temperature for 3 hours and then immersed in 0.1-M NaCl saline for 5-10 minutes. That is, a water removal step was performed for the bipolar arc plasma stimulation (BAP) technique. As shown in FIG. 3 (b), arc plasma was applied to the epidermis of pig skin for 5 to 7 minutes to observe the change in the stratum corneum of pig skin before and after stimulation with an optical microscope. applied.

A transformer has been used to induce a high voltage to generate an arc plasma [16, 17]. At this time, the voltage applied to the primary coil of the transformer is multiplied by the turns ratio of the secondary coil, and the voltage is boosted to a high voltage to generate plasma by the insulator or dielectric formed between the secondary coils. The generated plasma is connected to the user's skin by an electrode connected to the secondary coil or applied through the grounded skin. That is, plasma is generated through an insulator or dielectric formed between the secondary coils using a high voltage in which the voltage applied to the primary coil of the transformer is increased by the turns ratio of the secondary coil, and the generated plasma is An electrode electrically connected to the secondary coil is connected to the user's skin.

High voltages of 100 Vpp are commonly used in conventional hospital electronics. In addition, even when used for a long time at home, a device having a low voltage peak waveform of 30Vpp can be used without stressing the skin, and it exhibits the same effect as used in a hospital. The plasma waveform has an output voltage value of 1KVpp or more with a frequency of 30kHz or more to 100kHz or less. In particular, the plasma waveform of 40 kHz is more effective than the skin beautician who implements the lifting function by improving the absorption rate of wrinkle-improving ingredients such as oligonucleotides. The above-mentioned skin care apparatus may control the skin care apparatus to generate plasma in a frequency range of 30-100 kHz.

To confirm microchannel formation by the bipolar arc plasma stimulation (BAP) technique, the keratin and dermal layers of pig skin were observed before BAP was applied, and then using a marker The observation area was marked. Using the device of the present invention, bipolar arc plasma was stimulated step by step within the marked area of the pig-skin sample's stratum corneum for 10 minutes, and microchannels ( A light microscope was used to identify microchannels).

In all experiments, the keratin layer was measured with an optical microscope as shown in FIG. 3 of the manuscript, and micro-holes were not observed on the back of pig skin. In general, since the dermal layer is distributed to a depth of 2 to 3 mm, it means that the dermal layer is not damaged. Sample 1 was induced with Level-1 bipolar-plasma stimulation; The thickness of the pig skin was 2.16 mm.

4 is an optical microscopic image of the stratum corneum of pig skin before and after stimulation. The marked area shows the formation of microchannels of 9 μm x 10 μm. Sample 2 was provided with a Level-2 bipolar-plasma). The pig skin was 2.64 mm thick. 5 shows microscopic images of the kertain layer of pig skin before and after plasma stimulation on pig skin. The marked area shows microchannel formation of 30 μm x 30 μm. Sample 3 with 2.16 mm thick porcine skin was provided with level 3 bipolar plasma.

6 shows microscopic images of the stratum corneum of pig skin before and after stimulation. The marked area shows forming microchannels from 30 μm x 30 μm up to 77 μm x 55 μm.

III. DPEP technology

Conversely, if the time for applying a low voltage to the skin for the purpose of electroporation is prolonged, an efficiency close to the skin absorption rate can be seen at a high peak voltage, but at a low voltage, the skin There may be a limit to the probability of passing through. This problem can be solved using the DPEP technique [18-23]. The lifting effect is much higher than without electroporation. This is due to the absorption of components by electroporation [24, 25].

7 is an electroporation technique used in this study. (a) a device using the proposed electroporation technique, (b) before and during electroporation, (c) absorption of sweat and skin pores, and (d) electroporation.

7 shows an electroporation technique [26]. The results of schematically expressing the device using the electroporation technique on the skin surface and the absorption process of sweat and skin pores are shown in FIGS. 7(a) and (b), respectively.

The skin consists of three layers: the keratinized outer epidermis, the innermost connective tissue of the epidermis, the dermis, and the innermost subcutaneous tissue.

