Integrated double-frequency composite ultrasonic transducer, preparation method and transdermal drug delivery method

Abstract

The invention discloses an integrated double-frequency composite ultrasonic transducer, a preparation method and a transdermal drug delivery method. The ultrasonic transducer comprises a high-frequency piezoelectric layer, a low-frequency piezoelectric layer, an epoxy support material and an electrode group, the high-frequency piezoelectric layer and the low-frequency piezoelectric layer are coaxially nested, the low-frequency piezoelectric layer is of a flat annular structure, the high-frequency piezoelectric layer is of a flat circular structure, the high-frequency piezoelectric layer is located in a circular ring of the low-frequency piezoelectric layer, and an annular insulation gap completely filled with an epoxy supporting material is formed between the high-frequency piezoelectric layer and the low-frequency piezoelectric layer; the electrode group comprises a high-frequency piezoelectric layer positive electrode located on the first surface of the high-frequency piezoelectric layer, a low-frequency piezoelectric layer positive electrode located on the first surface of the low-frequency piezoelectric layer and a common-ground negative electrode located on the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer, and the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer are located on the same plane. The double-frequency ultrasonic integration is realized, the transdermal drug delivery operation process is simplified, and the double-frequency ultrasonic integration device is more suitable for a transdermal drug delivery scene.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of ultrasonic medical devices, and particularly relates to an integrated dual-frequency composite ultrasonic transducer, a preparation method and a transdermal drug delivery method. BACKGROUND

[0002] Transdermal drug delivery has become an important research direction in the field of medical devices due to its high safety, small side effects, strong patient compliance and other advantages. However, during transdermal drug delivery, macromolecules and hydrophilic drugs are difficult to be passively absorbed through the skin due to the barrier effect of the stratum corneum, which leads to low drug utilization rate of external drugs. Therefore, researchers have proposed physical / chemical enhancement technologies such as electroporation, iontophoresis and ultrasound penetration to break through the barrier of the stratum corneum and promote drug absorption.

[0003] The main mechanism of ultrasound penetration is cavitation effect, that is, bubbles are generated in liquid under the action of ultrasonic waves, and the generated bubbles and existing bubbles continuously grow, oscillate, break and release energy in the ultrasonic field. Ultrasound penetration is widely used in various drug delivery due to its non-invasiveness and low cost. However, the existing ultrasound penetration technology still has many deficiencies. The existing ultrasound penetration equipment mostly uses a single frequency ultrasonic transducer with a frequency of 20 kHz to 3 MHz. Under the condition of a certain power, low-frequency ultrasound (20 kHz to 0.7 MHz) has a low inertial cavitation threshold and is easy to cavitate to produce strong penetration effect, but it has high requirements for drug stability; while high-frequency ultrasound (0.7 MHz to 3 MHz) has low requirements for drug stability, but the penetration depth of high-frequency ultrasound is shallow, and higher power is required to achieve the same penetration effect as low-frequency ultrasound, and high power increases the risk of thermal damage. Therefore, the contradiction between the penetration effect and safety of single-frequency ultrasound leads to low efficiency and long time of drug delivery using single-frequency ultrasound.

[0004] Studies have shown that the combined action of ultrasonic waves with different frequencies can enhance the ultrasonic cavitation effect, therefore, a multi-frequency ultrasonic transducer has been proposed and applied in ultrasonic chemistry, tissue ablation and other fields. However, when multi-frequency ultrasound is applied to transdermal drug delivery, separate single-frequency ultrasonic transducers are usually used to achieve this, and the angle and position of the separate single-frequency ultrasonic transducers need to be strictly controlled during use, which is complex to operate and difficult to realize clinical transformation.

[0005] In summary, there is an urgent need in the art for an integrated multi-frequency composite ultrasonic transducer that is simple to operate and low in cost, so as to significantly improve the efficiency of transdermal drug delivery and simplify the operation process. SUMMARY

[0006] In order to solve the above problems existing in the prior art, the present application provides an integrated dual-frequency composite ultrasonic transducer, a preparation method and a transdermal drug delivery method.

[0007] The technical problems to be solved by the present application are achieved by the following technical solutions. In a first aspect, the present application provides an integrated dual-frequency composite ultrasonic transducer, comprising: a high-frequency piezoelectric layer, a low-frequency piezoelectric layer, an epoxy support material, and an electrode group. The high-frequency piezoelectric layer and the low-frequency piezoelectric layer are coaxially nested, the low-frequency piezoelectric layer has a flat circular ring structure, the high-frequency piezoelectric layer has a flat circular structure, and the high-frequency piezoelectric layer is located within the circular ring of the low-frequency piezoelectric layer. An annular insulating gap is provided between the high-frequency piezoelectric layer and the low-frequency piezoelectric layer, and the annular insulating gap is completely filled with the epoxy support material. The electrode group includes a high-frequency piezoelectric layer positive electrode on the first surface of the high-frequency piezoelectric layer, a low-frequency piezoelectric layer positive electrode on the first surface of the low-frequency piezoelectric layer, and a common ground negative electrode on the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer, and the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer are located in the same plane.

