CN117504631A - Drug carrier micro-bubble processing method, processing equipment and particle size regulating method - Google Patents

Drug carrier micro-bubble processing method, processing equipment and particle size regulating method Download PDF

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Publication number
CN117504631A
CN117504631A CN202311464552.3A CN202311464552A CN117504631A CN 117504631 A CN117504631 A CN 117504631A CN 202311464552 A CN202311464552 A CN 202311464552A CN 117504631 A CN117504631 A CN 117504631A
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CN
China
Prior art keywords
drug carrier
ring
microbubbles
gas
membrane shell
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Pending
Application number
CN202311464552.3A
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Chinese (zh)
Inventor
郑婷婷
陈芸
帅心涛
王梦欣
林淑萍
罗岚
姚荣权
曹众
胡会英
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Peking University Shenzhen Hospital (peking University Shenzhen Clinic Medical College)
SHENZHEN PKU-HKUST MEDICAL CENTER
Original Assignee
Peking University Shenzhen Hospital (peking University Shenzhen Clinic Medical College)
SHENZHEN PKU-HKUST MEDICAL CENTER
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Application filed by Peking University Shenzhen Hospital (peking University Shenzhen Clinic Medical College), SHENZHEN PKU-HKUST MEDICAL CENTER filed Critical Peking University Shenzhen Hospital (peking University Shenzhen Clinic Medical College)
Priority to CN202311464552.3A priority Critical patent/CN117504631A/en
Publication of CN117504631A publication Critical patent/CN117504631A/en
Pending legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/20—Mixing gases with liquids
    • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/20—Mixing gases with liquids
    • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
    • B01F23/2319—Methods of introducing gases into liquid media
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/20—Mixing gases with liquids
    • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
    • B01F23/2366—Parts; Accessories
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/20—Mixing gases with liquids
    • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
    • B01F23/237—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids characterised by the physical or chemical properties of gases or vapours introduced in the liquid media
    • B01F23/2373—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids characterised by the physical or chemical properties of gases or vapours introduced in the liquid media for obtaining fine bubbles, i.e. bubbles with a size below 100 µm
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/20—Mixing gases with liquids
    • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
    • B01F23/237—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids characterised by the physical or chemical properties of gases or vapours introduced in the liquid media
    • B01F23/2376—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids characterised by the physical or chemical properties of gases or vapours introduced in the liquid media characterised by the gas being introduced
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/20—Mixing gases with liquids
    • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
    • B01F23/237—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids characterised by the physical or chemical properties of gases or vapours introduced in the liquid media
    • B01F23/2376—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids characterised by the physical or chemical properties of gases or vapours introduced in the liquid media characterised by the gas being introduced
    • B01F23/23766—Sulphur containing gas
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/20—Mixing gases with liquids
    • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
    • B01F23/238—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids using vibrations, electrical or magnetic energy, radiations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/80—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/22—Control or regulation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/14—Production of inert gas mixtures; Use of inert gases in general
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/22—Mixing of ingredients for pharmaceutical or medical compositions

Abstract

The application belongs to the technical field of medicines, and particularly relates to a method for processing drug carrier microbubbles, processing equipment and a particle size regulating method. The drug carrier micro-bubble processing equipment comprises a container, a metal diaphragm, a PZT piezoelectric ring, an inflatable tile and an ultrasonic driving plate; the metal diaphragm and the PZT piezoelectric ring are respectively and electrically connected to the ultrasonic driving plate, and can atomize liquid substances in the container under the action of the ultrasonic driving plate and spray out from the micropores of the membrane shell on the microporous ring of the membrane shell; the inflatable tiles are used for introducing inert gas. The drug carrier microvesicle processing method comprises a preparation step, a charging step and a mixing step. The particle size of the drug carrier microbubbles is regulated and controlled by regulating parameters such as micropore size, ultrasonic power, frequency and the like. The method has the technical effects of high production efficiency of microbubbles, uniform granularity, capability of quantitatively regulating and controlling the granularity and the like.

