WO2020098601A1 - Dispositif d'administration de vaccin percutané utilisant un réseau de micropores induit acoustiquement - Google Patents

Dispositif d'administration de vaccin percutané utilisant un réseau de micropores induit acoustiquement Download PDF

Info

Publication number
WO2020098601A1
WO2020098601A1 PCT/CN2019/117138 CN2019117138W WO2020098601A1 WO 2020098601 A1 WO2020098601 A1 WO 2020098601A1 CN 2019117138 W CN2019117138 W CN 2019117138W WO 2020098601 A1 WO2020098601 A1 WO 2020098601A1
Authority
WO
WIPO (PCT)
Prior art keywords
ultrasonic
monitoring
ultrasonic transducer
skin
signal
Prior art date
Application number
PCT/CN2019/117138
Other languages
English (en)
Chinese (zh)
Inventor
胡亚欣
杨梅
陈昕
Original Assignee
深圳大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳大学 filed Critical 深圳大学
Publication of WO2020098601A1 publication Critical patent/WO2020098601A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061—Methods for using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/05—General characteristics of the apparatus combined with other kinds of therapy
    • A61M2205/058—General characteristics of the apparatus combined with other kinds of therapy with ultrasound therapy

Definitions

  • the present disclosure belongs to the technical field of transdermal administration and immunity, for example, a vaccine transdermal delivery device based on an acoustically induced micropore array.
  • the skin serves as the body's first line of defense against harmful substances in the external environment.
  • the superficial skin contains many immune cells in the epidermis and dermis, such as dendritic Langerhans cells and dermal dendritic cells. Langerhans cells on the one hand control the formation of keratin, on the other hand participate in skin immune response and are the main antigen presenting cells in the skin epidermis.
  • the epidermal layer of the skin is about 100 microns thick. If the antigen can reach the epidermal layer, it can activate the immune response of immune cells, thereby achieving a local to systemic immune response. Therefore, skin immunity is expected to become an ideal new needleless immunization route.
  • the commonly used stratum corneum permeation techniques include iontophoresis, electroporation, microneedle array technique, and acoustic perforation techniques.
  • the iontophoresis method can only be applied to the transdermal delivery of small-molecule drugs, and cannot deliver large-molecule vaccine antigens;
  • the electroporation technology has a hidden danger of biological safety due to the transient high-voltage pulses during administration, which can cause strong pain and discomfort;
  • the production of microneedle array technology carriers is complicated, and the cost is high, which cannot be promoted on a large scale. Because the delivery probe is a low-frequency, non-focusing probe, the delivery area is large, the delivery position is uncertain, and the consistency of the delivery area is poor.
  • the drug delivery by acoustic perforation technology is a small molecular weight drug, and there is also a delivery effect that cannot achieve the immunity of large molecule antigen.
  • the related transdermal drug delivery technology has problems such as the inability to deliver large-molecule vaccine antigens, painful delivery, complicated and costly process, and poor delivery area accuracy.
  • the present disclosure provides a vaccine transdermal delivery device based on an acoustically induced micropore array, to solve the related transdermal drug delivery technology, there is no delivery of macromolecular vaccine antigens, painful delivery process, complicated process and high cost, delivery Problems such as poor regional accuracy.
  • a vaccine percutaneous delivery device based on an acoustically induced micropore array, including: a main control system, a high-frequency intense focused ultrasound excitation component connected to the main control system, and a device for applying to An acoustically permeable immune patch for drug administration on the skin;
  • the high-frequency strong-focus ultrasound excitation component includes a high-frequency ultrasound signal generating system, a first ultrasound transducer connected to the high-frequency ultrasound signal generating system, and the A conical coupling catheter connected to the first ultrasonic transducer;
  • the conical coupling catheter is placed on the acoustically permeable immune patch during drug administration, and is used to conduct the acoustic energy of the first ultrasonic transducer to The immune patch;
  • the high-frequency ultrasonic signal generating system includes an electrical signal generator, a linear power amplifier, and an impedance matching circuit that are electrically connected in sequence;
  • the main control system sends a pulsed ultrasonic excitation signal to the high
  • the first ultrasonic transducer is a ring-shaped hollow first ultrasonic transducer; the ring-shaped hollow area is provided with a receiving cavity.
  • the ultrasonic echo signal monitoring system also includes an ultrasonic echo signal monitoring system connected to the main control system;
  • the ultrasonic echo signal monitoring system includes a second ultrasonic transducer and a signal monitoring component electrically connected to each other;
  • the outer diameter of the second ultrasonic transducer is not larger than the inner diameter of the accommodating cavity, and is used to be placed in the accommodating cavity during monitoring;
  • the echo signal monitoring component is used to send a signal and then pass the The second ultrasonic transducer converts and monitors the administration process of the vaccine transdermal delivery device based on the acoustically induced micropore array based on the received return signal.
  • the signal monitoring component includes a pulse transceiver connected to the second ultrasonic transducer, and a data acquisition card connected to the pulse transceiver; wherein, the pulse transceiver and the data acquisition The cards are connected to the main control system; when the sound-transmitting immune patch is encountered during the propagation of the monitoring sound signal, the monitoring sound signal is reflected to form a first monitoring echo, and is sent and received through the pulse Instrument amplification, the data acquisition card receives the amplified first monitoring echo and performs analog-to-digital conversion, and the record is stored as the first echo pulse; when the monitoring acoustic signal continues to encounter the skin during the propagation process, the monitoring is reflected The acoustic signal forms a second monitoring echo and is amplified by the pulse transceiver.
  • the data acquisition card receives the amplified second monitoring echo and performs analog-to-digital conversion.
  • the record is stored as a second echo pulse;
  • the first echo pulse and the second echo pulse monitor the administration process of the vaccine transdermal delivery device based on the acoustically induced micropore array.
  • the optical imaging monitoring system also includes an optical imaging monitoring system connected to the main control system;
  • the optical imaging monitoring system includes an imaging probe and an imaging processing unit connected to the imaging probe;
  • the outer diameter of the imaging probe is not greater than The inner diameter of the accommodating cavity is used to be placed in the accommodating cavity during monitoring;