[0008] Optionally, the thickness of the high-frequency piezoelectric layer is set according to its resonant frequency range, which is 1MHz-3MHz, and the thickness of the low-frequency piezoelectric layer is set according to its resonant frequency range, which is 20kHz-700kHz; the radial thickness of the annular insulating gap is 0.1mm-1mm.

[0009] Optionally, the materials of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer are one or more combinations of PZT-4, PZT-5, PZT-8, PZT-based composite materials, and doped modified lead-free ceramics.

[0010] Optionally, the second surfaces of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer are covered with a biocompatible matching layer; and the epoxy support material is embedded with a temperature sensor and / or a pressure sensor.

[0011] Optionally, it further comprises a metal shell and two BNC interfaces. The high-frequency piezoelectric layer, the low-frequency piezoelectric layer, the epoxy support material, and the electrode group are accommodated in the cavity formed by the metal shell, and the cavity gap is also filled with another part of the epoxy support material; the metal shell is provided with a negative electrode opening and a positive electrode opening, and the common ground negative electrode is embedded in the negative electrode opening. The inner cores of the two BNC interfaces are respectively connected to the high-frequency piezoelectric layer positive electrode and the low-frequency piezoelectric layer positive electrode through the positive electrode opening.

[0012] Optionally, the outer surface of the metal shell is provided with a cooling fin.

[0013] The application provides a kind of integrated dual-frequency composite ultrasonic transducer, the high-frequency piezoelectric layer and low-frequency piezoelectric layer of the ultrasonic transducer coaxial nesting, wherein, high-frequency piezoelectric layer is flat circular structure, low-frequency piezoelectric layer is flat circular ring structure, high-frequency piezoelectric layer is located in the circular ring of low-frequency piezoelectric layer, and annular insulation gap is provided between the two, and the two are axisymmetric and do not interfere with each other, the ultrasonic transducer also has independent high-frequency piezoelectric layer positive pole, independent low-frequency piezoelectric layer positive pole and common ground negative pole.The application realizes dual-frequency ultrasonic integration in limited volume, and realizes the independent driving of high-frequency ultrasonic and low-frequency ultrasonic, so as to simplify the operation process of ultrasonic transducer, without excessive adjustment and position.And, by designing high-frequency piezoelectric layer and low-frequency piezoelectric layer as flat structure, the cost is greatly reduced and the preparation process is simpler, good heat dissipation effect is obtained, and it is more suitable for transdermal drug delivery scene.In addition, the high-frequency ultrasonic and low-frequency ultrasonic of the application share the same acoustic axis, and the sound beams are coaxially coincident, so that the pointing deviation and energy loss caused by the traditional dual-frequency ultrasonic transducer are avoided.

[0014] In a second aspect, the application provides a preparation method of an integrated dual-frequency composite ultrasonic transducer, comprising: providing a high-frequency piezoelectric layer and a low-frequency piezoelectric layer; the low-frequency piezoelectric layer is flat circular ring structure, and the high-frequency piezoelectric layer is flat circular structure; depositing a metal film on the first surface of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer to form a positive electrode conductive layer, and connecting a wire to the positive electrode conductive layer; placing the high-frequency piezoelectric layer in the circular ring of the low-frequency piezoelectric layer to form a coaxial nesting structure; wherein the radius of the high-frequency piezoelectric layer is smaller than the inner radius of the low-frequency piezoelectric layer, so that an annular gap is formed between the high-frequency piezoelectric layer and the low-frequency piezoelectric layer; mechanically fixing the high-frequency piezoelectric layer and the low-frequency piezoelectric layer, and placing the fixed high-frequency piezoelectric layer and low-frequency piezoelectric layer into a metal shell; the metal shell is provided with a negative electrode opening and a positive electrode opening, and the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer are opposite to and flush with the negative electrode opening; leading the wire out through the positive electrode opening, and pouring epoxy support material into the metal shell through the positive electrode opening and curing; wherein a part of the epoxy support material in the annular gap forms an annular insulation gap; depositing a metal film on the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer at the negative electrode opening to form a common ground negative electrode.

[0015] The application provides a preparation method of the integrated dual-frequency composite ultrasonic transducer.

[0016] In a third aspect, the application provides a transdermal drug delivery method using the integrated dual-frequency composite ultrasonic transducer, which comprises: mixing the water-soluble drug with the ultrasonic coupling agent to form a drug-coupling agent mixture; uniformly applying the drug-coupling agent mixture to the skin treatment area; mounting the ultrasonic transducer on the skin treatment area so that the common ground negative electrode of the ultrasonic transducer directly contacts the skin treatment area or contacts the skin treatment area through a biocompatible matching layer; stimulating the high-frequency piezoelectric layer and the low-frequency piezoelectric layer in the ultrasonic transducer in sequence through time-division multiplexing to generate high-frequency ultrasonic waves and low-frequency ultrasonic waves acting on the skin treatment area, thereby realizing transdermal drug delivery.