Description

Drug carrier micro-bubble processing method, processing equipment and particle size regulating method
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a method for processing drug carrier microbubbles, processing equipment and a particle size regulating method.
Background
Microbubbles are liquids containing bubbles having a diameter of several micrometers, and can be used as ultrasound contrast agents by utilizing the characteristic that the liquid containing bubbles has strong scattering of ultrasound. The method is used for enhancing ultrasonic Doppler signals of blood flow and improving definition and resolution of ultrasonic images, thereby improving disease display rate and diagnosis rate. Currently, most of the commonly used microbubbles are filled with inert gases, such as sulfur hexafluoride microbubbles, perfluoropropane microbubbles, and the like. The medicine is loaded into the microbubbles to realize larger medicine loading, and local blasting is carried out under ultrasound to further improve the local medicine concentration, and focus treatment is carried out after the local blasting. The drug carrier can not only retain the contrast effect of microbubbles, but also can be used as a drug or drug carrier for treating various diseases.
The existing preparation method of the micro-bubbles comprises an ultrasonic cavitation method, a mechanical stirring method, a freeze drying method, a physicochemical method/chemical method, a laser induction method, a microfluidic method, a film hydration method, an ultrasonic microfluidic method and the like. The development of the micro-bubble preparation method which has uniform and stable granularity, can adjust the granularity according to the requirement, has high production efficiency and industrial application potential becomes a research hotspot in the field of micro-bubble preparation.
Disclosure of Invention
In view of this, the present application provides a method for processing drug carrier microbubbles, a processing apparatus, and a method for controlling particle size, to solve some or all of the technical problems described in the background of the present application.
The drug carrier microbubble processing equipment adopted for solving the technical problem is as follows:
drug carrier microbubble processing equipment, its characterized in that: the device comprises a container, a metal diaphragm, a PZT piezoelectric ring, an inflatable tile and an ultrasonic driving plate;
the PZT piezoelectric ring is arranged on the metal diaphragm, and a gas micropore ring and a film shell micropore ring are arranged on the metal diaphragm corresponding to the inner ring part of the PZT piezoelectric ring; the inflatable tile is arranged on the gas micropore ring;
the container comprises an upper opening and a lower opening, the metal diaphragm is arranged in the lower opening, the PZT piezoelectric ring is positioned in the container, and the inflatable tile is accommodated in the container and extends out of the upper opening;
the gas micropore ring comprises a plurality of gas micropores for passing gas, and the membrane shell micropore ring comprises a plurality of membrane shell micropores for passing membrane shell materials;
the metal diaphragm and the PZT piezoelectric ring are respectively and electrically connected to the ultrasonic driving plate, and the metal diaphragm and the PZT piezoelectric ring can atomize liquid substances in the container under the action of the ultrasonic driving plate and spray out from the micropores of the membrane shell on the microporous ring of the membrane shell.
Preferably, the gas micropore ring and the membrane shell micropore ring are respectively provided with a plurality of channels and are arranged at intervals.
Preferably, the metal membrane has a circular structure, and the lower opening is shaped and sized to fit the metal membrane.
Preferably, the metal membrane is made of SUS303 or SUS304 stainless steel, and the PZT piezoelectric ring is made of PZT piezoelectric ceramics.
Preferably, the metal diaphragm is provided with a piezoelectric ring accommodating groove, and the PZT piezoelectric ring is arranged in the piezoelectric ring accommodating groove.
Preferably, the inflatable tile comprises an inflatable chamber comprising an open end and a closed end, the closed end being provided with an inflatable aperture. Further preferably, a bubble stone is provided in the plenum. Wherein: the open end is arranged at the gas micropore ring position.
The processing method of the drug carrier microbubbles adopted for solving the technical problems comprises the following steps:
a method for processing drug carrier microbubbles is characterized in that: the drug carrier microbubbles are processed using the drug carrier microbubble processing apparatus according to any one of the preceding claims.
