CN117442863A - Wearable iontophoresis drug delivery device based on microneedles - Google Patents
Wearable iontophoresis drug delivery device based on microneedles Download PDFInfo
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- CN117442863A CN117442863A CN202311708868.2A CN202311708868A CN117442863A CN 117442863 A CN117442863 A CN 117442863A CN 202311708868 A CN202311708868 A CN 202311708868A CN 117442863 A CN117442863 A CN 117442863A
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Classifications
-
- 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
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- 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
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0472—Structure-related aspects
- A61N1/0492—Patch electrodes
-
- 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
- A61N1/306—Arrangements where at least part of the apparatus is introduced into the body
-
- 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
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- 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
- A61M2205/05—General characteristics of the apparatus combined with other kinds of therapy
- A61M2205/054—General characteristics of the apparatus combined with other kinds of therapy with electrotherapy
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Radiology & Medical Imaging (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Electrotherapy Devices (AREA)
Abstract
The invention provides a microneedle-based wearable iontophoresis drug delivery device, which comprises a shell, a microneedle patch and a constant current source circuit system, wherein the microneedle patch sequentially comprises a microneedle array, conductive hydrogel and an electrode sheet, the electrode sheet comprises a flexible substrate, a lead and an electrode are printed on the flexible substrate, the constant current source circuit system (4) comprises a power supply, a flexible circuit board, a I O interface, a key and an indicator lamp, the drug delivery device improves transdermal drug delivery efficiency while realizing pre-wearing, the drug keeps stable drug property in the conductive hydrogel, the situations that the drug is easy to inactivate and insufficient in delivery metering when attached to the microneedle are avoided, the passive diffusion of the drug is avoided, the active diffusion drug delivery mode accelerates the deep delivery of the drug to the skin, improves the delivery efficiency and the delivery precision of the drug, and can be widely applied to self-emergency.
Description
Technical Field
The invention relates to a transdermal drug delivery wearable device, in particular to a microneedle-based wearable iontophoresis drug delivery device.
Background
With the increasing problem of social aging, home health care and electronic medical care have attracted widespread attention. In the current clinical common administration route, the oral administration has the problems of slow effect, gastrointestinal metabolic loss and the like, the injection administration can produce pain, bleeding and skin injury, and the operation is complex and has a certain danger. Thus, skin patches for transdermal therapy have become a typical device for home healthcare, but rapid, controlled transdermal drug delivery system research is still lacking.
At present, ion transdermal drug delivery systems have been used for skin anesthesia, postoperative pain relief, and the like. However, in the application process, the ion transdermal technology often cannot generate stable transdermal direct current due to high electric barrier of the stratum corneum, so that the reduction of transdermal resistance is one of the problems to be solved by ion transdermal administration.
The microneedle array can breach the skin barrier for drug delivery. Meanwhile, the microneedle transdermal drug delivery has the advantages of reducing blood concentration fluctuation, reducing toxic and side effects, being convenient to use, having good patient compliance and the like, solves the problems that the conventional drug injection method needs medical care professionals to carry out injection and pain is accompanied, and can realize self-first aid at the first time after injury. Based on this, the application of microneedle arrays to transdermal drug delivery systems would have significant social application value.
Disclosure of Invention
The invention aims to provide a wearable iontophoresis drug delivery device based on microneedles.
In order to solve the technical problems, the technical scheme of the invention is as follows:
the utility model provides a wearable iontophoresis device based on microneedle, includes shell (5), microneedle paster (6) and constant current source circuit system (4), microneedle paster (6) are by microneedle array (1), electrically conductive hydrogel (3) and electrode slice (2) are constituteed in proper order, electrode slice (2) are including flexible substrate (2 a), printed on flexible substrate (2 a) wire (2 b) and electrode (2 e), constant current source circuit system (4) are by power, flexible circuit board, IO interface, button and pilot lamp are constituteed, power, IO interface, button and pilot lamp are connected with flexible circuit board electricity respectively, electrode (2 e) are connected to one end of wire (2 b), the other end passes through flexible circuit board connector (2 d) and is connected with the IO interface of constant current source circuit system (4), be equipped with the through-hole between microneedle array (1) and electrode slice (2) through 3M double-sided adhesive, this through-hole position is unanimous with electrode (2 e) place position, namely forms at electrode (2 e) place, electrically conductive reservoir (3) place as this through-hole in the drug reservoir; the shell (5) comprises an upper shell (5-1), an insulating spring (5 a) and a lower shell (5-2), wherein the insulating spring (5 a) is arranged in a space formed by the upper shell (5-1) and the lower shell (5-2), the two ends of the insulating spring are respectively connected with the upper shell (5-1) and the lower shell (5-2), the lower shell (5-2) is of a hollow structure, the microneedle patch (6) is fixedly clamped with the hollow structure, the microneedle array (1) of the microneedle patch (6) is exposed outside the lower shell (5-2), and the keys and the indicator lamps of the constant current source circuit system (4) are fixedly connected with the upper shell (5-1) and are exposed outside the upper shell (5-1).
