Targeted transdermal drug delivery system and method combining electroporation and intermediate frequency therapy

Abstract

This invention discloses a targeted transdermal drug delivery system and method combining electroporation and mid-frequency physiotherapy, belonging to the field of pharmaceuticals. It includes a housing support module, an array electroporation module, a mid-frequency vector physiotherapy module, a drug micro-pressure delivery module, a skin impedance acquisition module, a timing coupling control module, a gradient thermal stability adjustment module, and a closed-loop energy supply module. The array electroporation module and the mid-frequency vector physiotherapy module are coaxially arranged and alternately output. The skin impedance acquisition module provides feedback control of the output timing. The gradient thermal stability adjustment module forms a temperature difference isolation zone. The closed-loop energy supply module constitutes an impedance closed-loop adjustment structure. A phase interval of 0.8-6 milliseconds is formed between the outputs of the two modules. The drug micro-pressure delivery module is activated after the electroporation output to utilize the micropore opening window for targeted drug delivery. Beneficial effects: Improved controllability and transdermal efficiency of transdermal drug delivery.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more specifically, to a targeted transdermal drug delivery system and method that combines electroporation with mid-frequency physiotherapy. Background Technology

[0002] With the development of transdermal drug delivery technology, electroporation technology has improved skin permeability through transient microporous structures, gradually solving the problem of low penetration efficiency of traditional topical drugs; mid-frequency physiotherapy technology improves local tissue activity and drug diffusion through electrical stimulation. Subsequently, electrostimulation drug delivery, iontophoresis, and pulsed drug delivery technologies have continued to develop towards lower damage, higher penetration, and controllability, making transdermal drug delivery increasingly precise and intelligent.

[0003] While existing technologies can improve drug transdermal efficiency, most systems employ a single electric field introduction method or a fixed parameter output method. The lack of a synchronous coupling structure between the micropore opening stage and the drug migration stage leads to random drug diffusion direction. At the same time, existing mid-frequency stimulation structures are mostly linear output structures, which make it difficult to form a stable directional migration path and are prone to lateral diffusion. In addition, existing systems generally lack a dynamic energy switching mechanism based on changes in skin impedance, making it impossible to independently control the micropore opening, maintenance, and closing stages, resulting in insufficient consistency between local heat accumulation and drug delivery. Summary of the Invention

[0004] This invention proposes a targeted transdermal drug delivery system and method combining electroporation and mid-frequency physiotherapy to address the aforementioned problems: While existing technologies can improve transdermal drug delivery efficiency, most systems employ a single electric field delivery method or a fixed parameter output method, lacking a synchronous coupling structure between the micropore opening stage and the drug migration stage, resulting in random drug diffusion direction; simultaneously, existing mid-frequency stimulation structures are mostly linear output structures, making it difficult to form a stable directional migration path and easily causing lateral diffusion; furthermore, existing systems generally lack a dynamic energy switching mechanism based on changes in skin impedance, making it impossible to independently control the micropore opening, maintenance, and closing stages, resulting in insufficient consistency between local heat accumulation and drug delivery.

[0005] Technical solution: The targeted percutaneous drug delivery system combining electroporation and mid-frequency physiotherapy includes a shell support module, an array electroporation module, a mid-frequency vector physiotherapy module, a drug micro-pressure delivery module, a skin impedance acquisition module, a timing coupling control module, a gradient thermal stability adjustment module, and a closed-loop energy supply module. The housing support module includes an upper encapsulation cavity, a middle wire isolation cavity, and a bottom bonding cavity. The array electroporation module is embedded in the central region of the bottom bonding cavity. The mid-frequency vector therapy module is coaxially arranged around the array electroporation module. The drug micro-pressure delivery module runs longitudinally through the interior of the housing support module and communicates with the microporous drug delivery cavity of the array electroporation module. The skin impedance acquisition module is connected to both the array electroporation module and the timing coupling control module. The timing coupling control module uses a segmented peak-shifting method to control the alternating output of the array electroporation module and the mid-frequency vector therapy module. The gradient thermal stability adjustment module is located between the array electroporation module and the mid-frequency vector therapy module, forming a radial temperature difference isolation zone. The closed-loop energy supply module is connected to the array electroporation module, the mid-frequency vector therapy module, the skin impedance acquisition module, and the timing coupling control module, forming a synchronous coupling structure of pulse perforation and mid-frequency directional drive based on skin transient impedance changes. There is a phase interval of 0.8 milliseconds to 6 milliseconds between the output phase of the array electroporation module and the output phase of the mid-frequency vector therapy module. The drug micro-pressure transport module starts axial drug delivery after the output phase of the array electroporation module ends, so as to form a directional drug migration path during the micropore opening window period.

[0006] Preferably, the array electroporation module includes a ceramic insulating substrate, a needle array of conductive pillars, an annular confined electrode layer, a microgroove reservoir, and a pulse convergence layer; wherein, the ceramic insulating substrate adopts an aluminum nitride sintered structure, the needle array of conductive pillars is fixed to the surface of the ceramic insulating substrate in a hexagonal close-packed structure, the annular confined electrode layer covers the outer periphery of the needle array of conductive pillars, the microgroove reservoir is formed between adjacent needle array of conductive pillars, and the pulse convergence layer is disposed inside the ceramic insulating substrate and electrically connected to the needle array of conductive pillars to form a radially converged pulse electric field; wherein, a capillary infusion groove is formed at the bottom of the microgroove reservoir, the capillary infusion groove is connected to the drug micro-pressure delivery module, and an electric field shielding boundary is formed on the outer side of the annular confined electrode layer to limit the lateral diffusion of the pulse electric field along the skin surface.