Preferably, the drug carrier microvesicle processing method comprises the following steps:
a preparation step of uniformly dissolving a drug to be loaded in a buffer solution, and adding a phospholipid stock solution to form a uniform phospholipid suspension;
a charging step of adding the phospholipid suspension prepared in the preparation step into a container and feeding inert gas into the inflatable tile;
mixing, namely atomizing the phospholipid suspension by an ultrasonic driving plate, a metal diaphragm and a PZT piezoelectric ring and spraying the phospholipid suspension from the micropores of the membrane shell on the microporous ring of the membrane shell; simultaneously, inert gas is sprayed out from gas micropores in the gas micropore ring; and forming drug carrier microbubbles after mixing.
Preferably, the inert gas is sulfur hexafluoride microbubbles or perfluoropropane. The buffer solution is any one or combination of PBS solution, PBS solution and physiological saline.
Preferably, the drug carrier microbubbles are black phosphorus microbubbles or hydroxycamptothecin microbubbles.
The method for regulating the granularity of the drug carrier microbubbles adopted for solving the technical problems comprises the following steps:
a method for regulating and controlling the granularity of drug carrier microbubbles is characterized in that:
processing the drug carrier microbubbles using the drug carrier microbubble processing apparatus according to any one of the preceding claims;
the particle size of the drug carrier microbubbles is adjusted by adjusting one or any combination of the following process parameters:
the particle size of the gas micropores, the particle size of the membrane shell micropores, the output power of the ultrasonic driving plate, the oscillation frequency of the ultrasonic driving plate and the gas pressure of inert gas.
The beneficial technical effects are as follows:
1. according to the drug carrier microbubble processing equipment disclosed by the application, the metal membrane is provided with the plurality of gas micropore rings and the membrane shell micropore rings which are arranged at intervals, so that the membrane shell material in the container and the drug to be carried can be atomized and sprayed out of the membrane shell micropore rings, and meanwhile, high-pressure inert gas can be introduced through the inflatable tile and sprayed out of the gas micropores; the two can form drug carrier microbubbles with uniform granularity after being mixed and dissolved. The micropore size can be customized according to the needs and the membrane shell material is sufficiently sprayed and mixed with inert gas, so that the method for processing the drug carrier microbubbles has the technical effects of high production efficiency and uniform granularity.
2. According to the method for regulating and controlling the granularity of the drug carrier microbubbles, disclosed by the application, quantitative regulation of the drug carrier microbubbles can be realized by replacing metal diaphragms with micropores of different sizes or regulating the power, frequency or gas pressure of ultrasonic waves.
The technical scheme and technical effects of the present application will be described in detail below with reference to the drawings and the detailed description of the specification.
Drawings
Fig. 1: a top view of the drug carrier microbubble processing device;
fig. 2: test patterns of drug carrier microvesicle processing equipment;
fig. 3: schematic structural diagram of metal membrane;
fig. 4: schematic structural diagram of the inflatable tile;
fig. 5: microbubble photomicrographs of embodiment 1;
fig. 6: embodiment 2 microbubble photomicrographs;
10-a container, 20-a metal diaphragm, 30-a PZT piezoelectric ring and 40-an inflatable tile;
110-upper opening, 120-lower opening;
210-gas micropore ring, 220-membrane shell micropore ring, 230-gas micropore, 240-membrane shell micropore and 260-piezoelectric ring accommodating groove; 410-plenum chamber, 420-open end, 430-sealed end, 440-air-fill hole.
Detailed Description
Referring to fig. 1-4, the drug carrier microbubble processing apparatus disclosed herein includes a container 10, a metal diaphragm 20, a PZT piezoelectric ring 30, an inflatable tile 40, and an ultrasonic drive plate. Wherein: the metal diaphragm 20, the PZT piezoelectric ring 30 and the ultrasonic driving plate are used for forming an ultrasonic micropore atomization mechanism so as to atomize the film shell material and spray out from micropores; the gas-filled bladder 40 is used to introduce inert gas and the container 10 is used to hold the liquid membrane shell material and uniformly disperse the entrapped drug.
