WO2020224664A1 - 离子电渗透的给药装置 - Google Patents

离子电渗透的给药装置 Download PDF

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Publication number
WO2020224664A1
WO2020224664A1 PCT/CN2020/093888 CN2020093888W WO2020224664A1 WO 2020224664 A1 WO2020224664 A1 WO 2020224664A1 CN 2020093888 W CN2020093888 W CN 2020093888W WO 2020224664 A1 WO2020224664 A1 WO 2020224664A1
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Prior art keywords
power source
electrode
electrically connected
penetrated
skin
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PCT/CN2020/093888
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English (en)
French (fr)
Inventor
杨峰
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上海敬巽信息科技有限公司
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Application filed by 上海敬巽信息科技有限公司 filed Critical 上海敬巽信息科技有限公司
Priority to CA3140246A priority Critical patent/CA3140246A1/en
Priority to KR1020217039779A priority patent/KR102649114B1/ko
Priority to EP20801865.5A priority patent/EP3967359A4/en
Priority to JP2021566251A priority patent/JP7255921B2/ja
Priority to AU2020268935A priority patent/AU2020268935B2/en
Priority to US17/609,055 priority patent/US20220193396A1/en
Priority to CN202080034484.5A priority patent/CN114072198A/zh
Publication of WO2020224664A1 publication Critical patent/WO2020224664A1/zh
Priority to ZA2021/09315A priority patent/ZA202109315B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A61N1/303—Constructional details
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0444—Membrane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • 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
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/82—Internal energy supply devices

Definitions

  • This application relates to a drug delivery device, in particular to a drug delivery device for iontophoresis.
  • Transdermal administration refers to a method of administration on the surface of the skin to allow the drug to pass through the skin at a certain rate and enter the systemic circulation to produce systemic or local therapeutic effects. Because the transdermal drug delivery method has the advantages of not being affected by factors such as food in the digestive tract and continuously controlling the drug delivery speed, it has broad application prospects.
  • the stratum corneum of the skin has a barrier effect, which makes it difficult for the current penetration rate and permeation amount of drug delivery via the skin surface to achieve the desired effect.
  • the traditional scheme to increase the penetration rate and the amount of penetration is, for example, the microneedle transdermal drug delivery method, that is, the microneedle array is set on the drug delivery carrier to make the microneedles penetrate the stratum corneum of the skin, thereby improving the transdermal drug delivery rate.
  • the above-mentioned microneedle transdermal solution requires relatively high microneedle length, and if it is not well controlled, it is easy to damage the skin and cause pain.
  • the traditional method of improving transdermal drug delivery is also for example: iontophoretic drug delivery, that is, a non-invasive method that uses a charged charge to push a polar active agent into the skin through an electromotive force.
  • iontophoretic drug delivery that is, a non-invasive method that uses a charged charge to push a polar active agent into the skin through an electromotive force.
  • electrically driven single-point electrodes or multiple drug delivery carriers with electrodes are usually set for drug delivery.
  • the above iontophoretic drug delivery methods either have insignificant transdermal effects or are easy to cause Skin burns.
  • the shortcomings of the traditional transdermal drug delivery regimen are: either the transdermal effect is not obvious, or it is easy to cause skin burns or cause pain and other skin injuries.
  • an iontophoretic drug delivery device which can not only improve the transdermal efficiency, but also does not easily cause skin damage.
  • an iontophoresis drug delivery device in the first aspect of the present disclosure, includes: a power source, used to generate electricity required to penetrate the drug to be infiltrated into the administered area of the organism; an integrated medium layer, used to cover the administered area, the integrated medium layer includes: gel, And the gel includes a polar, free state drug to be permeated; and a plurality of electrodes for electrically connecting the power source and the integrated dielectric layer, so that the electricity generated by the power source flows through the drug delivery area and at least part of the The integrated dielectric layer, at least part of the integrated dielectric layer has a predetermined resistance value.
  • the gel includes at least one of the following components: polyethylene glycol, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylic acid, polymethacrylic acid, gelatin, alginic acid.
  • the plurality of electrodes is a plurality of flexible conductive electrode films separated by a predetermined interval.
  • the agent to be penetrated includes vitamin C and arbutin.
  • the agent to be penetrated includes vitamin C and tranexamic acid.
  • the molecular weight of the agent to be penetrated is less than or equal to 10,000 Daltons.
  • the thickness of the integrated dielectric layer is less than or equal to 50 mm.
  • the electricity generated by the power source is alternating current, and the current intensity of the electricity is less than or equal to 5 mA.
  • the electricity generated by the power source is direct current, and the current intensity of the electricity is less than or equal to 5 mA.
  • the current intensity of the electricity generated by the power source is greater than or equal to 0.01 mA.
  • the power source includes at least a first power source
  • the plurality of electrodes includes at least a first electrode and a second electrode.
  • the first electrode is electrically connected to the first terminal of the first power source
  • the second electrode is electrically connected to the second terminal of the first power source. Terminal electrical connection.
  • the power source further includes a second power source
  • the plurality of electrodes further includes a third electrode and a fourth electrode.
  • the third electrode is electrically connected to the first end of the second power source
  • the fourth electrode is electrically connected to the second power source of the second power source. Terminal electrical connection.
  • the power supply further includes a third power supply and a fourth power supply
  • the plurality of electrodes further includes a fifth electrode
  • the first end of the third power supply is electrically connected to the second end of the first power supply
  • the second end of the third power supply The terminal is electrically connected to the fifth electrode
  • the first terminal of the fourth power source is electrically connected to the first terminal of the first power source
  • the second terminal of the fourth power source is electrically connected to the second terminal of the third power source.
  • the iontophoresis drug delivery device further includes: a backing layer for covering the plurality of electrodes, the backing layer is made of insulating material; and a plurality of connecting members for electrically connecting the power source and the Each electrode of the plurality of connecting members is at least partially disposed in the backing layer.
  • the predetermined resistance value is greater than 100 ohms and less than or equal to 100K ohms.
  • the predetermined resistance value is greater than 1K ohms and less than or equal to 12K ohms.
  • the gel includes collagen.
  • FIG. 1 shows a schematic diagram of an iontophoresis drug delivery device 100 according to some embodiments of the present disclosure
  • FIG. 2 shows a schematic diagram of a partial structure of an iontophoretic drug delivery device 200 according to some embodiments of the present disclosure
  • FIG. 3 shows a schematic diagram of an iontophoresis drug delivery device 300 according to some embodiments of the present disclosure
  • FIG. 4 shows a schematic diagram of an iontophoresis drug delivery device 400 according to some embodiments of the present disclosure
  • FIG. 5 shows a schematic diagram of an iontophoresis drug delivery device 500 according to some embodiments of the present disclosure
  • FIG. 6 shows a schematic diagram of an iontophoresis drug delivery device 600 according to some embodiments of the present disclosure.
  • FIG. 7 shows a schematic diagram of an iontophoresis drug delivery device 700 according to some embodiments of the present disclosure.
  • the traditional iontophoresis drug delivery scheme is, for example, to provide a single electrode or multiple drug delivery carriers each with an electrode, and the power supply is electrically connected to the electrode.
  • the power supply is electrically connected to the electrode.
  • the skin condition such as water content, amount of drug accumulated in the skin
  • the skin resistance of the applied area will also change with the skin condition. Therefore, the power supply voltage and current value set before the administration do not consider the amount of change in skin resistance during the administration, and therefore will not be compatible with the changed skin resistance during the administration. For example, as the drug delivery process progresses, the skin's water or drug content will increase, and the skin's resistance will decrease accordingly.
  • the preset power supply voltage remains unchanged, the current intensity flowing through the skin will increase. , Which is likely to cause irritation and burns to the skin.
  • an exemplary embodiment of the present disclosure proposes an iontophoresis drug delivery device.
  • the device includes: a power source for generating electricity required to penetrate the drug to be infiltrated into the administered area of the organism; an integrated medium layer for covering the administered area, the integrated medium layer includes a gel and a belt A polar, free state drug to be infiltrated; and a plurality of electrodes for electrically connecting the power source and the integrated dielectric layer, so that the electricity generated by the power source flows through the drug delivery area and at least part of the integrated dielectric layer, at least Part of the integrated dielectric layer has a predetermined resistance value.
  • the electricity generated by the power source is caused to respectively flow through the drug administration area and at least part of the integrated dielectric layer having a predetermined resistance value, that is, the The integrated dielectric layer is connected in parallel with the skin resistance of the drug-administered area to shunt the current flowing through the drug-administered area, avoiding excessive current intensity from irritating or burning the skin.
