WO2020233604A1 - 电场发生装置及其用途以及使待透皮物质进入目标对象的方法 - Google Patents

电场发生装置及其用途以及使待透皮物质进入目标对象的方法 Download PDF

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Publication number
WO2020233604A1
WO2020233604A1 PCT/CN2020/091336 CN2020091336W WO2020233604A1 WO 2020233604 A1 WO2020233604 A1 WO 2020233604A1 CN 2020091336 W CN2020091336 W CN 2020091336W WO 2020233604 A1 WO2020233604 A1 WO 2020233604A1
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Prior art keywords
electric field
electrode
target object
transdermal
substance
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PCT/CN2020/091336
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English (en)
French (fr)
Inventor
乐飚
唐万福
王丽江
奚勇
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上海必修福企业管理有限公司
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Priority to CN202080037753.3A priority Critical patent/CN113924142A/zh
Publication of WO2020233604A1 publication Critical patent/WO2020233604A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

Definitions

  • the present invention relates to an electric field generating device for causing a substance to be transdermal to enter a target object, its use, and a method for causing a substance to be transdermal to enter a target object.
  • the transdermal substance it is necessary to wait for the transdermal substance to enter the target object, such as aqueous solutions, pharmaceutical preparations, beauty skin care products, and nutritional supplements, so that treatment, beauty skin care, and body care can be performed.
  • the common methods include oral, subcutaneous injection and transdermal.
  • the oral method has the advantages of pre-determining the dose, convenient carrying, and easy to complete by oneself. It is still one of the more commonly used methods. However, due to the rapid degradation of digestive enzymes in the gastrointestinal tract and the first pass effect in the liver, in some cases, for example, the availability of most therapeutic peptides and protein drugs is greatly reduced, resulting in the effect of direct oral administration greatly reduced;
  • the shortcomings of the subcutaneous injection method are also obvious, such as pain, discomfort to the human body, risk of infection, and the need for professional injections. It is especially not suitable for situations that require multiple administrations a day, such as insulin administration. ;
  • Transdermal method transdermal medication is common, which is a drug delivery technology that applies drugs to the skin for local delivery or delivery through the skin system. Compared with oral administration and subcutaneous injection, it has a good Controlled-release or sustained-release drug delivery has the advantages of avoiding liver first-pass metabolism, painless during use, self-administration, and no need for professional training. It is a convenient drug delivery method for patients.
  • One way to improve the efficiency of transdermal drug delivery is to increase skin permeability.
  • Common methods for promoting penetration include chemical penetration and physical penetration. Chemical penetration is the use of surfactants, fatty acids or some solvents to destroy the stratum corneum structure
  • chemical penetration is the use of surfactants, fatty acids or some solvents to destroy the stratum corneum structure
  • physical penetration methods including iontophoresis, electroporation, ultrasonic penetration, thermal ablation, etc.
  • the chemical penetration method will cause undesirable stimulation to the skin and even have a certain toxic effect
  • the electric iontophoresis method allows ionic substances to be transported through the skin biofilm under the action of an external current, but this method can only introduce ionic molecules and is not suitable for traditional Chinese medicine or multi-component administration;
  • the method of fumigation of traditional Chinese medicine is transdermal, which promotes the absorption of the medicine by the skin through hyperthermia, but this method escapes the small and medium-molecule Chinese medicine components and cannot achieve the established formula to reach the target site;
  • Ultrasound-induced transdermal drug delivery is a technology that combines electroporation technology, ultrasonic cavitation technology, and iontophoresis technology. This method has a small amount of introduction, limited ingredients, poor safety, and is harmful to the human body.
  • the skin mainly contains three layers from the outside to the inside: (1) the outermost epidermis, including the stratum corneum and the active epidermis; (2) the middle dermis; (3) the innermost subcutaneous tissue.
  • stratum corneum is the main obstacle.
  • the thickness of the stratum corneum is generally composed of dead flat keratinocytes, and the keratinocytes are surrounded by a liquid extracellular matrix.
  • the active epidermal layer is located under the stratum corneum. The thickness is generally between 50-100 ⁇ m. It contains active cells, has no blood vessels, has a basement membrane and tight junctions, and will produce a certain resistance to the molecular transport through the epidermal layer.
  • the deeper layer is the dermis, most of which is fibrous tissue, with a thickness of about 1-2mm.
  • the deeper layer is the dermis, most of which is fibrous tissue, with a thickness of about 1-2mm.
  • the invention provides an electric field generating device for allowing a substance to be transdermal to enter a target object, its use, and a method for allowing a substance to be transdermal to enter the target object.
  • An object of the present invention is to provide an electric field generating device for controlling the substance to be penetrated into a target object, which is characterized by comprising: a first electrode and a second electrode for forming an electric field, wherein the first electrode and the second electrode Only one of the two electrodes serves as a contact electrode to contact the target object, and the electric field controls the substance to be penetrated into the target object.
  • the substance to be penetrated is in conductive contact with the first electrode or the second electrode.
  • the substance to be transdermal is water or includes one or more components used in skin care, disease treatment, or living body nutrition and health care.
  • the contact between the first electrode and the target object is achieved through conductive contact between the substance to be transdermal and the first electrode.
  • the contact between the second electrode and the target object is achieved through conductive contact between the substance to be transdermal and the second electrode.
  • the electric field generating device of the present invention further includes one or more of the following features:
  • the electric field generated by the electric field generator can break through the stratum corneum and capillaries of the target object;
  • the voltage of the electric field is adjustable 0.001kV-120kV, and the working distance of the electric field is adjustable 0.1cm-100cm;
  • first electrodes There are multiple first electrodes, and the arrangement of all the first electrodes is selected from a lattice arrangement, which is a 2n lattice, where n is a non-zero natural number;
  • the position and electric field intensity of the first electrode are confirmed according to other diagnostic imaging data or doctor's consultation;
  • the electric field generating device also includes:
  • the power supply is used to provide electric energy to the electric field generating device; the regulating unit is used to adjust and control the performance of the electric field, including the type of electric field, the direction of the electric field, the strength of the electric field, voltage, current, voltage waveform, frequency, and the frequency, waveform, and amplitude of the power supply One or more of.
  • the electric field generating device of the present invention further includes one or more of the following features:
  • the voltage of the power supply is adjustable 0.001kV-120kV, and the working distance of the electric field is adjustable 0.1cm-100cm;
  • the regulating unit can regulate the generation of the first signal and the second signal.
  • the first signal is used to generate the direction of the electric field for transdermal drug delivery; the second signal is used to generate the electric field to promote the intracellular delivery of the bioactive agent. Electric field strength.
  • the power supply is a high-voltage output power supply.
  • the first signal controls the first electrode to generate an electric field strength of 100V/cm to 120KV/cm; the second signal adjusts the second electrode to generate 100V/cm Electric field strength to 120kV/cm.
  • the voltage working range of the electric field is 30kV-120kV, and the working value range of the working distance is 0.1cm-30cm.
  • the electric field generating device of the present invention wherein the voltage of the electric field is one of 30KV, 100KV or 120KV; the working distance is one of 0.1cm, 30cm or 100cm.
  • the time for continuously controlling the penetration of the substance to be transdermal into the target object for the same part of the target object is less than or equal to 16 hours.
  • the first electrode is provided with a hollow cavity, and the hollow cavity is used to infuse the substance to be transdermal.
  • the present invention also provides a use of an electric field generating device for making a substance to be penetrated into a target object, which is characterized in that the electric field device is the above-mentioned electric field device.
  • the use is one or more of transdermal medication, skin care, or nutritional supplement.
  • the present invention also provides a method for allowing a substance to be transdermal to enter a target object, which is characterized by comprising the following steps: Step 1, respectively placing the target object and the substance to be transdermal on the first electrode and the second electrode of the electric field generating device In the formed electric field; step 2, only one of the first electrode or the second electrode is used as a contact electrode to contact the target object; step 3, under the action of the electric field, control the substance to be penetrated into the target object.
  • step 2 wherein, in step 2, the substance to be transdermal is in conductive contact with the first electrode or the second electrode.
  • the substance to be transdermal is water or includes one or more ingredients used in skin care, disease treatment, or living body nutrition and health care.
  • the contact between the first electrode and the target object is achieved through conductive contact between the substance to be transdermal and the first electrode.
  • the contact between the second electrode and the target object is achieved through conductive contact between the substance to be transdermal and the second electrode.
  • the electric field generated by the electric field generating device can break through the stratum corneum and blood capillaries of the target object;
  • the voltage of the electric field is adjustable 0.001kV-120kV, the current is adjustable 0.001mA-10000mA, and the working distance of the electric field is adjustable 0.1cm-100cm;
  • first electrodes There are multiple first electrodes, and the arrangement of all the first electrodes is selected from a lattice arrangement, which is a 2n lattice, where n is a non-zero natural number;
  • the position, electric field intensity, voltage waveform or frequency of the first electrode is confirmed according to other diagnostic image data or doctor's consultation; and/or the position, electric field intensity, and voltage waveform of the first electrode are automatically tracked after diagnosis according to the electric field coupling current;
  • the electric field generating device also includes:
  • the power supply is used to provide electric energy to the electric field generating device
  • the control unit is used to adjust and control the performance of the electric field, including one or more of electric field type, electric field direction, electric field strength, voltage, current, voltage waveform, frequency, and power source frequency, waveform, and amplitude.