The edge of the metal diaphragm 20 is provided with a piezoelectric ring accommodating groove 260, and the pzt piezoelectric ring 30 is fixedly assembled in the piezoelectric ring accommodating groove 260. Three gas micropore rings 210 (shown as the annular band where the black filled micropores are located in fig. 1) and three membrane shell micropore rings 220 (shown as the annular band where the black filled micropores are not located in fig. 1) are arranged in the inner ring of the PZT piezoelectric ring 30 (i.e., the middle part of the metal membrane 20). The three gas microporous rings 210 and the three membrane shell microporous rings 220 are uniformly spaced apart to ensure that the inert gas and the membrane shell spray are sufficiently and uniformly mixed.
A plurality of gas micropores 230 (shown in fig. 1 as black filled micropores) for passing gas are provided in the gas micropore ring 210, and a plurality of membrane shell micropores 240 (shown in fig. 1 as non-black filled micropores) for passing membrane shell material are provided in the membrane shell micropore ring 220.
The inflatable tile 40 has an annular body structure, an inflatable chamber 410 is disposed within the inflatable tile 40, the inflatable chamber 410 includes an open end 420 and a closed end 430, and the closed end 430 is provided with an inflatable aperture 440. The open end 420 is used to attach to the metal membrane 20 at the location of the gas cell ring 210. To ensure a gas dispersion effect, a gas bubble stone may be further disposed in the plenum chamber 410.
The container 10 includes an upper opening 110 and a lower opening 120, a metal film sheet 20 is disposed in the lower opening 120, the metal film sheet 20 has a circular structure, and the lower opening 120 is shaped and sized to be fitted with the metal film sheet 20.
PZT piezoelectric ring 30 is positioned within container 10 and gas-filled tiles 40 are received within container 10 and extend out of upper opening 110. The metal diaphragm 20 and the PZT piezoelectric ring 30 are electrically connected to an ultrasonic driving plate, respectively, and the metal diaphragm 20 and the PZT piezoelectric ring 30 can atomize the liquid substance in the container 10 and spray out from the inside of the membrane shell micropores 240 on the membrane shell micropore ring 220 under the action of the ultrasonic driving plate.
The metal diaphragm 20 is made of SUS303 or SUS304 stainless steel, and the PZT piezoelectric ring 30 is made of PZT piezoelectric ceramics.
Description of principle and effect:
adding a liquid membrane shell material uniformly dispersed with the entrapped medicine into a container, starting an ultrasonic micropore atomization mechanism, atomizing the membrane shell material in the container and the medicine to be entrapped and spraying out from the membrane shell micropores 240 in the membrane shell micropore ring 220; simultaneously using an inflator pump to eject inert gas from the membrane shell micropores 240 in the gas micropore ring 210; by adjusting the distance between the blister receiving container, such as a blister tray, and the metal membrane 20, the drug carrier blisters can be collected. Because the membrane shell material is sprayed and is fully mixed with inert gas, and the atomization efficiency of the micropore atomization mechanism is ensured, the preparation of the microbubbles by adopting the drug carrier microbubble processing equipment disclosed by the application has the technical effects of high production efficiency, uniform granularity and the like.
The application also discloses a processing method for preparing the drug carrier microbubbles by adopting the equipment, which comprises a preparation step, a loading step and a mixing step. Wherein:
a preparation step of uniformly dissolving a drug to be loaded in a buffer solution, and adding a phospholipid stock solution to form a uniform phospholipid suspension; drugs to be loaded such as black phosphorus nanoplatelets, hydroxycamptothecin, and the like, and buffer solutions such as one or a combination of a plurality of PBS solutions, physiological saline, and the like;
a charging step of charging the phospholipid suspension prepared in the preparation step into the container 10 and charging inert gas into the gas-filled tiles 40;
a mixing step of atomizing the phospholipid suspension by an ultrasonic drive plate, the metal diaphragm 20 and the PZT piezoelectric ring 30 and spraying the phospholipid suspension from the inside of the membrane shell micropores 240 on the membrane shell micropore ring 220; simultaneously, inert gas is sprayed out from the gas micropores 230 in the gas micropore ring 210; and forming drug carrier microbubbles after mixing.
