Microsphere preparation apparatus

Abstract

The application relates to the technical field of microsphere preparation, in particular to a microsphere preparation device. The microsphere preparation device comprises a needle, a liquid supply assembly, a collection assembly and a vibration assembly; the collection assembly comprises a first container for containing a continuous phase medium; the needle is suspended above the first container and the needle tip is inserted into the continuous phase to a predetermined depth; the liquid supply assembly is in communication with the needle to transport a dispersed phase liquid to the needle; meanwhile, the needle is installed on the driving end of the vibration assembly, and the vibration assembly is used for driving the needle to reciprocate in a direction perpendicular to the flow direction of the liquid in the needle, so that the inertial force formed by the vibration of the needle can dominate the breaking of the liquid drops in the microdroplet generation process, the particle size of the formed liquid drops and microspheres has high uniformity, the device is suitable for the preparation of microdroplets or microspheres of low-viscosity liquid and is also suitable for the preparation of microdroplets or microspheres of high-viscosity liquid, the device has simple structure, and the preparation efficiency of the microdroplets and the microdroplets can be effectively improved.

Description

Technical Field

[0001] This application relates to the field of microsphere preparation technology, and in particular to a microsphere preparation apparatus. Background Technology

[0002] Microspheres, due to their controllable morphology and high specific surface area, are widely used in drug delivery and targeted therapy. Currently, the main methods for preparing microspheres include emulsification, microfluidics, spray drying, and mechanical fragmentation. However, existing methods often fail to simultaneously achieve both uniformity and efficiency in microsphere preparation. For example, emulsification is simple and low-cost, but produces microspheres with poor uniformity, a wide particle size distribution, and a tendency to generate large numbers of tiny microspheres. While microfluidics produces microspheres with better uniformity, the equipment is complex, channels are prone to clogging, making it unsuitable for preparing microspheres from high-viscosity solutions. Furthermore, it has low efficiency and low throughput, hindering large-scale production. Spray drying and mechanical fragmentation methods offer fast preparation speeds, but both suffer from poor microsphere uniformity. Summary of the Invention

[0003] The purpose of this invention is to provide a microsphere preparation device to improve the uniformity and preparation efficiency of microspheres to a certain extent.

[0004] This invention provides a microsphere preparation device, including a needle, a liquid supply assembly, a collection assembly, and a vibration assembly; The collection component includes a first container for containing a continuous phase medium of liquid or gas, and when the continuous phase medium is gas, the first container also contains a receiving liquid. The needle is suspended above the first container, and the tip of the needle at its lower end extends into the continuous phase medium; The upper end of the needle is connected to the liquid supply assembly, which is used to deliver the dispersed phase liquid to the needle. The needle is mounted on the drive end of the vibration assembly, which drives the needle to reciprocate. The vibration direction of the needle is perpendicular to the flow direction of the dispersed liquid in the needle, so that the dispersed liquid forms continuous microdroplets with a predetermined particle size at the needle tip and drips into the first container.

[0005] Furthermore, the vibration assembly includes a reciprocating vibrator and a vibration transmission rod, and the needle is connected to the drive end of the reciprocating vibrator via the vibration transmission rod; The microsphere preparation equipment also includes a support frame with a column, and the reciprocating vibrator is mounted on the column in an adjustable manner via a slider.

[0006] Furthermore, the liquid supply assembly includes a second container, a first delivery pump, and a connecting pipe; The second container is used to hold the dispersed phase liquid. The inlet of the first delivery pump is connected to the first container, and the outlet of the first delivery pump is connected to the needle through the connecting pipe.

[0007] Furthermore, the needle is a single-channel needle or a multi-channel coaxial needle; The number of needles is at least one; when the number of needles is multiple, the microsphere preparation device further includes a dispenser. The distributor is connected to the drive end of the vibration assembly. The distributor has a cavity, and the upper end of the distributor has a liquid inlet that communicates with the cavity. The liquid inlet is connected to the liquid supply assembly. The dispenser has a base plate, and a plurality of needles are inserted into the base plate, with the upper ends of the plurality of needles extending into the cavity by a predetermined length to communicate with the cavity.