  • the ratio of the current shunted by the dielectric layer is related to the ratio between the predetermined resistance value of the dielectric layer and the skin resistance of the drug administration area.
  • the iontophoresis drug delivery device of the present disclosure can not only solve the increase in current intensity caused by the decrease in skin resistance during drug delivery, in a simple manner. Technical problems caused by irritation or skin burns, and can adaptively adjust the size of the current flowing through the skin according to the differentiated skin conditions of different individuals. Furthermore, in the above-mentioned iontophoresis drug delivery device, since a part of the current flows between the electrodes, the integrated dielectric layer including the gel of the free-state drug and having a predetermined resistance value covers the surface of the drug delivery area.
  • the integrated dielectric layer and its gel will generate heat.
  • the epidermis is the stratum corneum, granular layer, spinous layer, and basal layer from outside to inside.
  • the key to transdermal absorption in the epidermis is the "skin barrier".
  • the skin barrier includes the stratum corneum and sebum membrane. Under normal circumstances, a proper increase in skin temperature will help increase the efficiency of the drug to be penetrated through the "skin barrier". Therefore, the heat generated by the current flowing through the integrated medium layer is beneficial to improve the efficiency of the drug to be penetrated through the "skin barrier".
  • FIG. 1 shows a schematic diagram of an iontophoresis drug delivery device 100 according to some embodiments of the present disclosure.
  • the iontophoresis drug delivery device 100 of this example includes a power supply 110, a plurality of electrodes 112-1 and 112-2, and an integrated dielectric layer 114.
  • the integrated medium layer 114 further includes a gel 118 and a polar, free state drug to be penetrated 130.
  • the integrated medium layer 114 covers the area 122 to be administered of the biological body 120 and conforms to the contour of the area 122 to be administered.
  • the administered area 122 is, for example, partial skin of the human body, such as, but not limited to, facial skin.
  • the integrated medium layer 114 is, for example, set in the contour of a facial mask.
  • the integrated dielectric layer 114 further includes a mesh structure (not shown).
  • the free-state drug 130 to be penetrated is dispersed in the cross-linked network structure of the gel 118.
  • the drug 130 to be infiltrated with a polar and free state is distributed on the surface of the gel 118.
  • the gel body 118 includes collagen or the gel body 118 is a collagen gel.
  • the power supply 110 it is used to generate electricity required to penetrate the drug to be penetrated into the area to be administered.
  • the iontophoresis drug delivery device 100 includes a power source.
  • the iontophoresis drug delivery device 100 includes multiple power sources. The multiple power sources can be connected in series and/or in parallel to provide suitable voltage and current to penetrate the drug to be infiltrated into the area to be administered.
  • the electricity generated by the power supply 100 may be constant or variable.
  • the power supply time, power supply voltage, and current intensity settings of the power supply are related to the amount of the drug to be osmotic.
  • the power supply voltage amplitude, current intensity, and power supply are adjusted. Time, frequency, duty cycle, etc.
  • the electricity provided by the power supply 110 is alternating current. This is because: on the one hand, direct current is likely to cause local anesthesia to the skin, and it is easy to cause damage to the skin that is not easily noticed by the person being administered. On the other hand, direct current is likely to cause the accumulation of electric charges in the skin layer, which leads to a decrease over time. The rate and total amount of the drug to be penetrated 130 delivered.
  • the alternating current direction of the alternating current provided by the power supply 110 can solve the accumulation of capacitive charges in the skin layer, thereby helping to improve the transdermal efficiency and total amount of the medicine.
  • the current intensity of the alternating current is less than or equal to 5 mA.
  • the current intensity of the alternating current is greater than or equal to 0.01 mA and less than 5 mA.
  • the above-mentioned current intensity setting range can not only avoid skin damage, but also ensure the penetration of the drug to be penetrated into the administered area. Sufficient potential energy.
  • the electrode 112 it is configured as an ion-permeable electrode.
  • the plurality of electrodes 112 are used to respectively connect the two output ends of the power source 110 to the integrated dielectric layer 114, so that the electricity generated by the power source flows through the administered area and at least part of the integrated dielectric layer respectively.
  • the electrode 112 includes a first electrode 112-1 and a second electrode 112-2, wherein the first electrode 112-1 is connected to the first end of the power source 110 through the connector 111-1 and the wire 113-1. Electrically connected, the second electrode 112-2 is electrically connected to the second end of the power source 110 through the connector 111-2 and the wire 113-2.
  • the electricity generated by the power supply 110 respectively flows through the administered area 122 and at least part of the integrated dielectric layer (for example, the electrical contact between the first electrode 112-1 and the integrated dielectric layer 114 to the second electrode 112-2 and the integrated dielectric layer 114).
  • the part of the integrated dielectric layer between the electrical contacts of the dielectric layer).
  • the portion of the integrated dielectric layer 114 through which the current flows has a predetermined resistance value.
  • the integrated medium layer containing the free state and polarized drug to be penetrated 130 with a predetermined resistance value is covered under a plurality of independent electrodes 112, and the integrated medium
  • the parallel connection of the skin resistance of the administering area 122 and the administering area 122 realizes the shunting of the current flowing through the skin of the administering area 122, thereby reducing the intensity of the current flowing through the skin under a given power supply voltage, effectively avoiding Skin irritation or burns.
  • R1 is set to be 10%-90% of R2. In some embodiments, R1 is set to be greater than 100 ohms and less than or equal to 100K ohms. In some embodiments, R1 is set to be greater than 1K ohms and less than or equal to 12K ohms, for example, 10K ohms.
  • the electrode 112 may be a sheet electrode, a dot electrode, a layered electrode, or other shapes.
  • the plurality of electrodes 112 are a plurality of flexible conductive electrode films separated by a predetermined interval.
  • the conductive electrode film is, for example, a low-resistance conductive film, a conductive carbon film, or a carbon-based conductive film.
  • the flexible conductive electrode film is made, for example, by mixing polyethylene with polymer superconducting nano carbon black, curing agent, auxiliary agent and the like.
  • a flexible conductive electrode membrane to set the ion permeation electrode has the advantages of uniform and stable resistance, good flexibility and flexibility, which is beneficial to make the integrated dielectric layer 114 and the electrode better fit the difference of the area to be administered
  • the outer contour is not easy to be eroded. Therefore, it has obvious advantages over the traditional sheet ion permeation electrode.
  • a plurality of electrodes in the form of flexible conductive electrode films may be attached to the backing layer 116 by an adhesive, and the plurality of electrodes in the form of flexible conductive electrode films are separated from each other on the backing layer 116 by a predetermined interval. Separate.
  • the predetermined interval is, for example, 0.1 to 10 mm, preferably 1 to 2 mm.
  • the gel body 118 includes, for example, but not limited to: a matrix, an active agent, and an additive.
  • the gel 118 is formed through processes such as cross-linking, drug dispersion, and curing.
  • the active agent is a polar, free state agent to be penetrated 130.
  • Additives include, for example, but not limited to: transdermal penetration enhancers, pharmaceutical solvents, and the like.
  • the gel 118 includes, for example, at least one or more of the following components: polyethylene glycol, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylic acid, polymethacrylic acid, gelatin, alginic acid .
  • the gel composed of the above components can not only form a polymer cross-linked structure with a certain strength, but also can freely disperse the drug to be penetrated 130 inside the gel. Such a setting is not only beneficial to shunt the current flowing through the skin of the dosing area 122, but also beneficial to significantly enhance the controlled release effect of the drug 130 to be penetrated.
  • Experimental results show that after transdermal administration of the gel provided by the present disclosure, the administration concentration of the drug 130 can be stabilized and the bioavailability is relatively ideal.
  • the drug 130 to be penetrated it is, for example, but not limited to: a drug for alleviating pain, treating joint inflammation or asthma, hormone regulation, beauty, and the like.
  • the molecular weight of the agent 130 to be penetrated is less than or equal to 10,000 Daltons. This is because studies have shown that the drug 130 to be permeated with a molecular weight less than or equal to 10,000 Daltons easily enters the skin through the intercellular space, which is beneficial to improve the efficiency of transdermal drug delivery.
  • a polar, free-state drug 130 to be permeated with a molecular weight less than or equal to 10,000 Daltons is uniformly dispersed in the gel 118, and is released from the gel 118 under the action of the charge provided by the electrode 112. It spreads to the stratum corneum of the skin, then spreads through the epidermis to the dermis, and even enters the capillaries of the skin.
  • the agent to be penetrated 130 includes vitamin C and arbutin.
  • the arbutin in the drug to be penetrated 130 is beneficial to inhibit the tyrosinase in the skin, block the formation of melanin, accelerate the decomposition and excretion of melanin, and also has anti-inflammatory effects.