Preferably, the microneedle-based wearable iontophoresis drug delivery device, wherein the power source is a 12-20V battery.
Preferably, in the wearable iontophoresis drug delivery device based on the microneedle, a self-locking structure (5 b) is further arranged in a space formed by the upper shell (5-1) and the lower shell (5-2) and used for limiting the insulating spring (5 a) after the insulating spring is compressed.
Preferably, the above-mentioned wearable iontophoresis device of dosing based on microneedle, go up casing (5-1) middle part and be equipped with the boss, be equipped with the gyro wheel on the boss, be equipped with the slide rail on the inner wall of inferior valve (5-2) hollow structure, the gyro wheel is arranged in on the slide rail, be equipped with the spacing groove that is used for fixed gyro wheel on the slide rail, in this hollow structure was arranged in to the boss, cooperation sliding connection through gyro wheel and slide rail and formation of boss and this hollow structure self-locking structure (5 b). After the microneedle patch (6) is used, the boss in the middle of the upper shell (5-1) can be pressed inwards to unlock and replace the microneedle patch.
Preferably, in the wearable iontophoresis drug delivery device based on the microneedle, the microneedle patch (6) is a square patch with a side length of 1-2 cm, and the side length of the square is longer than the side length of the negative electrode of the electrode (2 e).
Preferably, in the wearable iontophoresis drug delivery device based on the microneedles, the microneedle array (1) adopts sodium hyaluronate hydrogel microneedles, and is prepared by a PDMS (polydimethylsiloxane) mold.
Preferably, in the wearable iontophoresis drug delivery device based on the micro-needle, the thickness of the 3M double-sided adhesive tape is 0.25-1 mm, and a rectangular drug storage area is formed between the micro-needle array (1) and the electrode sheet (2).
Preferably, in the microneedle-based wearable iontophoresis drug delivery device, the material of the lead (2 b) and the electrode (2 e) is silver or silver chloride.
Preferably, in the wearable iontophoresis drug delivery device based on the microneedle, the flexible substrate is a flexible film.
Preferably, the flexible film is a polyimide film, a polypropylene film, a polyvinyl alcohol film or a polyethylene terephthalate film.
Preferably, in the wearable iontophoresis drug delivery device based on the microneedle, the electrode (2 e) is composed of a positive electrode conductive portion and a negative electrode conductive portion, the conductive hydrogel (3) corresponding to the positive electrode conductive portion does not contain a drug component, and the conductive hydrogel (3) corresponding to the negative electrode conductive portion contains a drug component.
Preferably, in the wearable iontophoresis drug delivery device based on the microneedle, the conductive hydrogel (3) corresponding to the negative electrode conductive portion stores negatively charged drug components, and under the action of the negative electrode, drug molecules are released under the action of an electric field force due to charge exclusion, and are delivered subcutaneously by the microneedle, so as to improve the drug delivery efficiency.
Preferably, in the wearable iontophoresis drug delivery device based on the microneedle, the drug component is epinephrine hydrochloride, the conductive hydrogel (3) is sulfobetaine-carboxylated nanocellulose hydrogel, epinephrine exists in the conductive hydrogel in a stable manner in a negatively charged form, and the device is used for self-emergency treatment under emergency conditions such as cardiac arrest or anaphylactic shock, and can also be used for treatment of other anaphylactic diseases (such as bronchial asthma and urticaria).
Preferably, in the wearable iontophoresis drug delivery device based on the microneedles, the microneedle array (1), the electrode sheet (2) and the flexible circuit board are arranged in parallel, and the insulating spring surrounds the periphery of the boss arranged on the upper shell (5-1).
Preferably, in the wearable iontophoresis drug delivery device based on the microneedle, the constant current source circuit system (4) is a one-key programmable constant current source circuit system.
Preferably, in the wearable iontophoresis drug delivery device based on the microneedles, the flexible circuit board of the constant current source circuit system (4) can control current output of different gears through keys, so that autonomous control is realized.