The stratum corneum serves as a major barrier to protect the body from moisture loss and percutaneous absorption (see Fig. 7(c)). It consists of numerous layers of lipids [27] that enable barrier function [28].

Lipids have a bilayer structure consisting of hydrophilic (ie, water-friendly) and hydrophobic (ie, oil-friendly) moieties. When a high voltage is applied to the skin, the electric current causes temporary structural oscillations in the lipids, resulting in rearrangement of the lipid bilayer. This in turn creates temporary pores towards the hydrophilic part of the cell membrane, which can deliver macro-molecules through the pores as shown in Fig. 7(d) [29]. It is very useful in functional cosmetics, which is a complex structure of polymers (eg, oligonucleotides, oligo nucleotides, peptide peptides) and soluble compounds (eg, vitamin C, minerals). In fact, all polymer components of 40,000 Dalton are transferable in Supplementary Fig. S4 [30].

IV. BAP-DPEP technology

The BAP-DPEP technology applies bipolar arc plasma to the skin, then creates electroporation, and forms a control unit over skin-care units to control the user's skin condition. BAP, DPEP, two technologies in order, using bipolar arc plasma (BAP) technology to generate arc plasma in the frequency range of 30 to 100 kHz using 100 Vpp high voltage to stimulate the skin through electrodes After that, it is a skin care method in which double pulse electroporation (DPEP) is performed through an electrode using a low voltage of 30 Vpp.

In the embodiment, the control unit of the hybrid skin-care unit using the BAP-DPEP technology includes an EP pulse generator providing a DC pulse voltage in the range of 1V to 20V and two photoMOS units, respectively. to output AC waveform or DC waveform plasma using different levels of high voltage and low voltage, respectively.

Arc plasma stimulation is applied to the skin with one electrode, and after arc plasma stimulation, electroporation is performed on the skin again with the electrode.

The skin care device using the BAP-DPEP technology uses the bipolar arc plasma (BAP) technology to generate an arc plasma using a high voltage of 1000 to 5000 Vpp in the frequency range of 30 to 100 kHz to form a plasma processing unit and an electrode ( electrode) can be controlled to stimulate arc plasma on the skin. A plasma output of at least 1 Vpp may be used by a control unit (MCU) of the skin care device. In addition, the skin care device changes the 30Vpp low voltage used for electroporation under the control of the control unit (MCU) to apply plasma to the skin through an EP pulse generator, two relays, and a plasma processing unit and electrodes. print out

A device for providing a highly effective effect of transdermal drug delivery (TDD) by bipolar arc plasma stimulation (BAP) and dual pulse electroporation (DPEP) is used in a skin care device using BAP-DPEP technology.

The device for providing a high efficiency effect of transdermal drug delivery (TDD) by bipolar arc plasma (BAP) and dual pulse electroporation (DPEP) of the present invention,

power supply;

Using the bipolar arc plasma (BAP) technology, the arc plasma is generated in the frequency range of 30-100 kHz using a high voltage of 1000-5000 Vpp through the voltage variable part, and the arc is applied to the skin through the plasma processing part and the electrode. Control to output plasma, or by performing electroporation using a low voltage of 30 to 80 Vpp using double pulse electroporation (DPEP) technology to provide control to the skin through the plasma processing unit and the electrode a control unit (MCU);

It is connected to the control unit (MCU) and includes two FET switching elements (photoMOS1, photoMOS2) connected in parallel to the secondary coil of the transformer, a resistor (R), a capacitor (C) and a transformer, a voltage variable unit that boosts the voltage of the primary coil of the transformer to the secondary coil by mutual induction according to the turns ratio of the coil using a bipolar arc plasma (BAP) technology;