  • the vitamin C in the medicine 130 to be penetrated has an antioxidant effect, which is beneficial to inhibit the formation of pigment spots and promote the regression of pigment spots.
  • the drug 130 to be permeated includes vitamin C and arbutin at the same time, and is polarized and uniformly dispersed in the gel 118 of the integrated medium layer 114 in a free state, and is administered via iontophoresis
  • the electrode of the device 100 applies a current to cause the polarized, free-state drug 130 to be penetrated into the administration area 122, which can make the administered area 122 and its surrounding area quickly turn white, and the whitening effect can last for a long time Some time.
  • the gel 118 of the one-piece media layer 114 arranged in the shape of a facial mask evenly distributes the drug to be penetrated 130 containing vitamin C and arbutin for the treatment of the human face by iontophoresis. Whitening.
  • the agent 130 to be penetrated includes vitamin C and tranexamic acid.
  • the tranexamic acid in the drug to be penetrated 130 is used to inhibit tyrosinase activity, thereby inhibiting the formation of melanin.
  • the drug 130 to be infiltrated includes vitamin C and tranexamic acid at the same time, is polarized, and is uniformly dispersed in the gel 118 of the integrated medium layer 114 in a free state, and is penetrated into The electrodes of the medicine device 100 apply electric current so that the polarized, free-state medicament 130 to be penetrated is introduced into the administration area 122, which can effectively remove the dark spots in the administration area 122.
  • the gel 118 of the one-piece media layer 114 arranged in the shape of a facial mask uniformly distributes the drug to be penetrated 130 containing vitamin C and tranexamic acid, which is used to perform human facial treatment by iontophoresis. The freckle.
  • the iontophoresis drug delivery device 100 further includes a backing layer 116 for covering the plurality of electrodes 112, and the backing layer 116 is an insulating material.
  • a plurality of connecting pieces 111-1 and 111-2 are used to electrically connect corresponding electrodes to a power source, respectively, and each connecting piece of the plurality of connecting pieces 111-1 and 111-2 is at least partially disposed in the backing layer 116 Each of the connecting pieces is at least partially disposed in the backing layer 116.
  • FIG. 2 shows a partial structural diagram of an iontophoresis drug delivery device 200 according to some embodiments of the present disclosure.
  • the iontophoresis drug delivery device 200 of this example includes a laminated structure.
  • the backing layer 216 is located on the surface layer of the laminated structure.
  • Under the backing layer 216 is an adhesive layer 232 for bonding the backing layer 216 and the flexible conductive electrode films 212-1 and 212-2;
  • Under the adhesive layer 232 is the flexible conductive electrode film 212- 1 and 212-2;
  • under the flexible conductive electrode films 212-1 and 212-2 is a gel layer 218 containing the drug 230 to be penetrated;
  • under the gel layer 218 is a peeling layer 234 for protecting the gel
  • the active ingredients in the layer 218 are not contaminated.
  • the adhesive layer 232 includes a conductive adhesive, such as, but not limited to, pressure-sensitive adhesive, oil-based adhesive, water-based adhesive, hot-melt adhesive, etc. containing conductive fillers such as carbon or metal.
  • a plurality of connecting pieces 211-1 and 211-2 made of conductive materials are provided on the backing layer 216, and each connecting piece is at least partially arranged in the backing layer 216 for connecting electrical power from the power source to the corresponding Of flexible conductive electrode films 212-1 and 212-2.
  • the connection between the connector and the power source or the wire connected to the power source can be in a variety of ways, such as but not limited to mechanical coupling connection such as snap connection, connection by magnet, bonding or welding. Among them, the buckle connection and the magnet connection mode are convenient to adjust the connection mode of the power supply and the electrode.
  • each connecting member 211 is a pair of connecting components (not shown in detail) that can be snap-coupled, one connecting component is connected to a wire connected to a power source, and the other connecting component is connected to a flexible conductive electrode film.
  • each connecting member 211 is a pair of magnet connecting elements (not specifically shown) capable of attracting each other, one magnet connecting element is connected to a wire connected to a power source, and the other magnet connecting element is connected to a flexible conductive electrode film. The magnets of the two magnet connecting elements are joined together to achieve electrical connection between the wire connected to the power source and the flexible conductive electrode film.
  • FIG. 3 shows a schematic diagram of an iontophoresis drug delivery device 300 according to some embodiments of the present disclosure.
  • the iontophoresis drug delivery device 300 of this example includes: a first power source 310-1, a second power source 310-2, a plurality of electrodes 312 (for example, a first electrode 312-1, a second electrode 312-2, a The three electrodes 312-3, the fourth electrode 312-4), and the integrated dielectric layer 314.
  • the integrated medium layer 314 includes a gel and a polar, free state drug to be penetrated.
  • the integrated medium layer 314 covers the administered area 322 of the living body.
  • the first electrode 312-1 and the second electrode 312-2, the third electrode 312-3 and the fourth electrode 312-4 are correspondingly covered on different sub-areas in the medication area 322.
  • the first electrode 312-1 is electrically connected to the first end of the first power source 310-1 through the first connector 311-1 and the first wire 313-1
  • the second electrode 312-2 is The second connector 311-2 and the second wire 313-2 are electrically connected to the second end of the first power source 310-1
  • the third electrode 312-3 is electrically connected to the first end of the second power source 310-2 through the third connector 311-3 and the third wire 313-3
  • the fourth electrode 312-2 is electrically connected through the fourth connector 311- 4 and the fourth wire 313-4 are electrically connected to the second end of the second power source 310-2.
  • the first power source and the second power source are provided, and the first electrode and the second electrode are electrically connected to the first power source, and the third electrode and the fourth electrode are electrically connected to the second power source.
  • the iontophoresis administration of different sub-regions of the drug-administered region 322 can be controlled independently of each other. For example, when the first power supply 310-1 supplies power, the second power supply 310-2 stops supplying power.
  • the power supply voltage amplitude, current intensity, frequency, duty cycle, and/or power supply time of the first power supply 310-1 are compared with the power supply voltage amplitude, current intensity, frequency, and duty cycle of the second power supply 310-2 And/or the power supply time is different, so that the different sub-areas of the drug delivery area 322 can be administered separately.
  • the face of an individual with mixed skin has oily skin in the T-shaped area and dry skin in the U-shaped area.
  • the sensitivity of the skin of the eye area and the skin of the cheek area is usually different.
  • FIG. 4 shows a schematic diagram of an iontophoresis drug delivery device 400 according to some embodiments of the present disclosure.
  • the iontophoresis drug delivery device 400 of this example includes: a first power source 410-1, a third power source 410-3, a fourth power source 410-4, a plurality of electrodes 412 (for example, the first electrode 412-1, the The second electrode 412-2, the fifth electrode 412-5) and the integrated dielectric layer 414.
  • the integrated medium layer 414 includes a gel and a polar, free state drug to be penetrated.
  • the integrated medium layer 414 covers the administered area 422 of the living body.
  • the first electrode 412-1 is electrically connected to the first end of the first power source 410-1 through the first connector 411-1 and the wire
  • the second electrode 412-2 is electrically connected through the second connector 411-1.
  • the 2 and wire is electrically connected to the second end of the first power source 410-1.
  • the first end of the third power source 410-3 is electrically connected to the second end of the first power source 410, and the second end of the third power source 410-3 passes through the fifth connector 411-5 and the fifth electrode 412-5. Electricity connection.
  • the first end of the fourth power source 410-4 is electrically connected to the first end of the first power source 410-1
  • the second end of the fourth power source 410-4 is electrically connected to the second end of the third power source 410-3.
  • the first power source 410-1 and the third power source 410-3 are connected in series and then connected in parallel with the fourth power source 410-4 to provide power to the first electrode 412-1, the second electrode 412-2 and the fifth electrode 412-1.
  • the electrode 412-5 supplies power, and the electricity flows through a part of the integrated dielectric layer 414 and the skin of the drug administration area 422 respectively.
  • the medicament to be penetrated in a polar and free state dispersed in the skeleton structure of the gel is guided into the skin of the area 422 to be administered under the action of electric charge.
  • the voltage amplitude required for iontophoretic drug delivery can be adjusted; by connecting two or more power supplies in parallel, it can be adjusted for iontophoretic drug delivery The required current intensity.
  • the first electrode 412-1, the second electrode 412-2, and the fifth electrode 412-5 By connecting the first electrode 412-1, the second electrode 412-2, and the fifth electrode 412-5 to different output terminals of the power supply connected in series and parallel, the first electrode 412-1 and the second electrode 412-2
  • the electrical parameters of iontophoresis and the electrical parameters of iontophoresis between the second electrode 412-2 and the fifth electrode 412-5 are relatively independently controllable and have a certain correlation. So as to realize the personalized control of transdermal drug delivery.