[0017] Optionally, time-division multiplexing is realized by adjusting the action time sequence and action frequency of the high-frequency ultrasonic waves and the low-frequency ultrasonic waves.

[0018] The application also discloses a transdermal drug delivery method using the integrated dual-frequency composite ultrasonic transducer, which generates high-frequency ultrasonic waves and low-frequency ultrasonic waves in sequence through time-division multiplexing. The high-frequency ultrasonic waves generate more microbubbles, and the low-frequency ultrasonic waves promote bubble growth and breakage to release more energy, thereby significantly enhancing the cavitation effect, improving skin permeability, and improving the treatment effect of transdermal drug delivery. In addition, the application avoids the risk of thermal damage caused by long-term use of high-frequency ultrasonic waves through time-division multiplexing, and has higher safety and stability.

[0019] The application will be further described in detail below with reference to the accompanying drawings and embodiments. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 is a half-section structural schematic diagram of an integrated dual-frequency composite ultrasonic transducer provided by an embodiment of the application; Figure 2 is a physical diagram of an integrated dual-frequency composite ultrasonic transducer provided by an embodiment of the application; Figure 3 is a flowchart of a preparation method of an integrated dual-frequency composite ultrasonic transducer provided by an embodiment of the application; Figure 4is an experimental schematic diagram of transdermal drug delivery effect verification of an integrated dual-frequency composite ultrasonic transducer provided by an embodiment of the present application; Figure 5 is an experimental effect diagram of transdermal drug delivery effect verification of an integrated dual-frequency composite ultrasonic transducer provided by an embodiment of the present application; Figure 6 is an experimental result of transdermal drug delivery effect verification of an integrated dual-frequency composite ultrasonic transducer provided by an embodiment of the present application; Reference signs: 11, high-frequency piezoelectric layer; 12, low-frequency piezoelectric layer; 13, epoxy support material; 14, common ground negative electrode; 151, high-frequency piezoelectric layer positive electrode; 152, low-frequency piezoelectric layer positive electrode. DETAILED DESCRIPTION

[0021] The present application will be further described in detail below in conjunction with specific embodiments, but the embodiments of the present application are not limited thereto.

[0022] In order to realize an integrated, easy-to-operate and low-cost multi-frequency composite ultrasonic transducer applied in the field of transdermal drug delivery, and improve the transdermal drug delivery efficiency and drug delivery effect, an integrated dual-frequency composite ultrasonic transducer, a preparation method and a transdermal drug delivery method are provided by an embodiment of the present application.

[0023] Embodiment one The integrated dual-frequency composite ultrasonic transducer provided by the embodiment of the present application, referring to Figure 1 , comprises a high-frequency piezoelectric layer 11, a low-frequency piezoelectric layer 12, an epoxy support material 13 and an electrode group. Among them, the high-frequency piezoelectric layer 11 and the low-frequency piezoelectric layer 12 are coaxially nested, the low-frequency piezoelectric layer 12 is a flat circular ring structure, the high-frequency piezoelectric layer 11 is a flat circular structure, and the high-frequency piezoelectric layer 11 is located in the circular ring of the low-frequency piezoelectric layer 12.

[0024] An annular insulating gap filled completely by the epoxy support material 13 is arranged between the high-frequency piezoelectric layer 11 and the low-frequency piezoelectric layer 12.

[0025] The electrode group comprises a high-frequency piezoelectric layer positive electrode 151 located on the first surface of the high-frequency piezoelectric layer, a low-frequency piezoelectric layer positive electrode 152 located on the first surface of the low-frequency piezoelectric layer, and a common ground negative electrode 14 located on the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer, the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer are located in the same plane.

[0026] In an optional implementation, the material of the high-frequency piezoelectric layer 11 and the low-frequency piezoelectric layer 12 is a combination of one or more of PZT-4, PZT-5, PZT-8, PZT-based composite material and doped modified lead-free ceramic. The PZT-based composite material can include 1-3 type PZT-8 / PDMS flexible piezoelectric composite material, but is not limited thereto.

[0027] In an optional implementation, the thickness of the high-frequency piezoelectric layer 11 is set according to its resonant frequency range, which is 1MHz-3MHz, and the thickness of the low-frequency piezoelectric layer 12 is set according to its resonant frequency range, which is 20kHz-700kHz. The radial thickness of the annular insulating gap is 0.1mm~1mm.

[0028] Specifically, the resonant frequencies of the high-frequency piezoelectric layer 11 and the low-frequency piezoelectric layer 12 are determined according to application requirements, and then the thicknesses of the high-frequency piezoelectric layer 11 and the low-frequency piezoelectric layer 12 are determined according to the materials thereof, respectively.

[0029] In an optional implementation, the material of the high-frequency piezoelectric layer positive electrode 151, the low-frequency piezoelectric layer positive electrode 152 and the common ground negative electrode 14 is preferably gold, silver or copper.

[0030] In an optional implementation, the epoxy support material 13 can be 1080 epoxy, but the material of the epoxy support material 13 in practice is not limited thereto, for example, the epoxy support material 13 can also be 301 epoxy resin.