In the secondary coil of the transformer connected to the voltage variable unit and connected to the primary coil of the transformer connected to the TR oscillation circuit of the voltage variable unit for bipolar arc plasma (BAP) technology under the control of the control unit (MCU) using the boosted 1000~5000Vpp high voltage to generate arc plasma in the frequency range of 30~100kHz and output it to the skin through the electrode to stimulate the arc plasma; Using the double pulse electroporation (DPEP) technology under the control of the control unit, the photoMOS1 that receives the two-path (+) pulse from the EP pulse generator and the photoMOS2 that receives the (-) pulse are generated through a plasma processing unit for generating plasma by receiving each high voltage pulse at one side and the other side of the secondary coil of the transformer, respectively;

An EP pulse generator connected to the control unit (MCU) and providing positive (+) and negative (-) high voltage pulses to the photo MOS1 and photo MOS2, respectively, by generating a positive (+) and negative (-) pulse of a DC voltage in the range of, for example, 1 to 20V; , a photoMOS1 receiving a (+) pulse of two paths and a photoMOS2 receiving a (-) pulse from the EP pulse generator, and applying the generated high voltage pulse to one side and the other side of the secondary coil of the transformer of the plasma processing unit provide,

(+) and (-) electrodes are respectively connected to one side and the other side of the secondary coil of the transformer of the plasma processing unit, and an insulator or dielectric is provided between the secondary coils of the transformer, It consists of electrodes that are in contact.

The control unit (MCU) uses a bipolar arc plasma (BAP) technology to generate an arc plasma in a frequency range of 30 to 100 kHz using a 100 Vpp high voltage through the voltage variable unit to connect the plasma processing unit and the electrode. control to stimulate arc plasma into the skin through, or

By using a double pulse electroporation (DPEP) technology, electroporation using a low voltage of 30 Vpp is performed to control plasma to be provided to the skin through the plasma processing unit and the electrode.

The plasma processing unit

In the secondary coil of the transformer connected to the voltage variable unit and connected to the primary coil of the transformer connected to the TR oscillation circuit of the voltage variable unit for bipolar arc plasma (BAP) technology under the control of the control unit (MCU) using the boosted 1000~5000Vpp high voltage to generate arc plasma in the frequency range of 30~100kHz and output it to the skin through the electrode to stimulate the arc plasma;

Using the double pulse electroporation (DPEP) technology under the control of the control unit, the photoMOS1 that receives the two-path (+) pulse from the EP pulse generator and the photoMOS2 that receives the (-) pulse are generated through Plasma is generated by receiving each high voltage pulse on one side and the other side of the secondary coil of the transformer, respectively.

It is connected to the control unit (MCU), the bipolar arc plasma (bipolar arc plasma) using the BAP technology or the electroporation method (electroporation) using the DPEP technology further includes an LED display for displaying the operation.

The skin care device using the BAP-DPEP technology is connected to the control unit (MCU) and further includes a power button, a BAP operation button, and a DPEP operation button.

A skin care device using BAP-DPEP technology is connected to the control unit (MCU), and if necessary, a skin patch-type biosensor that measures skin biochemical indicators, a flexible skin measurement sensor on a flexible substrate, It further includes a sensor unit including any one of a temperature sensor and a humidity sensor for measuring humidity.

The skin care apparatus using the BAP-DPEP technology is connected to the control unit (MCU) and further includes a housing unit for housing the manufactured device in various types of cases as needed.

The BAP-DPEP technology sequentially creates either bipolar arc plasma or electroporation on the user's skin. The control unit of the skin care system uses BAP technology, respectively, two TR switching elements, an oscillation circuit, a voltage variable unit having a resistor (R), a capacitor (C), and a transformer, a plasma generating unit and an electrode (electrode) ) to stimulate the skin with bipolar arc plasma, and then apply it to the skin using the electrode again using the electroporation method.

A skin care device using the BAP-DPEP technology uses a high voltage (100 Vpp) for arc plasma stimulation and a low voltage (30 Vpp) for electroporation at different voltage levels, respectively, and arc plasma in the form of an AC waveform or DC waveform. (Arc plasma) is controlled to generate.