Preferably, in the wearable iontophoresis drug delivery device based on the microneedle, the IO interface of the constant current source circuit system (4) is connected with the flexible circuit board connector (2 d) to output stable current, and the output current is divided into three steps by shifting through a key to change the output current: the low-grade output is 0.05-0.15 mA, the medium-grade output is 0.25-0.35 mA, and the high-grade output is 0.4-0.5 mA.
Preferably, in the microneedle-based wearable iontophoresis drug delivery device, the upper housing (5-1) and the lower housing (5-2) are formed by 3D printing.
Preferably, in the wearable iontophoresis drug delivery device based on the microneedle, the insulating spring is made of an insulating elastic substance such as insulating soft silica gel.
In the above-mentioned wearable iontophoresis drug delivery device based on the microneedles, when a downward external force is applied in a direction directly above the upper housing (5-1), the microneedle patch (6) moves downward so as to pierce the microneedle array (1) into the skin of the user. The key on the upper shell (5-1) is pressed, the circuit outputs stable currents of different gears (for example, three gears) in a programmable control mode, the micro-channel formed by the micro-needle array (1) by the drug components (for example, epinephrine) in the conductive hydrogel (3) under the action of the current is applied to the skin of a user, and the active transdermal drug delivery is realized by transmitting the stimulation current to the skin, so that the drug components can be infused in a mode of facilitating self-emergency of the user.
Because the insulating spring (5 a) contracts when external force is applied to the upper shell (5-1), the self-locking structure (5 b) enables the microneedle patch (6) to stably penetrate into the skin, the electrode plate (2) is oxidized after the medicine is applied to the skin, and medicine components in the conductive hydrogel (3) enter the skin of a user, so that the microneedle patch (6) needs to be replaced when the microneedle patch is reused.
The beneficial effects are that:
according to the wearable iontophoresis drug delivery device based on the microneedles, the transdermal drug delivery efficiency is improved while the pre-wearing is realized, the drug property of the drug in the conductive hydrogel is kept stable, the situations that the drug is easy to inactivate and the delivery metering is insufficient due to the adhesion of the drug on the microneedles are avoided, the passive diffusion of the drug is avoided, the drug delivery mode of active diffusion accelerates the deep subcutaneous delivery of the drug, the drug delivery efficiency and precision are improved, and the device can be widely applied to self-first aid.
Drawings
FIG. 1 is a schematic view of the structure of an electrode sheet of a microneedle-based wearable iontophoresis drug delivery device of the present invention;
FIG. 2 is a schematic structural view of a microneedle patch of a microneedle-based wearable iontophoresis drug delivery device of the present invention;
fig. 3 is an exploded view of the housing (5) of the microneedle-based wearable iontophoresis drug delivery device of the present invention;
FIG. 4 is a schematic illustration of the microneedle patch mounting location of a microneedle-based wearable iontophoresis drug delivery device of the present invention;
FIG. 5 is a graph of concentration versus absorbance for an in vitro transdermal drug delivery experiment.
In the figure: 1-microneedle array, 2-electrode sheet, 3-conductive hydrogel, 2 a-flexible substrate, 2 b-lead, 2c-3M double-sided tape, 2 d-flexible circuit board connector, 2 e-electrode, 4-constant current source circuitry, 4 a-key, 5-housing, 5-1-upper housing, 5-2-lower housing, 5 a-insulating spring, 5 b-self-locking structure, 6-microneedle patch
Detailed Description
The microneedle-based wearable iontophoresis drug delivery device, the optical fiber tip force sensing device, and the application method of the present invention will be described with reference to the examples and drawings.