  • the main control system is also used to control the imaging probe to perform on the acoustically permeable immune patch and / or skin Image acquisition, real-time or timing imaging, and imaging processing is performed on the imaging data by the imaging processing unit to perform imaging detection.
  • the imaging probe is placed in the middle of the receiving cavity of the first ultrasonic transducer; and, the imaging probe, the center of the imaging field corresponding to the imaging probe, and the first ultrasonic transducer
  • the relative position of the device is coaxial with the geometric center.
  • the optical imaging monitoring system further includes a probe fixing bracket connected to the imaging probe; and the high-frequency intense focusing ultrasound excitation component further includes A first ultrasonic transducer fixing bracket connected to the first ultrasonic transducer; the ultrasonic echo signal monitoring system further includes a second ultrasonic transducer fixing bracket connected to the second ultrasonic transducer; the probe The fixed bracket, the first ultrasonic transducer fixed bracket, and the second ultrasonic transducer fixed bracket are all connected to the three-dimensional movement controller.
  • the sound-permeable immune patch includes an isolation ring and an adhesive film; the adhesive film covers the isolation ring; and, a drug container is formed between the adhesive film and the isolation ring Cavity; when administering to the skin, use the viscosity of the adhesive film to apply the sound-permeable immune patch to the skin surface, wherein the drug containing cavity is filled with a drug for administration.
  • the isolation ring is a circular rubber isolation ring;
  • the adhesive film is a transparent plastic material adhesive film; the adhesive film faces away from the conical coupling catheter and faces the skin during administration One side is sticky;
  • the outer diameter of the isolation ring is 5-15 mm, the inner diameter is 3-10 mm, and the thickness is 1-3 mm.
  • the present disclosure also provides a method for using a vaccine transdermal delivery device based on an acoustically induced micropore array, which includes: applying an acoustically permeable immune patch and placing it in the cone of the vaccine transdermal delivery device based on an acoustically induced micropore array The lower end of the shape-coupled catheter; spatial positioning through the ultrasonic echo signal monitoring system and optical imaging monitoring system of the vaccine transdermal delivery device based on the acoustically induced micropore array to determine the site of skin administration; through the acoustically induced micropore Array high-frequency focused ultrasound excitation component of vaccine transdermal delivery device performs transdermal immunotherapy on the skin administration site; delivery effect on the skin administration site on the transdermal immunity administration through the optical imaging monitoring system Evaluation.
  • the present disclosure provides a vaccine transdermal delivery device based on an acoustically induced micropore array, which includes a main control system, a high-frequency intense focused ultrasound excitation component connected to the main control system, and a sound applied to the skin for drug administration Permeable immune patch;
  • the high-frequency strong-focus ultrasound excitation component includes a high-frequency ultrasonic signal generating system, a first ultrasonic transducer connected to the high-frequency ultrasonic signal generating system, and a first ultrasonic transducer connected to the first ultrasonic transducer A conical coupling catheter;
  • the conical coupling catheter is placed on the acoustically permeable immune patch during drug administration, and is used to conduct the acoustic energy of the first ultrasonic transducer to the immune patch;
  • the high-frequency ultrasonic signal generating system includes an electrical signal generator, a linear power amplifier, and an impedance matching circuit that are electrically connected in sequence.
  • the present disclosure controls the electrical signal generator in the high-frequency and strong-focus ultrasonic excitation assembly through the main control system to generate ultrasonic electrical signals, and transmits them to the high-intensity ultrasonic transducer through the linear power amplifier amplification and impedance matching circuit, and then uses the high-intensity ultrasonic transducer Acoustic energy conversion is performed to obtain acoustic energy, which is introduced into the skin under the patch through a conical coupling catheter to form skin micropores on the skin, and then delivers the drug through the skin micropores.
  • the present disclosure uses high-frequency high-intensity focused ultrasound technology to form skin micropores with different breadths and depths on the skin (as shown in FIG.
  • the administration method is simple and the administration process is minimally invasive.
  • the pain, delivery and delivery methods are safe and effective, and the delivery efficiency is high, the delivery area has high accuracy and the location is accurate, which greatly improves the user experience.
  • Embodiment 1 is a schematic structural view of Embodiment 1 of a vaccine transdermal delivery device based on an acoustically induced micropore array;
  • FIG. 2 is an XY plane ultrasonic focus measurement diagram of the first embodiment of the vaccine percutaneous delivery device based on an acoustically induced micropore array;
  • FIG. 3 is an XZ plane ultrasonic focus measurement diagram of the first embodiment of the vaccine percutaneous delivery device based on the acoustically induced micropore array;
  • Embodiment 4 is a schematic structural view of Embodiment 2 of a vaccine percutaneous delivery device based on an acoustically induced micropore array;
  • FIG. 5 is a schematic diagram of the second ultrasonic transducer echo monitoring method of the second embodiment of the vaccine transdermal delivery device based on the acoustically induced micropore array;
  • FIG. 6 is a schematic structural view of Embodiment 3 of a vaccine percutaneous delivery device based on an acoustically induced micropore array;
  • FIG. 7 is a diagram showing the delivery effect of the acoustically permeable immune patch of the third embodiment of the vaccine transdermal delivery device based on the acoustically induced micropore array;
  • FIG. 8 is a schematic structural diagram of a three-dimensional mobile controller according to Embodiment 4 of a vaccine percutaneous delivery device based on an acoustically induced micropore array;
  • FIG. 9 is a schematic diagram of the structure of an acoustically permeable immune patch of the fourth embodiment of the vaccine transdermal delivery device based on an acoustically induced micropore array;
  • FIG. 10 is an overall schematic diagram of Embodiment 4 of a vaccine transdermal delivery device based on acoustically induced micropore arrays;
  • FIG. 11 is a schematic flowchart of a method for using a vaccine transdermal delivery device based on an acoustically induced micropore array in Embodiment 5 of the present invention
  • FIG. 12 is another schematic flow chart of a method for using a vaccine percutaneous delivery device based on an acoustically induced micropore array in Embodiment 5 of the present invention.
  • FIG. 13 is an example diagram of different width and depth patterns of skin pores formed after immunization of a vaccine transdermal delivery device based on an acoustically induced pore array (H & E stained slice diagram);