The BAP-DPEP technique stimulates the skin through arc plasma stimulation through an electrode, and measures the skin condition through a sensor unit (temperature sensor, biosensor, etc.) connected to the control unit (MCU) to measure the user's skin condition. Provides a control function to determine

In addition, a skin pathway for skin regeneration may be formed by performing double pulse electroporation (DPEP). In addition, when generating plasma to increase the absorption rate of active ingredients, the BAP-DPEP technology outputs a plasma with a specified high-level voltage (eg, 1KVpp) within the 30-100 kHz intermediate frequency range. This increases the efficiency of the method because a voltage (eg, electro-organization voltage) is output to simultaneously perform the electroporation operation. Here, the electronic voltage has an intermediate frequency voltage coupled with one or more peak-to-peaks.

8 is an implemented circuit diagram of the BAP-DPEP technique according to the present invention.

The control unit (MCU) of the skin care device uses BAP technology to control to generate an arc plasma in the frequency range of 30 to 100 kHz using a high voltage (100 Vpp), and then sequentially double pulse electroporation ( DPEP) technology is used to control the (+) and (-) bipolar pulse levels of the DV voltage of the EP pulse generator to perform electroporation with one electrode. Through the double pulse electroporation (DPEP) technique, a specified high level voltage (1KVpp) is induced within the intermediate frequency range of 30 to 100 kHz, and the BMPS unit and electronic voltage and arc plasma ( A waveform that simultaneously outputs a high voltage (100 Vpp) and a low voltage (30 Vpp) is implemented by switching a voltage variable that generates arc plasma). In addition, since a high voltage (100 Vpp) is required to generate the arc plasma, the control unit MCU switches to the photoMOS1 and photoMOS2 to protect voltage generation for electroporation.

In the driver (TR driver), an oscillation circuit in which two units are connected together with a transformer is connected to a TR switching element (photoMOS1 and photoMOS2), a resistor (R), a capacitor (C), and a primary coil of a transformer.

A transformer is used to induce a high voltage to generate arc plasma, and arc plasma is generated in the secondary coil by multiplying the voltage applied to the primary coil of the transformer by the turns ratio of the secondary coil. The generated arc plasma is connected to the user's skin by an electrode connected to the secondary coil or applied through the grounded skin. That is, the voltage applied to the primary coil of the transformer rises to the turns ratio of the secondary coil to generate plasma through the insulator or dielectric formed between the secondary coils, and the generated plasma is the electrode electrically connected to the secondary coil. is connected to the skin of

The driving unit is composed of TR switching elements for the configuration of an oscillator electrically connected to the transformer, and each TR switching element is connected to the primary coil of the transformer. The capacitor C and the resistor R, respectively, the switching element TR and the primary coil operate as a stable device for stably inputting the output voltage of the inverter to the primary coil of the transformer. The secondary coil of the transformer is connected to each side of the electrode. The winding ratio of transformer is determined from 500 to 3000. Also, the transformer may include a dielectric between the primary coil and the secondary coil. A pulse generator configured with a voltage variable generates a high voltage pulse with alternating positive and negative levels. The pulse generator includes a triangle wave generator that generates a pulse voltage and a comparator that compares the level of the DC voltage provided. The pulse generator generates a pulse voltage of pulse width at the point where the triangle intersects to induce a DC voltage to determine the upper and lower levels. As the DC voltage level increases and decreases, the pulse width increases and decreases, respectively, which determines the frequency of the high voltage pulse. In addition, the pulse generator determines the high voltage and low voltage level according to the control device, and outputs the high voltage and the low voltage at the same time.

Fig. 9 shows (a) voltage shape of DPEP technology at 5°, AC (waveform) formed by high-voltage relay control, and (b) DC waveform display. A high voltage relay is a combination of high voltage and low voltage controlled through a control unit. Through this, it is possible to output the same type of voltage as in 5ㅀ, and this electronic voltage is transmitted to both ends of the electrode and outputted to the user's skin.