Example 1
As shown in fig. 1-4, a wearable iontophoresis drug delivery device based on a microneedle comprises a shell 5, a microneedle patch 6 and a constant current source circuit system 4, wherein the microneedle patch 6 is square with a side length of about 1.5cm, the microneedle patch 6 sequentially comprises a microneedle array 1, conductive hydrogel 3 and an electrode plate 2, the microneedle array 1 adopts a sodium hyaluronate hydrogel microneedle, the electrode plate 2 comprises a flexible substrate 2a, an Ag/AgC l lead 2b and an Ag/AgC l electrode 2e are printed on the flexible substrate 2a, the constant current source circuit system 4 comprises a power supply (12-20V), a flexible circuit board, an IO interface, a key 4a and an indicator lamp (not shown in the figure), one end of the lead 2b is connected with an electrode 2e, the other end of the lead is connected with the IO interface of the circuit system 4 through a flexible circuit board connector 2d, the circuit system 4 is a key type programmable circuit system, the constant current source circuit system is connected with the flexible circuit board connector through a three-level constant current source interface to output a stable current, and the current is changed into a three-level constant current output circuit, and the current is changed into a three-level current output stable circuit. The output current is changed by pressing the low-grade output of 0.05-0.15 mA, the middle-grade output of 0.25-0.35 mA and the high-grade output of 0.4-0.5 mA; the microneedle array 1, the electrode sheet 2 and the flexible circuit board are arranged in parallel, the microneedle array 1 and the electrode sheet 2 are adhered and fixed through a 3M double sided adhesive tape 2c, a through hole is formed in the 3M double sided adhesive tape 2c, the position of the through hole is consistent with that of the electrode 2e, namely two medicine storage areas are formed at the electrode 2e, the conductive hydrogel (sulfobetaine-carboxylated nanocellulose hydrogel) 3 is used as a medicine storage area and is arranged in the through hole, wherein the electrode 2e consists of an anode conductive part and a cathode conductive part, the corresponding conductive hydrogel 3 on the anode conductive part does not contain medicine components, the conductive hydrogel 3 corresponding to the cathode conductive part contains medicine components (epinephrine hydrochloride) with negative electricity, under the action of the cathode, medicine molecules are released under the action of electric field force due to charge exclusion, and the medicine molecules are conveyed to the skin by the microneedle so as to improve the medicine delivery efficiency;
the shell 5 comprises an upper shell 5-1, an insulating spring 5a and a lower shell 5-2, wherein the upper shell 5-1 and the lower shell 5-2 are formed by 3D printing, the insulating spring 5a is made of insulating soft silica gel, the insulating spring 5a is arranged in a space formed by the upper shell 5-1 and the lower shell 5-2, the two ends of the insulating spring are respectively connected with the upper shell 5-1 and the lower shell 5-2, the lower shell 5-2 is of a hollow structure, the microneedle array 1 of the microneedle patch 6 is fixedly clamped with the hollow structure, the microneedle array 1 of the microneedle patch 6 is exposed outside the lower shell 5-2, a button 4a of the constant current source circuit system is fixedly connected with the upper shell 5-1 and is exposed outside the upper shell 5-1, a self-locking structure 5b for limiting the upper shell 5-1 after the insulating spring 5a is compressed is further arranged in the space formed by the upper shell 5-1, the middle of the insulating spring is arranged on the boss, the insulating spring is arranged around the boss arranged on the periphery of the upper shell 5-1, the lower shell 5-2 is arranged on the boss, the boss is arranged on the boss on the lower shell 5-1, and is matched with the hollow structure to the lower shell 5-1, and the boss is arranged on the boss through the boss and is arranged on the boss in the boss side and is in the hollow structure. The key on the upper shell (5-1) is pressed, the circuit outputs stable currents with different gears in a programmable control mode, the micro-channel formed by the micro-needle array 1 under the action of the current is applied to the skin of a user by the epinephrine of the medicine component in the conductive hydrogel 3, and the active transdermal drug delivery is realized by transmitting the stimulation current to the skin, so that the medicine component can be infused in a mode of facilitating self-emergency of the user. Since the insulating spring 5a is contracted when an external force is applied to the upper case 5-1, the self-locking structure 5b makes the microneedle patch 6 stably penetrate into the skin, the electrode sheet 2 is oxidized after the drug is applied to the skin, and the drug components in the conductive hydrogel 3 enter the user's skin. After use, unlocking can be completed by inwards extruding the boss in the middle of the upper shell 5-1 and replacing the microneedle patch 6 with a new microneedle patch for reuse.