  • the voltage of the power supply is adjustable 0.001kV-120kV, and the working distance of the electric field is adjustable 0.1cm-100cm;
  • the regulating unit can regulate the generation of the first signal and the second signal, the first signal is used to generate the electric field direction of transdermal drug delivery; the second signal is used to make the electric field generation can promote the intracellular of the bioactive agent The delivered electric field strength.
  • the power supply is a high-voltage output power supply.
  • the first signal controls the first electrode to generate an electric field strength of 100V/cm to 120KV/cm; the second signal adjusts the first electrode to generate 100V/cm to 120kV/cm.
  • the electric field strength of cm In an example of the method of the present invention, in feature 3), the first signal controls the first electrode to generate an electric field strength of 100V/cm to 120KV/cm; the second signal adjusts the first electrode to generate 100V/cm to 120kV/cm.
  • the electric field strength of cm the first signal controls the first electrode to generate an electric field strength of 100V/cm to 120KV/cm
  • the voltage of the electric field is one of 30KV, 100KV or 120KV; the working distance is one of 0.1cm, 30cm or 100cm.
  • the time for continuously controlling the penetration of the substance to be transdermal into the target object for the same part of the target object is less than or equal to 16 hours.
  • step 2 using the second electrode as the contact electrode includes: step 2.1, the substance to be transdermal conductively contacts the first electrode, and the first electrode is fixed on the target object. Near the target site, but not in direct contact with the target object; step 2.2, adjust the position of the first electrode to adjust the coverage area of the electric field so that the electric field covers the target site, step 3 specifically: the substance to be transdermal acts on the electric field It is controlled to move directionally toward the second electrode, and during the movement, it penetrates the skin into the target object.
  • the substance to be transdermal is stored in the hollow cavity of the first electrode.
  • the second electrode is a contact electrode, including: step 2.1, conductive contact between the second electrode and the target object through the substance to be transdermal; step 2.2, adjust the position of each first electrode to adjust the electric field The electric field covers the target area of the target object.
  • Step 3 is specifically: the substance to be transdermal moves toward the first electrode under the control of the electric field, and penetrates the skin into the target object during the movement.
  • the second electrode is a contact electrode, including: step 2.1, the substance to be transdermal does not contact the first electrode and the second electrode, and the first electrode is fixed Near the target site on the target object, but not in direct contact with the target object; step 2.2, adjust the position of the first electrode to adjust the coverage area of the electric field so that the electric field covers the target site; step 3 is specifically: to be penetrated
  • the skin material is directed to move toward the second electrode under the control of the electric field, and penetrates the skin into the target object during the movement.
  • the electric field generating device and its use as well as the method for making the substance to be penetrated into the target object provided by the present invention have a first electrode and a second electrode to form an electric field, and only one of the first electrode and the second electrode serves as a contact electrode with the target
  • the object is in contact, so the equipotential formed by the contact electrode and the target object can be adjusted to break through the stratum corneum and capillaries through the electric field control, and induce the full components of the substance to be transdermal to reach the target site, which can achieve non-invasive transdermal penetration
  • Drug administration, beauty and skin care, and nutrition and health care, etc. can more directly act on the target site, which is conducive to the absorption of the substance to be breathable, and can improve transdermal drug delivery, beauty and skin care, and nutrition and health care.
  • Fig. 1 is a structural diagram of an electric field generating device related to embodiment 1;
  • FIG. 2 is a schematic diagram of the use of the electric field generating device involved in embodiment 1 when it is directed to a living body;
  • Fig. 3 is a schematic diagram of the first pole arrangement of the space electric field generating device involved in embodiment 1;
  • FIG. 4 is a configuration diagram of an electric field generating device according to Embodiment 2.
  • FIG. 4 is a configuration diagram of an electric field generating device according to Embodiment 2.
  • the target object referred to herein can refer to the entire living body, tissue samples, or a certain part or parts of the living body.
  • the living body is mainly mammals.
  • the mammals are preferably rodents, artiodactyls, odd-hoofed animals, lagomorphs, primates, and the like.
  • the primates are preferably monkeys, apes or humans.
  • the following embodiments are intended to specifically describe the electric field generating device and its use according to the present invention, and the method for allowing the substance to be transdermal to enter the target object.
  • FIG. 1 is a configuration diagram of an electric field generating device according to Example 1.
  • the electric field generating device 100 is used to control the substance 2 to be penetrated into the target object 1.
  • the electric field generating device 100 includes a first electrode 10 and a second electrode 20 for forming an electric field. . Only one of the first electrode 10 and the second electrode 20 is used as a contact electrode to contact the target object 1, thereby forming an equipotential, while the electric field controls the substance 2 to be penetrated into the target object 1.
  • Only one of the first electrode 10 and the second electrode 20 is used as a contact electrode to contact the target object 1 to form an equipotential, that is: either the first electrode 10 contacts the target object 1 to form an equipotential, or the second electrode 20 contacts the target object 1 Contact forms an equipotential.
  • the other first electrode 10 or second electrode 20 that is not in contact with the target object 1 is called a non-contact electrode.
  • the second electrode 20 is in contact with the target object, that is, the second electrode is a non-contact electrode
  • the first electrode 10 is a non-contact electrode.
  • FIG. 2 is a schematic diagram of the use of the electric field generating device related to Embodiment 1 for a living body.
  • the entire living body is placed in an electric field, the second electrode 20 is in contact with the sole of the living body, and the first electrode 10 is distributed near the target site to be transdermal.
  • the transdermal substance 2 in this embodiment is water or a substance containing one or more components used in skin care, disease treatment, or living body nutrition and health care, such as ionic agents, cosmetic preparations, and stimulating agents.
  • Preparations related to blood circulation or human metabolism and fitness can also be biologically active agents, which include immunologically active agents, such as vaccines or antigens.
  • Exemplary vaccines include viruses and bacteria, protein-based vaccines, polysaccharide-based vaccines, and nucleotide-based vaccines.
  • Bioactive agents may also include agents that are active in one of the main therapeutic fields, including but not limited to: anti-infective drugs, such as antibiotics and antiviral drugs; analgesics, including fentanyl, sufentanil, and remi Combinations of fentanyl, buprenorphine and analgesics; anesthetics; anorectics; antiarthritis drugs; antiasthmatic drugs such as terbutaline; anticonvulsants; antidepressants; antidiabetics; antidiarrheals; Antihistamines; Anti-inflammatory drugs; Anti-migraine agents; Anti-motion sickness drugs such as scopolamine and Ondansetron; Anti-nausea drugs; Anti-tumor drugs; Anti-tremor paralysis drugs; Antipruritic drugs; Antipsychotics; Antispasmodics, including gastrointestinal and urinary; anticholinergics; sympathomimetic drugs; xanthine derivatives; cardiovascular agents, including calcium
  • the substance to be penetrated 2 can itself be a charged substance, called a charged substance, or a charged body, such as a charged medicine, which has a positive or negative charge, so that it can directly move in an electric field.
  • this charged body is also It can be in conductive contact with the first electrode or the second electrode, and the electric field can also accelerate the electroporation of the charged body to strengthen the ability of directional movement;
  • the transdermal substance can also be an uncharged substance, such as certain Chinese medicines.
  • the material to be transdermal 2 conducts electron conduction through conductive contact with the corresponding first electrode or second electrode, so that the transdermal material becomes a charged body, so as to perform directional movement under the action of an electric field.
  • the first electrode 10 is fixed to the skin surface of the object to be detected by using a cuff or chest strap.
  • the substance 2 to be transdermal will penetrate into the target object 1 under the action of the electric field force.
  • the voltage, the polarity of the first electrode 10 and the second electrode 20 can be adjusted according to the charging characteristics, and the frequency and amplitude of the action can be adjusted to increase the force in the electric field so that the transdermal substance 2 can pass through the cell wall of the target object 1. .
  • the substance 2 to be transdermal can be placed at the non-contact electrode, that is, the first electrode 10 is in conductive contact. In this way, at the beginning, the substance 2 to be transdermal is non-contact with the target object 1. Distance, under the action of the electric field, the substance to be transdermal 2 moves to the target object 1 until it penetrates into the target object 1 through the skin.
  • the electric field generating device 100 as shown in Fig. 1 is used, the entry position of the substance 2 to be transdermal through the skin is called the target site, and the target site can be located by adjusting the position or number of the first electrode 10.
  • FIG. 3 is a schematic diagram of the first pole arrangement of the spatial electric field generating device according to Embodiment 1.
  • FIG. 3 is a schematic diagram of the first pole arrangement of the spatial electric field generating device according to Embodiment 1.
  • the electric field generating device 100 provided in this embodiment further includes one or more of the following features:
  • the electric field generated by the electric field generating device 100 can break through the stratum corneum and capillaries of the target object 1;
  • the voltage of the electric field is adjustable 0.001kV-120kV
  • the current is adjustable 0.001mA-10000mA
  • the working distance of the electric field is adjustable 0.1cm-100cm.
  • the voltage is selected according to the depth of action and the distance of the electric field,
  • the voltage working range of the electric field generated by the electric field generating device 100 is 30kV-120kV, preferably 30KV, 100KV, 120KV; the working range of working distance is 0.1cm-30cm, preferably 0.1cm, 30cm, 100cm.