  • FIG. 14 is a diagram showing examples of different array patterns of skin micropores formed in the vaccine transdermal delivery device based on the acoustically induced micropore array.
  • Embodiment 1 discloses a vaccine transdermal delivery device 1 based on an acoustically induced micropore array.
  • the vaccine transdermal delivery device 1 based on an acoustically induced micropore array includes: a master control System 11, a high-frequency intense focused ultrasound excitation assembly 12 connected to the main control system 11, and an acoustically permeable immune patch 13 applied to the skin for drug delivery;
  • the high-frequency intense focused ultrasound excitation assembly 12 includes high Frequency ultrasonic signal generating system 121, a first ultrasonic transducer 122 connected to the high frequency ultrasonic signal generating system 121, a conical coupling conduit 123 connected to the first ultrasonic transducer 122; the conical coupling The catheter 123 is placed on the acoustically permeable immune patch 13 at the time of drug administration, and is used to conduct the acoustic energy of the first ultrasound transducer 122 to the immune patch; the high-frequency ultrasound signal
  • the main control system 11 sends a pulsed ultrasonic excitation signal to the high-frequency ultrasonic signal generation system 121, and then the high-frequency ultrasonic signal generation system 121 generates an ultrasonic electric signal according to the pulsed ultrasonic excitation signal, and passes the first
  • the ultrasonic transducer 122 converts the ultrasonic electrical signal into an acoustic signal, and introduces the acoustic energy of the acoustic signal into the skin under the acoustically permeable immune patch 13 through the conical coupling catheter 123 to facilitate the formation of the skin Micropores in the skin for transdermal delivery of immune antigens.
  • the high-frequency ultrasonic signal generating system 121 includes an electrical signal generator 121a, a linear power amplifier 121b, and an impedance matching circuit 121c that are electrically connected in sequence;
  • the main control system 11 is used to send pulsed ultrasonic excitation signal parameters to the electrical signal generator 121a, and the electrical signal generator 121a generates an ultrasonic electrical signal according to the pulsed ultrasonic excitation signal parameters; through the linear power
  • the amplifier 121b amplifies the ultrasonic electrical signal, and transmits the amplified ultrasonic electrical signal to the first ultrasonic transducer 122 through the impedance matching circuit 121c, and the first ultrasonic transducer 122 performs the ultrasonic electrical signal Conversion to an acoustic signal, and the acoustic energy of the acoustic signal is introduced into the skin under the acoustically permeable immune patch 13 through a conical coupling catheter 123, so as to form skin pores on the skin for the immune antigen to pass through ⁇ DELIVERY.
  • the stratum corneum serves as the outermost shielding protective layer of the skin, and its thickness is 15-20 microns.
  • the complete stratum corneum can well regulate the transdermal absorption of the substance.
  • the rate of transdermal diffusion of a substance is inversely related to its molecular weight. The smaller the molecular weight, the easier it is to pass through the stratum corneum. It is generally believed that only compounds with a molecular weight of less than 500 Daltons can penetrate the stratum corneum. If the skin is damaged, the stratum corneum can lose its shielding effect, thereby greatly increasing the speed and degree of substance absorption, especially for the transdermal delivery of macromolecular proteins such as antigens.
  • the vaccine-derived transdermal delivery device 1 based on the acoustically induced micropore array provided in this embodiment is applied to the transdermal administration of immune antigens of macromolecules, and utilizes the acoustically induced micropore technology to pass the drug through the stratum corneum. Thus delivery achieves immunity.
  • the high-frequency strong-focus ultrasonic excitation assembly 12 is composed of the electric signal generator 121a, the linear power amplifier 121b, the impedance matching circuit 121c, and the first ultrasonic transducer 122.
  • the parameters of the pulsed ultrasonic excitation signal may include, but are not limited to, parameters such as duty cycle, pulse repetition frequency, and peak negative sound pressure.
  • the main control system 11 performs edit control based on this parameter through the electric signal generator 121a, and edits the generated
  • the signal is amplified by the linear power amplifier 121b, and the amplified electrical signal drives the first ultrasonic transducer 122 to output a pulsed ultrasonic excitation signal of high frequency, high intensity, and strong focus.
  • the high-frequency high-intensity focused ultrasound excitation component 12 is a high-frequency high-intensity strong focused ultrasound excitation component, where high frequency, in this embodiment, may refer to a signal with a frequency greater than 1 MHz ; High intensity means that the output ultrasonic peak negative sound pressure is greater than 5MPa; strong focusing means that the lateral diameter of the ultrasonic focus point is less than 0.8mm and the longitudinal diameter is less than 3mm.
  • the first ultrasonic transducer 122 is a high-intensity ultrasonic transducer in this embodiment.
  • the half-height width of the transverse focus of the sound field measured in the XY plane (ie: the corresponding sound field diameter when its negative sound pressure drops to half the peak value) is about 0.76mm.
  • the longitudinal half-height width of this sound field measured in the XZ plane is about 2.4mm.
  • the sound-permeable immune patch 13 is a carrier for applying to the skin for administration, that is, the immune vaccine antigen or the vaccine antigen mixed liquid added with phase-change droplets can be filled into the cavity of the patch , And then apply the patch to the skin surface to complete the preparation of the skin immune patch.
  • the phase-change droplets can be a film-enhanced agent whose original core is liquid.
  • the internal low-boiling liquid such as perfluoropentane with a boiling point of 42 ° C
  • the internal low-boiling liquid such as perfluoropentane with a boiling point of 42 ° C
  • the first ultrasonic transducer 122 can realize the conversion of electrical signals into acoustic signals.
  • the transducer can include a probe whose front end is placed on the sound-transmitting immune patch through a cone-shaped acoustic coupling catheter.
  • the cone-shaped acoustic coupling The catheter is filled with degassed ultrapure water as a sound propagation medium.
  • ultrasonic coupling agents can achieve the acoustic coupling of the cone-shaped acoustic coupling catheter and the acoustically transparent immune patch, thereby introducing the acoustic energy output from the high-intensity transducer into the acoustic permeability
  • the skin under the immune patch creates micropores in the skin, allowing the antigen solution in the acoustically permeable immune patch to diffuse into the skin.