The specific preparation steps of the wearable iontophoresis drug delivery device based on the microneedles are as follows:
(1-1) preparing an iontophoresis electrode, manufacturing an Ag/AgC l electrode by a screen printing method, designing a square with a side length smaller than 1cm (a side length smaller than a microneedle patch), designing a positive electrode without medicines, preparing a series of preparation work before printing, preparing a polyimide film (a flexible film such as a polypropylene film, a polyvinyl alcohol film or a polyethylene terephthalate film) with a thickness of 50 mu m as a flexible substrate, cutting into square blocks with a length of 5cm multiplied by 5cm, soaking the cut film in alcohol, ultrasonically cleaning for 5min, taking out and airing for later use. Before the screen printing table is used, the screen printing table should be cleaned with clean dust-free paper, the conductive layer screen printing plate is fixed in a fixture in the positive direction, and then the screen printing plate is turned up to finish the preparation of the screen printing table. The back of the polyimide film is slightly wet and then flatly attached under the screen printing plate, and bubbles in the polyimide film are discharged to enable the polyimide film to be closely attached to the table top. 30g of silver ink was removed and placed in a petri dish, 30 μl of ink diluent was added and thoroughly stirred for further use, and 30g of silver/silver chloride ink was removed to a second petri dish. And then printing, namely firstly coating conductive silver ink on the screen plate at the position close to the upper side, putting down the screen plate, fully dipping the ink by using a scraper, pressing the screen plate downwards to enable the screen plate to be in contact with a substrate, moving the scraper from top to bottom to uniformly print the ink on the substrate through patterns, lifting the scraper and rotating the scraper direction, uniformly covering the ink on the whole patterns again, taking out the device after turning up the screen plate, and placing the device in a baking tray or an oven to be heated at 120 ℃ for 10min for curing. After the printing of the conductive layer and the negative electrode part is completed, the corresponding screen is taken down and replaced by a positive electrode, and the scraper is cleaned by screen washing water and dried. The method comprises the steps of coating silver chloride ink on a screen plate at a position close to the upper side, fully dipping the ink by a scraper after the screen plate is put down, pressing the screen plate to enable the screen plate to be in contact with a substrate, moving the scraper from top to bottom to uniformly print the ink on a table top through patterns, lifting the scraper and rotating the scraper direction, uniformly covering the ink on the whole patterns again, turning up the screen plate, heating a baking gun at 100 ℃ for 30 seconds to print patterns to be solidified, then aligning a left base of a solidified device to an electrode position solidified on the table top to print a silver chloride electrode, fully dipping the ink by the scraper and pressing the screen plate to enable the screen plate to be in contact with the substrate, moving the scraper from top to bottom to uniformly print the ink on the table top through the patterns, lifting the scraper and rotating the scraper direction, uniformly covering the ink on the whole patterns again, turning up the screen plate, taking out the device, and placing the device in a baking tray or a baking oven to be heated at 120 ℃ for 10 minutes to be solidified. After curing, the transparent adhesive tape is cut into a size larger than 3cm multiplied by 3cm and is stuck to the lead part of the electrode plate without affecting the conductivity of the electrode, so that simple insulation is finished.
(1-2) cutting the 3M double-sided adhesive tape by using a laser engraving machine, putting the whole piece of 3M double-sided adhesive tape with the size of 21 x 29.7 x 0.1cm into a laser cutting machine, connecting computer equipment with the laser cutting machine, adjusting the cutting times to be 3 times, cutting with the power of 80 percent in equal proportion, tearing off one piece of paper by using the 3M double-sided adhesive tape cut by using a CAD design drawing, and sticking the paper back on the prepared iontophoresis electrode to expose the positive electrode and the negative electrode. And then connecting the interface with the tail end of the lead of the electrode, inserting a DuPont wire into the connection part of the interface, and stably connecting the DuPont wire with the circuit board through soldering tin.
(1-3) secondly, preparing hydrogel microneedle, and preparing a hydrogel microneedle array by taking sodium hyaluronate as a matrix. First, the number of arrays is prepared: greater than 20 x 20, tip distance: 500-700 mu m, patch size: d = 10mm, microneedle length: 600-800 μm, needle low diameter: a polydimethylsiloxane microneedle mould with corresponding size of 200-500 mu m. Adding 2g of HA into 6mL of deionized water to obtain a colloidal microneedle tip solution; 2g of HA was added to 6mL of deionized water to give a gummy microneedle base solution. And (3) placing the microneedle tip solution into a PDMS microneedle mould, centrifuging for 15min at a rotational speed of 5500r/min, enabling the microneedle tip solution to completely enter the tip part of the microneedle mould, carefully scraping the microneedle tip solution at the bottom of the microneedle base, placing the microneedle base solution into the PDMS microneedle mould, centrifuging for 10min at a rotational speed of 5500r/min, and removing bubbles in the solution to prepare the sodium hyaluronate microneedle.