[0008] Furthermore, the first container and / or the second container are provided with temperature control elements for temperature regulation; The collection assembly also includes a third container and a second delivery pump, the inlet of the second delivery pump being connected to the third container and the outlet of the second delivery pump being connected to the first container; The collection assembly further includes a fourth container, and the first container is provided with a drain outlet, which is connected to the fourth container; The microsphere preparation equipment also includes a controller; The liquid supply component, the collection component, and the vibration component are all communicatively connected to the controller.

[0009] Furthermore, the needle is a flat-headed needle or a tapered needle; The contact angle between the needle tip and the continuous phase medium is 0 to 140°; the inner diameter of the needle is 82 μm to 3800 μm.

[0010] When the continuous phase medium is a liquid phase, the depth to which the needle penetrates the continuous phase medium is 0.1 cm to 5 cm; The needle vibrates at a frequency of 10 Hz to 50,000 Hz and an amplitude of 0.001 cm to 0.1 cm under the drive of the vibration component.

[0011] Furthermore, the vibrational Weber number We during the microdroplet formation stage v Satisfy: We v >1; The number of capillaries Ca during the microdroplet formation stage satisfies: 0.01 <Ca<1; The reciprocal Z of the Onezog number during the microdroplet formation stage satisfies: 2 <Z<15; Furthermore, the viscosity of the dispersed phase liquid is greater than 500 cPa·s but less than 10000 cPa·s. The vibration frequency of the needle is not less than 50Hz and the amplitude is not less than 0.2mm; The flow velocity v of the continuous phase medium in the liquid phase c The flow rate v of the dispersed phase liquid d Satisfy v c >0.1v d ; The interfacial tension γ between the continuous liquid phase medium and the dispersed liquid phase satisfies γ < 50 mN / m.

[0012] Furthermore, the needle and the microdroplet form a resonance effect; The amplitude h of the needle meets the condition that h < 0.5 a, where a is the inner diameter of the needle; The vibration waveform of the needle is an asymmetric waveform.

[0013] Furthermore, the microsphere size Vd formed by the microdroplets satisfies:

[0014] Where k is a dimensionless fitting constant ranging from 0.1 to 1.0; The value of α ranges from 0.2 to 0.5, the value of β ranges from -0.3 to 0.6, and the value of δ ranges from 0.7 to 1.0. , These are the viscosities of the dispersed liquid and the continuous phase medium, respectively. γ is the interfacial tension, g is the vibration frequency, h is the vibration amplitude, and v is the flow rate of the dispersed phase liquid.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: The microsphere preparation device provided by this invention includes a needle, a liquid supply component, a collection component, and a vibration component. The collection component includes a first container for containing a continuous phase medium (hereinafter referred to as the continuous phase) of liquid or gas. When the continuous phase medium is gas, the first container also contains a receiving liquid to carry and disperse microdroplets. The needle is suspended above the first container and extends into the continuous phase medium. The liquid inlet end of the needle is connected to the liquid supply component, which is used to supply the dispersed phase liquid (hereinafter referred to as the dispersed phase) to the needle. At the same time, the needle assembly is installed on the drive end of the vibration component. The needle can reciprocate under the drive of the vibration component, and the vibration direction is perpendicular to the flow direction of the dispersed phase liquid inside it, so that the dispersed phase breaks into microdroplets at the needle tip due to the needle vibration. The microdroplets can react with the continuous phase in the first container to solidify into microspheres, or the microdroplets can be prepared into microspheres through a subsequent solidification process.