  • the working distance here refers to the distance from the non-contact electrode to the target location of the target object 1, for example, in this embodiment, it is the distance from the first electrode 10 to the target location of the target object 1.
  • first electrodes 10 there may be multiple first electrodes 10, and the arrangement is selected from a lattice arrangement, which is a 2n lattice, where n is a non-zero natural number; the arrangement of spatially different electrodes may be selected from a matrix arrangement
  • the specific 64 dot matrix, 4096 dot matrix, 16777216 dot matrix, etc. are shown in Figure 2.
  • the density of the lattice depends on the accuracy of the electric field. The use of precise electric field to improve the efficiency of the action on nerve cells and reduce the effect on normal tissues. However, limited by the size of the output electric field power source, the lattice is dense and the power source is bulky.
  • any one or more warp lines from a ⁇ b ⁇ c to xx and any one or more weft lines from 1 ⁇ 2 ⁇ 3 to nn activate one or more lattice first electrodes 10.
  • These first electrodes 10 and The two electrodes 20 form an applied electric field, and the electric field coverage is determined by the activated lattice poles.
  • This range can come from digital signals of medical diagnostic images. It is confirmed that this electric field range can accurately act on nerve cells and reduce the impact on other tissues.
  • a 64 dot matrix can only distinguish 64 electric field positions
  • a 4096 dot matrix can distinguish 4096 electric field positions
  • a 16777216 dot matrix can distinguish 16,777216 electric field positions.
  • the effect of this dot matrix is relatively accurate, and the impact on the surrounding normal tissues is small.
  • the arrangement diagram of the specific spatially different electrodes on the helmet frame is shown in Figure 2.
  • the first electrode 10 is arranged in a similar lattice according to the principle of the lattice formed by medical diagnostic images, so that the first electrode 10 can be accurately positioned to the target site to be acted on during use.
  • the position of an electrode 10 is adjustable, and can be adjusted according to the medical diagnostic image obtained each time, so as to correspond to the lattice of the medical diagnostic image, so that the position to be acted on (targeted part) can be quickly and accurately located.
  • the first electrode 10 is a matrix of multiple first electrodes 10 arranged outside the helmet frame.
  • the position and electric field intensity of the first electrode 10 are confirmed according to other diagnostic image data or doctor's consultation, that is, the target treatment site or doctor's consultation or skin care plan or nutritional supplement determined according to the medical image data of the target object 1.
  • the target location determined by the scheme is confirmed; the position, electric field intensity, and voltage waveform of the first electrode 10 can also be automatically tracked after diagnosis based on the electric field coupling current, that is, the electric field performance is continuously tracked during use to ensure effectiveness.
  • the electric field generating device 100 further includes: a power supply 30 and a control unit.
  • the power supply 30 is used to provide electric energy to the electric field generating device
  • the control unit is used to adjust and control the performance of the electric field.
  • the parameters related to the electric field performance mainly include one or more of electric field type, electric field direction, electric field strength, voltage, current, voltage waveform, frequency, and power frequency, waveform, and amplitude. Essentially, the performance of the electric field is confirmed by the target site (target site) and/or target concentration (action concentration) and the electric field strength.
  • the generated electric field is preferably a low-intensity medium-frequency electric field.
  • Low intensity refers to the electric field intensity of 1-200V/m
  • medium frequency refers to the frequency of 1 Hz-500 kHz.
  • the different electrode may also be fixed to the skin surface of the target object 1 by using a cuff or chest strap.
  • first electrode 10 may also be provided with a hollow cavity, which is used to infuse the substance to be transdermal, and the hollow cavity may also be provided with a scale to facilitate control of the amount of transdermal penetration.
  • the bottom of the first electrode 10 may also be coated with insulating material or made of insulating material to prevent mutual interference between adjacent first electrodes 10.
  • the electric field generating device 100 provided in this embodiment further includes one or more of the following features:
  • the voltage of the power supply is adjustable 0.001kV-120kV, the working distance of the electric field is adjustable 0.1cm-100cm; the power supply is selected as a high-voltage output power source;
  • the regulating unit can regulate the generation of the first signal and the second signal, the first signal is used to generate the electric field direction of transdermal drug delivery; the second signal is used to make the electric field generation can promote the intracellular of the bioactive agent The delivered electric field strength.
  • the first signal controls the first electrode to generate an electric field strength of 100V/cm to 120KV/cm; the second signal adjusts the second electrode to generate an electric field strength of 100V/cm to 120kV/cm; A motor and one end of the different electrode (including the second electrode) are connected to a zero line.
  • the electric field generating device 100 can be applied to allow the substance 2 to be transdermal to enter the target object 1, and the application can be one or more of transdermal medication, skin care, or nutritional supplement.
  • the method for making the substance 2 to be transdermal into the target object 1 in this embodiment is characterized in that it includes the following steps:
  • Step 1 Place the target object 1 and the substance to be penetrated 2 respectively in the electric field formed by the first electrode 10 and the second electrode 20 of the electric field generating device 100;
  • Step 2 Only one of the first electrode 10 or the second electrode 20 is used as a contact electrode to contact the target object 1.
  • the second electrode 20 is used as a contact electrode;
  • Step 3 Control the substance 2 to be penetrated into the target object 1 under the action of the electric field. Specifically, under the action of an electric field, the substance 2 to be transdermal is controlled to move toward the second electrode 20, and in the process of movement, penetrates the skin into the target object 1. This process passes voltage, working distance, and the first electrode 10 The adjustment of the position, etc., and the adjustment of the electric field performance, so that the substance to be penetrated 2 enters the target object 1.
  • step 2 it includes:
  • the substance 2 to be transdermal is in conductive contact with the first electrode 10 or the second electrode 20. In this embodiment, it is in conductive contact with the first electrode 10, and the first electrode 10 is fixed on the target part of the target object 1. Nearby, but not in direct contact with the target object 1, specifically, the substance 2 to be transdermal can be stored in the hollow cavity of the first electrode 10;
  • Step 2.2 Adjust the position of the first electrode 10 to adjust the coverage area of the electric field so that the electric field covers the target site.
  • Embodiment 1 the description of the same parts as in Embodiment 1 is omitted.
  • FIG. 3 is a configuration diagram of an electric field generating device according to the second embodiment.
  • the electric field generating device 300 includes a first electrode 310 and a second electrode 320, wherein the second electrode 320 is a contact electrode.
  • Embodiment 1 The difference between this embodiment and Embodiment 1 is that in this embodiment, the substance 2 to be transdermal is brought into contact with the target object 1, but the transdermal substance does not contact the first electrode 310 nor the second electrode 320.
  • the transdermal substance 2 itself is a charged body. Through the adjustment of the electric field performance, the substance to be transdermal 2 is moved toward the contact electrode. In this process, the substance to be transdermal 2 covering the skin surface of the target object 1 is directly transdermal Enter target object 1.
  • the transdermal skin can be positioned to the target site and entered as in the first embodiment.
  • the electric field generating device 300 can also be used to allow the substance 2 to be transdermal to enter the target object 1, and the application can be one or more of transdermal medication, skin care, or nutritional supplement.
  • the method for making the substance 2 to be transdermal into the target object 1 in this embodiment is characterized in that it includes the following steps:
  • Step 1 Place the target object 1 and the substance to be penetrated 2 respectively in the electric field formed by the first electrode 310 and the second electrode 320 of the electric field generating device 300;
  • Step 2 Only one of the first electrode 310 or the second electrode 320 is used as a contact electrode to contact the target object 1.
  • the second electrode 320 is used as a contact electrode;
  • Step 3 Control the substance 2 to be penetrated into the target object 1 under the action of the electric field. Specifically, the substance 2 to be transdermal moves toward the second electrode 320 under the control of the electric field, and penetrates the skin into the target object 1 during the movement. The process is adjusted by the voltage, the working distance, the position of the first electrode 310, etc. , And the electric field performance adjustment, so that the substance to be penetrated 2 enters the target object 1.
  • step 2 it includes:
  • Step 2.1 the substance to be transdermal is not in contact with the first electrode 310 and the second electrode 320, and the first electrode 310 is fixed near the target site on the target object 1, but does not directly contact the target object 1;
  • Step 2.2 Adjust the position of the first electrode 310 to adjust the coverage area of the electric field so that the electric field covers the target site.
  • Example 1 the electric field generating device 100 provided in Example 1 and the electric field generating device 300 provided in Example 3 were used to conduct transdermal drug delivery experiments. details as follows.
  • the electric field is applied by the electric field generating device to deliver DNA into the mouse, and then the DNA absorption is detected by detecting gene expression at the mRNA level.
  • This embodiment includes two treatment groups, an experimental group and a control group.
  • Control group DNA delivery (specific fragments of the nucleotide sequence of DNA) encoding ⁇ -galactosidase protein using a delivery system that is not powered on.
  • the PCR conditions of this example are as follows.
  • the primers used include intron RT5' primers -5'CCG GGA ACGGTGCATTGGAA3' (SEQ ID NO: 2) and #1057b-gal intron RT 3'primer -5'ATCGGCCTCAGGAAGATCGC3' (SEQ ID NO: 3).