  • the linear power amplifier 121b is used to amplify the ultrasonic electrical signal; that is, the impedance of the matching signal source is equal to the characteristic impedance of the connected transmission line and the phase is the same, or the characteristic impedance of the transmission line and the impedance of the connected load Equivalent in size and phase, the input end or output end of the transmission line is in impedance matching state, referred to as impedance matching; and the impedance matching circuit 121c is mainly used on the transmission line to reach all high-frequency microwave signals. For the purpose of reaching the load point, no signal will be reflected back to the source point, thereby improving energy efficiency.
  • the main control system 11 can be a main control computer to coordinate and control various sub-systems.
  • the main control system 11 controls the electric signal generator 121a in the high-frequency and strong-focus ultrasonic excitation assembly 12 to generate ultrasonic electric signals, which are amplified by a linear power amplifier, and transmitted to a high-intensity ultrasonic transducer by an impedance matching circuit 121c.
  • the intensity ultrasonic transducer converts the acoustic energy to obtain the acoustic energy, which is introduced into the skin under the patch through the conical coupling catheter 123, forms a skin micropore in the skin, and then delivers the drug through the skin micropore (wherein, an array formed on the skin (The model is shown in Figure 14).
  • This embodiment uses high-frequency high-intensity focused ultrasound technology to form skin micropores with different breadths and depths on the skin for the transdermal delivery of immune antigens of large molecules.
  • the method of administration is simple, the process of administration is minimally invasive, painless, and delivered to
  • the medicine method is safe and effective, and the drug delivery efficiency is high, the delivery area accuracy is high, and the location is accurate, which greatly improves the user experience.
  • Embodiment 2 Referring to FIGS. 4-5, based on the foregoing embodiment, this embodiment provides a vaccine percutaneous delivery device 1 based on an acoustically induced micropore array, wherein,
  • the first ultrasonic transducer 122 is a ring-shaped hollow first ultrasonic transducer 122; the ring-shaped hollow region is provided with a receiving cavity 122a.
  • the vaccine transdermal delivery device 1 based on an acoustically induced micropore array further includes an ultrasound echo signal monitoring system 14 connected to the main control system 11;
  • the ultrasonic echo signal monitoring system 14 includes a second ultrasonic transducer 141 and a signal monitoring assembly 142 electrically connected to each other; the outer diameter of the second ultrasonic transducer 141 is not larger than the accommodating cavity 122a The inner diameter of is used to be placed in the accommodating cavity 122a during monitoring;
  • the echo signal monitoring component 142 is used to send a signal, and then converted by the second ultrasonic transducer 141, and according to the received return signal to the acoustically induced micropore array-based vaccine transdermal delivery device 1. Monitor the administration process.
  • the signal monitoring component 142 includes a pulse transceiver 142a connected to the second ultrasonic transducer 141, and a data acquisition card 142b connected to the pulse transceiver 142a; wherein, the pulse Both the transceiver 142a and the data acquisition card 142b are connected to the main control system 11;
  • the main control system 11 controls the pulse transceiver 142a to output an electrical pulse, Exciting the second ultrasonic transducer 141 to emit a monitoring acoustic signal according to the electrical pulse, the monitoring acoustic signal entering the accommodating cavity 122a and propagating through the conical coupling conduit 123;
  • the monitoring sound signal is reflected to form a first monitoring echo, which is amplified by the pulse transceiver 142a, and the data acquisition card 142b receives the amplified first monitoring echo and performs analog-to-digital conversion, and the record is stored as the first echo pulse;
  • the monitoring acoustic signal continues to spread and encounters the skin, the monitoring acoustic signal is reflected to form a second monitoring echo Wave, and amplified by the pulse transceiver 142a, the data acquisition card 142b receives the amplified second monitoring echo and performs analog-to-digital conversion, and the record is stored as a second echo pulse; by the first echo pulse And the second echo pulse to monitor the administration process of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array.
  • the ultrasonic signal echo monitoring system is a low-intensity ultrasonic signal echo system
  • the second ultrasonic transducer 141 in this embodiment, is a low-intensity ultrasonic transducer, low Intensity, in this embodiment, may be a signal whose peak time sound field sound intensity is lower than 720mW and greater than a frequency above 1MHz.
  • the first ultrasonic transducer 122 is a ring-shaped hollow design, wherein the ring-shaped hollow region is provided with a receiving cavity 122a, so that the imaging probe 151 with a smaller diameter can be placed in the receiving cavity 122a inside the first ultrasonic transducer 122 Perform inspection and imaging.
  • the ultrasonic echo signal monitoring system 14 includes the second ultrasonic transducer 141 and the echo signal monitoring component 142, and the echo signal monitoring component 142 includes the pulse transceiver 142a and the data acquisition card 142b.
  • the second ultrasonic transducer 141 mainly emits acoustic signals and receives acoustic echoes, and its diameter is not greater than the inner diameter of the annular first ultrasonic transducer 122, and can be placed in the intermediate space of the annular first ultrasonic transducer 122.
  • the pulse transceiver 142a is a device with dual functions of transmitting and receiving.
  • the pulse transceiver 142a first outputs an electrical pulse to excite the second ultrasonic transducer 141 to emit a monitoring sound signal, and the monitoring sound signal enters the cone-shaped acoustic coupling catheter to propagate, when When the transmission encounters the diaphragm of the sound-transmitting immune patch, it reflects back an echo and enters the pulse transceiver 142a for amplification, and after further undergoing the analog-to-digital conversion of the data acquisition card 142b, it can be recorded as the first echo pulse.
  • the reception time t1 of the first monitoring echo and the reception time t2 of the second monitoring echo are separated by 2 microseconds.
  • the main functions and principles of the ultrasonic echo signal monitoring system 14 include: z-axis positioning of the first ultrasonic transducer 122 assisted by low-intensity ultrasonic echo and microbubble generation and blasting monitoring in enhanced ultrasonic mode.
  • the following implementation method may be included: During the process of the automatic positioning of the first ultrasonic transducer 122 in the z-axis, The ultrasound echo signal monitoring system 14 is activated to calculate, move and determine the position between the first ultrasound transducer 122 and the skin. As shown in Fig.
  • the main functions and principles of microbubble generation and blast monitoring used in enhanced ultrasound mode include: in enhanced ultrasound mode, the phase-change droplets mixed with the vaccine antigen solution in the acoustically permeable immune patch 13 first To achieve gasification at the ultrasound focus. Therefore, in the enhanced ultrasonic mode, after the positioning of the first ultrasonic transducer 122 is completed, the high-intensity excitation pulse is released, first the phase-change activation of the phase-change droplet from the liquid core to the gaseous core is completed, and then the low-intensity ultrasonic pulse signal is released Detection. As shown in Fig.