[0016] In the microdroplet generation process, this application utilizes the inertial force generated by vibration perpendicular to the flow direction of the liquid in the needle to dominate the breakage of the droplets, thereby ensuring high uniformity in the particle size of the formed droplets and thus ensuring high uniformity in the formed microspheres. Simultaneously, this application's microsphere preparation equipment is suitable not only for the preparation of microdroplets (or microspheres) from low-viscosity liquids but also for the preparation of microdroplets (or microspheres) from high-viscosity liquids. Furthermore, the equipment has a simple structure and can effectively improve the generation efficiency of microdroplets, thereby improving the preparation efficiency of microspheres. Attached Figure Description

[0017] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0018] Figure 1 This is a schematic diagram of the microsphere preparation equipment provided in an embodiment of the present invention; Figure 2 This is a schematic diagram of the structure of the multi-needle head and dispenser provided in an embodiment of the present invention; Figure 3 This is a schematic diagram of the structure of a dual-channel coaxial needle provided in an embodiment of the present invention.

[0019] Figure label: 1-Second container; 2-First delivery pump; 3-Needle; 4-Reciprocating vibrator; 5-Vibration transmission rod; 6-First container; 7-Third container; 8-Second delivery pump; 9-Fourth container. Detailed Implementation

[0020] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0021] The components of the embodiments of the invention described and shown in the accompanying drawings can typically be arranged and designed in a variety of different configurations. Therefore, the following detailed description of the embodiments of the invention provided in the drawings is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention.

[0022] Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] In the description of this invention, it should be noted that the terms "center," "upper," "lower," "left," "right," "vertical," "horizontal," "inner," and "outer," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing the invention and for simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the invention. Furthermore, the terms "first," "second," and "third" are used for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0024] In the description of this invention, it should be noted that, unless otherwise explicitly specified and limited, the terms "installation," "connection," and "linking" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal connection of two components. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0025] The following reference Figure 1 This application describes a microsphere preparation apparatus according to some embodiments.

[0026] This application provides a microsphere preparation device, such as... Figure 1 As shown, the microsphere preparation equipment includes a needle 3, a liquid supply component, a collection component, and a vibration component; the collection component includes a first container 6, which is used to contain a continuous phase medium (hereinafter referred to as the continuous phase). The continuous phase can be a liquid phase or a gas phase. When the continuous phase is a gas phase, the first container 6 also contains liquid phase material, which is used to carry and disperse the microdroplets (or microspheres) generated during the preparation process.

[0027] The upper end of the needle 3 is connected to the liquid supply component, which is used to deliver the dispersed phase liquid (hereinafter referred to as the dispersed phase) to the needle 3. Simultaneously, the needle 3 is mounted on the drive end of the vibration component, which drives the needle 3 to reciprocate, ensuring that the vibration direction of the needle is perpendicular to the flow direction of the dispersed phase within the needle. This utilizes the inertial force generated by the vibration to dominate the breakage of the droplets, ensuring high uniformity in the particle size of the formed microdroplets, and consequently, high uniformity in the formed microspheres. Furthermore, the microsphere preparation equipment of this application is suitable not only for the preparation of microdroplets (or microspheres) from low-viscosity liquids but also for the preparation of microdroplets (or microspheres) from high-viscosity liquids. The equipment also features a simple structure and effectively improves the generation efficiency of microdroplets, thereby increasing the preparation efficiency of microspheres.

[0028] During the preparation process, the needle tip at the lower end of the needle penetrates into the continuous phase. Specifically, if the continuous phase is a liquid phase, the needle tip penetrates to a predetermined depth below the surface of the continuous phase liquid. If the continuous phase is a gas phase, the first container contains a receiving liquid, and the needle tip is suspended above the receiving liquid. Due to the vibration of the needle 3, the dispersed phase forms microdroplets at the needle tip, which are dispersed in the liquid phase material (i.e., the receiving liquid or the dispersed phase of the liquid phase) in the first container 6 and carried away with the flow of the liquid phase material, preventing the formed microdroplets from agglomerating and merging at the same location.

[0029] The microdroplets formed can interact with the continuous phase in the first container 6 to solidify into microspheres, or they can be further solidified into microspheres through subsequent solidification processes.