[0031] Specifically, by setting an annular insulating gap between the high-frequency piezoelectric layer 11 and the low-frequency piezoelectric layer 12 and filling with an epoxy support material, the independence of high-frequency signals and low-frequency signals can be maintained, mutual interference can be reduced, and the performance of the entire ultrasonic transducer can be improved.

[0032] In an optional implementation, the second surface of the high-frequency piezoelectric layer 11 and the low-frequency piezoelectric layer 12 can also be covered with a biocompatible matching layer to improve the transmission efficiency of sound waves.

[0033] Further, the epoxy support material 13 can also be embedded with a temperature sensor and / or a pressure sensor for real-time monitoring of temperature and / or pressure changes during operation of the ultrasonic transducer, so as to timely adjust the ultrasonic transducer and improve the safety and stability of the ultrasonic transducer.

[0034] In an optional implementation, referring to Figure 2 , the ultrasonic transducer can further include a metal shell and two BNC interfaces.

[0035] The high-frequency piezoelectric layer 11, the low-frequency piezoelectric layer 12, the epoxy support material 13 and the electrode group are accommodated in the cavity formed by the metal shell, and the cavity gap is also filled with another part of the epoxy support material 13. The metal shell is provided with a negative electrode opening and a positive electrode opening, and the common ground negative electrode 14 is embedded in the negative electrode opening. The inner cores of the two BNC interfaces are connected with the high-frequency piezoelectric layer positive electrode 151 and the low-frequency piezoelectric layer positive electrode 152 respectively through the positive electrode opening.

[0036] Specifically, the high-frequency piezoelectric layer 11, the low-frequency piezoelectric layer 12, the epoxy support material 13 and the electrode group are accommodated in the cavity of the metal shell, and the common ground negative electrode 14 and the negative electrode opening of the metal shell are located in the same plane. The high-frequency piezoelectric layer positive electrode 151 and the low-frequency piezoelectric layer positive electrode 152 are led out from the positive electrode opening of the metal shell through wires and connected with the inner cores of the two BNC interfaces. The cavity gap of the metal shell is filled with the epoxy support material 13, that is, the epoxy support material 13 covers the surfaces of the high-frequency piezoelectric layer positive electrode 151 and the low-frequency piezoelectric layer positive electrode 152, and the epoxy support material 13 covers the outer surface of the low-frequency piezoelectric layer 12. Exemplarily, the material of the metal shell is stainless steel, aluminum or copper, etc.

[0037] Optionally, the outer surface of the metal shell can also be provided with a heat sink for heat dissipation of the ultrasonic transducer.

[0038] The present application provides an integrated dual-frequency composite ultrasonic transducer, which has a coaxial nesting of a high-frequency piezoelectric layer and a low-frequency piezoelectric layer. The high-frequency piezoelectric layer is a flat circular structure, and the low-frequency piezoelectric layer is a flat circular ring structure. The high-frequency piezoelectric layer is located in the circular ring of the low-frequency piezoelectric layer, and an annular insulating gap is arranged between the two. The two are axisymmetric and do not interfere with each other. The ultrasonic transducer also has an independent high-frequency piezoelectric layer positive electrode, an independent low-frequency piezoelectric layer positive electrode and a common ground negative electrode. The present application realizes dual-frequency ultrasonic integration in a limited volume, and realizes independent driving of high-frequency ultrasonic and low-frequency ultrasonic, thereby simplifying the operation process of the ultrasonic transducer, without the need for excessive adjustment and position. Moreover, the present application designs the high-frequency piezoelectric layer and the low-frequency piezoelectric layer as flat structures, greatly reducing the cost and making the preparation process simpler, and achieving good heat dissipation effect, which is more suitable for transdermal drug delivery scenarios. In addition, the high-frequency ultrasonic and the low-frequency ultrasonic of the present application share the same acoustic axis, and the sound beams are coaxially coincident, thereby avoiding the pointing deviation and energy loss caused by the traditional dual-frequency ultrasonic transducer. At the same time, the ultrasonic transducer has a large area of radiation surface, which is suitable for skin disease treatment, medical cosmetology and other clinical applications requiring large-area transdermal drug delivery.

[0039] Embodiment two Based on the same inventive concept as the above-mentioned integrated dual-frequency composite ultrasonic transducer, the present application embodiment also provides a preparation method of the integrated dual-frequency composite ultrasonic transducer, which is described in detail below. Figure 3 The preparation method comprises the following steps: Step 1: providing a high-frequency piezoelectric layer and a low-frequency piezoelectric layer. The low-frequency piezoelectric layer is a flat circular ring structure, and the high-frequency piezoelectric layer is a flat circular structure.

[0040] In this embodiment, optionally, one or more combinations of PZT-4, PZT-5, PZT-8, PZT-based composite materials and doped modified lead-free ceramics are selected as the high-frequency piezoelectric layer and the low-frequency piezoelectric layer, and a plasma surface treatment system is used to clean the surfaces of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer. The thickness of the high-frequency piezoelectric layer is set according to its resonant frequency range, which is 1 MHz-3 MHz, and the thickness of the low-frequency piezoelectric layer is set according to its resonant frequency range, which is 20 kHz-700 kHz.