  • the air core ultrasound intensifier will generate a strong reflection between the diaphragm and the skin, forming a third monitoring echo in the echo waveform. Further release the high-intensity excitation pulse blasting gas nuclear ultrasound enhancer, thereby generating a stronger mechanical effect on the skin and inducing the formation of skin pores. When the gas nuclear ultrasound enhancer blasts, its third monitoring echo will disappear. Therefore, as shown in FIG. 5 (4), the low-intensity ultrasonic pulse signal is released again for detection, it is determined that the third monitoring echo disappears, and the single-shot enhanced ultrasound skin pore induction is completed.
  • an ultrasound echo signal monitoring system 14 connected to the main control system 11 is provided in the vaccine transdermal delivery device 1 based on the acoustically induced micropore array; wherein, the pulse is transmitted and received in the monitoring system
  • the instrument 142a and the data acquisition card 142b based on the second ultrasonic transducer 141 in the detection system, monitor the drug delivery process of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array, which may include
  • the z-axis positioning of the first ultrasonic transducer 122 assisted by low-intensity ultrasonic echo, and for the monitoring and generation of microbubbles in the enhanced ultrasonic mode, through the monitoring of the ultrasonic echo signal monitoring system 1414,
  • the z-axis positioning of the first ultrasound transducer 122 is realized, so that the area of the target skin of the ultrasound percutaneous administration is more accurate, and the accuracy of the administration is improved on the positioning level.
  • Embodiment 3 Referring to FIGS. 6-7, based on the above-mentioned Embodiment 2, this embodiment provides a vaccine transdermal delivery device 1 based on an acoustically induced micropore array, the vaccine transdermal delivery device based on an acoustically induced micropore array 1 also includes an optical imaging monitoring system 15 connected to the main control system 11;
  • the optical imaging monitoring system includes an imaging probe 151, and an imaging processing unit 152 connected to the imaging probe 151;
  • the outer diameter of the imaging probe 151 is not larger than the inner diameter of the accommodating cavity 122a, and is used to be placed in the accommodating cavity 122a during monitoring;
  • the main control system 11 is also used to control the imaging probe 151 to perform image acquisition on the acoustically permeable immune patch and / or skin, perform real-time or timed imaging, and perform imaging data on the imaging processing unit 152 Recognition process for imaging detection.
  • the imaging probe 151 is placed in the middle of the receiving cavity 122a of the first ultrasonic transducer 122; and,
  • the relative positions of the imaging probe 151, the center of the imaging field corresponding to the imaging probe 151, and the first ultrasound transducer 122 are geometric centers coaxial.
  • the optical imaging monitoring system is composed of the imaging probe 151 and the imaging processing unit 152, wherein the imaging probe 151 has zoom and zoom functions, and its diameter is not larger than the inner diameter of the ring-shaped first ultrasonic transducer 122, so that it can be placed in the ring-shaped first
  • An accommodating cavity 122a in an ultrasonic transducer 122 performs imaging monitoring of the acoustically permeable immune patch (rubber ring) and skin damage below the annular first ultrasonic transducer 122.
  • the realized functions include the xy axis positioning of the first ultrasonic transducer 122 assisted by optical imaging, and the quantitative evaluation of skin micropore damage.
  • the working principle includes: 1. When positioning the xy axis of the first ultrasonic transducer 122 with the aid of optical imaging, as shown in FIG. 7 (1), the The isolation ring can be imaged in real time.
  • the imaging probe 151 is placed in the middle of the ring-shaped first ultrasonic transducer 122, and the centers of the two are coaxial, and the center of the imaging field of view is coaxial with the geometric center of the imaging probe 151 and the first ultrasonic transducer 122.
  • the first ultrasound transducer 122 and the imaging probe 151 placed therein can be moved by a three-axis movement control system to isolate the center of the imaging field of view from the acoustically permeable immunopatch
  • the center of the ring is coaxial, so that the acoustic energy focus (located on the center axis of the first ultrasonic transducer 122) and the center of the sound-transmitting immune patch isolation ring are aligned in the xy plane.
  • the imaging probe 151 obtains the vaccine-derived transdermal delivery device 1 based on the acoustically induced micropore array provided in this example to perform acoustic induction
  • the high-definition image of skin damage after micropore immunization passes through the imaging processing unit 152 to perform image processing analysis and calculate the skin damage range. Examples include:
  • the skin damage HD result image is converted to 8-bit grayscale image, and the size is re-set (such as: 600pixels * 600pixels) and the contrast is improved;
  • Threshold screening select the damaged area marked with black biological dye in the skin, and count the sum of its pixels
  • the imaging probe 151 of the optical imaging monitoring system is moved into the accommodating cavity 122 a in the annular hollow first ultrasonic transducer 122 to acquire an image
  • the imaging processing unit 152 Permeable immune patch and / or skin image acquisition to achieve the positioning of the xy axis of the first ultrasound transducer 122 with the aid of optical imaging during the ultrasound transdermal drug delivery through the immune array device, or Quantitative evaluation of skin micropore damage can, on the one hand, improve the positioning accuracy of the drug delivery area by positioning to achieve precise drug delivery; on the other hand, it can be accurately quantified during the drug delivery process to achieve precise delivery of immune antigens control.
  • Embodiment 4 Referring to FIGS. 8-10, based on the foregoing Embodiment 3, this embodiment provides a vaccine transdermal delivery device 1 based on an acoustically induced micropore array, wherein,
  • the vaccine transdermal delivery device 1 based on an acoustically induced micropore array further includes a three-dimensional mobile controller 16 connected to the main control system 11;
  • the optical imaging monitoring system 15 further includes a probe fixing bracket 153 connected to the imaging probe 151;
  • the high-frequency strong-focus ultrasonic excitation assembly 12 further includes a first ultrasonic transducer fixing bracket 124 connected to the first ultrasonic transducer 122;
  • the ultrasonic echo signal monitoring system 14 further includes a second ultrasonic transducer fixing bracket 143 connected to the second ultrasonic transducer;
  • the probe fixing bracket 153, the first ultrasound transducer fixing bracket 124, and the second ultrasound transducer fixing bracket are all connected to the 16.
  • the sound-permeable immune patch 13 includes an isolation ring 131 and an adhesive film 132;