  • each space electrode contains 40 ⁇ g DNA; use tape to suspend the electrode on the skin surface (as shown in Figure 6) or Fix to skin (as shown in Figure 7); deliver DNA to mouse skin.
  • 10 healthy mice in group H were prepared as a control group and injected subcutaneously.
  • rtPCR was used to determine the level of mRNA encoding ⁇ -galactosidase protein to quantify the intracellular uptake of plasmid DNA.
  • One day (24 hours) after DNA delivery the animals were killed, 8mm skin was obtained from the center of all treatment sites, intradermal injection sites, and untreated skin sites. The biopsy was weighed and minced and briefly Ultrasound treatment is homogenized.
  • the PCR conditions of this example are as follows.
  • the primers used include intron RT5' primer-5'CCG GGA ACGGTGCATTGGAA3' (SEQ ID NO: 2) and #1057b-gal intron RT 3'primer-5'ATCGGCCTCAGGAAGATCGC3' (SEQ ID NO: 3).
  • the PCR reaction conditions were: 95°C, 5 minutes; 92°C, 1 minute for 40 cycles; 66°C, 30 seconds; 72°C, 1 minute; and 72°C, additional 10 minutes.
  • the presence of specific fragments of ⁇ -galactosidase mRNA in the PCR reaction was analyzed by gel electrophoresis. This method can semi-qualitatively detect ⁇ -galactosidase expression.
  • the drug detection rate was about 70%.
  • the electric field administration group when the therapeutic voltage is lower than 1KV, there is almost no administration effect.
  • the voltage intensity reaches 3KV slight therapeutic effects begin to appear.
  • the voltage intensity is proportional to the effect of administration, that is, the stronger the voltage, the more obvious the effect of administration.
  • the electric field generating device provided by the present invention has the advantages of improving the person’s QOL (quality of life) and reducing physical pain. the use of.
  • this experiment column The purpose of this experiment column is to observe the change in the amount of the substance to be transdermal that can penetrate the skin as the transdermal time increases.
  • this experiment series adopts the electric field generating device in the simulation embodiment of the double-chamber diffusion cell connected to the positive and negative electrodes respectively.
  • the substance to be penetrated is sinomenine.
  • mice weight 20g, healthy, and shiny fur
  • the experiment uses 4-6 weeks old mice (weight 20g, healthy, and shiny fur), and put them to death, peel off the skin on the abdomen, shave off the hair on the abdomen, carefully remove the fat, rinse it with normal saline, and observe it under microscopic observation. Use immediately after breakage.
  • Chromatographic conditions Chromatographic column: Hypersil C18 (250mm ⁇ 4.6mm, 10 ⁇ m), mobile phase: methanol-water-ethylenediamine [52:48(300:10)]; volume flow rate: 1mL/min; detection wavelength: 262nm; Injection volume: 10 ⁇ L.
  • Drawing the standard curve accurately weigh 40mg of sinomenine, place it in a 100mL measuring flask, add double distilled water to dissolve, add to the mark, and shake well. Take out 0.25, 0.50, 1.00, 1.50, 2.00, 2.50mL respectively into a 10mL measuring flask, add double distilled water to the mark, shake well for use.
  • a mouse weighing 20g was taken, killed by removing the neck, peeling off the skin on the abdomen, cutting off the hair on the abdomen, carefully removing the subcutaneous fat, repeatedly washing it with normal saline, and then adding it to the double-chamber diffusion pool, the stratum corneum facing the supply pool
  • the dermis layer faces the receiving pool, and the diffusion pool is fixed on a magnetic stirrer to stir evenly while keeping the temperature of the receiving pool at 32°C.
  • the change and trend of the dose was similar to that at 30KV. As time extends, it becomes a linear upward trend. And when the electric field intensity is increased to a certain situation, the proportion of the dose increase with time gradually gets rid of the linear growth trend, similar to a parabola. Finally, 16 hours after the start of the administration, the experimental skin (mice) can load the drug to be administered close to the upper limit, and a bottleneck effect appears between 16 hr and 24 hr.

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Abstract