[0041] For example, when preparing an integrated dual-frequency composite ultrasonic transducer with a high-frequency ultrasonic resonant frequency of 2 MHz and a low-frequency ultrasonic resonant frequency of 400 kHz, PZT-4 is selected as the high-frequency piezoelectric layer and the low-frequency piezoelectric layer, wherein the diameter of the high-frequency piezoelectric layer is 14.8 mm, and the thickness is 1 mm, and the outer diameter of the low-frequency piezoelectric layer is 38 mm, the inner diameter is 15 mm, and the thickness is 5 mm.

[0042] Step 2: depositing a metal thin film on the first surface of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer to form a positive electrode conductive layer, and connecting a wire to the positive electrode conductive layer.

[0043] For example, an electrode sputtering system is used to deposit a gold thin film on one side of each of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer to form a positive electrode conductive layer, i.e. a high-frequency piezoelectric layer positive electrode and a low-frequency piezoelectric layer positive electrode, and a wire is connected to each of the high-frequency piezoelectric layer positive electrode and the low-frequency piezoelectric layer positive electrode to realize electrical signal extraction.

[0044] Step 3: placing the high-frequency piezoelectric layer inside the circular ring of the low-frequency piezoelectric layer to form a coaxial nested structure, wherein the radius of the high-frequency piezoelectric layer is smaller than the inner radius of the low-frequency piezoelectric layer, so that an annular gap is formed between the high-frequency piezoelectric layer and the low-frequency piezoelectric layer.

[0045] For example, the high-frequency piezoelectric layer is placed inside the circular ring of the low-frequency piezoelectric layer to form a coaxial nested structure, so that an annular gap with a radial width of 0.1 mm is formed between the high-frequency piezoelectric layer and the low-frequency piezoelectric layer, and the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer are located in the same plane.

[0046] Step 4: mechanically fixing the high-frequency piezoelectric layer and the low-frequency piezoelectric layer, and placing the fixed high-frequency piezoelectric layer and the low-frequency piezoelectric layer into a metal shell, the metal shell is provided with a negative electrode opening and a positive electrode opening, and the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer are opposite to and flush with the negative electrode opening.

[0047] Specifically, the nested high-frequency piezoelectric layer and low-frequency piezoelectric layer are mechanically fixed to ensure structural stability, and the fixed high-frequency piezoelectric layer and low-frequency piezoelectric layer are placed in the stainless steel metal shell, and the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer are opposite to the negative electrode opening and flush with the negative electrode opening.

[0048] Step 5: Lead wires are led out through the positive electrode opening, and epoxy support material is poured into the metal shell through the positive electrode opening and cured; wherein a part of the epoxy support material located in the annular gap forms an annular insulating gap.

[0049] Specifically, the lead wire connecting the high-frequency piezoelectric layer positive electrode and the low-frequency piezoelectric layer positive electrode is led out from the positive electrode opening of the stainless steel metal shell, and epoxy support material is poured into the cavity of the stainless steel metal shell through the positive electrode opening, and placed in an electric heating constant temperature air drying oven for curing to provide mechanical support and environmental isolation.

[0050] Step 6: Deposit a metal film on the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer at the negative electrode opening to form a common ground negative electrode.

[0051] Specifically, an electrode sputtering system is used to deposit a gold film on the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer at the negative electrode opening to form a common ground negative electrode.

[0052] In an alternative implementation, after pouring epoxy support material into the metal shell and curing, the inner core of the two BNC interfaces can also be connected to the lead wires of the high-frequency piezoelectric layer positive electrode and the low-frequency piezoelectric layer positive electrode through the positive electrode opening, and the two BNC interfaces are fixed in a mechanical fastening manner.

[0053] In an alternative implementation, after the common ground negative electrode is prepared, a physical vapor deposition protective film can also be applied to the surface of the ultrasonic transducer to form a dense barrier to prevent moisture, dust and other environmental pollutants from entering the ultrasonic transducer, ensuring long-term reliability.

[0054] The preparation method of the integrated dual-frequency composite ultrasonic transducer provided by the application can complete the assembly of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer through one-time coaxial assembly, and can realize mechanical fixation and acoustic coupling through single pouring of epoxy after being placed in the metal shell, thereby greatly simplifying the alignment and packaging operation requirements during preparation. The two flat high-frequency piezoelectric layers and low-frequency piezoelectric layers are positioning references for each other, one-time forming, common ground negative electrode design eliminates "two-layer ground" wiring, solves cross talk, and shortens the heat dissipation path, thereby helping to reduce temperature rise and improve service life.

[0055] Example Three Based on the above integrated dual-frequency composite ultrasonic transducer, the embodiment of the present application also provides a transdermal drug delivery method of the integrated dual-frequency composite ultrasonic transducer, comprising: S1, mixing a water-soluble drug with an ultrasonic coupling agent to form a drug-coupling agent mixture.

[0056] S2, uniformly coating the drug-coupling agent mixture on the skin treatment area.