[0007] Preferably, the needle array conductive pillars adopt a titanium-iridium composite sintered structure, with a hemispherical puncture end formed at the top of each pillar. The length of each needle array conductive pillar is 0.45 mm to 0.85 mm, and the spacing between them is 0.18 mm to 0.42 mm. An insulating gap of 15 μm to 45 μm is formed between the annular confinement electrode layer and the needle array conductive pillars. The pulse convergence layer adopts a multi-layer spiral copper foil stacked structure. An axial conductive ridge is formed inside each needle array conductive pillar, extending spirally along the length of the pillar. A nano-coarsening layer is formed on the surface of the hemispherical puncture end to improve the local field strength concentration during pulse release.

[0008] Preferably, the pulse convergence layer includes a primary pulse ring, a secondary delay ring, and a tertiary reflection ring; wherein the primary pulse ring is directly electrically connected to the needle array conductive pillar, the secondary delay ring is arranged around the outside of the primary pulse ring, and the tertiary reflection ring is arranged on the outer periphery of the secondary delay ring; phase delay regions are formed between the primary pulse ring, the secondary delay ring, and the tertiary reflection ring to form an axial gradient pulse leading edge at the output end of the needle array conductive pillar; wherein the primary pulse ring adopts a low-resistivity copper-nickel composite layer structure, the secondary delay ring adopts a high-resistivity molybdenum alloy layer structure, and the tertiary reflection ring adopts a closed silver paste conductive layer structure; the phase delay region is filled with a silicon dioxide insulating dielectric layer to form a layered pulse wavefront compression path.

[0009] Preferably, the mid-frequency vector therapy module includes an arc-shaped mid-frequency electrode sheet, an interleaved conductive layer, a magnetic bias ring, and a phase switching plate; wherein, the arc-shaped mid-frequency electrode sheet is distributed in a ring around the outer periphery of the array electroporation module, the interleaved conductive layer is disposed below the arc-shaped mid-frequency electrode sheet, the magnetic bias ring is fixed to the periphery of the arc-shaped mid-frequency electrode sheet, and the phase switching plate is connected to the arc-shaped mid-frequency electrode sheet and the timing coupling control module respectively to form a rotating mid-frequency vector field; wherein, the inner edge of the arc-shaped mid-frequency electrode sheet forms a current-guiding surface, the interior of the interleaved conductive layer forms a circumferential conductive channel, and the magnetic bias ring forms alternating magnetic poles arranged circumferentially to form a deflection-type current migration trajectory in the superficial skin region.

[0010] Preferably, the number of arc-shaped intermediate frequency electrode sheets is eight, with an included angle of 22 to 38 degrees between adjacent arc-shaped intermediate frequency electrode sheets. The interleaved conductive layer adopts a silver-carbon alternating deposition structure, the magnetic bias ring adopts a neodymium iron boron closed-loop magnet structure, and the phase switching plate adopts a four-quadrant bridge commutation structure to form a circumferential migration current channel on the skin surface. The four-quadrant bridge commutation structure switches the phase output sequentially in a clockwise direction, and the silver deposition layer and carbon deposition layer inside the interleaved conductive layer form an alternating impedance region to make the intermediate frequency current rotate and migrate along a preset direction.

[0011] Preferably, the timing coupling control module includes an impedance analysis unit, a pulse framing unit, an intermediate frequency commutation unit, and a synchronization locking unit; wherein, the impedance analysis unit is connected to the skin impedance acquisition module, the pulse framing unit is connected to the array electroporation module, the intermediate frequency commutation unit is connected to the intermediate frequency vector therapy module, and the synchronization locking unit is connected to the impedance analysis unit, the pulse framing unit, and the intermediate frequency commutation unit respectively, to form a staged energy switching structure based on the skin impedance decrease slope; wherein, the impedance analysis unit adopts a dual-channel sampling structure, the dual-channel sampling structure corresponding to the epidermal impedance sampling path and the dermal impedance sampling path respectively, and the synchronization locking unit adjusts the output sequence of the intermediate frequency commutation unit according to the difference between the epidermal impedance change and the dermal impedance change.

[0012] Preferably, the pulse framing unit divides the output pulse into a pre-breakdown frame, a stabilizing frame, and a closing frame. The pulse width of the pre-breakdown frame is 20 microseconds to 80 microseconds, the pulse width of the stabilizing frame is 100 microseconds to 400 microseconds, and the pulse width of the closing frame is 5 microseconds to 25 microseconds. The intermediate frequency commutation unit switches the conduction direction of the arc-shaped intermediate frequency electrode within 3 milliseconds to 15 milliseconds after the stabilizing frame ends to form a directional drug flow driving structure during the channel maintenance period. The pre-breakdown frame adopts a stepped voltage rise structure, the stabilizing frame adopts a constant voltage pulse structure, and the closing frame adopts a reverse decay pulse structure. The intermediate frequency commutation unit reduces the intermediate frequency output amplitude before the closing frame starts to suppress heat accumulation at the micropore edge.

[0013] Preferably, the synchronization locking unit adopts a dual-crystal oscillator frequency-locking structure. The synchronization locking unit internally sets an impedance threshold matrix, which is divided into an activation zone, an introduction zone, and a closure zone according to the skin impedance decrease rate. The synchronization locking unit switches the output order of the array electroporation module and the mid-frequency vector therapy module according to the impedance threshold matrix to complete the directional migration of drugs before the micropores close. The activation zone corresponds to the impedance decrease rate in the pre-breakdown stage, the introduction zone corresponds to the impedance stabilization range in the pore stabilization stage, and the closure zone corresponds to the impedance recovery range in the pore closure stage. When the closure zone is activated, the synchronization locking unit controls the drug micro-pressure transport module to reduce the output pressure to form a residual drug reabsorption structure in the micropore closure stage.