一种使待透皮物质（2）进入目标对象（1）的电场发生装置（100）及其用途，以及使待透皮物质（2）进入目标对象（1）的方法，其中的电场发生装置（100）包括：用于形成电场的第一电极（10）和第二电极（20），其中，第一电极（10）和第二电极（20）中仅一个作为接触电极与目标对象（1）接触，电场控制待透皮物质（2）进入目标对象（1）。

Description

电场发生装置及其用途以及使待透皮物质进入目标对象的方法 技术领域
本发明涉及一种使待透皮物质进入目标对象的电场发生装置及其用途以及使待透皮物质进入目标对象的方法。
背景技术
重力、摩擦力、库伦力、万有引力广泛分布作用在我们周围，很容易理解和观察到，包括磁场会产生磁力，用两块磁铁就很容易展示给我们看到、感觉到，电场也会产生作用力，我们可以把它称为电力。由于这个电力只表现在带不同电性物质间或有差异电荷物质间，我们几乎不能直接或经常观察到，并不引起注意。但它实际存在。
目前，在一些时候，需要让例如水溶液、药物制剂、美容护肤品、营养补充剂等待透皮物质进入目标对象，以能进行治疗、美容护肤以及身体保健等。而常见的方式包括口服、皮下注射和透皮等。
然而：
口服方式，具有可提前确定剂量、方便携带、便于可自行完成等优点，仍然是目前较为常用的方式之一。然而，由于胃肠道消化酶的快速降解作用和肝脏首过效应等原因，在一些时候，例如使大多数治疗性多肽和蛋白质药物的利用度大大降低，导致直接口服给药的效果大打折扣；
皮下注射方式，其具有的缺点也显而易见，如会产出疼痛感使人 体感到不适、感染风险、需要专业人员进行注射等，特别不适合用于需要一天多次给药的情形，如胰岛素给药；
透皮方式：常见的有透皮用药，是一种将药物施用到皮肤局部输送或透过皮肤系统输送的一种给药技术，与口服给药和皮下注射给药方式相比较，具有良好的控释给药或缓释给药效果、能够避免肝首过代谢作用、使用过程无痛感、能够自行给药、不需要专业培训等优点，是一种便于患者使用的给药方式。
然而传统的透皮给药方式由于受到皮肤最外层角质层的阻隔作用，大多数药物给药效率低，应用受到很大限制。
提高透皮给药效率的一个途径是增加皮肤渗透性，常见的促渗方法有化学促渗法和物理促渗法，化学促渗法是利用表面活性剂、脂肪酸或一些溶剂通过破坏角质层结构来增加药物渗透率；物理促渗法种类比较多，包括电离子透入疗法、电致孔、超声波促渗法、热消融法等。尽管这些方法能够克服传统的透皮贴给药的局限性，能够破坏皮肤角质层结构，从而增加药物的透皮给药速率，然而：
化学促渗法会对皮肤产生不良的刺激，甚至会有一定的毒性作用；
电离子导入的方式在外加电流作用下，使得离子型物质通过皮肤生物膜转运，但该方式只能导入离子型分子，不适宜中药或多组分给药；
中药熏蒸的方式透皮，通过热疗促进皮肤对药物的吸收，但该方式中小分子中药成分逃逸，不能实现既定配方达到靶向部位；
超声诱导进行透皮给药，是将电致孔技术、超声空化技术和离子 导入技术相结合的技术，该方式导入量少，成分有限，安全性差，对人体有一定危害。
皮肤从外到内主要包含三层：(1)最外层的表皮层，又包括角质层和活性表皮层；(2)中间的真皮层；(3)最内层的皮下组织。对于透皮给药来说，角质层是主要障碍，角质层厚度一般为由死亡的扁平角化细胞组成，角化细胞周围是液态的细胞外基质。活性表皮层位于角质层下，厚度一般在50-100μm之间，含有活性细胞，没有血管，具有基底膜和紧密连接作用，会对通过表皮层的分子输送产生一定的阻力。更深一层是真皮层，大部分是纤维组织，厚度约为1-2mm，在靠近表皮层的真皮层表面下含有丰富的毛细血管网，药物输送到此即可进入系统循环。因此，实现透皮应该至少将要透皮的待透皮物质输送到真皮层表面下的毛细血管网。
发明内容
本发明提供一种让待透皮物质进入目标对象的电场发生装置及其用途以及使待透皮物质进入目标对象的方法。
为了实现上述目的，本发明采用了如下技术方案：
本发明的一个目的是提供一种电场发生装置，用于控制待透皮物质进入目标对象，其特征在于，包括：用于形成电场的第一电极和第二电极，其中，第一电极和第二电极中仅一个作为接触电极与目标对象接触，电场控制待透皮物质进入目标对象。
于本发明的电场发生装置的一示例中：待透皮物质与第一电极或 第二电极导电接触。
于本发明的电场发生装置的一示例中：其中，待透皮物质为水或包括用于皮肤护理、疾病治疗的药物或活体营养保健中的一种或多种成分。
于本发明的电场发生装置的一示例中：其中，当第一电极作为接触电极时，第一电极与目标对象之间的接触通过待透皮物质与该第一电极的导电接触实现。
于本发明的电场发生装置的一示例中：其中，当第二电极作为接触电极时，第二电极与目标对象的之间的接触通过待透皮物质与该第二电极的导电接触实现。
于本发明的电场发生装置的一示例中：还包括以下特征中的一项或多项：
a.电场发生装置产生的电场能突破目标对象的角质层和毛细血管；
b.电场的电压为可调的0.001kV-120kV，电场的工作距离为可调的0.1cm-100cm；
c.第一电极多个，所有第一电极的排布方式选自点阵排布，为2n点阵，其中n为非0自然数；
d.第一电极的位置、电场强度根据其他诊断影像数据或者医生问诊确认；；
e.电场发生装置还包括：
供电电源，用于给发生电场发生装置提供电能；调控单元，用于 调节控制电场的性能，包括电场类型、电场方向、电场强度、电压、电流、电压波形、频率，电源的频率、波形、幅度中的一种或多种。
于本发明的电场发生装置的一示例中：还包括以下特征中的一项或多项：
1)特征e中，供电电源的电压为可调的0.001kV-120kV，电场的工作距离为可调的0.1cm-100cm；
2)特征e中，调控单元可调控产生第一信号和第二信号，第一信号用于产生透皮给药的电场方向；第二信号用于使电场产生能够促进生物活性剂胞内递送的电场场强。
于本发明的电场发生装置的一示例中，其中，特征e中，所述供电电源为高压输出电源。
于本发明的电场发生装置的一示例中：其中，特征2)中，第一信号控制第一电极产生100V/cm至120KV/cm的电场场强；第二信号调节第二电极产生100V/cm至120kV/cm的电场场强。
于本发明的电场发生装置的一示例中：其中，电场的电压工作范围为30kV-120kV，工作距离的工作取值范围为0.1cm-30cm。
于本发明的电场发生装置的一示例中：其中，电场的电压为30KV、100KV或120KV中的一个；工作距离为0.1cm、30cm或100cm中的一个。
于本发明的电场发生装置的一示例中：其中，针对目标对象的同一部位持续控制待透皮物质进入目标对象的时间小于等于16小时。
于本发明的电场发生装置的一示例中：其中，第一电极设有中空 腔，中空腔用于灌注待透皮物质。
本发明还提供一种电场发生装置在使待透皮物质进入目标对象中的用途，其特征在于：电场装置上述的电场装置。
于本发明的用途的一示例中：其中，用途为透皮用药、皮肤护理或营养补充中的一种或多种。
本发明还提供一种使待透皮物质进入目标对象的方法，其特征在于，包括以下步骤：步骤1，分别将目标对象与待透皮物质置于电场发生装置的第一电极和第二电极形成的电场中；步骤2，第一电极或第二电极中仅一个作为接触电极与目标对象接触；步骤3，在电场作用下，控制待透皮物质进入目标对象。
于本发明的方法的一示例中：其中，在步骤2中，待透皮物质与第一电极或第二电极导电接触。
于本发明的方法的一示例中：其中，待透皮物质为水或包括用于皮肤护理、疾病治疗的药物或活体营养保健中的一种或多种成分。
于本发明的方法的一示例中：其中，当第一电极作为接触电极时，第一电极与目标对象之间的接触通过待透皮物质与该第一电极的导电接触实现。
于本发明的方法的一示例中：其中，当第二电极作为接触电极时，第二电极与目标对象的之间的接触通过待透皮物质与该第二电极的导电接触实现。
于本发明的方法的一示例中：还包括以下特征中的一项或多项：
a.电场发生装置产生的电场能突破目标对象的角质层和毛细血 管；
b.电场的电压为可调的0.001kV-120kV，电流为可调的0.001mA-10000mA，电场的工作距离为可调的0.1cm-100cm；
c.第一电极多个，所有第一电极的排布方式选自点阵排布，为2n点阵，其中n为非0自然数；
d.第一电极的位置、电场强度、电压波形或频率根据其他诊断影像数据或者医生问诊确认；和/或，第一电极的位置、电场强度、电压波形根据电场耦合电流诊断后自动跟踪；
e.电场发生装置还包括：
供电电源，用于给发生电场发生装置提供电能；
调控单元，用于调节控制电场的性能，包括电场类型、电场方向、电场强度、电压、电流、电压波形、频率，电源的频率、波形、幅度中的一种或多种。
于本发明的方法的一示例中：还包括以下特征中的一项或多项：
1)特征e中，供电电源的电压为可调的0.001kV-120kV，电场的工作距离为可调的0.1cm-100cm；
2)特征e中，调控单元可调控产生第一信号和第二信号，所述第一信号用于产生透皮给药的电场方向；第二信号用于使电场产生能够促进生物活性剂胞内递送的电场场强。
于本发明的方法的一示例中，其中，特征e中，所述供电电源为高压输出电源。
于本发明的方法的一示例中其中，特征3)中，第一信号控制第一电极产生100V/cm至120KV/cm的电场场强；第二信号调节第一电极产生100V/cm至120kV/cm的电场场强。
于本发明的方法的一示例中：其中，电场的电压工作范围为30kV-120kV，工作距离的工作取值范围为0.1cm-30cm。
于本发明的方法的一示例中：其中，电场的电压为30KV、100KV或120KV中的一个；工作距离为0.1cm、30cm或100cm中的一个。
于本发明的方法的一示例中：其中，针对目标对象的同一部位持续控制待透皮物质进入目标对象的时间小于等于16小时。
于本发明的方法的一示例中：其中，在步骤2中，以第二电极为接触电极，包括：步骤2.1，待透皮物质导电接触第一电极，将第一电极固定于目标对象上的靶向部位的附近，但不与目标对象直接接触；步骤2.2，调节第一电极的位置，以调整电场的覆盖面积，使电场覆盖靶向部位，步骤3具体是：待透皮物质在电场作用下，被控制向第二电极定向移动，并在该移动过程中，透皮进入目标对象。