  • FIG. 5 shows a schematic diagram of an iontophoresis drug delivery device 500 according to some embodiments of the present disclosure.
  • the iontophoresis drug delivery device 500 of this example includes at least: a first power source 510-1, a fifth power source 510-5, a first switch 540, a second switch 542, and a plurality of electrodes 512 (for example, the first electrode 512). -1.
  • the integrated medium layer 514 has the same structure as the integrated medium layer shown in FIGS. 1-4, and will not be repeated here.
  • the first power supply 510-1 and the fifth power supply 510-5 are DC power supplies.
  • the current intensity of the direct current is less than or equal to 5 mA. In some embodiments, the current intensity of the direct current is greater than or equal to 0.01 mA. For example, the current intensity is greater than or equal to 0.1 mA and is less than the safe current threshold of the skin.
  • the first switch 540 and the second switch 542 are, for example but not limited to, relays that are controlled to be turned on or off by a controller (not shown).
  • the first electrode 512-1 is electrically connected to the positive electrode of the first power supply 510-1 via at least the first connector 511-1 and the first switch 540
  • the second electrode 512-2 is electrically connected via at least the second connector 511-2 is electrically connected to the negative electrode of the first power supply 510-1
  • the first electrode 512-1 is also electrically connected to the negative electrode of the fifth power source 510-5 via the second switch 542, and the second electrode 512-2 is also electrically connected to the positive electrode of the fifth power source 510-5.
  • the first power supply 510-1 is connected in series with the first switch 540, it is connected in anti-phase and parallel connection with the series circuit of the fifth power supply 510-5 and the second switch 540, and then electrically connected to the first electrode 512- 1.
  • the second electrode 512-2 is the first electrode 512-1.
  • the controller outputs a high-level first signal to turn on the first switch 540, and simultaneously outputs a low-level second signal to turn off the second switch 542, thereby enabling the first power supply 510-
  • the positive electrode of 1 is electrically connected to the first electrode 512-1
  • the negative electrode of the first power source 510-1 is electrically connected to the second electrode 512-2, which means that the current to be penetrated in the first direction is introduced in the first time period.
  • the controller In the second time period, the controller outputs a low-level first signal to turn off the first switch 540, and at the same time outputs a high-level second signal to turn on the second switch 542, so that in the second time period ,
  • the negative pole of the fifth power source 510-5 is electrically connected to the first electrode 512-1
  • the positive pole of the fifth power source 510-5 is electrically connected to the second electrode 512-2, that is, the second time period
  • the direction of the current is introduced into the medicine to be penetrated.
  • FIG. 6 shows a schematic diagram of an iontophoresis drug delivery device 600 according to some embodiments of the present disclosure.
  • the iontophoresis drug delivery device 600 of this example includes at least: a first power supply 610-1, a first switch 640, a second switch 642, a third switch 644, a fourth switch 644, and a plurality of electrodes 612 (for example, the An electrode 612-1, a second electrode 612-2), an integrated dielectric layer 614 and a controller (not shown).
  • the integrated medium layer 614 has the same structure as the integrated medium layer shown in FIGS. 1-5, and will not be repeated here.
  • the first power supply 610-1 is a DC power supply.
  • the first switch 640, the second switch 642, the third switch 644, and the fourth switch 644 are, for example, but not limited to, relays that are controlled to be turned on or off by a controller (not shown).
  • the first electrode 612-1 is electrically connected to the positive electrode of the first power source 610-1 through at least the first switch 640, and the first electrode 612-1 is electrically connected to the first power source 610-1 through at least the third switch 644.
  • the negative pole is electrically connected.
  • the second electrode 612-2 is electrically connected to the negative electrode of the first power source 610-1 through at least the second switch 642, and the second electrode 612-2 is electrically connected to the positive electrode of the first power source 610-1 through the fourth switch 646.
  • the controller turns on the first switch 640 and the second switch 642 at the same time, and turns off the third switch 644 and the fourth switch 646 at the same time, so that the positive pole of the first power supply 610-1 is
  • the electrode 612-1 is electrically connected
  • the negative electrode of the first power supply 610-1 is electrically connected to the second electrode 612-2, that is, the current in the first direction is used to introduce the medicine to be infiltrated in the third time period.
  • the controller turns off the first switch 640 and the second switch 642 at the same time, and turns on the third switch 644 and the fourth switch 646 at the same time, so that the negative pole of the first power supply 610-1 is
  • the electrode 612-1 is electrically connected, and the positive electrode of the first power supply 610-1 is electrically connected to the second electrode 612-2, that is, the current in the second direction is used to introduce the medicine to be infiltrated in the fourth time period.
  • FIG. 7 shows a schematic diagram of an iontophoresis drug delivery device 700 according to some embodiments of the present disclosure.
  • the iontophoresis drug delivery device 700 of this example includes at least: a first power source 710-1, a second power source 710-2, a plurality of electrodes 712 (for example, a first electrode 712-1, a second electrode 712-2, The third electrode 712-3, the fourth electrode 712-4), a plurality of connectors (for example, including the first connector 711-1, the second connector 711-2, the third connector 711-3, and the fourth connector 711-4), an integrated media layer 714 and a controller (not shown).
  • the integrated dielectric layer 714 has the same structure as the integrated dielectric layer shown in FIGS. 1-6, and will not be repeated here.
  • Both the first power source 710-1 and the second power source 710-2 are DC power sources.
  • the power supplies included in the iontophoresis drug delivery device 700 are all DC power supplies.
  • the first electrode 712-1 is electrically connected to one end of the first power source 710-1 via at least a first connector 711-1, and the other end of the first power source 710-1 is electrically connected via a fourth connector 711-1. 4 is connected to the fourth electrode 712-1.
  • the second electrode 712-2 is electrically connected to one end of the second power source 710-2 via at least the second connector 711-2, and the other end of the second power source 710-2 is electrically connected to the third electrode 712 via the third connector 711-3. -3 connected.
  • the first power supply 710-1 is turned off (that is, working in the "OFF” state and does not output current) through the control of the controller (not shown); at the same time, the second power supply 710 is turned off.
  • -2 is turned on (that is, working in the "ON” state), the output current at least partially flows through the second connector 711-2, the second electrode 712-2, at least part of the integrated dielectric layer 714, and the third The electrode 712-3 and the third connector 711-2.
  • the positive pole of the second power source 710-2 is connected to the second connector 711-2. If the second power source 710-2 is reversely connected, the current flow sequence will be different).
  • the direction of the direct current flowing in the integrated dielectric layer 714 is shown by the arrow in the upper half of FIG. 7, that is, the direct current in the first direction is introduced to be penetrated in the first time period. Medicament.
  • the second power supply 710-2 is turned off (that is, working in the "OFF” state and does not output current) through the control of the controller (not shown); at the same time, the first power supply 710-2 is turned off. 1 is turned on (that is, working in the "ON” state), the output current at least partially flows through the fourth connector 711-4, the fourth electrode 712-4, at least part of the integrated dielectric layer 714, and the first electrode in sequence 712-1 and the first connecting piece 711-2. It can be seen that in the second time period, the direction of the direct current flowing in the integrated dielectric layer 714 is shown by the arrow in the lower half of FIG. 7, that is, the direct current in the second direction is introduced to be penetrated in the second time period. Medicament.
  • the problem of the accumulation of capacitive charges in the skin layer can be solved by using only a DC power supply, thereby improving the transdermal efficiency and total amount of the medicine.