[0014] Preferably, the targeted percutaneous drug delivery method combining electroporation and intermediate frequency therapy, used to implement the targeted percutaneous drug delivery system combining electroporation and intermediate frequency therapy as described in any one of claims 1-9, includes the following steps: S1. The housing support module is attached to the surface of the target skin area, the array electroporation module is located at the center of the target drug delivery area, the mid-frequency vector therapy module surrounds the target drug delivery area, and the initial impedance data of the target drug delivery area is collected through the skin impedance acquisition module. S2. The timing coupling control module establishes an impedance reference range based on the initial impedance data and controls the closed-loop energy supply module to output a pre-breakdown frame pulse to the array electroporation module, so that the needle array conductive pillars form an initial transient microporous structure in the target skin area. S3. After the pre-breakdown frame pulse output ends, the pulse framing unit switches to the stable aperture frame output state, so that the first-level pulse ring, the second-level delay ring and the third-level reflection ring in the pulse convergence layer sequentially form the axial gradient pulse leading edge, and form a radial convergence pulse electric field at the output end of the needle array conductive column, so as to maintain the transient micropore structure in a stable open state. S4. During the stable hole frame output stage, the drug micro-pressure transport module delivers the drug solution to the micro-groove storage cavity, and introduces the drug solution into the transient microporous structure through the capillary infusion groove, so that the drug solution forms an axial permeation path along the circumferential area of ​​the needle array conductive pillars. S5. After the stabilization frame is completed, the timing coupling control module controls the start of the intermediate frequency vector therapy module, and the phase switching plate switches the conduction state of the arc-shaped intermediate frequency electrode sheet according to the preset phase switching sequence, so that a rotating intermediate frequency vector field is formed inside the interlaced conduction layer, and a circumferential migration current channel is formed on the surface of the target skin area. S6. The rotating intermediate frequency vector field is magnetically deflected by the magnetic bias ring, so that the intermediate frequency current generates a rotating migration trajectory along a preset direction, and drives the liquid medicine inside the transient microporous structure to diffuse directionally along the superficial skin area. S7. The impedance analysis unit continuously collects the changes in epidermal impedance and dermal impedance. The synchronization locking unit adjusts the output sequence of the intermediate frequency commutation unit based on the difference between the changes in epidermal impedance and dermal impedance, and synchronously adjusts the pulse output rhythm of the array electro-aperture module. S8. After detecting that the target skin area has entered the impedance stable range, the pulse framing unit switches to the closed-hole frame output state, and controls the transient micropore structure to gradually close through the reverse attenuation pulse. At the same time, the intermediate frequency commutation unit reduces the intermediate frequency output amplitude to suppress heat accumulation at the micropore edge. S9. After the impedance analysis unit detects that the impedance of the target skin area has risen back to the preset closed range, the synchronization locking unit controls the drug micro-pressure delivery module to reduce the output pressure, so that the residual drug liquid inside the transient microporous structure is drawn back along the capillary infusion groove, and the output of the array electroporation module and the intermediate frequency vector therapy module is terminated. S10. The gradient thermal stability adjustment module forms a radial temperature difference isolation zone around the target skin area and maintains a stable thermal distribution between the array electroporation module and the mid-frequency vector therapy module, thereby completing the targeted percutaneous drug delivery process to the target skin area. Compared with the prior art, the advantages of the present invention are: (1) The array electroporation module and the mid-frequency vector therapy module are coupled in a time-sharing staggered peak structure to form a directional drug migration path during the transient micropore opening window period, which is different from the existing synchronous superposition drug delivery structure.

[0015] (2) An axial gradient pulse leading edge is formed by using a pulse convergence layer to form a convergence local electric field at the end of the needle array conductive pillar, which is different from the existing uniform diffusion electroporation structure.

[0016] (3) A rotating mid-frequency vector field structure is adopted, so that the mid-frequency current forms a circumferentially migrating drug-conducting field around the transient micropore, which is different from the existing linear mid-frequency stimulation method.

[0017] (4) A magnetic bias ring is used to deflect the rotating medium frequency vector field, so that the migration trajectory of the drug liquid forms a directional rotation path and reduces the disordered lateral diffusion of the drug liquid.

[0018] (5) A staged energy switching structure based on the slope of skin impedance decrease is adopted so that the output order of the array electroporation module and the mid-frequency vector therapy module can be dynamically switched according to the impedance change.

[0019] (6) A framed pulse structure consisting of pre-breakdown frames, stable aperture frames, and closed aperture frames is adopted to achieve independent control of the transient micro-aperture opening, maintenance, and closing stages.

[0020] (7) A composite drug-conducting field coupling structure is adopted to synchronously couple the pulse electric field, the rotating intermediate frequency current field, the magnetic bias field and the thermal gradient field to form a directional migration drug-conducting mechanism. Attached Figure Description

[0021] Figure 1 This is a schematic diagram of the overall module of the targeted percutaneous drug delivery system combining electroporation and mid-frequency physiotherapy of the present invention; Figure 2 This is a schematic diagram of the overall process of the targeted percutaneous drug delivery system combining electroporation and mid-frequency physiotherapy of the present invention. Detailed Implementation

[0022] For examples, please refer to Figures 1-2 The targeted percutaneous drug delivery system combining electroporation and mid-frequency physiotherapy includes a shell support module, an array electroporation module, a mid-frequency vector physiotherapy module, a drug micro-pressure delivery module, a skin impedance acquisition module, a timing coupling control module, a gradient thermal stability adjustment module, and a closed-loop energy supply module. The housing support module includes an upper encapsulation cavity, a middle wire isolation cavity, and a bottom bonding cavity. An array electroporation module is embedded in the central area of ​​the bottom bonding cavity. A mid-frequency vector therapy module is coaxially arranged around the array electroporation module. A drug micro-pressure delivery module runs longitudinally through the interior of the housing support module and communicates with the microporous drug delivery cavity of the array electroporation module. A skin impedance acquisition module is connected to both the array electroporation module and the timing coupling control module. The timing coupling control module uses a segmented peak-shifting method to control the alternating output of the array electroporation module and the mid-frequency vector therapy module. A gradient thermal stability adjustment module is located between the array electroporation module and the mid-frequency vector therapy module, forming a radial temperature difference isolation zone. A closed-loop energy supply module is connected to the array electroporation module, the mid-frequency vector therapy module, the skin impedance acquisition module, and the timing coupling control module, forming a synchronous coupling structure of pulse perforation and mid-frequency directional drive based on changes in skin transient impedance. There is a phase interval of 0.8 milliseconds to 6 milliseconds between the output phase of the array electroporation module and the output phase of the mid-frequency vector physiotherapy module. After the output phase of the array electroporation module ends, the drug micro-pressure transport module starts axial drug propulsion to form a directional drug migration path during the micropore opening window.