于本发明的方法的一示例中：其中，待透皮物质存储在第一电极的中空腔中。其中，在步骤2中，第二电极为接触电极，包括：步骤2.1，第二电极与目标对象之间通过待透皮物质为导电接触；步骤2.2，调节各个第一电极的位置，以调整电场的覆盖面积，使电场覆盖目标对象上的靶向部位；步骤3具体是：待透皮物质在电场控制下向第一电极定向移动，并在该移动过程中透皮进入目标对象。
于本发明的方法的一示例中：其中，在步骤2中，第二电极为接触电极，包括：步骤2.1，待透皮物质与第一电极和第二电极均不接触，将第一电极固定于目标对象上的靶向部位的附近，但不与目标对象直接接触；步骤2.2，调节第一电极的位置，以调整电场的覆盖面积，使电场覆盖靶向部位；步骤3具体是：待透皮物质在电场控制下向第二电极定向移动，并在该移动过程中透皮进入目标对象。
本发明提供的电场发生装置及其用途以及使待透皮物质进入目标对象的方法，由于具有第一电极和第二电极形成电场，且第一电极和第二电极中仅一个作为接触电极与目标对象接触，所以通过接触电极与目标对象接触形成的等电位，通过电场控制能调节突破角质层和毛细血管，诱导待透皮物质全组分直达靶向部位，既能实现非侵袭性的透皮给药、美容护肤以及营养保健等，又能更更直接作用于靶向部位，有利于待透气物质的吸收，能提高透皮给药、美容护肤以及营养保健等；而且，避免了皮下注射，静脉给药等由于穿刺给当事人带来的不便，适用性更强，且形成的等电位更能提供一种安全可靠的电场使用，在提高QOL(生活质量)的同时，兼顾装置的小型化，轻量化和安全性，适用性更强，透皮效果更好。
附图说明
图1为实施例1涉及的电场发生装置的结构图；
图2为实施例1涉及的电场发生装置针对活体时的一种使用示意图；
图3为实施例1涉及的空间电场发生装置的第一极排布方式是 示意图；
图4为实施例2涉及的电场发生装置的结构图。
具体实施方式
以下具体说明本发明的具体实施方式。
本文所指的目标对象，可以是指整个活体、组织样本或活体身上的某个或某些部位。活体主要为哺乳动物。哺乳动物优选为啮齿目动物、偶蹄目动物、奇蹄目动物、兔形目动物、灵长目动物等。灵长目动物优选为猴、猿或人。
以下实施例中所使用的方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，均可从商业途径获得。
实施例1
以下实施例是为了对本发明涉及的电场发生装置及其用途以及使待透皮物质进入目标对象的方法进行具体说明。
图1为实施例1涉及的电场发生装置的结构图。
如图1所示，本实施例提供的电场发生装置100，用于控制待透皮物质2进入目标对象1，该电场发生装置100包括：用于形成电场的第一电极10和第二电极20。第一电极10和第二电极20中仅一个作为接触电极与目标对象1接触，由此形成等电位，而电场控制待透皮物质2进入目标对象1。
第一电极10和第二电极20中仅一个作为接触电极与目标对象1接触，形成等电位，也即：要么第一电极10和目标对象1接触形成等电位，要么第二电极20和目标对象1接触形成等电位，以下说明中，为了便于说明，另外一个未与目标对象1接触的第一电极10或第二电极20称为非接触电极。图1所示中，第二电极20与目标对象接触，也即第二电极为非接触电极，则第一电极10为非接触电极。
图2为实施例1涉及的电场发生装置针对活体的一种使用示意图。
在如图2的示意中，整个活体置于电场中，第二电极20与活体的脚底接触，第一电极10分布于要透皮的靶向部位附近。
本实施例的待透皮物质2为水或包括用于皮肤护理、疾病治疗的药物或活体营养保健中的一种或多种成分的物质，比如可以为离子型药剂、美容美颜制剂、促血液循环或人体新陈代谢健身关联制剂，也可以为生物活性剂，生物活性剂包括免疫活性剂，例如疫苗或抗原。示范性的疫苗包括病毒和细菌，蛋白-基疫苗，多糖-基疫苗，和核苷酸-基疫苗。生物活性剂还可包括在主要治疗学领域之一具有活性的药剂，包括但不限于：抗感染药物，例如抗生素和抗病毒药；镇痛药，包括芬太尼，舒芬太尼，雷米芬太尼，丁丙诺啡和镇痛药组合；麻醉药；减食欲药；抗关节炎药；止喘药例如特布他林；抗惊厥剂；抗抑郁药；抗糖尿病药；止泻药；抗组胺剂；消炎药；抗偏头痛剂；抗动晕症药例如东莨菪碱和昂丹司琼；止恶心药；抗肿瘤药；抗震颤麻痹药；止痒药；抗精神病药；清热药；解痉药，包括胃肠的和泌尿的； 抗胆碱能药；拟交感神经药；黄嘌呤衍生物；心血管制剂，包括钙通道阻断剂例如硝苯地平；β阻断剂；β-激动剂例如多巴酚丁胺和利托君；抗心律失常药；抗高血压药例如阿替洛尔；ACE抑制剂例如雷尼替丁；利尿剂；血管扩张剂，包括常规的、冠状动脉的、外周的和大脑的；中枢神经系统兴奋剂；咳嗽和伤风制剂；解充血药；诊断制剂；激素例如甲状旁腺激素；催眠药；免疫抑制剂；肌肉松弛药；抗副交感神经药；拟副交感神经药；前列腺素；蛋白质；肽；神经兴奋药；镇静剂；和安定剂。其它合适药剂包括血管收缩剂、抗修补剂和路径开放调节剂。皮肤护理则可以包括护肤美容水、护肤美容制剂等。
待透皮物质2可以本身为带电的物质，称为带电物质，或者叫做带电体，比如带电药剂，带有正电荷或负电荷，这样可以直接在电场中做定向移动，当然，这个带电体也可以与第一电极或第二电极导电接触，电场也能够加速带电体电穿孔细胞膜以加强定向移动的能力；透待皮物质还可以为不带电荷的物质，例如某些中药，此时，将待透皮物质2通过与相应第一电极或第二电极导电接触，进行电子传导，让该透皮物质变成带电体，从而在电场作用下做定向移动。
在一种实施方式中，第一电极10采用袖带或胸带固定到待检测对象的皮肤表面。
而在上述定向移动过程中，该待透皮物质2将在电场力作用下，透皮进入目标对象1。实际实施中，可以根据带电特性调整电压、第一电极10和第二电极20的极性，同时可以调整作用频率与幅度，提高电场中作用力，以待透皮物质2穿越目标对象1的细胞壁。
如图1中，待透皮物质2可以置于非接触电极处，也即第一电极10处导电接触，这样，在开始时，待透皮物质2与目标对象1之间非接触，具有一定距离，在电场作用下，待透皮物质2向目标对象1移动，直至透皮进入目标对象1。如图1的电场发生装置100，使用时，将待透皮物质2透皮的进入位置称为靶向部位，通过对第一电极10的位置或数量调整，可以定位到到靶向部位。
图3为实施例1涉及的空间电场发生装置的第一极排布方式是示意图。
另外，本实施例提供的电场发生装置100，还包括以下的一个或多个特征：
a.电场发生装置100产生的电场能突破目标对象1的角质层和毛细血管；
b.电场的电压为可调的0.001kV-120kV，电流为可调的0.001mA-10000mA，电场的工作距离为可调的0.1cm-100cm，具体地，电压根据作用深度以及电场距离取值，本实施例中，电场发生装置100发生电场的电压工作范围为30kV-120kV，优选为30KV、100KV、120KV；工作距离的工作取值范围为0.1cm-30cm，优选为0.1cm、30cm、100cm。这里的工作距离是指非接触电极到目标对象1的靶向部位的距离，例如本实施例中，为从第一电极10到目标对象1的靶向部位的距离。
c.本实施例中，第一电极10可以为多个，排布方式选自点阵排布，为2n点阵，其中n为非0自然数；空间异电极的排布方式可选自矩阵排布，具体的64点阵、4096点阵、16777216点阵等，如图2所示。点阵密集程度取决于电场作用精确度。利用精确作用电场提高对神经细胞的作用效率、减少对正常组织作用影响。但受输出电场电 源体积限制，点阵密集而电源体积庞大。其中a\b\c一直到xx的任意一或多条经线和1\2\3一直到nn任意一或多条纬线激活一个或多个点阵第一电极10，这些第一电极10和第二电极20组成作用电场，电场覆盖范围是激活的点阵极决定的。这个范围可以来自医学诊断影像数字信号。确认了这个电场范围，可以精确作用神经细胞，减少对其他组织影响。一般64点阵只能区分64个电场位置，4096点阵可以区分4096个电场位置，16777216点阵可以分辨16777216个电场位置，这个点阵作用就相对精确，对周围正常组织影响就较小。具体的空间异电极在头盔式框架上的排列示意图，见图2。事实上，就是根据医学诊断影像形成的点阵原理，对第一电极10进行类似的点阵排布，从而能在使用时，将第一电极10精准定位到要作用的靶向部位，并且第一电极10位置可调，可以根据每次拿到的医学诊断影像进行调整，以能与医学诊断影像的点阵对应，从而能快速精准定位到要作用的位置(靶向部位)。在一种实施方式中，第一电极10为多个矩阵第一电极10排布于头盔式框架的外部。
d.第一电极10的位置、电场强度根据其他诊断影像数据或者医生问诊确认，也即是根据对目标对象1的医疗影像数据确定的治疗靶向部位或者医生问诊或护肤方案或营养补充方案确定的靶向部位进行确认；第一电极10的位置、电场强度、电压波形还能根据电场耦合电流诊断后自动跟踪，也即在使用过程中，持续跟踪电场性能，保证有效性。
本实施例中，电场发生装置100还包括：供电电源30和调控单元。
供电电源30，用于给发生电场发生装置提供电能；
调控单元，用于调节控制电场的性能，电场性能相关参数主要包 括电场类型、电场方向、电场强度、电压、电流、电压波形、频率，电源的频率、波形、幅度中的一种或多种。本质上，电场的性能根据目标位点(靶向部位)和/或目标浓度(作用浓度)与电场场强确认。
产生的电场优选为低强度中等频率电场。低强度是指电场强度为1-200V/m，中等频率是指频率为1赫兹-500千赫兹。
在一种实施方式中，异电极还可以为采用袖带或胸带固定到目标对象1的皮肤表面。
另外，第一电极10还可以设有中空腔，该中空腔用于灌注待透皮物质，中空腔还可以设有刻度，方便控制透皮的量。另外，第一电极10底部还可以涂有绝缘材料或是由绝缘材料构成，用于防止邻近第一电极10之间的相互干扰。
进一步地，本实施例提供的电场发生装置100，还包括以下特征中的一项或多项：
1)特征e中，供电电源的电压为可调的0.001kV-120kV，电场的工作距离为可调的0.1cm-100cm；供电电源选为高压输出电源；