[0057] S3, mounting the ultrasonic transducer on the skin treatment area, so that the common ground negative electrode of the ultrasonic transducer directly contacts or contacts the skin treatment area through a biocompatible matching layer.

[0058] Specifically, the ultrasonic transducer is fixed on the skin area to be treated, and the common ground negative electrode of the ultrasonic transducer (i.e. the emitting surface of the ultrasonic transducer) is directly attached to the skin to transmit ultrasonic waves to the skin. Or through a layer of biocompatible matching layer (such as medical gel or special film) to contact the skin, which can not only optimize the efficiency of sound wave transmission, but also avoid the irritation or allergy caused by direct contact of metal, and improve the safety.

[0059] S4, exciting the high-frequency piezoelectric layer and the low-frequency piezoelectric layer in the ultrasonic transducer in turn by time division multiplexing to generate high-frequency ultrasonic waves and low-frequency ultrasonic waves acting on the skin treatment area, and realizing transdermal drug delivery.

[0060] Specifically, an external signal generator generates an electrical signal with a specific waveform and frequency, which is amplified by a power amplifier and applied to the ultrasonic transducer. The high-frequency piezoelectric layer and the low-frequency piezoelectric layer of the ultrasonic transducer are excited in turn by time division multiplexing to generate high-frequency ultrasonic waves and low-frequency ultrasonic waves acting on the skin treatment area, and realize transdermal drug delivery. Here, time division multiplexing is realized by adjusting the action time sequence and action frequency of high-frequency ultrasonic waves and low-frequency ultrasonic waves. It can be understood that the time sequence not only includes the order of time, but also includes the time length information. Specifically, the time division multiplexing mechanism alternately excites ultrasonic waves of different frequencies through time sequence control to realize the synergistic effect of high-frequency ultrasonic waves and low-frequency ultrasonic waves; high-frequency ultrasonic excitation generates more microbubbles, and low-frequency ultrasonic excitation promotes bubble growth and rupture to release more energy, enhances cavitation effect, and improves skin permeability. By adjusting the action time, time sequence and frequency parameters, different drug characteristics can be adapted to realize safe and efficient transdermal drug delivery.

[0061] Here, the main mechanism of ultrasound penetration is cavitation effect, that is, the liquid produces bubbles under the action of ultrasonic waves, and the generated bubbles and the existing bubbles grow, oscillate and break in the ultrasonic field, and release energy. According to the movement mode of the bubbles, the cavitation effect can be divided into stable cavitation and inertial cavitation. The process that the existing bubbles (i.e. the bubbles generated by the ultrasonic action and the bubbles that already exist) continuously oscillate around a certain balance radius without collapsing under the action of low sound intensity is called stable cavitation; when the sound intensity or sound pressure exceeds a certain threshold, the micro-bubbles rapidly expand and contract and collapse instantaneously, generating local high temperature and high pressure, and releasing shock waves, which is inertial cavitation. In the process of stable cavitation, micro-jets and shear forces are generated, thereby reversibly increasing the skin permeability, and inertial cavitation generates instantaneous high temperature and high pressure and shock waves, thereby forming micro-pores in the stratum corneum of the skin. Therefore, both stable cavitation and inertial cavitation can improve the drug delivery efficiency. Studies have shown that within a certain range, the lower the ultrasonic frequency, the lower the inertial cavitation threshold, and the easier the inertial cavitation occurs, that is, low-frequency ultrasound is easy to cause inertial cavitation of the liquid; while the inertial cavitation threshold of high-frequency ultrasound is high, and under the same conditions, it is difficult to cause inertial cavitation, but high-frequency ultrasound can generate more micro-bubble nuclei, so the action of high-frequency ultrasound is mainly stable cavitation and generation of more micro-bubble nuclei. Therefore, the combined action of high-frequency ultrasound and low-frequency ultrasound can enhance the cavitation effect and achieve the enhancement of transdermal drug delivery effect.

[0062] The transdermal drug delivery method of the integrated dual-frequency composite ultrasonic transducer provided by the application excites high-frequency ultrasound and low-frequency ultrasound in sequence through time division multiplexing, the high-frequency ultrasound generates more micro-bubbles, and the low-frequency ultrasound promotes the growth and rupture of the bubbles to release more energy, thereby significantly enhancing the cavitation effect, improving the skin permeability, and improving the treatment effect of transdermal drug delivery. In addition, through time division multiplexing, the application avoids the risk of thermal damage caused by long-term use of high-frequency ultrasound, and has higher safety and stability.

[0063] The application will be further described below through transdermal drug delivery effect verification experiments.

[0064] The device materials and size parameter settings during the experiment are as follows: The integrated dual-frequency composite ultrasonic transducer used in the experiment is as shown in Figure 2 The high-frequency ultrasonic resonance frequency is 2MHz, and the low-frequency ultrasonic resonance frequency is 400kHz; the material of the high-frequency piezoelectric layer is PZT-4, the diameter is 14.8mm, and the thickness is 1mm; the material of the low-frequency piezoelectric layer is PZT-4, the outer diameter is 38mm, the inner diameter is 15mm, and the thickness is 5mm; the radial width of the annular insulating gap is 0.1mm.