[0023] Specifically, in this embodiment, the gradient thermal stability adjustment module is disposed in the annular spacer layer between the array electroporation module and the mid-frequency vector therapy module, and forms a thermal-electric composite isolation structure with the middle wire isolation cavity of the housing support module, so as to achieve spatial decoupling between the high transient heat of the electroporation and the continuous heat of the mid-frequency.

[0024] The gradient thermal stability adjustment module includes a heat-conducting layer, a phase change buffer layer, a heat insulation and blocking layer, and a micro-circulation heat dissipation layer, which are stacked sequentially from bottom to top.

[0025] The thermally conductive layer is attached to the outer peripheral surface of the array electro-optical aperture module. The thermally conductive layer is made of a high thermal conductivity ceramic composite substrate, which is used to quickly absorb the transient local heat generated by the array electro-optical aperture module during the pulse output stage and diffuse it uniformly in the radial direction.

[0026] A phase change buffer layer is placed above the heat-conducting layer. The phase change buffer layer is made of phase change temperature control material. During the output stage of the electroporation hole, a solid-liquid phase change occurs to absorb heat, and during the output stage of the medium-frequency physiotherapy, a liquid-solid phase change occurs to release heat, thereby smoothing the temperature fluctuation over time.

[0027] A thermal insulation barrier layer is placed above the phase change buffer layer. The thermal insulation barrier layer is made of a low thermal conductivity aerogel structural material to block the axial heat conduction path between the array electroporation module and the mid-frequency vector physiotherapy module, thereby forming the main structural boundary of the radial thermal gradient isolation zone.

[0028] The microcirculation heat dissipation layer is located outside the heat insulation barrier layer and close to the mid-frequency vector therapy module. The microcirculation heat dissipation layer has a closed-loop microchannel structure inside, which is connected to the heat dissipation circuit inside the shell support module to conduct residual heat to the external environment and achieve continuous thermal balance control.

[0029] In terms of structural installation, the gradient thermal stability adjustment module is an overall ring-shaped sandwich structure embedded in the coaxial gap area between the array electroporation module and the mid-frequency vector therapy module. Its radial inner side is closely attached to the outer peripheral insulating shell of the array electroporation module, and its radial outer side is attached to the electrode support ring of the mid-frequency vector therapy module. This allows the gradient thermal stability adjustment module to simultaneously cover the interface between the transient heat source area of ​​the electroporation module and the continuous heat source area of ​​the mid-frequency module in space, thereby forming a stable radial temperature difference isolation zone structure.

[0030] Specifically, the skin impedance acquisition module acquires transient impedance change data of the target skin area using high-frequency continuous sampling, and inputs the impedance change rate, impedance minimum point, and rise slope as control parameters to the timing coupling control module. The timing coupling control module determines whether the micropores enter the steady-state conduction window based on the impedance change rate, and uses this window as the sole trigger condition for starting the mid-frequency vector therapy module. The impedance acquisition data is also used to adjust the pulse output interval of the array electroporation module to achieve synchronous control of the micropore opening state and the electric field output rhythm.

[0031] Specifically, the closed-loop energy supply module includes a graded energy distribution unit and a dynamic power reconfiguration unit. The graded energy distribution unit dynamically adjusts the power supply priority of the array electroporation module and the mid-frequency vector therapy module based on the real-time impedance change data output by the skin impedance acquisition module.

[0032] When skin impedance is decreasing, the array electroporation module receives priority power to form stable micropore channels. When skin impedance enters a low-resistance plateau, the mid-frequency vector therapy module receives increased energy allocation to enhance directional current migration. The dynamic power reconfiguration unit reconfigures and adjusts the output power according to the impedance change rate, ensuring that the overall system energy output is synchronized with the skin conductivity state.

[0033] Specifically, the timing-coupled control module establishes a three-stage timing model based on impedance change curves, including a micropore formation stage, a low-resistance conduction stage, and a pore closure recovery stage, each corresponding to a different module output strategy. In the micropore formation stage, the output of the array electro-orifice module is prioritized; in the low-resistance conduction stage, the intermediate-frequency vector therapy module and the drug micro-pressure delivery module are synchronously activated; in the pore closure recovery stage, all output modules are gradually attenuated until they are shut down. The timing-coupled control module automatically identifies the switching nodes of each stage through impedance change inflection points, achieving an adaptive control mechanism with non-fixed-time triggering.

[0034] The array electroporation module includes a ceramic insulating substrate, a needle array of conductive pillars, an annular confinement electrode layer, a microgroove reservoir, and a pulse convergence layer. The ceramic insulating substrate employs an aluminum nitride sintered structure. The needle array of conductive pillars is fixed to the surface of the ceramic insulating substrate in a hexagonal close-packed structure. The annular confinement electrode layer covers the outer periphery of the needle array of conductive pillars. The microgroove reservoir is formed between adjacent needle array conductive pillars. The pulse convergence layer is disposed inside the ceramic insulating substrate and electrically connected to the needle array of conductive pillars to form a radially converged pulsed electric field. A capillary infusion groove is formed at the bottom of the microgroove reservoir, which is connected to the drug micro-pressure delivery module. An electric field shielding boundary is formed on the outer side of the annular confinement electrode layer to limit the lateral diffusion of the pulsed electric field along the skin surface.