  • the adhesive film 132 covers the isolation ring 131; and, a drug accommodating cavity 133 is formed between the adhesive film 132 and the isolation ring 131;
  • the acoustically permeable immune patch 13 When administering to the skin, using the viscosity of the adhesive film 132, the acoustically permeable immune patch 13 is applied to the surface of the skin, wherein the drug accommodating cavity 133 is filled with a drug for administration.
  • the isolation ring 131 is a circular rubber isolation ring 131; the adhesive film 132 is a transparent plastic adhesive film 132; the adhesive film 132 faces away from the drug during administration
  • the conical coupling catheter 123 has adhesiveness on the side facing the skin; the outer diameter of the isolation ring 131 is 5-15 mm, the inner diameter is 3-10 mm, and the thickness is 1-3 mm.
  • the three-dimensional positioning movement control system uses echo signals to detect the relative position of the skin site and the excitation source, and cooperates with the three-dimensional movement controller 16 to adjust the skin site to the ultrasonic focus point area, and is also used to vaporize the phase change droplets into Bubble detection and process evaluation of ultrasonic cavitation effects, real-time monitoring, is the leading role of the system.
  • the three-dimensional movement control system is connected to the main control system 11, and the probe fixing bracket 153, the first ultrasonic transducer fixing bracket 124, and the second ultrasonic transducer 141 are all connected with the three-dimensional movement
  • the controller 16 is connected.
  • the movement of the three-dimensional positioning movement control system can be controlled by the main control device, that is, the probe fixing bracket 153, the first ultrasonic transducer fixing bracket 124, and the second
  • the ultrasonic transducer 141 controls the spatial orientation of the first ultrasonic transducer 122 and the cone-shaped acoustic coupling catheter, the spatial orientation of the second ultrasonic transducer 141, and the spatial orientation of the imaging probe 151;
  • the spatial orientation of the second ultrasonic transducer 141 and the imaging probe 151 are adjusted separately, and the second ultrasonic transducer 141 or The imaging probe 151 is moved into the annular hollow accommodating cavity 122a of the first ultrasonic transducer 122, respectively to perform the corresponding functions of the immune array device provided in this embodiment, so that When medicine is taken, accurate drug delivery can be achieved by moving the corresponding device, and the corresponding imaging probe 151 or the second ultrasonic transducer 141 can
  • the sound-permeable immune patch 13 is used to apply to the target immunized area of the user or patient, that is, the drug carrier corresponding to the immune array device provided by the present disclosure.
  • the structure of the sound-permeable immune patch 13 may be composed of an isolation ring and a single-sided adhesive transparent plastic film.
  • the outer diameter of the isolation ring is 8 mm
  • the inner diameter is 6.5 mm
  • the thickness is 1.5 mm.
  • the mechanical coefficient is small and the weak reflection can reduce the loss of ultrasonic energy and can Avoid echo energy causing additional damage to the ultrasonic transmitter and echo receiver.
  • the thickness of the single-sided adhesive plastic film is 75 microns or less, and the plastic film in this thickness range has acoustic permeability, that is, more than 80% of the acoustic energy can be transmitted through the film into the skin.
  • Immune patch means that the vaccine antigen, or the vaccine antigen mixed liquid added with phase change droplets can be filled into the annular cavity of the patch, and then the skin surface is applied with a single-sided adhesive transparent film to complete the skin immune patch. ready.
  • the isolation ring By setting the isolation ring, it can be used to locate and administer the target immune area of the skin on the basis of achieving a small mechanical coefficient, if reflecting, reducing energy damage or injury, and to a certain extent, improve the spatial orientation of the administration area Accuracy, and reduce energy damage and mechanical damage to the skin.
  • Embodiment 5 In addition, referring to FIGS. 11-12, this embodiment provides a method for using a vaccine transdermal delivery device 1 based on an acoustically induced micropore array, including:
  • Step S10 applying an acoustically permeable immune patch 13 and placing it on the lower end of the conical coupling catheter 123 of the vaccine percutaneous delivery device 1 based on the acoustically induced micropore array;
  • Step S20 spatial positioning is performed by the ultrasonic echo signal monitoring system 14 and the optical imaging monitoring system 15 of the vaccine-derived transdermal delivery device 1 based on the acoustically induced micropore array to determine the skin administration site;
  • Step S30 Transcutaneous immunization administration to the skin administration site by the high-frequency intensity focused ultrasound excitation assembly 12 of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array;
  • step S40 the delivery effect evaluation is performed on the skin administration site of percutaneous immune administration through the optical imaging monitoring system 15.
  • the present disclosure can provide a method for using a vaccine transdermal delivery device 1 based on an acoustically induced micropore array for transdermal patch administration to a target location of a user's skin to achieve the purpose of transdermal immunity.
  • a vaccine transdermal delivery device 1 based on an acoustically induced micropore array for transdermal patch administration to a target location of a user's skin to achieve the purpose of transdermal immunity.
  • Figure 12 for its workflow, which may include:
  • Mode 1 Skin pore formation and transdermal vaccine delivery:
  • mode two enhanced ultrasound mode.
  • Mode 2 has higher delivery efficiency than Mode 1.
  • the enhanced ultrasound mode first release high-intensity ultrasound pulses to excite the vaporization of liquid-nuclear phase-change droplets, confirm the generation of the gas-nuclear ultrasound enhancer by low-energy ultrasound echoes, and then release the high-energy ultrasound pulses to induce gas-nuclear ultrasound enhancement The agent exploded, and again confirmed the disappearance of the air core ultrasound enhancer by low-energy ultrasound echo, thus completing a single delivery.
  • the width of the skin pores in the width mode 1 is 0.1 ⁇ 0.03 mm2, the area of the skin pores in the width mode 2 is 0.3 ⁇ 0.05, and the width of the skin pores in the width 3 is 0.6 ⁇ 0.1;
  • the depth of the skin micropores in Mode 1 is 100 ⁇ 50 microns, the depth of the skin micropores in Depth Mode 2 is 200 ⁇ 50 microns, and the depth of the skin micropores in Depth Mode 3 is 300 ⁇ 50 microns; where black is marked by Indian ink.
  • the total vaccine delivery dose can be further designed and optimized through the combination of skin micropores, thereby regulating the total transdermal delivery dose.
  • the 1 ⁇ 1 array mode is a single skin micropore
  • the 1 ⁇ 2 array mode is two skin micropores
  • the 2 ⁇ 2 array mode is four skin micropores
  • the 3 ⁇ 3 array mode is nine skin micropores hole.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Medical Informatics (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