Embodiment 1: black phosphorus sulfur hexafluoride microbubbles:
adding black phosphorus nano-sheets or black phosphorus quantum dots into normal saline, forming uniform and stable mixed solution through an ultrasonic oscillator, and adding phospholipid stock solution into the mixed solution to form uniform phospholipid suspension, wherein the phospholipid stock solution can be formed by polyethylene glycol 4000, distearyl phosphorylcholine (DSPC), dipalmitoyl sodium phosphatidyl glycerol (DPPG-Na), palmitic acid and the like;
adding the phospholipid suspension to the vessel 10 while connecting the gas-filled tiles 40 with an inert gas source such as sulfur hexafluoride, for example, by connecting the gas-filled holes 440 to the gas outlet of the inflator via a plastic hose;
a mixing step of atomizing the phospholipid suspension by an ultrasonic drive plate, the metal diaphragm 20 and the PZT piezoelectric ring 30 and spraying the phospholipid suspension from the inside of the membrane shell micropores 240 on the membrane shell micropore ring 220; simultaneously, inert gas is sprayed out from the gas micropores 230 in the gas micropore ring 210; the distance between the microbubble receiving container and the metal membrane 20 is adjusted, and the aerosol is mixed to form drug carrier microbubbles. The technological parameters are as follows: resonant frequency: 165.+ -.10 kHz, resonance impedance: electrostatic capacity of less than or equal to 500 ohm: 1300PF, pore size: 4.5 μm. The technical parameters of the microbubbles are as follows:
the morphology of the microbubbles is shown in FIG. 5.
Embodiment 2: hydroxycamptothecin perfluoropropane microbubbles
Adding hydroxycamptothecin into PBS solution, adding phospholipid stock solution (DSPC, DSPE-PEG 2000), heating and ultrasonic oscillating to form uniform phospholipid stock solution;
adding the phospholipid suspension to the vessel 10 while connecting the inflatable tile 40 with a source of perfluoropropane, such as by a plastic hose connecting the inflation port 440 to the air outlet of the inflator;
a mixing step of atomizing the phospholipid suspension by an ultrasonic drive plate, the metal diaphragm 20 and the PZT piezoelectric ring 30 and spraying the phospholipid suspension from the inside of the membrane shell micropores 240 on the membrane shell micropore ring 220; simultaneously, inert gas is sprayed out from the gas micropores 230 in the gas micropore ring 210; the distance between the microbubble receiving container and the metal membrane 20 is adjusted, and the aerosol is mixed to form drug carrier microbubbles. The technological parameters are as follows: resonant frequency: 165.+ -.10 kHz, resonance impedance: electrostatic capacity of less than or equal to 500 ohm: 1300PF, pore size: 4.5 μm. The technical parameters of the microbubbles are as follows:
the morphology of the microbubbles is shown in FIG. 6.
From the above description, the present application further relates to a process control method for processing drug carrier microbubbles using the aforementioned drug carrier microbubble processing apparatus: the method adjusts the granularity of the drug carrier microbubbles by adjusting one or any combination of the following process parameters: the particle size of the gas micropores, the particle size of the membrane shell micropores, the output power of the ultrasonic driving plate, the oscillation frequency of the ultrasonic driving plate and the gas pressure of inert gas. When microbubbles with different granularities are needed, quantitative adjustment of the drug carrier microbubbles can be realized by changing metal diaphragms with micropores with different sizes in combination with other parameters such as power, frequency or gas pressure of ultrasonic waves.