(1-4) finally, the preparation of a hydrogel reservoir carrying the pharmaceutical ingredient; 600mL of PBS (Ph=7) was taken, 0.342g of SBMA monomer (sulfobetaine methacrylate), 5mg of MBAA, 3mg of APS thermal initiator were added thereto, 400mL of 2.4% carboxylated nanocellulose was formed into a uniformly mixed solution, and 20. Mu.L of 0.2g/mL of epinephrine (AD) solution was added thereto, each time 0.4mg of epinephrine was contained in the hydrogel formed. The sulfobetaine-carboxylated nanocellulose hydrogel is adhered with the backing layer of the hydrogel microneedle before being cured, and the backing layer of the hydrogel microneedle can form stable connection between the two after being cured. And (3) attaching the prepared combination body containing the medicinal liquid gel and the microneedles to the other side of the 3M double-sided adhesive tape to complete the integration of the microneedle patch system.
(2-1) a constant current source circuit system, wherein an NRF52832 is adopted for a low-power consumption Bluetooth MCU chip of the handheld device, after receiving a key instruction, the MCU outputs a corresponding DAC analog voltage value, and a later-stage circuit realizes constant current control through voltage-current conversion. The post-stage voltage-controlled constant current source circuit is a conventional circuit system and comprises circuit elements such as an operational amplifier (LM 358), a MOSFET (I RF 540N), a shunt resistor (1Ω), a 1KΩ resistor, a 10KΩ resistor, a 12v battery power supply and the like. When the key is not pressed, the IO port corresponding to the MCU detects a high level, when the key is pressed, the high level on the IO port can be changed into a low level, and the MCU judges whether the key is pressed or not by detecting the level change. When the on-off operation is executed, the key-press time, namely the low level time, is mainly judged, if the low level time exceeds 2-3S, the MCU considers the key-press instruction as the on-off instruction, if the key-press instruction is in the on-state at present, the off-state is executed, and if the key-press instruction is in the off-state at present, the on-state is executed. Meanwhile, combining the current working state, under the condition of short key pressing (non-on-off key operation), if the current state is a low gear, switching to a middle gear under the key instruction; the current is a middle grade, and the key instruction is switched to a high grade; similarly, the high gear is the low gear in the switching process, and the low, medium and high states are circularly switched. The circuit is used as an adjustable constant current source output circuit for providing the pulse direct current required by the iontophoresis circuit, and in the on state of the circuit, the skin part directly contacted with the electrode or the drug reservoir can generate tingling or itching feeling, and the feeling becomes strong along with the increase of the current density, and even tingling is caused. Thus, the current density is often set within the pain threshold of the skin, i.e., less than 0.5mA cm 2 The current output range of the designed adjustable constant current source is three-gear with 0.05-0.15 mA, 0.25-0.35 mA and 0.4-0.5 mA, and the error is less than +/-0.02 mA. For convenient wearing, button battery or small battery with constant 12v power supply voltage and three-gear outputThe current can realize one-key regulation and control of the epinephrine infusion rate within the range of the skin pain threshold, and simultaneously, the self-one-key regulation and control of the acting time and the infusion rate of percutaneous administration according to specific conditions is convenient to realize. In order to prevent false touch, a circuit is designed to be switched on when the three-second key S1 is pressed for a long time, and the output current is about 0.1mA which is an adjustable minimum value when the circuit is switched on so as to avoid damage to a human body caused by overlarge current. The three-gear output current is displayed by three different indicator lamps D2, D3 and D4, so that the observation is convenient.
(3-1) finally, the housing of the drug delivery system is fabricated by using a 3D printing method, and after packaging, the overall size is not more than 5cm×4cm×2cm, so that the display module is not shielded, internal devices and wires are prevented from being exposed, and voltage or current which damages and threatens the health of a human body during the period is prevented from being generated in the contactable part. First, the design of the shell is performed using SOLIWORKS modeling software, and the overall structure is composed of three parts. The integrated support structure can be provided with a PCB circuit board, a power supply, conductive hydrogel (used as a PDMS hydrogel drug storage library) and other components of an adjustable constant current source, the bottom is of a hollow structure, the periphery can be stuck and fixed on human skin by using medical adhesive tapes, the middle is used for placing a spring with a microneedle patch, and when a rear shell is pressed from the top, the spring is loosened, and the microneedle is contacted with and penetrates into the skin cuticle.