L'invention concerne un dispositif d'administration de vaccin percutané (1) utilisant un réseau de micropores induit acoustiquement. Le dispositif (1) comprend un système de commande principal (11), un ensemble d'excitation ultrasonore focalisé intense de haute fréquence (12), et un timbre d'immunisation acoustiquement perméable (13). L'ensemble d'excitation ultrasonore focalisé intense de haute fréquence (12) comprend un système de génération de signal ultrasonore haute fréquence (121), un premier transducteur ultrasonore (122) connecté au système de génération de signal ultrasonore haute fréquence (121), et un conduit de couplage conique (123) connecté au premier transducteur ultrasonore (122). Le conduit de couplage conique (123) est placé sur le timbre d'immunisation acoustiquement perméable (13) pendant l'administration de vaccin, de telle sorte qu'une énergie ultrasonore focalisée intense de haute fréquence est délivrée à partir d'une extrémité avant du conduit pour induire la formation de micropores et de réseaux de micropores sur la peau.
PCT/CN2019/117138 2018-11-12 2019-11-11 Dispositif d'administration de vaccin percutané utilisant un réseau de micropores induit acoustiquement WO2020098601A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811341239.XA CN109513104B (zh) 2018-11-12 2018-11-12 一种基于声诱导微孔阵列的疫苗经皮递送装置
CN201811341239.X 2018-11-12