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Abstract

一种离子电渗透给药装置（100, 200, 300, 400, 500, 600, 700），该离子电渗透给药装置（100, 200, 300, 400, 500, 600, 700）包括：电源（110），用于产生将待渗透药剂（130, 230）渗透入生物体的被给药区域（122, 322, 422）所需的电；一体式介质层（114, 314, 414, 514, 614, 714），用于覆盖被给药区域（122, 322, 422），一体式介质层（114, 314, 414, 514, 614, 714）包括：凝胶体（118），以及带有极性的、游离态的待渗透药剂（130, 230）；以及多个电极（112, 312, 412, 512, 612, 712），用于分别电连接电源（110）和一体式介质层（114, 314, 414, 514, 614, 714），以便使得电源（110）产生的电分别流经被给药区域（122, 322, 422）和至少部分的一体式介质层（114, 314, 414, 514, 614, 714），至少部分的一体式介质层（114, 314, 414, 514, 614, 714）具有预定电阻值。该离子电渗透给药装置（100, 200, 300, 400, 500, 600, 700）不仅能够提高透皮效率,而且不易造成皮肤伤害。

Description

离子电渗透的给药装置 技术领域
本申请涉及一种给药装置，具体涉及一种用于离子电渗透的给药装置。
背景技术
透皮给药是指在皮肤表面给药，使药物以一定速率通过皮肤，进入体循环产生全身或局部治疗作用的给药方法。由于透皮给药方法具有不受消化道内食物等因素影响、可持续控制给药速度等优势，具有广阔的应用前景。
在透皮给药的过程中，皮肤角质层具有屏障作用，该屏障作用使得目前经由皮肤表面给药的透皮速率和渗透量都难以达到预期的效果。传统的提高透皮速率和渗透量的方案例如是：微针透皮给药方式，即通过在给药载体上设置微针阵列，使微针穿过皮肤角质层，进而提高给药的透皮速率。上述微针透皮方案对于微针长度要求比较高，如果控制不好容易损伤皮肤和引发疼痛。
传统的提高透皮给药方案还例如是：离子电渗透给药方式，即使用带电电荷通过电动势将具有极性的活性药剂推送入皮肤的非侵入性方法。在传统的离子电渗透给药方式中，通常设置电驱动的单点电极或者带有电极的多个给药载体进行给药，上述离子电渗透给药方式要么透皮效果不明显，要么容易造成皮肤灼伤。
因此，传统的透皮给药方案存在的不足之处在于：要么透皮效果不明显，要么容易造成皮肤灼伤或引发疼痛等皮肤伤害。
发明内容
根据本公开的示例实施例，提供了一种离子电渗透的给药装置，其不仅能够提高透皮效率,而且不易造成皮肤伤害。
在本公开的第一方面中，提供了一种离子电渗透给药装置。该装置包括：电源，用于产生将待渗透药剂渗透入生物体的被给药区域所需的电；一体式介质层，用于覆盖被给药区域，一体式介质层包括：凝胶体，以及凝胶体包括带有极性的、游离态的待渗透药剂；以及多个电极，用于分别电连接电源和一体式介质层，以便使得电源产生的电分别流经给药区域和至少部分的一体式介质层，至少部分的一体式介质层具有预定电阻值。
在一些实施例中，凝胶体包括以下至少一个组分：聚乙二醇、聚乙烯醇、聚甲基丙烯酸羟乙脂、聚丙烯酸、聚甲基丙烯酸、明胶、海藻酸。
在一些实施例中，多个电极为以预定间隔隔开的多片柔性导电电极膜。
在一些实施例中，待渗透药剂包括维生素C和熊果苷。
在一些实施例中，待渗透药剂包括维生素C和氨甲环酸。
在一些实施例中，待渗透药剂的分子量小于或等于10000道尔顿。
在一些实施例中，一体式介质层的厚度小于或等于50毫米。
在一些实施例中，电源所产生的电为交流，并且电的电流强度小于或等于5毫安。
在一些实施例中，电源所产生的电为直流，并且电的电流强度小于或等于5毫安。
在一些实施例中，电源所产生的电的电流强度大于或等于0.01毫安。
在一些实施例中，电源至少包括第一电源，多个电极至少包括第一电极、第二电极，第一电极与第一电源的第一端电连接，第二电极与第一电源的第二端电连接。
在一些实施例中，电源还包括第二电源，多个电极还包括第三电极、第四电极，第三电极与第二电源的第一端电连接，第四电极与第二电源的第二端电连接。
在一些实施例中，电源还包括第三电源和第四电源，多个电极还包括第五电极，第三电源的第一端与第一电源的第二端电连接，第三电源的第二端与第五电极电连接，第四电源的第一端与第一电源的第一端电连接，第四电源的第二端与第三电源的第二端电连接。
在一些实施例中，离子电渗透给药装置还包括：背衬层，用于覆盖在多个电极之上，背衬层为绝缘材料；以及多个连接件，用于分别电连接电源和多个电极，多个连接件中的每一个连接件至少部分设置在背衬层中。
在一些实施例中，预定电阻值大于100欧姆，并且小于或等于100K欧姆。
在一些实施例中，预定电阻值大于1K欧姆，并且小于或等于12K欧姆。
在一些实施例中，凝胶体包括胶原蛋白。
应当理解，发明内容部分中所描述的内容并非旨在限定本公开的实施例的关键或重要特征，亦非用于限制本公开的范围。本公开的其它特征将通过以下的描述变得容易理解。
附图说明
结合附图并参考以下详细说明，本公开各实施例的上述和其他特征、优点及方面将变得更加明显。在附图中，相同或相似的附图标记表示相同或相似的元素，其中：
图1示出了根据本公开一些实施例的离子电渗透给药装置100的示意图；
图2示出了根据本公开一些实施例的离子电渗透给药装置200的局部结构示意图；
图3示出了根据本公开一些实施例的离子电渗透给药装置300的示意图；
图4示出了根据本公开一些实施例的离子电渗透给药装置400的示意图；
图5示出了根据本公开一些实施例的离子电渗透给药装置500的示意图；
图6示出了根据本公开一些实施例的离子电渗透给药装置600的示意图；以及
图7示出了根据本公开一些实施例的离子电渗透给药装置700的示意图。
在各个附图中，相同或对应的标号表示相同或对应的部分。
具体实施方式
下面将参照附图更详细地描述本公开的实施例。虽然附图中显示了本公开的某些实施例，然而应当理解的是，本公开可以通过各种形式来实现，而且不应该被解释为限于这里阐述的实施例，相反提供这些实施例是为了更加透彻和完整地理解本公开。应当理解的是，本公开的附图及实施例仅用于示例性作用，并非用于限制本公开的保护范围。
在本公开的实施例的描述中，术语“包括”及其类似用语应当理解为开放性包含，即“包括但不限于”。术语“基于”应当理解为“至少部分地基于”。术语“一个实施例”或“该实施例”应当理解为“至少一个实施例”。术语“第一”、“第二”等等可以指代不同的或相同的对象。下文还可能包括其他明确的和隐含的定义。
如上文提及的，传统的离子电渗透给药方案例如是设置单个电极或者各自带有电极的多个给药载体，电源与电极电连接。在给药之前，测量待给药生物体的皮肤电阻，并根据所测电阻设置安全的电源电压、电流，或者根据皮肤电阻的一般经验值，设置安全的电源电压、电流，以便保障待给药生物体的皮肤不受伤害。
在上述传统的离子电渗透给药方案中，一方面，随着给药过程的推进，被施药区域的皮肤状态(例如含水量、累积于皮肤中的药物量)会发生变化。同时，被施药区域的皮肤电阻也会随着皮肤状 态的变化而变化。因此，在给药之前所设置的电源电压、电流值，因没有考虑给药期间皮肤电阻的变化量，因此会与给药过程中的变化了的皮肤电阻不相适应。例如，随着给药过程的进行，皮肤含水或含药量随之提高，皮肤的电阻随之降低，在预先设定的电源电压不变的情况下，流经皮肤的电流强度将会增大，这很有可能给皮肤带来刺激和灼伤。
为了解决上述问题中的至少一个以及其他潜在问题中的一个或者多个，本公开的示例实施例提出了一种离子电渗透给药装置。该装置包括：电源，用于产生将待渗透药剂渗透入生物体的被给药区域所需的电；一体式介质层，用于覆盖被给药区域，一体式介质层包括凝胶体以及带有极性的、游离态的待渗透药剂；以及多个电极，用于分别电连接电源和一体式介质层，以便使得电源产生的电分别流经给药区域和至少部分的一体式介质层，至少部分的一体式介质层具有预定电阻值。