2)特征e中，调控单元可调控产生第一信号和第二信号，所述第一信号用于产生透皮给药的电场方向；第二信号用于使电场产生能够促进生物活性剂胞内递送的电场场强。
另外，在上述特征3)中，第一信号控制第一电极产生100V/cm至120KV/cm的电场场强；第二信号调节第二电极产生100V/cm至120kV/cm的电场场强；第一电机与异电极(含第二电极)的一端接通零线。
另外，针对目标对象1的同一部位持续控制待透皮物质2进入目标对象1的时间，不要过长，可以在小于等于16小时，这样才能保持让待透皮物质2在持续时间内一直有效透皮进入目标对象1。
根据本实施例的电场发生装置100可以在使待透皮物质2进入目标对象1中应用，用途可以为透皮用药、皮肤护理或营养补充中的一种或多种。
根据上述，本实施例使待透皮物质2进入目标对象1的方法，其特征在于，包括以下步骤：
步骤1，分别将目标对象1与待透皮物质2置于电场发生装置100的第一电极10和第二电极20形成的电场中；
步骤2，第一电极10或第二电极20中仅一个作为接触电极与目标对象1接触，本实施例中以第二电极20作为接触电极；
步骤3，在电场作用下，控制待透皮物质2进入目标对象1。具体地，待透皮物质2在电场作用下，被控制向第二电极20定向移动，并在该移动过程中，透皮进入目标对象1，该过程通过电压、工作距离、第一电极10的位置等的调整，以及电场性能调整，以实现待透皮物质2进入目标对象1。
其中，在步骤2中，包括：
步骤2.1，待透皮物质2与第一电极10或第二电极20导电接触，本实施例中与第一电极10导电接触，并将第一电极10固定于目标对象1上的靶向部位的附近，但不与目标对象1直接接触，具体地，可以将待透皮物质2存储在第一电极10的中空腔中；
步骤2.2，调节第一电极10的位置，以调整电场的覆盖面积，使电场覆盖靶向部位。
实施例2
本实施例中省略与实施例1中相同部分的说明。
图3为实施例2涉及的电场发生装置的结构图。
如图3所示，本实施例中，电场发生装置300包括第一电极310和第二电极320，其中以第二电极320为接触电极。
本实施例与实施例1的不同在于，本实施例中，是将待透皮物质2接触目标对象1，但该透皮物质既不接触第一电极310，也不接触第二电极320，待透皮物质2本身为带电体，通过对电场性能的调整，让待透皮物质2向接触电极定向移动，在此过程中，覆盖在目标对象1的皮肤表面的待透皮物质2直接透皮进入目标对象1。
在该实施例中，通过第一电极310的数量和排布，可以让待透皮如实施例1一样定位到靶向部位进入。
根据本实施例的电场发生装置300也可以在使待透皮物质2进入目标对象1中应用，用途可以为透皮用药、皮肤护理或营养补充中的一种或多种。
根据上述，本实施例使待透皮物质2进入目标对象1的方法，其特征在于，包括以下步骤：
步骤1，分别将目标对象1与待透皮物质2置于电场发生装置300的第一电极310和第二电极320形成的电场中；
步骤2，第一电极310或第二电极320中仅一个作为接触电极与目标对象1接触，本实施例中以第二电极320为接触电极；
步骤3，在电场作用下，控制待透皮物质2进入目标对象1。具体地，待透皮物质2在电场控制下向第二电极320定向移动，并在该移动过程中透皮进入目标对象1，该过程通过电压、工作距离、第一电极310的位置等的调整，以及电场性能调整，以实现待透皮物质2进入目标对象1。
其中，在步骤2中，包括：
步骤2.1，待透皮物质与第一电极310和第二电极320均不接触，将第一电极310固定于目标对象1上的靶向部位的附近，但不与目标对象1直接接触；
步骤2.2，调节第一电极310的位置，以调整电场的覆盖面积，使电场覆盖靶向部位。
实验列1
本实验列分别采用实施例1提供的电场发生装置100和实施例3提供的电场发生装置300，进行透皮给药实验。具体如下。
在该实施例中，在通过该电场发生装置施加电场将DNA递送入小鼠，再通过检测mRNA水平上的基因表达来检测DNA的吸收。该实施例包括两个治疗组，实验组和对照组。对照组：使用没有通电的递送系统进行编码β-半乳糖苷酶蛋白的DNA递送(DNA的核苷酸序列的特定片段。该实施例的PCR条件如下。使用的引物包括内显子RT5′引物-5′CCG GGA ACGGTGCATTGGAA3′(SEQ ID NO：2)和#1057b-gal内含子RT 3′引物-5′ATCGGCCTCAGGAAGATCGC3′(SEQ ID NO：3)。
(1)实验方法
使用钛合金制作空间中空微电极；将β-半乳糖苷酶的表达质粒灌入至该电极，每个空间电极含有40μg DNA；使用胶带将此电极悬浮于皮肤表面(如图6所示)或固定到皮肤上(如图7所示)；将DNA递送至小鼠皮肤中。根据参数电压不同分为A-G组共6组，分别实施不同场强【即不同电压强度以及不同电场距离(工作距离)】下的 治疗验证(n＝10)。另行准备H组10只健康小鼠为对照组，实施皮下注射。
DNA递送之后，使用rtPCR测定编码β-半乳糖苷酶蛋白的mRNA水平，进而定量质粒DNA的细胞内吸收量。DNA递送一天(24小时)之后，将动物杀死，从所有治疗位点的中心、皮内注射位点和未经处理的皮肤位点处获得8mm皮肤，称量活检，通过切碎和短暂的超声处理进行均匀化。使用RNA提取试剂盒提取RNA，反转录获取cDNAs。再使用试剂盒进行RTPCR反应，根据结果进行定量分析。
该实施例的PCR条件如下。使用的引物包括内显子RT5′引物-5′CCG GGA ACGGTGCATTGGAA3′(SEQ ID NO：2)和#1057b-gal内含子RT 3′引物-5′ATCGGCCTCAGGAAGATCGC3′(SEQ ID NO：3)。PCR反应条件是：95℃，5分钟；92℃、1分钟进行40个循环；66℃、30秒；72℃、1分钟；和72℃、附加10分钟。通过凝胶电泳分析PCR反应中的β-半乳糖苷酶mRNA特定片段的存在。这种方法可以半定性检测β-半乳糖苷酶表达。
实验结果如下所示：
Figure PCTCN2020091336-appb-000001
Figure PCTCN2020091336-appb-000002
Figure PCTCN2020091336-appb-000003
Figure PCTCN2020091336-appb-000004
Figure PCTCN2020091336-appb-000005
Figure PCTCN2020091336-appb-000006
Figure PCTCN2020091336-appb-000007
Figure PCTCN2020091336-appb-000008
各组小鼠(N＝10)除对照组通过皮下注射给药(给药40μg)以外，其余在不同电压强度，不同工作距离及两种不同给药模式(实施例1和实施例3药)下实施透皮给药。给药后对照组小鼠经24hr药代后，药物检测率约为70％。电场给药组在治疗用电压低于1KV时，几乎没有给药效果。当电压强度达到3KV时，开始出现轻微疗效。继续调整电压强度到10KV，30KV时，疗效持续提高，当电压强度达到30KV时，给药效果等同甚至超越对照组。显见电压强度与给药效果呈正比例效应，即电压越强给药效果越明显。
其次，电场与透皮药物间的距离越远，其给药效果越弱。实验结果显示，当电流超过30KV时，距离对给药效果的影响逐渐减弱，效应
当然不同给药模式(实施例1-悬浮给药与实施例3-固定给药)对比，虽然在总给药效果上悬浮给药略逊色与固定给药，但是与皮下注射相对比，均能实现在电场控制下，待透皮物质能进入目标对象， 所以本发明提供的电场发生装置具有提高当事人QOL(生活质量)，减少肉体痛苦等优势，能用于使待透皮物质进入目标对象中的用途。
实验列2
本实验列的目的在于观察随着透皮时间增加，待透皮物质能透皮的量的变化。为了便于实验，本实验列采用分别连接正负极的双室扩散池模拟实施例中的电场发生装置进行，本实验列中，待透皮物质为青藤碱。
(1)离体皮肤的制备:
实验用4-6周龄小鼠(体重20g,健康、皮毛光泽),将其脱颈处死,剥离腹部的皮肤,剃去腹部的毛,小心除去脂肪,用生理盐水冲洗干净,显微观察没有破损后即用。
(2)青藤碱的HPLC法测定
色谱条件:色谱柱:Hypersil C18(250mm×4.6mm,10μm),流动相:甲醇-水-乙二胺[52∶48(300∶10)]；体积流量:1mL/min；检测波长:262nm；进样量:10μL。标准曲线的绘制:精密称取青藤碱40mg,置于100mL量瓶中,加双蒸水溶解,并加至刻度,摇匀。分别取出0.25、0.50、1.00、1.50、2.00、2.50mL放入10mL量瓶内,加双蒸水至刻度,摇匀备用。分别取10μL进样(每个水平重复3次),以峰面积(A)对质量浓度(C)回归的标准曲线方程为A＝1 213.21C-24 083,r＝0.999 6。接收液中青藤碱的测定:在线性范围内配青藤碱对照品溶液,进样10.0μL(3次)；接收 液经微孔滤膜滤过后进样10.0μL(3次),采用外标法计算。
(3)透皮试验:
取体重为20g的小鼠，脱颈处死，剥离腹部的皮肤，剪净腹部的毛，仔细除去皮下脂肪，用生理盐水反复冲洗干净，然后加于双室扩散池中，角质层面向供给池,真皮层面向接收池，扩散池固定在磁力搅拌器上，均匀搅拌，同时保持接收池的温度在32℃。供给池中加入青藤碱溶液(6mg/mL)，接收池中加入25mL林格氏溶液,供给池中接正极，接收池中接负极(接收池内以星状磁珠不断缓慢搅拌以保持药物质量浓度的均匀)，进行电致孔条件(不同电场信息)下不同参数的给药试验，设定电压强度为30KV与120KV定时(导电开始后1hr，2hr，4hr，8hr与24hr，n＝10)取出接收液补加等量接收液，取出的接收液采用HPLC法测定青藤碱的质量浓度,计算总的累积给药量。结果分别见表7和表8
Figure PCTCN2020091336-appb-000009
电场给药组在电压30KV时，给药剂量变化随时间延长成线性上涨趋势。