DPEP technology shows voltage in the form of AC and DC waveforms as shown in the figure. 9(a) and (b). The AC waveform is formed using a photoMOS control unit. The photoMOS unit generates a voltage by combining a high voltage and a low voltage according to the control unit as shown in FIG. 8 . These electroporation voltages are transmitted to both ends of the electrode and output to the user's skin. As shown in FIG. 7 , the controller controls a driver of a plasma-processing unit and a photoMOS unit of a voltage variable to separately generate plasma and perform an electrical operation. Fig. 10(a) shows the voltage at which the control unit is operated simultaneously with the plasma processing unit for plasma generation and the voltage variable unit for electronic operation. At a given time (or as time is changed), the voltage at which the motion shape is changed is shown in Fig. 10(b). As shown in FIG. 10( b ), the voltage may change with time or a new waveform may be created suitable for the user's skin.

Figure 10 (a) Voltage obtained using the BAP-DPEP technique. (b) Voltages obtained when BAP and DPEP techniques are used separately and simultaneously at different time periods.

11 is an absorption depth effect result of Raman spectroscopy.

Therefore, when the BAP-DPEP technology stimulates the user's skin, a high voltage and a low voltage effective to form a skin passage are simultaneously generated, resulting in a deeper penetration of the effective ingredient into the skin. Together with this, a new channel is created that can be absorbed in a large amount into the skin. BMP-DPEP technology generates plasma and peaks for electroporation for high-efficiency transdermal drug delivery (TDD) effects on the user's skin by outputting high and/or low voltages at a specified frequency.

12 shows skin absorption when not in use (blue) and when using BAP and DPEP (orange).

V. Measurement

The measurement test involved 20 female subjects with a mean age of 44 years. To evaluate the performance of the device, the skin surface temperature and humidity were adapted to the environment in a stable state for 30 minutes in a waiting room with an indoor temperature of 20-25°C and a humidity of 40-60%. In addition, water intake during stabilization was limited. The results of 20 female patients before/after using the device + ampoule and before/after using the ampoule are shown in the Supplementary Figure. S.8-12. Two methods were used to determine the change in skin absorption. Both the ampoule group and the ampoules with arc plasma and electroporation device groups increased significantly after 30 min (p <0.05). In addition, the ampoules using arc plasma and electroporation ampoules showed a significant difference (p <0.05) after 30 minutes of use compared to the ampoules alone group. The significant difference (p <0.05) between the skin absorption rate and depth of the electroporation group and the results of the ampoule group using the ampoule group is shown in Table 2 and Supplementary Figure S7. No skin adverse reactions were reported during the period of use of the test product, and no abnormal findings were observed by dermatologists.

Ⅵ. Course using BAP-DPEP technology

의 앰플을 적용했다. 플라즈마 장치는 앰플과 장치가 모두 사용되는 영역에서만 사용되었다. 기계적 평가를 위해 시험 대상은 20 ~ 25℃의 상온, 40 ~ 60%의 습도 하에서 실온에서 30 분 동안 안정되었다. 피부 표면의 온도와 습도는 측정 공간의 환경에 맞게 조정되었으며, 휴식 중에는 수분 섭취를 제한했습니다. 연구자가 객관적인 측정을 수행했다.The technique using the present invention can be defined in two stages. (1) Before applying Fusion Plasma, use a cleansing cream to remove makeup, and if there is water left on the face, plasma may not form properly, so the skin should be naturally dried for 1 to 2 minutes. (2) After the skin is completely dry, apply the hyaluronic acid ampoule first, and apply it evenly over the entire face with the device. Both steps (1) and (2) take 5 minutes each to apply the solution to the face surface. The ampoule was divided into two parts on the subject's forearm and applied to the designated area. (1) the area where the ampoule and the device are used simultaneously, and (2) the area where only the ampoule is used (3cm (width) x 4cm (length)). 4 μL/in each site

of ampoule was applied. Plasma devices were only used in areas where both ampoules and devices were used. For mechanical evaluation, the test subject was stabilized for 30 minutes at room temperature under a room temperature of 20 to 25 °C and a humidity of 40 to 60%. The temperature and humidity of the skin surface were adjusted to the environment of the measurement space, and water intake was limited during rest. The investigator performed objective measurements.