Publications (1)

Publication Number Publication Date
WO2020098601A1 true WO2020098601A1 (fr) 2020-05-22

Family

ID=65774187

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/117138 WO2020098601A1 (fr) 2018-11-12 2019-11-11 Dispositif d'administration de vaccin percutané utilisant un réseau de micropores induit acoustiquement

Country Status (2)

Country Link
CN (1) CN109513104B (fr)
WO (1) WO2020098601A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109513104B (zh) * 2018-11-12 2020-10-02 深圳大学 一种基于声诱导微孔阵列的疫苗经皮递送装置
CN112023243B (zh) * 2020-09-15 2022-03-25 南京大学 超声循环聚焦发射的透皮给药装置及控制方法
CN113616917B (zh) * 2021-07-12 2024-04-09 重庆医科大学 基于超声及微流控的智能经皮给药装置、方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101466432A (zh) * 2006-06-14 2009-06-24 皇家飞利浦电子股份有限公司 用于经皮给药的设备和操作这种设备的方法
CN101698121A (zh) * 2009-10-23 2010-04-28 西安交通大学 促进药物透过血脑屏障的适型超声系统
CN102406979A (zh) * 2010-09-22 2012-04-11 田德扬 将大分子物质导入活体标靶细胞的方法及系统
CN102755692A (zh) * 2012-07-30 2012-10-31 王路 一种超声波和离子导入透皮药物或美容品导入装置
CN103861204A (zh) * 2014-03-25 2014-06-18 王安 一种调制超声波装置及其经皮给药的促渗透方法
CN204995996U (zh) * 2015-09-29 2016-01-27 广州三得医疗科技有限公司 一种高低双频超声电导治疗仪
CN106621024A (zh) * 2017-01-17 2017-05-10 湖南省健缘医疗科技有限公司 超声药透诊疗装置
US20180071505A1 (en) * 2016-09-13 2018-03-15 National Tsing Hua University Ultrasonic device for transversely manipulating drug delivery carriers and method using the same
CN109513104A (zh) * 2018-11-12 2019-03-26 深圳大学 一种基于声诱导微孔阵列的疫苗经皮递送装置

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110040171A1 (en) * 2003-12-16 2011-02-17 University Of Washington Image guided high intensity focused ultrasound treatment of nerves
CN101920064A (zh) * 2009-06-13 2010-12-22 翁春晓 一种超声波和电场叠加靶位透药的方法和仪器
CN103463732B (zh) * 2013-09-18 2015-07-15 北京中美联医学科学研究院有限公司 一种超声波靶位致孔的装置和方法
CN104383646B (zh) * 2014-12-12 2020-04-24 黄晶 一种超声介入治疗系统
CN105361904A (zh) * 2015-11-25 2016-03-02 青岛金智高新技术有限公司 水凝胶超声耦合装置
CN206391368U (zh) * 2016-10-18 2017-08-11 苏州国科昂卓医疗科技有限公司 一种超声治疗仪

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101466432A (zh) * 2006-06-14 2009-06-24 皇家飞利浦电子股份有限公司 用于经皮给药的设备和操作这种设备的方法
CN101698121A (zh) * 2009-10-23 2010-04-28 西安交通大学 促进药物透过血脑屏障的适型超声系统
CN102406979A (zh) * 2010-09-22 2012-04-11 田德扬 将大分子物质导入活体标靶细胞的方法及系统
CN102755692A (zh) * 2012-07-30 2012-10-31 王路 一种超声波和离子导入透皮药物或美容品导入装置
CN103861204A (zh) * 2014-03-25 2014-06-18 王安 一种调制超声波装置及其经皮给药的促渗透方法
CN204995996U (zh) * 2015-09-29 2016-01-27 广州三得医疗科技有限公司 一种高低双频超声电导治疗仪
US20180071505A1 (en) * 2016-09-13 2018-03-15 National Tsing Hua University Ultrasonic device for transversely manipulating drug delivery carriers and method using the same
CN106621024A (zh) * 2017-01-17 2017-05-10 湖南省健缘医疗科技有限公司 超声药透诊疗装置
CN109513104A (zh) * 2018-11-12 2019-03-26 深圳大学 一种基于声诱导微孔阵列的疫苗经皮递送装置

Also Published As

Publication number Publication date
CN109513104A (zh) 2019-03-26
CN109513104B (zh) 2020-10-02

Similar Documents

Publication Publication Date Title
WO2020098601A1 (fr) Dispositif d'administration de vaccin percutané utilisant un réseau de micropores induit acoustiquement
Child et al. Lung damage from exposure to pulsed ultrasound
US9636083B2 (en) High quality closed-loop ultrasound imaging system
CA2773181C (fr) Systemes, procedes et support lisible par ordinateur pour imagerie de contraste a haute frequence et therapeutique guidee par l'image
JPH0643242A (ja) 超音波イメージ化システム
CN101854854A (zh) 用于定位如神经的结构的非侵入性设备和方法
CN204410838U (zh) 超声探头无菌保护套
US10271733B2 (en) Photo-acoustic signal enhancement with microbubble-based contrast agents
CN106621024B (zh) 超声药透诊疗装置
Xu et al. Optical and acoustic monitoring of bubble cloud dynamics at a tissue-fluid interface in ultrasound tissue erosion
Pouliopoulos et al. Pulse inversion enhances the passive mapping of microbubble-based ultrasound therapy
EP3326538B1 (fr) Dispositif d'affichage d'énergie ultrasonore
Rota et al. Detection of acoustic cavitation in the heart with microbubble contrast agents in vivo: A mechanism for ultrasound-induced arrhythmias
US20150351724A1 (en) Real time ultrasound thermal dose monitoring system for tumor ablation therapy
Hu et al. Programmable and monitorable intradermal vaccine delivery using ultrasound perforation array
Yang et al. Photoacoustic imaging of biological tissues based on annular transducer array
Sutin et al. Prospective medical applications of nonlinear time reversal acoustics
Sapozhnikov et al. Ultrasound-guided localized detection of cavitation during, lithotripsy in pig kidney in vivo
Khokhlova et al. The use of twinkling artifact of Doppler imaging to monitor cavitation in tissue during high intensity focused ultrasound therapy
JP4387947B2 (ja) 超音波治療装置
US11896253B2 (en) System and method for detecting and aligning acoustic beam in situ to a target using wide-beam, low frequency (<1 mhz) ultrasound
Rich Characterization of cavitation effects in therapeutic ultrasound: Sonophoresis experiments and quantitative emission measurements
Tung et al. Identifying the inertial cavitation pressure threshold and skull effects in a vessel phantom using focused ultrasound and microbubbles
van Blokland Instigating and monitoring transdermal drug delivery using ultrasound-mediated cavitation
Slayton et al. Feasibility of tissue effects produced by noninvasive high frequency intense therapy ultrasound via inertial cavitation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19885061

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19885061

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 23.08.2021)

122 Ep: pct application non-entry in european phase

Ref document number: 19885061

Country of ref document: EP

Kind code of ref document: A1