Figure PCTCN2020091336-appb-000010
首先电场给药组在电压120KV时，给药剂量变化情况与趋势与30KV时类似。伴随时间延长成线性上涨趋势。且电场强度提高到一定情况下，给药剂量随时间增加的比例逐渐摆脱线性增长趋势，类似与抛物线。最终在给药开始16小时后，实验用皮肤(小鼠)能够负荷的给药药物接近上限，在16hr到24hr间出现瓶颈效应。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。

Claims (31)

  1. 一种电场发生装置，用于控制待透皮物质进入目标对象，其特征在于，包括：
    用于形成电场的第一电极和第二电极，
    其中，所述第一电极和所述第二电极中仅一个作为接触电极与所述目标对象接触，
    所述电场控制所述待透皮物质进入所述目标对象。
  2. 根据权利要求1所述的电场发生装置，其特征在于：
    其中，所述待透皮物质与所述第一电极或所述第二电极导电接触。
  3. 根据权利要求1所述的电场发生装置，其特征在于：
    其中，所述待透皮物质为水或包括用于皮肤护理、疾病治疗的药物或活体营养保健中的一种或多种成分。
  4. 根据权利要求2所述的电场发生装置，其特征在于：
    其中，当所述第一电极作为所述接触电极时，所述第一电极与所述目标对象之间的所述接触通过所述待透皮物质与该第一电极的导电接触实现。
  5. 根据权利要求2所述电场发生装置，其特征在于：
    其中，当所述第二电极作为所述接触电极时，所述第二电极与所述目标对象的之间的所述接触通过所述待透皮物质与该第二电极的导电接触实现。
  6. 根据权利要求1所述的电场发生装置，其特征在于：
    还包括以下特征中的一项或多项：
    a.所述电场发生装置产生的电场能突破目标对象的角质层和毛细血管；
    b.所述电场的电压为可调的0.001kV-120kV，所述电场的工作距离为可调的0.1cm-100cm；
    c.所述第一电极多个，所有所述第一电极的排布方式选自点阵排布，为2n点阵，其中n为非0自然数；
    d.第一电极的位置、电场强度根据其他诊断影像数据或者医生问诊确认；
    e.所述电场发生装置还包括：
    供电电源，用于给所述发生电场发生装置提供电能；
    调控单元，用于调节控制所述电场的性能，包括电场类型、电场方向、电场强度、电压、电流、电压波形、频率，电源的频率、波形、幅度中的一种或多种。
  7. 根据权利要求5所述的电场发生装置，其特征在于：
    还包括以下特征中的一项或多项：
    1)特征e中，所述供电电源的电压为可调的0.001kV-120kV，电场的工作距离为可调的0.1cm-100cm；
    2)特征e中，所述调控单元可调控产生第一信号和第二信号，所述第一信号用于产生透皮给药的电场方向；所述第二信号用于使所述电场产生能够促进生物活性剂胞内递送的电场场强。
  8. 根据权利要求7所述的电场发生装置，其特征在于：
    其中，特征e中，所述供电电源为高压输出电源。
  9. 根据权利要求7所述的电场发生装置，其特征在于：
    其中，特征2)中，所述第一信号控制所述第一电极产生100V/cm至120KV/cm的电场场强；所述第二信号调节所述第二电极产生100V/cm至120kV/cm的电场场强。
  10. 根据权利要求6所述的电场发生装置，其特征在于：
    其中，所述电场的电压工作范围为30kV-120kV，
    所述工作距离的工作取值范围为0.1cm-30cm。
  11. 根据权利要求10所述的电场发生装置，其特征在于：
    其中，所述电场的电压为30KV、100KV或120KV中的一个；
    所述工作距离为0.1cm、30cm或100cm中的一个。
  12. 根据权利要求10所述的电场发生装置，其特征在于：
    其中，针对所述目标对象的同一部位持续控制待透皮物质进入目标对象的时间小于等于16小时。
  13. 根据权利要求1至12任意一项所述的电场发生装置，其特征在于：
    其中，所述第一电极设有中空腔，所述中空腔用于灌注所述待透皮物质。
  14. 一种电场发生装置在使待透皮物质进入目标对象中的用途，其特征在于：
    所述电场装置为权利要求1-13中任意一项所述的电场装置。
  15. 根据权利要求14所述的用途，其特征在于：
    其中，所述用途为透皮用药、皮肤护理或营养补充中的一种或多种。
  16. 一种使待透皮物质进入目标对象的方法，其特征在于，包括以下步骤：
    步骤1，分别将所述目标对象与待透皮物质置于电场发生装置的第一电极和第二电极形成的电场中；
    步骤2，所述第一电极或所述第二电极中仅一个作为接触电极与所述目标对象接触；
    步骤3，在所述电场作用下，控制所述待透皮物质进入所述目标对象。
  17. 根据权利要求16所述的方法，其特征在于：
    其中，在步骤2中，所述待透皮物质与所述第一电极或所述第二电极导电接触。
  18. 根据权利要求16所述的方法，其特征在于：
    其中，所述待透皮物质为水或包括用于皮肤护理、疾病治疗的药物或活体营养保健中的一种或多种成分。
  19. 根据权利要求17所述的方法，其特征在于：
    其中，当所述第一电极作为接触电极时，所述第一电极与所述目标对象之间的接触通过所述待透皮物质与该第一电极的导电接触实现。
  20. 根据权利要求17所述的方法，其特征在于：
    其中，当所述第二电极作为接触电极时，所述第二电极与所述目标对象的之间的接触通过所述待透皮物质与该第二电极的所述导电接触实现。
  21. 根据权利要求16所述的方法，其特征在于：
    还包括以下特征中的一项或多项：
    a.所述电场发生装置产生的电场能突破目标对象的角质层和毛细血管；
    b.所述电场的电压为可调的0.001kV-120kV，电流为可调的0.001mA-10000mA，所述电场的工作距离为可调的0.1cm-100cm；
    c.所述第一电极多个，所有所述第一电极的排布方式选自点阵排布，为2n点阵，其中n为非0自然数；
    d.第一电极的位置、电场强度、电压波形或频率根据其他诊断影像数据或者医生问诊确认；和/或，所述第一电极的位置、电场强度、电压波形根据电场耦合电流诊断后自动跟踪；
    e.所述电场发生装置还包括：
    供电电源，用于给所述发生电场发生装置提供电能；
    调控单元，用于调节控制所述电场的性能，包括电场类型、电场方向、电场强度、电压、电流、电压波形、频率，电源的频率、波形、幅度中的一种或多种。
  22. 根据权利要求21所述的方法，其特征在于：
    还包括以下特征中的一项或多项：
    1)特征e中，所述供电电源的电压为可调的0.001kV-120kV，电 场的工作距离为可调的0.1cm-100cm；
    2)特征e中，所述调控单元可调控产生第一信号和第二信号，所述第一信号用于产生透皮给药的电场方向；所述第二信号用于使所述电场产生能够促进生物活性剂胞内递送的电场场强。
  23. 根据权利要求22所述的方法，其特征在于：
    其中，特征e中，所述供电电源为高压输出电源。
  24. 根据权利要求22所述的方法，其特征在于：
    其中，特征2)中，所述第一信号控制所述第一电极产生100V/cm至120KV/cm的电场场强；所述第二信号调节所述第一电极产生100V/cm至120kV/cm的电场场强。
  25. 根据权利要求21所述的方法，其特征在于：
    其中，所述电场的电压工作范围为30kV-120kV。
    所述工作距离的工作取值范围为0.1cm-30cm。
  26. 根据权利要求25所述的方法，其特征在于：
    其中，所述电场的电压为30KV、100KV或120KV中的一个；
    所述工作距离为0.1cm、30cm或100cm中的一个。
  27. 根据权利要求26所述的电场发生装置，其特征在于：
    其中，针对所述目标对象的同一部位持续控制待透皮物质进入目标对象的时间小于等于16小时。
  28. 根据权利要求16-27任意一项所述的方法，其特征在于：
    其中，在步骤2中，以所述第二电极为接触电极，包括：
    步骤2.1，所述待透皮物质导电接触所述第一电极，将所述第一电极固定于所述目标对象上的靶向部位的附近，但不与所述目标对象直接接触；
    步骤2.2，调节所述第一电极的位置，以调整电场的覆盖面积，使电场覆盖所述靶向部位，
    步骤3具体是：所述待透皮物质在所述电场作用下，被控制向所述第二电极定向移动，并在该移动过程中，透皮进入所述目标对象。
  29. 根据权利要求28所述的方法，其特征在于：
    其中，所述待透皮物质存储在所述第一电极的中空腔中。
  30. 根据权利要求16-27任意一项所述的方法，其特征在于：
    其中，在步骤2中，所述第二电极为接触电极，包括：
    步骤2.1，所述第二电极与所述目标对象之间通过所述待透皮物质为导电接触；
    步骤2.2，调节各个所述第一电极的位置，以调整所述电场的覆盖面积，使所述电场覆盖所述目标对象上的靶向部位；
    步骤3具体是：所述待透皮物质在电场控制下向所述第一电极定向移动，并在该移动过程中透皮进入所述目标对象。
  31. 根据权利要求16-27任意一项所述的方法，其特征在于：
    其中，在步骤2中，所述第二电极为接触电极，包括：
    步骤2.1，所述待透皮物质与第一电极和第二电极均不接触，将所述第一电极固定于所述目标对象上的靶向部位的附近，但不与所述目 标对象直接接触；
    步骤2.2，调节所述第一电极的位置，以调整电场的覆盖面积，使电场覆盖所述靶向部位；
    步骤3具体是：所述待透皮物质在电场控制下向所述第二电极定向移动，并在该移动过程中透皮进入所述目标对象。
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