[0065] As shown in Figure 4As shown, the experiment coats the methylene blue solution-coupling agent mixed solution on the fresh pigskin, and uses different ways to promote drug penetration, cuts the pigskin after a period of time, and observes the diffusion of methylene blue in the fresh pigskin section under a microscope. Specifically, the diffusion time of the experiment is 10 minutes, and the transdermal drug delivery effects of four different drug delivery methods are compared under the conditions of voltage peak value of 50V and 100V, and the four different drug delivery methods are: (1) Free: free diffusion; (2) L: only low-frequency ultrasound; (3) H+L: first high-frequency action for 5 minutes, then low-frequency action for 5 minutes; (4) HL+HL: first high-frequency ultrasound for 2 minutes, then low-frequency ultrasound for 3 minutes, and so on for 2 times.

[0066] Referring to Figure 5 and Figure 6 , Figure 5 The experimental results of the experiment are shown, in which the upper two groups of results are methylene blue dye diffusion images of the pigskin section, and the lower two groups are methylene blue dye diffusion images after image processing of the upper two groups of results. The lighter the color, the higher the concentration of methylene blue dye. Figure 6 The experimental results of the experiment are shown, in which the upper two groups of results are methylene blue dye diffusion images of the pigskin section, and the lower two groups are methylene blue dye diffusion images after image processing of the upper two groups of results. The lighter the color, the higher the concentration of methylene blue dye.

[0067] From Figure 5 and Figure 6 It can be seen that under the same diffusion time and the same voltage peak value, the methylene blue dye diffusion area of each group from large to small is: HL+HL>H+L>L>Free, and twice high-frequency ultrasound followed by low-frequency ultrasound is better than single high-frequency ultrasound followed by low-frequency ultrasound. Therefore, by using the integrated dual-frequency composite ultrasonic transducer of the present application, independent driving of high-frequency ultrasound and low-frequency ultrasound can be realized, the operation process of transdermal drug delivery is simplified, and better transdermal drug delivery efficiency is achieved. And by time-sharing multiplexing to sequentially excite high-frequency ultrasound and low-frequency ultrasound, the cavitation effect can be significantly enhanced, the skin permeability can be improved, and the treatment effect of transdermal drug delivery can be improved.

[0068] In the description of the present application, the terms "center", "longitudinal", "transverse", "length", "width", "thickness", "upper", "lower", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", and the like indicate the orientation or positional relationship shown in the drawings, which are only for the convenience of describing the present application and simplifying the description, and do not indicate or imply that the devices or elements referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore cannot be understood as limiting the present application.

[0069] In the description of the present application, unless otherwise explicitly specified and limited, the terms "mounting", "connecting", "connecting", "fixing" and the like should be understood broadly, for example, it can be fixedly connected, or it can be detachably connected, or it can be integrated; it can be mechanically connected, or it can be electrically connected; it can be directly connected, or it can be indirectly connected through an intermediate medium; it can be the internal communication of two elements or the interaction relationship between two elements. For those skilled in the art, the specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0070] In the description of the present application, unless otherwise explicitly specified and limited, the first feature "on" or "under" the second feature can include that the first and second features are in direct contact, or that the first and second features are not in direct contact but are in contact through another feature between them. Moreover, the first feature "on", "above" and "above" the second feature includes that the first feature is directly above and obliquely above the second feature, or only indicates that the horizontal height of the first feature is higher than that of the second feature. The first feature "under", "below" and "below" the second feature includes that the first feature is directly below and obliquely below the second feature, or only indicates that the horizontal height of the first feature is less than that of the second feature.

[0071] It should be noted that the terms "first", "second", etc. are used to distinguish similar objects, and do not necessarily have to describe a specific order or sequence. It should be understood that the data thus used can be interchanged under appropriate circumstances, so that the embodiments of the application described herein can be implemented in an order other than those illustrated or described herein. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present application. Rather, they are merely examples of devices and methods consistent with some aspects of the present application.

[0072] In the description of the specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" etc. means that the specific features or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in the specification.

[0073] Although the present application is described herein in conjunction with various embodiments, those skilled in the art, with the benefit of the drawings and the disclosure, can understand and implement other variations of the disclosed embodiments in the implementation of the claimed application. In the description of the present application, the word "comprising" does not exclude other components or steps, "a" or "one" does not exclude a plurality, and "plurality" means two or more, unless otherwise expressly specified. In addition, some measures are described in different embodiments, but this does not mean that these measures cannot be combined to produce good results.

[0074] The above is a further detailed description of the present application in conjunction with specific preferred embodiments, and cannot be considered as limiting the specific implementation of the present application to these descriptions. For those skilled in the art, without departing from the concept of the present application, a number of simple deductions or substitutions can be made, which should be considered as falling within the scope of protection of the present application.