在本公开所提供的上述离子电渗透给药装置中，由于使得电源产生的电分别流经被给药区域和具有预定电阻值的至少部分的一体式介质层，即通过将具有预定电阻值的一体式介质层与被给药区域的皮肤电阻的相并联，对流经被给药区域的电流进行分流，避免了过高电流强度刺激或灼伤皮肤。另外，根据并联电路的原理可知，介质层所分流的电流的比例与介质层的预定电阻值与给药区域的皮肤电阻之间的比例相关联，因此，在介质层的电阻值恒定的情况下，其所分流的电流也会随着被给药区域的皮肤电阻的变化而变化。由于不同个体的皮肤状态变化的情况是存在差异的，因此，本公开的离子电渗透给药装置能够以一种简便的方式不仅能够解决给药过程中因皮肤电阻下降而导致的电流强度增加而引发的刺激或者灼伤皮肤的技术问题，而且能够根据不同个体差异化的皮肤情况自适应地调整流经皮肤电流的大小。再者，在上述离子电渗透给药装置中，由于一部分电流流经电极之间的、包括游离态药剂的凝胶体的、具有预定电阻值的、一体式介质层，覆盖在被给药区域表面的一体式 介质层及其凝胶体会产生热量。表皮层从外到内分别是角质层，颗粒层，棘层，基底层。表皮层中影响经皮吸收的关键在于“皮肤屏障”。而皮肤屏障包括角质层和皮脂膜。一般情况下，皮肤温度适当升高，利于提升待渗透药剂透过“皮肤屏障”的效率。因此，电流流经一体式介质层所产生的热量利于提高待渗透药剂透过“皮肤屏障”的效率。
图1示出了根据本公开一些实施例的离子电渗透给药装置100的示意图。在该示例的离子电渗透给药装置100中，包括：电源110、多个电极112-1和112-2、一体式介质层114。其中，一体式介质层114进一步包括凝胶体118以及带有极性的、游离态的待渗透药剂130。一体式介质层114覆盖在生物体120的被给药区域122上，并与被给药区域122的轮廓相适应。在一些实施例中，被给药区域122例如是人体的局部皮肤，例如而不限于是面部皮肤。一体式介质层114例如被设置成面膜的轮廓。在一些实实施例中，一体式介质层114进一步包括网状结构(未示出)。在一些实实施例中，带有极性的、游离态的待渗透药剂130分散在凝胶体118交联的网状结构中。在一些实施例中，带有极性的、游离态的待渗透药剂130分布在凝胶体118的表面。在一些实施例中，凝胶体118包括胶原蛋白或者凝胶体118为胶原蛋白凝胶。
关于电源110，其用于产生将待渗透药剂渗透入被给药区域所需的电。在一些实施例中，离子电渗透给药装置100包括一个电源。在一些实施例中，离子电渗透给药装置100包括多个电源。该多个电源可以彼此串联和/或并联，以用于提供合适的电压、电流，来将待渗透药剂渗透入被给药区域。电源100所产生的电可以是恒定的、也可以是可变的。在一些实施例中，电源的供电时间、供电电压、电流强度的设置与待渗透药剂量的多少相关联。在一些实施例中，根据给药量的大小，给药模式的不同(例如瞬间剂量给药模式、恒定给药模式、脉冲给药模式等)，调节电源的供电电压幅值、电流强度、供电时间、频率、占空比等。
在一些实施例中，电源110所提供的电为交流电。这是因为：一方面，直流电容易造成对皮肤的局部麻醉作用，容易导致被给药者不易察觉对皮肤的损伤，另一方面，直流电容易导致电荷在皮肤层中的累积，进而导致降低随时间输送的待渗透药剂130的速率和总量。通过电源110提供的交流电的电流方向的交替变换，能够解决电容性电荷在皮肤层中的累积，进而利于提高药剂透皮效率和总量。在一些实施例中，该交流电的电流强度小于或等于5毫安。在一些实施例中，交流电的电流强度大于或等于0.01毫安并且小于5毫安，上述电流强度的设置范围不仅能够避免皮肤伤害，而且能够保证将待渗透药剂渗透入被给药区域所需的足够电势能。
关于电极112，其被配置为离子渗透电极。多个电极112用于分别将电源110的两输出端连接至一体式介质层114，进而使得电源产生的电分别流经被给药区域和至少部分的一体式介质层。例如，如图1所示，电极112包括第一电极112-1和第二电极112-2，其中第一电极112-1通过连接件111-1和导线113-1与电源110的第一端电连接，第二电极112-2通过连接件111-2和导线113-2与电源110的第二端电连接。电源110产生的电分别流经被给药区域122和至少部分的一体式介质层(例如，第一电极112-1与一体式介质层114的电接触处到第二电极112-2与一体式介质层的电接触处之间的一体式介质层的部分)。该电流流经的一体式介质层114的部分具有预定电阻值。
就被给药对象而言，由于个体皮肤的差异(例如在水油比例、干燥程度、毛孔情况等方面存在差异)，个体皮肤电阻值存在一定差异。由于电流流经皮肤会因为皮肤电阻值所产生热量可能灼伤皮肤，因此，传统的离子电渗透给药方案为了避免给被给药对象的皮肤带来伤害，通常基于极限情况下的皮肤阻值严格限制输出电流强度，这会导致透皮给药效率降低的副作用。而在本公开的上述方案中，通过将一体的、具有预定电阻值的包含有游离态、带极性的待渗透药剂130的介质层覆盖在相互独立的多个电极112的下方，利用一 体的介质层与被给药区域122的皮肤电阻的并联，实现对流经被给药区域122的皮肤的电流进行分流，进而在给定电源电压的情况下，降低流经皮肤的电流强度，有效避免了对皮肤的刺激或灼伤。
关于一体式介质层114的预定电阻值，假设流经电流的一体式介质层的电阻为R1,被给药区域122的皮肤电阻为R2。根据电阻并联原理，如果R1>R2，则电源所提供的大部分电流用于激活皮肤内的活性物质；如果R1<R2,则电源所提供的大部分电流用于将分散于凝胶体内的活性物质推送入皮肤。在一些实施例中，设置R1为R2的10％-90％。在一些实施例中，设置R1大于100欧姆，并且小于等于100K欧姆，在一些实施例中，设置R1大于1K欧姆，并且小于等于12K欧姆，例如是10K欧姆。
关于电极112的形状，其可以是片状电极、点状电极、层状电极、也可为其他形状。在一些实施例中，多个电极112为以预定间隔隔开的多片柔性导电电极膜。该导电电极膜例如是低电阻导电膜、导电碳膜、碳基导电膜。该柔性导电电极膜例如是经由高分子超导纳米碳黑、固化剂、助剂等混合聚乙烯制作而成。采用柔性导电电极膜形式来设置离子渗透电极，具有电阻值均匀稳定、饶曲性能和柔韧性能良好的优势，利于使得一体化介质层114及电极较好地贴合被给药区域的差异性的外部轮廓，而且不易电蚀。因此，相对于传统的片式离子渗透电极具有明显的优势。在一些实施例中，多个柔性导电电极膜形式的电极可以通过粘结剂贴附在背衬层116之上，多个柔性导电电极膜形式的电极通过预定间隔在背衬层116上彼此分隔开。该预定间隔例如是为0.1至10mm，优选为1至2mm。如此设置，可以通过控制离子渗透电极的覆盖面积来改善透皮效率。
关于凝胶体118，其例如而不限于包括：基质、活性药剂和添加剂。该凝胶体118经由交联、药剂分散和固化等工艺形成。其中，活性药剂为带有极性的、游离态的待渗透药剂130。添加剂例如而不限于包括：透皮促渗剂、药物溶剂等。在一些实施例中，凝胶体118例如包括以下至少一个或者多个组分：聚乙二醇、聚乙烯醇、聚甲 基丙烯酸羟乙脂、聚丙烯酸、聚甲基丙烯酸、明胶、海藻酸。实验表明，采用上述组分构成的凝胶体不仅可以形成有具一定强度的高分子交联网状结构，而且可以使待渗透药剂130游离分散在凝胶体内部。如此设置不仅利于分流流经被给药区域122的皮肤的电流，而且利于显著提升待渗透药剂130的控释效果。实验结果表明：经本公开所提供的凝胶体透皮给药后，能够使药剂130的给药浓度平稳、而且生物利用度较为理想。
关于待渗透药剂130，其例如而不限于是：用于缓解疼痛、治疗关节炎症或哮喘、激素调节、美容等目的的药剂。在一些实施例中，待渗透药剂130的分子量小于或等于10000道尔顿。这是因为，研究表明，分子量小于或等于10000道尔顿的待渗透药剂130容易通过细胞间隙进入皮肤，利于提升透皮给药效率。例如，分子量小于或等于10000道尔顿的带有极性的、游离态的待渗透药剂130均匀分散于凝胶体118中，在电极112所提供电荷的作用下，从凝胶体118中释放、扩散至皮肤的角质层，然后经由表皮扩展至真皮，甚至进入皮肤的毛细血管。
在一些实施例中，待渗透药剂130包括维生素C和熊果苷。待渗透药剂130中的熊果苷利于抑制皮肤中的酪氨酸酶，阻断黑色素的形成，并加速黑色素的分解与排泄，同时兼具消炎的功效。待渗透药剂130中的维生素C具有抗氧化作用，利于抑制色素斑的生成，促进色素斑消退。实验表明，将待渗透药剂130同时包括维生素C和熊果苷成分，并使其带有极性、以游离态均匀分散于一体式介质层114的凝胶体118中，并经由离子电渗透给药装置100的电极施加电流，使得带有极性的、游离态的待渗透药剂130导入给药区域122，能够使得被给药区域122及其周围区域快速变白，并且该变白效果能够持续相当长的一段时间。在一些实施例中，被设置成面膜形状的一体式介质层114的凝胶体118中均匀分布含有维生素C和熊果甘的待渗透药剂130，用于通过离子电渗透给方式进行人体面部的美白。