VII. skin absorption measurement

Arc plasma stimulation or electroporation is made on the skin through the electrode,

의 두 테스트/대조군 영역에서 수행되었다. 전체 영역이 장비에 고정되었다. 각 영역은 제품 사용 전후 30분 동안 측정되었다. 도 11에서, 30분 후 처리는 표피층의 흡수율이 418% 증가하였다. 측정에 사용된 레이저는 785nm 파장의 레이저를 사용하고, 스캐닝 단계는 5μm로 고정되었다. Skin absorption was measured using a 3D Raman Microscopy System Nanofinder 30 (TOKYO INSTRUMENTS, Japan). Raman spectroscopy can detect a wavelength change that occurs during a scattering phenomenon due to irradiation of light on a material. This method has the advantage of being able to measure skin in vivo in a non-destructive way. In particular, the 3D Raman system used in the test is a device manufactured to have fine spacing in the x, y, and z directions, and the z-axis focal length can be moved from the skin surface to the inside of the skin in micrometers. Therefore, it is possible to obtain a 3D Raman spectral image according to the depth of the skin without damaging the skin of the subject. Through this, it is possible to determine whether or not the cosmetic is absorbed into the skin. 3D Raman scanning is 3x4 each of the skin of the left forearm of the test subject.

were performed in the two test/control regions of The entire area was fixed to the equipment. Each area was measured for 30 minutes before and after product use. 11 , after 30 minutes, the absorption rate of the epidermal layer increased by 418%. The laser used for the measurement was a 785 nm wavelength laser, and the scanning step was fixed at 5 μm.

For the safety of the test subject, the incidence rate of adverse reactions was calculated by summing all adverse reactions identified for all subjects who used the test product and all adverse reactions reported during the trial period. This information was used as data for product safety evaluation. A statistical analysis program, SPSS 19.0, was used to determine whether the measurements were significant before using the test product. Significance was confirmed when the significance probability p <0.05 entered the 95% confidence interval. Significance probabilities are rounded to three decimal places. For comparison before and after normalization, paired t-test, a parametric method, and Wilcoxon signed rank test, a nonparametric method, were used after normality test. The groups before and after using the product were compared according to the rate of change (skin absorption) and raw data (skin absorption depth and absorption rate). After the normality test, the Mann-Whitney U test (non-parametric method) was used (Table 1 and Supplementary Figures). S5, S6. Then, the change in skin absorption according to the use of the test product was confirmed. In particular, both the group using the ampoule + device at the same time and the group using only the ampoule showed a significant increase in skin absorption (p <0.05) after 30 minutes of using the product. Also, a significant difference (p <0.05) was observed between the two groups. The permeability of samples collected from non-stimulating skin and irritated skin was compared through a high-performance liquid chromatography system as shown in FIG. 12 . analyzed.

Table 1 is an arbitrary unit, the measurement result of skin absorption.

13 is a cosmetic absorption experiment by BAP-DPEP a) Franz diffusion cell: Receptor - 1X_PBS → A donor is placed on pig skin and fixed with forceps, b) Sample 5ml to a donor dosing, c) collection and storage of 1 ml in the Receptor every hour

S4. Steps in a technique for creating transient pores in cell membranes using electroporation (see: Two sequential electroporation using the MedPulser DNA Delivery System (DDS) in healthy adults) Tolerability of electroporation therapy, Moleculare Therapy, DOI: 10.1038 / mt. 27. 2009 Source: PubMed)

14 is a skin absorption measurement result (* p<0.05 by Paired t-test, # p<0.05 by Wilcoxon signed rank test)

As a result of checking the change in skin absorption according to the use of the test product, both the ampoule + device simultaneous use group and the ampoule alone use group use the product compared to before use Significantly increased (p <0.05) after 30 min.

Also, a significant difference (p<0.05) was found in the ampoule + device simultaneous use group compared with the ampoule alone group.

15 shows that the skin absorption rate of S6: BAP + EP was 96 times higher than that of the skin coated with only the sample.