[0030] Regarding the principle of microdroplet formation, when the static needle 3 is inserted below the surface of the flowing liquid continuous phase, the formation of droplets mainly depends on the balance between the shear force of the continuous phase perpendicular to its flow direction and the interfacial tension. However, when the viscosity of the dispersed phase is high, the simple axial shear force is often insufficient to effectively shear the liquid column, resulting in the formation of a jet or non-uniform droplets.

[0031] This application introduces oscillating motion into the needle tip 3, applying additional shear disturbance during droplet formation. When the needle tip 3 reciprocates at a predetermined frequency and amplitude, the trajectory of the needle tip forms a periodic displacement. This motion generates periodically varying shear stress at the interface between the droplet and the needle tip 3. Furthermore, according to research on the OsciDrop system, the inertial force Fi generated by the vibration is proportional to the square of the vibration frequency f and the amplitude A, i.e., Fi∝f²A.

[0032] The core mechanism of vibration-induced droplet formation lies in the fact that the inertial force generated by vibration dominates the droplet fragmentation process. In the OsciDrop system, when the Weber number is much larger than the Capillary number, it indicates that the inertial force is the dominant force determining droplet fragmentation. This Weber number-dominated mechanism contrasts sharply with the Capillary number-dominated mechanism in traditional microfluidics, providing a new solution for droplet generation of high-viscosity fluids.

[0033] During vibration, droplet formation undergoes two key stages: droplet growth and droplet segmentation. In the growth stage, when the vibration frequency or amplitude is low, the droplet primarily grows at the tip of the needle 3, with interfacial tension playing a dominant role. In the segmentation stage, when the inertial force generated by vibration exceeds the interfacial tension, the droplet neck breaks, forming independent droplets. Therefore, the microdroplet preparation method of this application, by controlling the frequency and amplitude of transverse vibration, can effectively control the size of the generated droplets, ensuring uniform size of both microdroplets and microspheres, and is applicable to the preparation of microdroplets (or microspheres) from liquids of different viscosities.

[0034] In this embodiment, preferably, the vibration assembly includes a reciprocating vibrator 4 and a vibration transmission rod 5. One end of the vibration transmission rod 5 is connected to the drive end of the reciprocating vibrator 4, and the other end of the vibration transmission rod 5 is connected to the needle 3, so that under the transmission of the vibration transmission rod 5, the reciprocating vibrator 4 can drive the needle 3 to perform transverse reciprocating vibration, even if the vibration direction of the needle 3 is perpendicular to the axial direction of the needle 3 (which is also the flow direction of the dispersed phase inside the needle 3).

[0035] Preferably, the reciprocating vibrator 4 includes, but is not limited to, an electromagnetic vibrator, a precision vibrator driven by a servo motor, a high-frequency pneumatic reciprocating vibrator, and a diaphragm hydraulic vibrator.

[0036] In this embodiment, preferably, the microsphere preparation equipment further includes a support frame with a column. The reciprocating vibrator 4 is mounted on the column in an adjustable manner via a slider, thereby adjusting the height of the needle 3 to determine whether the needle 3 is inserted into the liquid phase material in the first container 6, and the depth of insertion below the liquid phase material surface. Specifically, when the liquid phase material is a continuous liquid phase, the needle is inserted below the liquid surface and the insertion depth is controlled; when the liquid phase is only used as the receiving liquid and the continuous phase is the gas phase above the liquid surface, the needle is not inserted below the liquid surface.

[0037] In this embodiment, preferably, the liquid supply assembly includes a second container 1, a first delivery pump 2, and a connecting pipe; the second container 1 is used to contain the dispersed phase, the inlet of the first delivery pump 2 is connected to the first cavity, and the outlet of the first delivery pump 2 is connected to the upper end of the needle 3, so that the dispersed phase in the second container 1 is delivered to the needle 3 by the first delivery pump 2, so that the dispersed phase breaks at the needle tip to form microdroplets.

[0038] Preferably, the first delivery pump 2 is capable of pulse-free, constant-speed delivery of the dispersed phase, with a precisely adjustable delivery rate. The first delivery pump 2 includes, but is not limited to, high-precision gear pumps, syringe pumps, etc.