在一些实施例中，待渗透药剂130包括维生素C和氨甲环酸。待渗透药剂130中的氨甲环酸用于抑制酪氨酸酶活性，从而抑制黑色素形成。实验表明，将待渗透药剂130同时包括维生素C和氨甲环酸成分，并使其带有极性、以游离态均匀分散于一体式介质层114的凝胶体118中，并经由离子电渗透给药装置100的电极施加电流，使得带有极性的、游离态的待渗透药剂130导入给药区域122，能够有效祛除被给药区域122的黑斑。在一些实施例中，被设置成面膜形状的一体式介质层114的凝胶体118中均匀分布含有维生素C和氨甲环酸的待渗透药剂130，用于通过离子电渗透给方式进行人体面部的祛斑。
在一些实施例中，离子电渗透给药装置100还包括背衬层116，其用于覆盖在多个电极112之上，该背衬层116为绝缘材料。多个连接件111-1和111-2用于分别将对应电极电连接到电源，所述多个连接件111-1和111-2中的每一个连接件至少部分设置在背衬层116中的每一个连接件至少部分设置在背衬层116中。
图2示出了根据本公开一些实施例的离子电渗透给药装置200的局部结构示意图。在该示例的离子电渗透给药装置200中，包括层叠结构。背衬层216位于层叠结构的表层。位于背衬层216之下的是用于粘结背衬层216和柔性导电电极膜212-1和212-2的粘结层232；在粘结层232之下的是柔性导电电极膜212-1和212-2；柔性导电电极膜212-1和212-2之下是含有待渗透药剂230的凝胶体层218；凝胶体层218之下是剥离层234，用于保护凝胶体层218中的活性成分不被污染。当使用离子电渗透给药装置200时，剥离层234将被剥离，以便凝胶体层218覆盖在被给药区域的皮肤之上。粘结层232包括具有导电性的粘结剂，例如而不限于是含有碳或金属等导电填料的压敏胶、油性胶、水性胶、热熔胶等。
在背衬层216上设置有多个由导电材料制成的连接件211-1和211-2，每一个连接件至少部分设置在背衬层216中，用于将来自电源的电连接至对应的柔性导电电极膜212-1和212-2。该连接件与电 源或连接至电源的导线的连接方式可以是多种方式，例如而不限于为卡扣连接等机械耦合式连接、磁体作用连接、粘结或者焊接。其中卡扣连接和磁体作用连接方式便于调整电源与电极的连接方式。例如每个连接件211是一对儿可以卡扣耦合的连接组件(未具体示出)，一个连接组件与连接至电源的导线连接，另一个连接组件与柔性导电电极膜连接。通过两个连接组件的卡扣耦合，进而实现连接至电源的导线与柔性导电电极膜之间的电连接。再例如，每个连接件211是一对儿能够相互吸引的磁体连接元件(未具体示出)，一个磁体连接元件与连接至电源的导线连接，另一个磁体连接元件与柔性导电电极膜连接。通过两个磁体连接元件的磁体作用接合在一起，进而实现连接至电源的导线与柔性导电电极膜之间的电连接。
图3示出了根据本公开一些实施例的离子电渗透给药装置300的示意图。在该示例的离子电渗透给药装置300中，包括：第一电源310-1、第二电源310-2、多个电极312(例如第一电极312-1、第二电极312-2、第三电极312-3、第四电极312-4)、一体式介质层314。其中，一体式介质层314包括凝胶体以及带有极性的、游离态的待渗透药剂。一体式介质层314覆盖在生物体的被给药区域322上。例如，第一电极312-1和第二电极312-2、第三电极312-3和第四电极312-4被对应覆盖在给药区域322中的不同子区域上。
如图3所示，其中第一电极312-1通过第一连接件311-1和第一导线313-1与第一电源310-1的第一端电连接，第二电极312-2通过第二连接件311-2和第二导线313-2与第一电源310-1的第二端电连接。此外，第三电极312-3通过第三连接件311-3和第三导线313-3与第二电源310-2的第一端电连接，第四电极312-2通过第四连接件311-4和第四导线313-4与第二电源310-2的第二端电连接。在上述方案中，通过设置第一电源和第二电源，并且使得第一电极和第二电极与第一电源电连接，第三电极和第四电极与第二电源电连接。可以使得被给药区域322的不同子区域的离子电渗透给药相互独立地被控制。例如，第一电源310-1供电时，第二电源310-2停止供电。 再例如，第一电源310-1的供电电压幅值、电流强度、频率、占空比和/或供电时间，与第二电源310-2的供电电压幅值、电流强度、频率、占空比和/或供电时间不同，以便针对给药区域322不同子区域的差异性特点进行分别给药。例如，具有混合型皮肤的个体面部，其T型区域呈现油性肤质、U型区域呈现干性肤质。再例如，眼部区域的皮肤和脸颊区域的皮肤的敏感程度通常存在差异。通过在同一离子电渗透给药装置300中设置彼此独立的电源分别给对应于不同皮肤子区域的不同位置的电极供电，可以实现针对不同皮肤子区域的不同肤质分别设置匹配的透皮给药供电参数。
图4示出了根据本公开一些实施例的离子电渗透给药装置400的示意图。在该示例的离子电渗透给药装置400中，包括：第一电源410-1、第三电源410-3、第四电源410-4、多个电极412(例如第一电极412-1、第二电极412-2、第五电极412-5)和一体式介质层414。其中，一体式介质层414包括凝胶体和带有极性的、游离态的待渗透药剂。一体式介质层414覆盖在生物体的被给药区域422上。
如图4所示，其中第一电极412-1通过第一连接件411-1和导线与第一电源410-1的第一端电连接，第二电极412-2通过第二连接件411-2和导线与第一电源410-1的第二端电连接。此外，第三电源410-3的第一端与所述第一电源410的第二端电连接，第三电源410-3的第二端通过第五连接件411-5第五电极412-5电电连接。另外，第四电源410-4的第一端与第一电源410-1的第一端电电连接，第四电源410-4的第二端与第三电源410-3的第二端电连接。在上述方案中，第一电源410-1和第三电源410-3串联后再与第四电源410-4相并联，用以给第一电极412-1、第二电极412-2和第五电极412-5供电，进而将使电分别流经部分的一体式介质层414和被给药区域422的皮肤。分散在凝胶体的骨架结构中的、带有极性的、游离态的待渗透药剂在电荷的作用下，被导入被给药区域422的皮肤。
在上述方案中，通过将两个或更多电源串联，可以调节用于离子电渗透给药所需的电压幅值；通过将两个或更多电源并联，可以 调节用于离子电渗透给药所需的电流强度。通过将第一电极412-1、第二电极412-2、第五电极412-5分别连接到彼此串并联的电源的不同输出端，使得第一电极412-1和第二电极412-2间的离子电渗透给药电参数，与第二电极412-2和第五电极412-5间的离子电渗透给药电参数即相对独立可控、又存在一定的关联。从而实现透皮给药的个性化控制。
图5示出了根据本公开一些实施例的离子电渗透给药装置500的示意图。在该示例的离子电渗透给药装置500中，至少包括：第一电源510-1、第五电源510-5、第一开关540、第二开关542、多个电极512(例如第一电极512-1、第二电极512-2)、一体式介质层514和控制器(未示出)。其中，一体式介质层514与图1-4所示的一体式介质层结构相同，在此不再赘述。第一电源510-1、第五电源510-5为直流电源。在一些实施例中，直流电的电流强度小于或等于5毫安。在一些实施例中，直流电的电流强度大于或等于0.01毫安。例如，电流强度大于等于0.1毫安小于皮肤的安全电流阈值。第一开关540和第二开关542例如而不限于是：由控制器(未示出)控制接通或断开的继电器。
如图5所示，第一电极512-1至少经由第一连接件511-1和第一开关540与第一电源510-1的正极电连接，第二电极512-2至少经由第二连接件511-2与第一电源510-1的负极电连接。第一电极512-1还经由第二开关542与第五电源510-5的负极电连接，第二电极512-2还与第五电源510-5的正极电连接。即，将第一电源510-1与第一开关540串联连接后，再与第五电源510-5与第二开关540的串联电路反相并联，之后，再分别电连接至第一电极512-1、第二电极512-2。
例如在第一时间段内，控制器输出高电平的第一信号以接通第一开关540，同时输出低电平的第二信号以断开第二开关542，进而使得第一电源510-1的正极与第一电极512-1电连接，第一电源510-1的负极与第二电极512-2电连接，即实现在第一时间段内、以第一方向的电流来导入待渗透药剂。而在第二时间段内，控制器输出低平 的第一信号以断开第一开关540，同时输出高电平的第二信号以接通第二开关542，进而使得在第二时间段内，第五电源510-5的负极与第一电极512-1电连接，以及第五电源510-5的正极与第二电极512-2电连接，即实现在第二时间段内、以第二方向的电流导入待渗透药剂。通过采用上述方案，利用多个直流电源组合开关来解决电容性电荷在皮肤层中的累积的问题，进而提高药剂透皮效率和总量。