[0035] The needle array conductive pillars adopt a titanium-iridium composite sintered structure. The top of the needle array conductive pillars forms a hemispherical puncture end. The length of the needle array conductive pillars is 0.45 mm to 0.85 mm, and the spacing between the needle array conductive pillars is 0.18 mm to 0.42 mm. An insulating gap of 15 micrometers to 45 micrometers is formed between the annular confinement electrode layer and the needle array conductive pillars. The pulse convergence layer adopts a multi-layer spiral copper foil stacked structure. Axial conductive ridges are formed inside the needle array conductive pillars. The axial conductive ridges extend spirally along the length of the needle array conductive pillars. A nano-coarsening layer is formed on the surface of the hemispherical puncture end to improve the local field strength concentration during pulse release.

[0036] The pulse convergence layer comprises a primary pulse ring, a secondary delay ring, and a tertiary reflection ring. The primary pulse ring is directly electrically connected to the conductive pillars of the needle array. The secondary delay ring is arranged around the outer side of the primary pulse ring, and the tertiary reflection ring is arranged around the outer periphery of the secondary delay ring. Phase delay regions are formed between the primary pulse ring, the secondary delay ring, and the tertiary reflection ring to form an axial gradient pulse leading edge at the output end of the conductive pillars of the needle array. The primary pulse ring adopts a low-resistivity copper-nickel composite layer structure, the secondary delay ring adopts a high-resistivity molybdenum alloy layer structure, and the tertiary reflection ring adopts a closed silver paste conductive layer structure. The phase delay regions are filled with a silicon dioxide insulating dielectric layer to form a layered pulse wavefront compression path.

[0037] The mid-frequency vector therapy module includes an arc-shaped mid-frequency electrode, an interlaced conductive layer, a magnetic bias ring, and a phase switching plate. The arc-shaped mid-frequency electrode is distributed in a ring around the outer periphery of the array electroporation module. The interlaced conductive layer is located below the arc-shaped mid-frequency electrode. The magnetic bias ring is fixed to the periphery of the arc-shaped mid-frequency electrode. The phase switching plate connects the arc-shaped mid-frequency electrode and the timing coupling control module to form a rotating mid-frequency vector field. The inner edge of the arc-shaped mid-frequency electrode forms a current-guiding surface, the interior of the interlaced conductive layer forms a circumferential conductive channel, and the magnetic bias ring forms alternating magnetic poles along the circumference to create a deflection-type current migration trajectory in the superficial skin region.

[0038] There are eight sets of arc-shaped intermediate frequency electrode sheets, with an angle of 22 to 38 degrees between adjacent arc-shaped intermediate frequency electrode sheets. The staggered conduction layer adopts a silver-carbon alternating deposition structure, the magnetic bias ring adopts a neodymium iron boron closed-loop magnet structure, and the phase switching plate adopts a four-quadrant bridge commutation structure to form a circumferential migration current channel on the skin surface. Among them, the four-quadrant bridge commutation structure switches the phase output sequentially in a clockwise direction. The silver deposition layer and carbon deposition layer inside the staggered conduction layer form an alternating impedance region to make the intermediate frequency current rotate and migrate along the preset direction.

[0039] The timing coupling control module includes an impedance analysis unit, a pulse framing unit, an intermediate frequency commutation unit, and a synchronization locking unit. The impedance analysis unit is connected to the skin impedance acquisition module, the pulse framing unit is connected to the array electroporation module, the intermediate frequency commutation unit is connected to the intermediate frequency vector therapy module, and the synchronization locking unit is connected to the impedance analysis unit, the pulse framing unit, and the intermediate frequency commutation unit, respectively, to form a staged energy switching structure based on the skin impedance decrease slope. The impedance analysis unit employs a dual-channel sampling structure, corresponding to the epidermal impedance sampling path and the dermal impedance sampling path, respectively. The synchronization locking unit adjusts the output sequence of the intermediate frequency commutation unit based on the difference between the changes in epidermal impedance and dermal impedance.

[0040] The pulse framing unit divides the output pulse into pre-breakdown frames, stabilization frames, and closure frames. The pulse width of the pre-breakdown frame is 20 microseconds to 80 microseconds, the pulse width of the stabilization frame is 100 microseconds to 400 microseconds, and the pulse width of the closure frame is 5 microseconds to 25 microseconds. The intermediate frequency commutation unit switches the conduction direction of the arc-shaped intermediate frequency electrode within 3 milliseconds to 15 milliseconds after the stabilization frame ends to form a directional drug flow driving structure during the channel maintenance period. Among them, the pre-breakdown frame adopts a stepped voltage rise structure, the stabilization frame adopts a constant voltage pulse structure, and the closure frame adopts a reverse decay pulse structure. The intermediate frequency commutation unit reduces the intermediate frequency output amplitude before the closure frame starts to suppress heat accumulation at the micropore edge.

[0041] The synchronous locking unit adopts a dual-crystal frequency-locking structure. An impedance threshold matrix is ​​set inside the synchronous locking unit. The impedance threshold matrix is ​​divided into an activation zone, an introduction zone, and a closure zone according to the skin impedance decrease rate. The synchronous locking unit switches the output order of the array electroporation module and the mid-frequency vector therapy module according to the impedance threshold matrix to complete the directional migration of drugs before the micropores close. Among them, the activation zone corresponds to the impedance decrease rate in the pre-breakdown stage, the introduction zone corresponds to the impedance stabilization range in the pore stabilization stage, and the closure zone corresponds to the impedance recovery range in the pore closure stage. When the closure zone is activated, the synchronous locking unit controls the drug micro-pressure transport module to reduce the output pressure to form a residual drug reabsorption structure in the micropore closure stage.