In the use, the user can wear in advance and fix the device, exerts pressure to pressing device main part during the use, and spring coil's thickness is compressed, and the laminating of microneedle paster structure is user's skin, and the microneedle array punctures to the skin to pressing direction, takes place to swell after the subcutaneous tissue interstitial fluid is absorbed to the microneedle, and the inside microchannel that makes the medicine molecule pass through that forms of electrically conductive hydrogel because the diameter size of microneedle is the micron order, and the microneedle is little invasive and painless at the puncture process of skin surface formation microchannel, has realized that the microneedle paster "pre-applies" or the device "pre-dresses", when pressure removes, self-locking structure makes insulating spring compressed and not reset, the microneedle paster contact skin always. The electrode plate is connected with a flexible circuit board of the constant current source circuit system, the key is pressed, the circuit board generates constant current through the rear-stage voltage-controlled constant current source circuit according to a key instruction through programmable control so as to transfer stimulation current to the skin at the joint, the electrode plate transfers the current to the conductive hydrogel, the conductive hydrogel is stimulated to release medicine components, and the medicine components quickly and efficiently enter the skin through micro-channels generated by the microneedle patch and the skin.
Example 2
Determining the average delivery rate of the microneedle-based wearable iontophoretic delivery device
The concentration of the epinephrine solution is measured based on ultraviolet spectrophotometry by adopting the transdermal administration of epinephrine, the absorbance at 281nm is measured, the concentration of epinephrine and the absorbance show good positive correlation linear relation in the range of 0.08-6 mug/m l, and the content of epinephrine drug molecules in a receiving chamber of a diffusion cell is measured after a period of administration. First, an epinephrine standard solution of known concentration is prepared, and an epinephrine concentration-absorbance standard curve is obtained by measurement, as shown in fig. 5; secondly, using a sample machine of a patch type active transdermal drug delivery system to deliver epinephrine into a liquid to be tested through simulated skin to obtain a sample to be tested; then, measuring the absorbance of a sample to be measured by using an ultraviolet spectrophotometer, and calculating to obtain the concentration of epinephrine in the sample to be measured by using an epinephrine concentration-absorbance standard curve; and finally, calculating and obtaining the administration rate according to the measured epinephrine concentration, the volume of the liquid to be measured and the administration time. The specific method comprises the following steps:
first, a standard sample was prepared: as standard samples, epinephrine solutions 2m l of 0.1. Mu.g/m l, 0.5. Mu.g/m l, 1. Mu.g/m l, 2. Mu.g/m l, 3. Mu.g/m l, 4. Mu.g/m l, 5. Mu.g/m l were prepared and placed into a light-resistant centrifuge tube for storage. Secondly, preparing a sample to be tested: three groups are divided, and the three groups are respectively applied to artificial skin by a sample machine of a patch type active transdermal drug delivery system to deliver drugs to a diffusion cell (containing 8m l phosphate buffer solution) for 15 minutes, 25 minutes and 60 minutes; after administration, the 2m l solutions were each placed into a light-resistant centrifuge tube and stored for later use. Finally, a blank sample was prepared: since the solvent used for the epinephrine standard solution is a phosphate buffer solution having a pH of 7, a phosphate buffer solution having a pH of 7 was used as a blank solution.
Testing a sample, taking a blank sample solution into a cuvette by using a liquid-transferring gun, and zeroing an ultraviolet spectrophotometer; sequentially taking 2ml of epinephrine standard samples from low concentration to high concentration into a cuvette, measuring absorbance at 281nm by using an ultraviolet spectrophotometer, and measuring the same standard solution for 4 times; processing the obtained absorbance data, taking the average value of 4 groups of data, drawing a standard curve by using the obtained absorbance average value and the corresponding epinephrine mass fraction concentration, and performing linear fitting; respectively taking 2ml of epinephrine samples to be detected into a cuvette, and measuring absorbance at 281nm by using an ultraviolet spectrophotometer to obtain absorbance information of three groups of epinephrine samples to be detected.