Claims (11)

1. Drug carrier microbubble processing equipment, its characterized in that:
comprises a container (10), a metal diaphragm (20), a PZT piezoelectric ring (30), an inflatable tile (40) and an ultrasonic driving plate;
the PZT piezoelectric ring (30) is arranged on the metal diaphragm (20), and a gas micropore ring (210) and a film shell micropore ring (220) are arranged on the metal diaphragm (20) corresponding to the inner ring part of the PZT piezoelectric ring (20); the inflatable tiles (40) are arranged on the gas micropore ring (210);
the container (10) comprises an upper opening (110) and a lower opening (120), the metal diaphragm (20) is arranged in the lower opening (120), the PZT piezoelectric ring (30) is positioned in the container (10), and the inflatable tile (40) is accommodated in the container (10) and extends out of the upper opening (110);
the gas microporous ring (210) comprises a number of gas micropores (230) for passing a gas, and the membrane shell microporous ring (220) comprises a number of membrane shell micropores (240) for passing a membrane shell material;
the metal diaphragm (20) and the PZT piezoelectric ring (30) are respectively and electrically connected to the ultrasonic driving plate, and the metal diaphragm (20) and the PZT piezoelectric ring (30) can atomize liquid substances in the container (10) and spray out from the inside of the membrane shell micropores (240) on the membrane shell micropore ring (220) under the action of the ultrasonic driving plate.
2. The drug carrier microbubble processing apparatus of claim 1, wherein: the gas microporous ring (210) and the membrane shell microporous ring (220) are both multi-channel and spaced apart.
3. The drug carrier microbubble processing apparatus of claim 1, wherein: the metal membrane (20) has a circular structure, and the shape and size of the lower opening (120) are matched with those of the metal membrane (20).
4. The drug carrier microbubble processing apparatus of claim 1, wherein: the material of the metal diaphragm (20) is SUS303 or SUS304 stainless steel, and the material of the PZT piezoelectric ring (30) is PZT piezoelectric ceramics.
5. The drug carrier microbubble processing apparatus of claim 1, wherein: the piezoelectric ring containing groove (260) is formed in the metal diaphragm (20), and the PZT piezoelectric ring (30) is arranged in the piezoelectric ring containing groove (260).
6. The drug carrier microbubble processing apparatus of claim 1, wherein:
the inflatable tile (40) comprises an inflatable chamber (410), the inflatable chamber (410) comprises an open end (420) and a closed end (430), and the closed end (430) is provided with an inflatable hole (440).
7. The drug carrier microbubble processing apparatus of claim 6, wherein: a gas bubble stone is arranged in the plenum chamber (410).
8. The drug carrier micro-bubble processing method is characterized in that:
processing of drug carrier microbubbles using a drug carrier microbubble processing device according to any of claims 1-7.
9. The method of claim 8, wherein the drug carrier microbubbles are processed: the method comprises the following steps:
a preparation step of uniformly dissolving a drug to be loaded in a buffer solution, and adding a phospholipid stock solution to form a uniform phospholipid suspension;
a charging step of charging the phospholipid suspension prepared in the preparation step into a container (10) and charging inert gas into an inflatable tile (40);
a mixing step, wherein phospholipid suspension is atomized through an ultrasonic drive plate, a metal diaphragm (20) and a PZT piezoelectric ring (30) and sprayed out from a membrane shell micropore (240) on a membrane shell micropore ring (220); simultaneously, inert gas is sprayed out from the gas micropores (230) in the gas micropore ring (210); and forming drug carrier microbubbles after mixing.
10. The method of claim 9, wherein the drug carrier microbubbles are processed: the inert gas is sulfur hexafluoride microbubbles or perfluoropropane; the buffer solution is any one or combination of PBS solution, PBS solution and physiological saline; the drug carrier microbubbles are black phosphorus microbubbles or hydroxycamptothecin microbubbles.
11. The method for regulating the granularity of the drug carrier microbubbles is characterized by comprising the following steps of:
processing of drug carrier microbubbles using a drug carrier microbubble processing device according to any one of claims 1-7;
the particle size of the drug carrier microbubbles is adjusted by adjusting one or any combination of the following process parameters: the particle size of the gas micropores (230), the particle size of the membrane shell micropores (240), the output power of the ultrasonic driving plate, the oscillation frequency of the ultrasonic driving plate and the gas pressure of inert gas.
CN202311464552.3A 2023-11-06 2023-11-06 Drug carrier micro-bubble processing method, processing equipment and particle size regulating method Pending CN117504631A (en)

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