[0042] A targeted percutaneous drug delivery method combining electroporation and mid-frequency physiotherapy, for realizing the targeted percutaneous drug delivery system combining electroporation and mid-frequency physiotherapy as described in any one of claims 1-9, includes the following steps: S1. The housing support module is attached to the surface of the target skin area, the array electroporation module is located at the center of the target drug delivery area, the mid-frequency vector therapy module surrounds the target drug delivery area, and the initial impedance data of the target drug delivery area is collected through the skin impedance acquisition module. S2. The timing coupling control module establishes an impedance reference range based on the initial impedance data and controls the closed-loop energy supply module to output a pre-breakdown frame pulse to the array electroporation module, so that the needle array conductive pillars form an initial transient microporous structure in the target skin area. S3. After the pre-breakdown frame pulse output ends, the pulse framing unit switches to the stable aperture frame output state, so that the first-level pulse ring, the second-level delay ring and the third-level reflection ring in the pulse convergence layer form the axial gradient pulse leading edge in sequence, and form a radial convergence pulse electric field at the output end of the needle array conductive column to maintain the transient micro-aperture structure in a stable open state. S4. During the stable hole frame output stage, the drug micro-pressure transport module delivers the drug solution to the micro-groove storage cavity, and introduces the drug solution into the transient microporous structure through the capillary infusion groove, so that the drug solution forms an axial permeation path along the circumferential area of ​​the needle array conductive pillars. S5. After the stabilization frame is completed, the timing coupling control module controls the start of the intermediate frequency vector therapy module. The phase switching board switches the conduction state of the arc-shaped intermediate frequency electrode sheet according to the preset phase switching sequence, so that a rotating intermediate frequency vector field is formed inside the interlaced conduction layer, and a circumferential migration current channel is formed on the surface of the target skin area. S6. The rotating intermediate frequency vector field is magnetically deflected by the magnetic bias ring, so that the intermediate frequency current generates a rotating migration trajectory along the preset direction, and drives the drug liquid inside the transient microporous structure to diffuse directionally along the superficial skin area; S7. The impedance analysis unit continuously collects the changes in epidermal impedance and dermal impedance. The synchronization locking unit adjusts the output sequence of the intermediate frequency commutation unit based on the difference between the changes in epidermal impedance and dermal impedance, and synchronously adjusts the pulse output rhythm of the array electro-optic module. S8. After the target skin area is detected to have entered the impedance stable range, the pulse framing unit switches to the closed-hole frame output state and controls the transient micropore structure to gradually close through the reverse attenuation pulse. At the same time, the intermediate frequency commutation unit reduces the intermediate frequency output amplitude to suppress heat accumulation at the micropore edge. S9. After the impedance analysis unit detects that the impedance of the target skin area has risen back to the preset closed range, the synchronous locking unit controls the drug micro-pressure delivery module to reduce the output pressure, so that the residual drug liquid inside the transient microporous structure is drawn back along the capillary infusion groove, and the output of the array electroporation module and the medium frequency vector therapy module is terminated. S10. The gradient thermal stability adjustment module forms a radial temperature difference isolation zone around the target skin area and maintains a stable thermal distribution between the array electroporation module and the mid-frequency vector therapy module to complete the targeted percutaneous drug delivery process to the target skin area.

[0043] Specifically, the system identifies the effective conduction window of the micropores based on the rate of change in skin impedance, and defines this window as the only effective time interval for activating the mid-frequency vector therapy module. When the rate of impedance decrease approaches zero and enters a stable plateau state, the system determines that the micropores have entered the optimal drug delivery window, thereby triggering the activation of the mid-frequency vector therapy module. Before the end of the window period, the system reduces the mid-frequency output amplitude in advance based on the impedance recovery trend to achieve smooth attenuation of the drug delivery path.

[0044] Specifically, the magnetic bias ring alters the directional distribution of the equivalent conductivity of the skin surface, causing a directional shift in the mid-frequency current path. This shift, combined with the microporous conductive channels formed by the electro-induced apertures, creates a superimposed migration path. Drugs preferentially migrate along the low-resistance conductive direction within this superimposed path, thereby achieving asymmetric directional diffusion control.

[0045] Specifically, as the pore-closing frame is triggered, the micropore structure gradually contracts and forms an impedance recovery gradient. This gradient causes the local current path to gradually break, thus causing the drug migration channel to decay naturally. During this stage, the mid-frequency vector therapy module simultaneously reduces its output amplitude to avoid local energy accumulation in the pore-closing edge region.

[0046] Specifically, as skin impedance rises back to the closed range, the system generates a reverse pressure gradient, which drives the drug micro-pressure delivery module to produce a backflow effect. The backflow process occurs synchronously with the closure of the micropores, thereby reducing the retention of residual drug solution on the skin surface.

[0047] Specifically, the system is based on the low-resistance conductive channel formed during the transient micropore opening window of the skin. Driven by the dynamic change of impedance, it realizes a time-coupled closed-loop control mechanism between the electro-porous pulse field, the mid-frequency rotating vector field, the thermally stable regulation field and the drug micro-pressure transport.