As a result of checking the skin absorption depth using the test product, a significant difference (p <0.05) was found in the ampoule + device simultaneous use group compared to the ampoule alone group.

S7: Skin absorption depth (comparison of groups)

16 is a 3D Raman microscopy result for skin absorption of Ampoule and Device + Ampoule in 4 patients (RS1-17 to 20): (a) Before Device + Ampoule; (b) after Device + Ampoule; (c) before ampoule; and (d) after Ampoule.

17 is a calibration peak (calibration peak) (a) ferulic acid sample (b) sample collected after plasma stimulation.

Ⅷ. conclusion

BAP-DPEP technology using hybrid bipolar arc plasma (BAP) and dual pulse electroporation (DPEP) creates microchannels in the skin and introduces transdermal drug delivery (TDD) deep into the skin. It was effective in building a channel unit for In particular, bipolar arc plasma (BAP) was applied to the skin of pigs whose microchannels were measured with an optical microscope. The BAP technology has been shown to be ozone-free in the epidermal layer, which is safe for application on human skin. Most microchannels were 30 μm x 30 μm, with a maximum of 77 μm x 55 μm. The second technique, double pulse electroporation (DPEP), was sequentially applied to form a skin pathway for skin regeneration. Finally, the BAP-DPEP technology resulted in a very efficient transdermal drug delivery (TDD) effect on the skin of the user (20 female subjects with an average age of 44 years). The test subject's solution passed through the stratum corneum after 30 minutes and was absorbed into the epidermis, and the skin absorption rate increased by 418%. The proposed BAP-DPEP technology can be used for transdermal drug delivery (TDD) as well as other applications such as wound healing, skin rejuvenation, anesthetic treatment and wrinkle treatment. can

Although described with reference to a specific embodiment of the present invention, the present invention is not limited to the same configuration and operation as the specific embodiment in order to illustrate the technical idea as described above, and within the limit that does not depart from the technical spirit and scope of the present invention It can be implemented with various modifications, and the scope of the present invention should be determined by the claims to be described later.

BAP: bipolar arc plasma
DPEP: dual pulse electroporation
TDD: transdermal drug delivery

Claims (12)