If the concentration of the sample to be detected is c (mug/ml), the volume of the solution of the diffusion tank is V (ml), and the administration area of the microneedle patch is S (cm) 2 ) When the administration time is t (h), the average administration rate v (mg/h.cm) -2 ) The method comprises the following steps:
ν＝(c·V)/(1000·t·S)
and (3) calculating to obtain: v 1 ＝0.105mg/h·cm -2 、v 2 ＝0.1185mg/h·cm -2 、v 3 ＝0.09114mg/h·cm -2 Maximum rate of administration v of the prototype max ＝max{v 1 ，v 2 ，v 3 }＝0.1185mg/h·cm -2 。
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. A microneedle-based wearable iontophoresis drug delivery device, characterized in that: the micro-needle patch (6) sequentially comprises a micro-needle array (1), conductive hydrogel (3) and an electrode plate (2), wherein the electrode plate (2) comprises a flexible substrate (2 a), a lead (2 b) and an electrode (2 e) are printed on the flexible substrate (2 a), the constant-current source circuit system (4) comprises a power supply, a flexible circuit board, an IO interface, a key and an indicator lamp, the power supply, the IO interface, the key and the indicator lamp are respectively electrically connected with the flexible circuit board, one end of the lead (2 b) is connected with the electrode (2 e) and the other end of the lead is connected with the IO interface of the constant-current source circuit system (4) through a flexible circuit board connector (2 d), the micro-needle array (1) is fixedly bonded with the electrode plate (2) through 3M double-sided adhesive tape, a through hole is formed in the 3M double-sided adhesive tape, the position of the through hole is consistent with that of the electrode (2 e), namely, a medicine storage area is formed at the electrode (2 e), and the conductive hydrogel (3) is used as a medicine storage area in the through hole; the shell (5) comprises an upper shell (5-1), an insulating spring (5 a) and a lower shell (5-2), wherein the insulating spring (5 a) is arranged in a space formed by the upper shell (5-1) and the lower shell (5-2), the two ends of the insulating spring are respectively connected with the upper shell (5-1) and the lower shell (5-2), the lower shell (5-2) is of a hollow structure, the microneedle patch (6) is fixedly clamped with the hollow structure, the microneedle array (1) of the microneedle patch (6) is exposed outside the lower shell (5-2), and the keys and the indicator lamps of the constant current source circuit system (4) are fixedly connected with the upper shell (5-1) and are exposed outside the upper shell (5-1).
2. The microneedle-based wearable iontophoretic drug delivery device of claim 1, wherein: the power supply is a 12-20V battery.
3. The microneedle-based wearable iontophoretic drug delivery device of claim 1, wherein: the space formed by the upper shell (5-1) and the lower shell (5-2) is also internally provided with a self-locking structure (5 b) for limiting the insulating spring (5 a).
4. The microneedle-based wearable iontophoretic drug delivery device of claim 3, wherein: the middle part of the upper shell (5-1) is provided with a boss, the boss is provided with a roller, the inner wall of the hollow structure of the lower shell (5-2) is provided with a slide rail, the roller is arranged on the slide rail, the slide rail is provided with a limit groove for fixing the roller, the boss is arranged in the hollow structure, and the boss is in sliding connection with the hollow structure through the cooperation of the roller and the slide rail and forms the self-locking structure (5 b).
5. The microneedle-based wearable iontophoretic drug delivery device of claim 1, wherein: the microneedle patch (6) is a square patch with the side length of 1-2 cm, the side length of the square is longer than the side length of the cathode of the electrode (2 e), and the thickness of the 3M double faced adhesive tape is 0.25-1 mm.
6. The microneedle-based wearable iontophoretic drug delivery device of claim 1, wherein: the microneedle array (1) adopts sodium hyaluronate hydrogel microneedles, and is prepared by a PDMS mould; the conducting wire (2 b) and the electrode (2 e) are made of silver or silver chloride; the flexible substrate adopts a polyimide film, a polypropylene film, a polyvinyl alcohol film or a polyethylene terephthalate film.
7. The microneedle-based wearable iontophoretic drug delivery device of claim 1, wherein: the electrode (2 e) is composed of a positive electrode conductive part and a negative electrode conductive part, the corresponding conductive hydrogel (3) on the positive electrode conductive part does not contain a medicine component, and the conductive hydrogel (3) corresponding to the negative electrode conductive part contains the medicine component.
8. The microneedle-based wearable iontophoretic drug delivery device of claim 7, wherein: the medicine component is epinephrine hydrochloride.
9. The microneedle-based wearable iontophoretic drug delivery device of claim 1, wherein: the micro-needle array (1), the electrode plate (2) and the flexible circuit board are arranged in parallel, and the insulating spring surrounds the periphery of the boss arranged on the upper shell (5-1).
10. The microneedle-based wearable iontophoretic drug delivery device of claim 1, wherein: the constant current source circuit system (4) is a one-key programmable constant current source circuit system, the IO interface of the constant current source circuit system (4) is connected with the flexible circuit board connector (2 d) to output stable current, the flexible circuit board of the constant current source circuit system (4) shifts gears through keys to change the output current, and the output current is divided into three steps: the low-grade output is 0.05-0.15 mA, the medium-grade output is 0.25-0.35 mA, and the high-grade output is 0.4-0.5 mA.
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