[0048] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely preferred examples and are not intended to limit the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A targeted transdermal drug delivery system combining electroporation and intermediate frequency therapy, characterized in that, The targeted percutaneous drug delivery system combining electroporation and mid-frequency physiotherapy includes a housing support module, an array electroporation module, a mid-frequency vector physiotherapy module, a drug micro-pressure delivery module, a skin impedance acquisition module, a timing coupling control module, a gradient thermal stability adjustment module, and a closed-loop energy supply module. The housing support module includes an upper encapsulation cavity, a middle wire isolation cavity, and a bottom bonding cavity. The array electroporation module is embedded in the central region of the bottom bonding cavity. The mid-frequency vector therapy module is coaxially arranged around the array electroporation module. The drug micro-pressure delivery module runs longitudinally through the interior of the housing support module and communicates with the microporous drug delivery cavity of the array electroporation module. The skin impedance acquisition module is connected to both the array electroporation module and the timing coupling control module. The timing coupling control module uses a segmented peak-shifting method to control the alternating output of the array electroporation module and the mid-frequency vector therapy module. The gradient thermal stability adjustment module is located between the array electroporation module and the mid-frequency vector therapy module, forming a radial temperature difference isolation zone. The closed-loop energy supply module is connected to the array electroporation module, the mid-frequency vector therapy module, the skin impedance acquisition module, and the timing coupling control module, forming a synchronous coupling structure of pulse perforation and mid-frequency directional drive based on skin transient impedance changes. There is a phase interval of 0.8 milliseconds to 6 milliseconds between the output phase of the array electroporation module and the output phase of the mid-frequency vector therapy module. The drug micro-pressure transport module starts axial drug delivery after the output phase of the array electroporation module ends, so as to form a directional drug migration path during the micropore opening window period.

2. The target transdermal drug delivery system according to claim 1, wherein the electrically assisted iontophoresis is combined with the medium frequency therapy. The array electroporation module includes a ceramic insulating substrate, a needle array of conductive pillars, an annular confined electrode layer, a microgroove reservoir, and a pulse convergence layer. The ceramic insulating substrate employs an aluminum nitride sintered structure. The needle array of conductive pillars is fixed to the surface of the ceramic insulating substrate in a hexagonal close-packed structure. The annular confined electrode layer covers the outer periphery of the needle array of conductive pillars. The microgroove reservoir is formed between adjacent needle array of conductive pillars. The pulse convergence layer is disposed inside the ceramic insulating substrate and electrically connected to the needle array of conductive pillars to form a radially converged pulsed electric field. A capillary infusion groove is formed at the bottom of the microgroove reservoir, and the capillary infusion groove communicates with the drug micro-pressure delivery module. An electric field shielding boundary is formed on the outer side of the annular confined electrode layer to limit the lateral diffusion of the pulsed electric field along the skin surface.

3. The target transdermal drug delivery system combined electroporation with intermediate frequency physiotherapy according to claim 2, characterized in that, The needle array conductive pillars adopt a titanium-iridium composite sintered structure. A hemispherical puncture end is formed at the top of each needle array conductive pillar. The length of each needle array conductive pillar is 0.45 mm to 0.85 mm, and the spacing between each needle array conductive pillar is 0.18 mm to 0.42 mm. An insulating gap of 15 μm to 45 μm is formed between the annular confinement electrode layer and the needle array conductive pillars. The pulse convergence layer adopts a multi-layer spiral copper foil stacked structure. Axial conductive ridges are formed inside each needle array conductive pillar, and the axial conductive ridges extend spirally along the length of the needle array conductive pillars. A nano-coarsening layer is formed on the surface of the hemispherical puncture end to improve the local field strength concentration during pulse release.

4. The target transdermal drug delivery system combined electroporation with intermediate frequency physiotherapy of claim 3, wherein, The pulse convergence layer includes a primary pulse ring, a secondary delay ring, and a tertiary reflection ring. The primary pulse ring is directly electrically connected to the conductive pin array. The secondary delay ring surrounds the primary pulse ring. The tertiary reflection ring is disposed around the outer periphery of the secondary delay ring. Phase delay regions are formed between the primary pulse ring, the secondary delay ring, and the tertiary reflection ring to create an axial gradient pulse leading edge at the output end of the conductive pin array. The primary pulse ring employs a low-resistivity copper-nickel composite layer structure, the secondary delay ring employs a high-resistivity molybdenum alloy layer structure, and the tertiary reflection ring employs a closed silver paste conductive layer structure. The phase delay regions are filled with a silicon dioxide insulating dielectric layer to form a layered pulse wavefront compression path.

5. The targeted transdermal drug delivery system combining electroporation and mid-frequency physiotherapy according to claim 1, characterized in that, The mid-frequency vector therapy module includes an arc-shaped mid-frequency electrode sheet, an interleaved conductive layer, a magnetic bias ring, and a phase switching plate. The arc-shaped mid-frequency electrode sheet is distributed in a ring around the outer periphery of the array electroporation module. The interleaved conductive layer is disposed below the arc-shaped mid-frequency electrode sheet. The magnetic bias ring is fixed to the periphery of the arc-shaped mid-frequency electrode sheet. The phase switching plate connects the arc-shaped mid-frequency electrode sheet to the timing coupling control module to form a rotating mid-frequency vector field. The inner edge of the arc-shaped mid-frequency electrode sheet forms a current-guiding surface. The interleaved conductive layer forms a circumferential conductive channel. The magnetic bias ring forms alternating magnetic poles along the circumference to create a deflection-type current migration trajectory in the superficial skin region.

6. The targeted transdermal drug delivery system combining electroporation and mid-frequency physiotherapy according to claim 5, characterized in that, The number of arc-shaped intermediate frequency electrode sheets is eight, and the adjacent arc-shaped intermediate frequency electrode sheets form an angle of 22 degrees to 38 degrees. The staggered conductive layer adopts a silver-carbon alternating deposition structure, the magnetic bias ring adopts a neodymium iron boron closed-loop magnet structure, and the phase switching plate adopts a four-quadrant bridge commutation structure to form a circumferential migration current channel on the skin surface. The four-quadrant bridge commutation structure switches the phase output sequentially in a clockwise direction. The silver deposition layer and carbon deposition layer inside the staggered conductive layer form an alternating impedance region to make the intermediate frequency current rotate and migrate along a preset direction.