power supply;
a control unit (MCU) for controlling plasma output to the skin through a plasma processing unit and an electrode by selectively using a bipolar arc plasma (BAP) technology or a double pulse electroporation (DPEP) technology;
It is connected to the control unit (MCU) and includes two TR switching elements (photoMOS1, photoMOS2), a resistor (R), a capacitor (C) and a transformer, which are connected to a transformer to form an oscillation circuit, and the bipolar arc plasma ( BAP) a voltage variable unit that boosts the voltage of the primary coil of the transformer to the secondary coil so that the technology is used;
a plasma processing unit connected to the voltage variable unit and generating plasma by applying a bipolar arc plasma (BAP) technique or a double pulse electroporation (DPEP) technique under the control of the control unit (MCU);
an EP pulse generator connected to the control unit (MCU);
An apparatus for providing a high-efficiency effect of transdermal drug delivery through bipolar arc plasma and dual pulse electroporation including an electrode connected to the plasma processing unit. According to claim 1,
The control unit (MCU) generates an arc plasma in a frequency range of 30 to 100 kHz using a high voltage of 1000 to 5000 Vpp through the voltage variable unit using the bipolar arc plasma (BAP) technology, and the plasma processing unit and the control to stimulate arc plasma to the skin through electrodes, or
By using the double pulse electroporation (DPEP) technology to perform electroporation using a low voltage of 20 to 80 Vpp to control the plasma to be provided to the skin through the plasma processing unit and the electrode, bipolar arc plasma and a device for providing high-efficiency effects of transdermal drug delivery through dual pulse electroporation. According to claim 1,
The plasma processing unit
In the secondary coil of the transformer connected to the voltage variable unit and connected to the primary coil of the transformer connected to the TR oscillation circuit of the voltage variable unit for bipolar arc plasma (BAP) technology under the control of the control unit (MCU) using the boosted 1000~5000Vpp high voltage to generate arc plasma in the frequency range of 30~100kHz and output it to the skin through the electrode for arc plasma stimulation;
Using the double pulse electroporation (DPEP) technology under the control of the control unit, the photoMOS1 receiving (+) pulses and the photoMOS2 receiving the (-) pulses are generated through the EP pulse generator in parallel, respectively. A device for providing high-efficiency effect of transdermal drug delivery by bipolar arc plasma stimulation and dual pulse electroporation, which generates plasma by receiving each high voltage pulse on one side and the other side of the secondary coil of the transformer, respectively. According to claim 1,
The EP pulse generator provides a high efficiency effect of transdermal drug delivery by bipolar arc plasma stimulation and dual pulse electroporation, providing positive (+) and negative (-) bipolar pulses of DC voltage within the range of 1 to 80V. . According to claim 1,
The electrode has (+) and (-) electrodes connected to one side and the other side of the secondary coil of the transformer of the plasma processing unit, respectively, and an insulator or dielectric is provided between the secondary coils of the transformer, and is applied to the skin. A device for providing a highly efficient effect of transdermal drug delivery through contact, bipolar arc plasma stimulation and dual pulse electroporation. According to claim 1,
Transdermal administration by bipolar arc plasma stimulation and dual pulse electroporation, which is connected to the control unit (MCU) and further includes an LED display unit for displaying whether an electroporation operation is performed using a bipolar arc plasma using BAP technology or DPEP technology A device that provides a highly effective effect of drug delivery. According to claim 1,
It is connected to the control unit (MCU) and further comprises a power button, a BAP operation button, and a DPEP operation button. According to claim 1,
Any one of a skin patch type biosensor that is connected to the control unit (MCU) and measures biochemical indicators of the skin as needed, a flexible skin measurement sensor on a flexible substrate, a temperature sensor that measures the temperature and humidity of the skin surface, and a humidity sensor A device for providing a high-efficiency effect of transdermal drug delivery to the skin by bipolar arc plasma stimulation and dual pulse electroporation, further comprising a sensor unit having a single sensor. According to claim 1,
High efficiency effect of transdermal drug delivery by bipolar arc plasma stimulation and dual pulse electroporation, which is connected to the control unit (MCU) and further includes a housing for housing the manufactured device in various types of cases as needed . According to claim 1,
When using bipolar arc plasma stimulation (BAP) and double pulse electroporation (DPEP) techniques to form microchannels and analyze the effects of high-efficiency transduced drug delivery (TDD) on the skin,
The BAP technique was applied to pig skin to form microchannels with biological samples, and plasma was measured and observed with micropores. During BAP, an output voltage of 1 kVpp at 40 kHz was applied at duty rates of 20%, 40% and 60%. BAP technique was applied to the stratum corneum layer, and microchannels with an average size of 30μm x 30μm and 77μm x 55μm were formed only in the stratum corneum without damaging the dermal layer.
Next, by stimulating the double pulse electroporation (DPEP) to increase the permeability of the endothelial cell membrane in the structure with microchannels, the bipolar arc plasma stimulation and dual pulse electroporation provide a high-efficiency effect of transdermal drug delivery Device. According to claim 1,
Arc plasma stimulation or electroporation is made on the skin through the electrode, and skin absorption is measured using a 3D Raman Microscopy System, and Raman spectroscopy non-destructively illuminates the skin in vivo. It detects the wavelength change that occurs during the scattering phenomenon due to the irradiation of is a device that provides a high-efficiency effect of transdermal drug delivery by bipolar arc plasma stimulation and dual pulse electroporation, which increases the absorption rate of the epidermal layer of the skin by 418%. According to claim 1,
The device's BAP-DPEP technology is a bipolar arc used for transdermal drug delivery (TDD) as well as wound healing, skin rejuvenation, anesthetic treatment and wrinkle treatment. A device that provides a high-efficiency effect of transdermal drug delivery to the skin by plasma stimulation and dual pulse electroporation.

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