Claims

1. An integrated dual-frequency composite ultrasonic transducer, characterized in that: include: A high-frequency piezoelectric layer, a low-frequency piezoelectric layer, an epoxy support material, and an electrode assembly; The high-frequency piezoelectric layer and the low-frequency piezoelectric layer are coaxially nested, the low-frequency piezoelectric layer is a flat annular structure, the high-frequency piezoelectric layer is a flat circular structure, and the high-frequency piezoelectric layer is located inside the annular ring of the low-frequency piezoelectric layer; An annular insulating gap completely filled with the epoxy support material is provided between the high-frequency piezoelectric layer and the low-frequency piezoelectric layer; The electrode group includes a high-frequency piezoelectric layer positive electrode located on the first surface of the high-frequency piezoelectric layer, a low-frequency piezoelectric layer positive electrode located on the first surface of the low-frequency piezoelectric layer, and a common ground negative electrode located on the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer. The second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer are located in the same plane.

2. The integrated dual-frequency composite ultrasonic transducer according to claim 1, characterized in that: The thickness of the high-frequency piezoelectric layer is set according to its resonant frequency range, which is 1MHz-3MHz. The thickness of the low-frequency piezoelectric layer is set according to its resonant frequency range, which is 20kHz-700kHz. The radial thickness of the annular insulating gap is 0.1mm-1mm.

3. The integrated dual-frequency composite ultrasonic transducer according to claim 1, characterized in that: The materials of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer are both one or more combinations of PZT-4, PZT-5, PZT-8, PZT-based composite materials, and doped modified lead-free ceramics.

4. The integrated dual-frequency composite ultrasonic transducer according to claim 1, characterized in that: The second surfaces of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer are both covered with a biocompatible matching layer; and a temperature sensor and / or a pressure sensor are embedded in the epoxy supporting material.

5. The integrated dual-frequency composite ultrasonic transducer according to claim 1, characterized in that: It also includes a metal housing and two BNC connectors; The high-frequency piezoelectric layer, the low-frequency piezoelectric layer, the epoxy support material, and the electrode group are accommodated in the cavity formed by the metal shell, and the cavity gap is also filled with another portion of the epoxy support material; the metal shell is provided with a negative electrode opening and a positive electrode opening, and the common negative electrode is embedded in the negative electrode opening; The inner cores of the two BNC interfaces are respectively connected to the positive electrode of the high-frequency piezoelectric layer and the positive electrode of the low-frequency piezoelectric layer through the positive electrode opening.

6. The integrated dual-frequency composite ultrasonic transducer according to claim 5, characterized in that: The outer surface of the metal shell is provided with a heat sink.

7. A method for preparing an integrated dual-frequency composite ultrasonic transducer, characterized in that: include: Providing a high-frequency piezoelectric layer and a low-frequency piezoelectric layer; the low-frequency piezoelectric layer is a flat annular structure, and the high-frequency piezoelectric layer is a flat circular structure; Depositing a metal film on the first surface of the high-frequency piezoelectric layer and the low-frequency piezoelectric layer to form a positive conductive layer, and connecting a wire to the positive conductive layer; Placing the high-frequency piezoelectric layer within the circular ring of the low-frequency piezoelectric layer to form a coaxial nested structure; wherein the radius of the high-frequency piezoelectric layer is smaller than the inner radius of the low-frequency piezoelectric layer, so that an annular gap is formed between the high-frequency piezoelectric layer and the low-frequency piezoelectric layer; Mechanically fixing the high-frequency piezoelectric layer and the low-frequency piezoelectric layer, and placing the fixed high-frequency piezoelectric layer and the low-frequency piezoelectric layer into a metal shell, wherein the metal shell is provided with a negative electrode opening and a positive electrode opening, and the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer are opposite to the negative electrode opening and are flush with the negative electrode opening; Leading the wire out through the positive electrode opening, and pouring epoxy support material into the metal shell through the positive electrode opening and curing it; wherein a portion of the epoxy support material located in the annular gap forms an annular insulating gap; A metal film is deposited on the second surface of the high-frequency piezoelectric layer and the second surface of the low-frequency piezoelectric layer at the negative electrode opening to form a common negative electrode.

8. A transdermal drug delivery method using an integrated dual-frequency composite ultrasonic transducer, characterized in that: include: mixing a water-soluble drug with an ultrasonic coupling agent to form a drug-coupling agent mixture; Evenly applying the drug-coupling agent mixture to the skin treatment area; Mounting the ultrasonic transducer according to any one of claims 1 to 6 on a skin treatment area, so that the common ground negative electrode of the ultrasonic transducer is in direct contact with the skin treatment area or in contact with the skin treatment area through a biocompatible matching layer; The high-frequency piezoelectric layer and the low-frequency piezoelectric layer in the ultrasonic transducer are stimulated in sequence by time-sharing multiplexing, generating high-frequency ultrasound and low-frequency ultrasound that act on the skin treatment area, thereby achieving transdermal drug delivery.

9. The transdermal drug delivery method using the integrated dual-frequency composite ultrasonic transducer according to claim 8, characterized in that: Time-division multiplexing is achieved by adjusting the action sequence and action frequency of high-frequency ultrasound and low-frequency ultrasound.

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