7. The targeted transdermal drug delivery system combining electroporation and mid-frequency physiotherapy according to claim 1, characterized in that, The timing coupling control module includes an impedance analysis unit, a pulse framing unit, an intermediate frequency commutation unit, and a synchronization locking unit. The impedance analysis unit is connected to the skin impedance acquisition module, the pulse framing unit is connected to the array electroporation module, the intermediate frequency commutation unit is connected to the intermediate frequency vector therapy module, and the synchronization locking unit is connected to the impedance analysis unit, the pulse framing unit, and the intermediate frequency commutation unit, respectively, to form a staged energy switching structure based on the skin impedance decrease slope. The impedance analysis unit employs a dual-channel sampling structure, corresponding to the epidermal impedance sampling path and the dermal impedance sampling path, respectively. The synchronization locking unit adjusts the output sequence of the intermediate frequency commutation unit based on the difference between the epidermal impedance change and the dermal impedance change.

8. The targeted transdermal drug delivery system combining electroporation and mid-frequency physiotherapy according to claim 7, characterized in that, The pulse framing unit divides the output pulse into a pre-breakdown frame, a stabilizing frame, and a closing frame. The pulse width of the pre-breakdown frame is 20 microseconds to 80 microseconds, the pulse width of the stabilizing frame is 100 microseconds to 400 microseconds, and the pulse width of the closing frame is 5 microseconds to 25 microseconds. The intermediate frequency commutation unit switches the conduction direction of the arc-shaped intermediate frequency electrode within 3 milliseconds to 15 milliseconds after the stabilizing frame ends to form a directional drug flow driving structure during the channel maintenance period. The pre-breakdown frame adopts a stepped voltage rise structure, the stabilizing frame adopts a constant voltage pulse structure, and the closing frame adopts a reverse decay pulse structure. The intermediate frequency commutation unit reduces the intermediate frequency output amplitude before the closing frame starts to suppress heat accumulation at the micropore edge.

9. The targeted transdermal drug delivery system combining electroporation and mid-frequency physiotherapy according to claim 8, characterized in that, The synchronization locking unit adopts a dual-crystal frequency-locking structure. An impedance threshold matrix is ​​set inside the synchronization locking unit. This matrix is ​​divided into an activation zone, an introduction zone, and a closure zone according to the skin impedance decrease rate. The synchronization locking unit switches the output order of the array electroporation module and the mid-frequency vector therapy module based on the impedance threshold matrix to complete the directional migration of drugs before the micropores close. The activation zone corresponds to the impedance decrease rate during the pre-breakdown stage, the introduction zone corresponds to the impedance stabilization range during the pore stabilization stage, and the closure zone corresponds to the impedance recovery range during the pore closure stage. When the closure zone is activated, the synchronization locking unit controls the drug micro-pressure transport module to reduce its output pressure to form a residual drug reabsorption structure during the micropore closure stage.

10. A targeted percutaneous drug delivery method combining electroporation and mid-frequency physiotherapy, characterized in that, To implement the targeted percutaneous drug delivery system combining electroporation and mid-frequency physiotherapy as described in any one of claims 1-9, the system comprises the following steps: S1. The housing support module is attached to the surface of the target skin area, the array electroporation module is located at the center of the target drug delivery area, the mid-frequency vector therapy module surrounds the target drug delivery area, and the initial impedance data of the target drug delivery area is collected through the skin impedance acquisition module. S2. The timing coupling control module establishes an impedance reference range based on the initial impedance data and controls the closed-loop energy supply module to output a pre-breakdown frame pulse to the array electroporation module, so that the needle array conductive pillars form an initial transient microporous structure in the target skin area. S3. After the pre-breakdown frame pulse output ends, the pulse framing unit switches to the stable aperture frame output state, so that the first-level pulse ring, the second-level delay ring and the third-level reflection ring in the pulse convergence layer sequentially form the axial gradient pulse leading edge, and form a radial convergence pulse electric field at the output end of the needle array conductive column, so as to maintain the transient micropore structure in a stable open state. S4. During the stable hole frame output stage, the drug micro-pressure transport module delivers the drug solution to the micro-groove storage cavity, and introduces the drug solution into the transient microporous structure through the capillary infusion groove, so that the drug solution forms an axial permeation path along the circumferential area of ​​the needle array conductive pillars. S5. After the stabilization frame is completed, the timing coupling control module controls the start of the intermediate frequency vector therapy module, and the phase switching plate switches the conduction state of the arc-shaped intermediate frequency electrode sheet according to the preset phase switching sequence, so that a rotating intermediate frequency vector field is formed inside the interlaced conduction layer, and a circumferential migration current channel is formed on the surface of the target skin area. S6. The rotating intermediate frequency vector field is magnetically deflected by the magnetic bias ring, so that the intermediate frequency current generates a rotating migration trajectory along a preset direction, and drives the liquid medicine inside the transient microporous structure to diffuse directionally along the superficial skin area. S7. The impedance analysis unit continuously collects the changes in epidermal impedance and dermal impedance. The synchronization locking unit adjusts the output sequence of the intermediate frequency commutation unit based on the difference between the changes in epidermal impedance and dermal impedance, and synchronously adjusts the pulse output rhythm of the array electro-aperture module. S8. After detecting that the target skin area has entered the impedance stable range, the pulse framing unit switches to the closed-hole frame output state, and controls the transient micropore structure to gradually close through the reverse attenuation pulse. At the same time, the intermediate frequency commutation unit reduces the intermediate frequency output amplitude to suppress heat accumulation at the micropore edge. S9. After the impedance analysis unit detects that the impedance of the target skin area has risen back to the preset closed range, the synchronization locking unit controls the drug micro-pressure delivery module to reduce the output pressure, so that the residual drug liquid inside the transient microporous structure is drawn back along the capillary infusion groove, and the output of the array electroporation module and the intermediate frequency vector therapy module is terminated. S10. The gradient thermal stability adjustment module forms a radial temperature difference isolation zone around the target skin area and maintains a stable thermal distribution between the array electroporation module and the mid-frequency vector therapy module to complete the targeted percutaneous drug delivery process to the target skin area.

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