图6示出了根据本公开一些实施例的离子电渗透给药装置600的示意图。在该示例的离子电渗透给药装置600中，至少包括：第一电源610-1、第一开关640、第二开关642、第三开关644、第四开关644、多个电极612(例如第一电极612-1、第二电极612-2)、一体式介质层614和控制器(未示出)。其中，一体式介质层614与图1-5所示的一体式介质层结构相同，在此不再赘述。第一电源610-1为直流电源。第一开关640、第二开关642、第三开关644、第四开关644例如而不限于是由控制器(未示出)控制接通或断开的继电器。
如图6所示，第一电极612-1至少经由第一开关640与第一电源610-1的正极电连接，并且第一电极612-1至少经由第三开关644与第一电源610-1的负极电连接。第二电极612-2至少经由第二开关642与第一电源610-1的负极电连接，并且第二电极612-2经由第四开关646与第一电源610-1的正极电连接。
例如在第三时间段内，控制器同时接通第一开关640和第二开关642，并且同时断开第三开关644和第四开关646，进而使得第一电源610-1的正极与第一电极612-1电连接，第一电源610-1的负极与第二电极612-2电连接，即实现在第三时间段内以第一方向的电流导入待渗透药剂。而在第四时间段内，控制器同时断开第一开关640和第而开关642，并且同时接通第三开关644和第四开关646，进而使得第一电源610-1的负极与第一电极612-1电连接，第一电源610-1的正极与第二电极612-2电连接，即实现在第四时间段内以第二方向的电流导入待渗透药剂。通过采用上述方案，利用一个直流电源组 多个合开关来解决电容性电荷在皮肤层中的累积的问题，进而提高药剂透皮效率和总量。
图7示出了根据本公开一些实施例的离子电渗透给药装置700的示意图。在该示例的离子电渗透给药装置700中，至少包括：第一电源710-1、第二电源710-2、多个电极712(例如第一电极712-1、第二电极712-2、第三电极712-3、第四电极712-4)、多个连接件(例如包括第一连接件711-1、第二连接件711-2、第三连接件711-3、第四连接件711-4)、一体式介质层714和控制器(未示出)。其中，一体式介质层714与图1-6所示的一体式介质层结构相同，在此不再赘述。第一电源710-1和第二电源710-2均为直流电源。在一些实施例中，离子电渗透给药装置700所包括的电源均为直流电源。
如图7所示，第一电极712-1至少经由第一连接件711-1与第一电源710-1的一端电连接，并且第一电源710-1的另一端经由第四连接件711-4与第四电极712-1相连。第二电极712-2至少经由第二连接件711-2与第二电源710-2的一端电连接，并且第二电源710-2的另一端经由第三连接件711-3与第三电极712-3相连。
例如在第一时间段内，通过由控制器(未示出)的控制，使得第一电源710-1关断，(即工作在“OFF”状态，不输出电流)；同时使得第二电源710-2打开(即工作在“ON”状态)，其所输出的电流至少部分地依次流经第二连接件711-2、第二电极712-2、至少部分的一体式介质层714、第三电极712-3和第三连接件711-2。(此时，第二电源710-2的正极连接第二连接件711-2。如果第二电源710-2反接，电流流经顺序会有所不同)。可见，在第一时间段内，直流电流在一体式介质层714中流动的方向如图7上半部分的箭头所示，即实现在第一时间段内以第一方向的直流电流导入待渗透药剂。
例如在第二时间段内，通过由控制器(未示出)的控制，使得第二电源710-2关断(即工作在“OFF”状态，不输出电流)；同时使得第一电源710-1打开(即工作在“ON”状态)，其所输出的电流至少部分地依次流经第四连接件711-4、第四电极712-4、至少部分 的一体式介质层714、第一电极712-1和第一连接件711-2。可见，在第二时间段内，直流电流在一体式介质层714中流动的方向如图7下半部分的箭头所示，即实现在第二时间段内以第二方向的直流电流导入待渗透药剂。
通过采用上述方案，仅利用直流电源就能够解决电容性电荷在皮肤层中的累积的问题，进而提高药剂透皮效率和总量。
以上已经描述了本公开的各实施例，上述说明是示例性的，并非穷尽性的，并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下，对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。本文中所用术语的选择，旨在最好地解释各实施例的原理、实际应用或对市场中的技术改进，或者使本技术领域的其它普通技术人员能理解本文披露的各实施例。
以上所述仅为本公开的可选实施例，并不用于限制本公开，对于本领域的技术人员来说，本公开可以有各种更改和变化。凡在本公开的精神和原则之内，所作的任何修改、等效替换、改进等，均应包含在本公开的保护范围之内。

Claims (17)

  1. 一种离子电渗透给药装置，包括：
    电源，用于产生将待渗透药剂渗透入生物体的被给药区域所需的电；
    一体式介质层，用于覆盖所述被给药区域，所述一体式介质层包括：凝胶体，以及带有极性的、游离态的所述待渗透药剂；以及
    多个电极，用于分别电连接所述电源和所述一体式介质层，以便使得所述电源产生的所述电分别流经所述给药区域和至少部分的所述一体式介质层，所述至少部分的所述一体式介质层具有预定电阻值。
  2. 根据权利要求1所述的装置，其中所述凝胶体包括以下至少一个组分：聚乙二醇、聚乙烯醇、聚甲基丙烯酸羟乙脂、聚丙烯酸、聚甲基丙烯酸、明胶、海藻酸。
  3. 根据权利要求1所述的装置，其中所述多个电极为以预定间隔隔开的多片柔性导电电极膜。
  4. 根据权利要求1所述的装置，其中所述待渗透药剂包括维生素C和熊果苷。
  5. 根据权利要求1所述的装置，其中所述待渗透药剂包括维生素C和氨甲环酸。
  6. 根据权利要求1所述的装置，其中所述待渗透药剂的分子量小于或等于10000道尔顿。
  7. 根据权利要求1所述的装置，其中所述一体式介质层的厚度小于或等于50毫米。
  8. 根据权利要求1所述的装置，其中所述电为交流，并且所述电的电流强度小于或等于5毫安。
  9. 根据权利要求1所述的装置，其中所述电为直流，并且所述电的电流强度小于或等于5毫安。
  10. 根据权利要求8和9中任一项所述的装置，其中所述电的 电流强度大于或等于0.01毫安。
  11. 根据权利要求1所述的装置，其中所述电源至少包括第一电源，所述多个电极至少包括第一电极、第二电极，所述第一电极与所述第一电源的第一端电连接，所述第二电极与所述第一电源的第二端电连接。
  12. 根据权利要求11所述的装置，其中所述电源还包括第二电源，所述多个电极还包括第三电极、第四电极，所述第三电极与所述第二电源的第一端电连接，所述第四电极与所述第二电源的第二端电连接。
  13. 根据权利要求11所述的装置，其中所述电源还包括第三电源和第四电源，所述多个电极还包括第五电极，所述第三电源的第一端与所述第一电源的第二端电连接，所述第三电源的第二端与所述第五电极电连接，所述第四电源的第一端与所述第一电源的第一端电连接，所述第四电源的第二端与所述第三电源的第二端电连接。
  14. 根据权利要求1所述的装置，其中还包括：
    背衬层，用于覆盖在所述多个电极之上，所述背衬层为绝缘材料；以及
    多个连接件，用于分别电连接所述电源和所述多个电极，所述多个连接件中的每一个连接件至少部分设置在所述背衬层中。
  15. 根据权利要求1所述的装置，其中所述预定电阻值大于100欧姆，并且小于或等于100K欧姆。
  16. 根据权利要求15所述的装置，其中所述预定电阻值大于1K欧姆，并且小于或等于12K欧姆。
  17. 根据权利要求1所述的装置，其中所述凝胶体包括胶原蛋白。
PCT/CN2020/093888 2019-05-06 2020-06-02 离子电渗透的给药装置 WO2020224664A1 (zh)

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CN112999144B (zh) * 2021-01-27 2023-03-21 杭州医学院 一种离子电渗透经皮给药系统
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