[0039] Preferably, the connecting pipe is a medical-grade stainless steel pipe, a medical-grade silicone hose, or a medical-grade PEEK pipe, etc.

[0040] In this embodiment, preferably, needle 3 is a single-channel needle; or, needle 3 is a multi-channel coaxial needle, for example, needle 3 is a dual-channel coaxial needle (see reference). Figure 3 As shown in the figure, it can also be a three-channel coaxial needle for preparing core-shell or multilayer material-encapsulated microspheres.

[0041] Taking a dual-channel coaxial needle as an example, it has a coaxial inner channel and an outer channel. The inner channel is used to introduce the dispersed phase core liquid, and the outer channel is used to introduce the dispersed phase shell liquid.

[0042] In this embodiment, preferably, as follows: Figure 2 As shown, the number of needles 3 is at least one. When the number of needles is multiple, the microsphere preparation device also includes a distributor. Multiple needles 3 are installed on the drive end of the vibration assembly through the distributor and are also connected to the outlet of the first delivery pump 2 through the distributor. Specifically, the distributor forms a cavity, and its upper end forms a liquid inlet communicating with the cavity. This liquid inlet is connected to the outlet of the first delivery pump 2 through a hose. At the same time, the distributor forms a base plate, and the upper end of the needle 3 is inserted into the base plate and extends into the cavity by a predetermined length. The number of needles 3 is multiple, and the multiple needles 3 are arranged at intervals. Thus, the dispersed phase can be uniformly dispersed into the multiple needles 3 using the distributor, and the multiple needles 3 can be synchronously reciprocated laterally under the drive of the vibration assembly, thereby effectively improving the preparation efficiency of microdroplets and microspheres.

[0043] In this embodiment, preferably, the first container 6 and / or the second container 1 are provided with temperature control elements to control the temperature of the dispersed phase and / or the continuous phase, as well as the reaction temperature of the dispersed phase within the continuous phase.

[0044] In this embodiment, preferably, the collection assembly further includes a third container 7 and a second delivery pump 8. The inlet of the second delivery pump 8 is connected to the third container 7, and the outlet of the third delivery pump is connected to the first container 6. Simultaneously, the first container 6 is provided with a drain port, which is connected to a fourth container 9, allowing microdroplets or microspheres in the first container 6 to be discharged into the fourth container 9.

[0045] When the continuous phase contained in the first container 6 is a liquid phase, the third container 7 also contains a continuous phase. The second delivery pump 8 can deliver the continuous phase in the third container 7 to the first container 6 at a predetermined flow rate to cooperate with the drainage of the first container 6, thereby agitating the continuous phase in the first container 6 and preventing the accumulation of microdroplets or microspheres.

[0046] When the continuous phase contained in the first container 6 is gas, the first container contains a liquid receiving liquid (which is immiscible with the dispersed phase), and the third container 7 contains the same receiving liquid. The second delivery pump 8 can deliver the receiving liquid in the third container 7 to the first container 6 at a predetermined flow rate. In conjunction with the drainage of the first container 6, the receiving medium in the first container 6 is stirred to prevent the accumulation of microdroplets or microspheres.

[0047] Preferably, the microsphere preparation equipment also includes a controller, and the liquid supply component, the collection component and the vibration component are all connected to the controller for communication, so that the controller can control the liquid supply flow rate and liquid supply temperature of the liquid supply component, the temperature of the collection component, the flow rate of the circulating stirring, and the vibration frequency and amplitude of the vibration component.

[0048] In one embodiment of this application, preferably, the needle 3 is a flat-headed needle 3 or a tapered needle 3.

[0049] Preferably, the needle 3 is a conical needle 3, so that the contact angle between the needle 3 and the continuous phase is 0-140°, which can optimize the spraying pattern of the dispersed phase liquid, enhance the vibration shearing effect, and avoid droplet adhesion.

[0050] Preferably, the needle 3 is inserted into the continuous phase medium to a depth of 0.1 cm to 5 cm to ensure that the dispersed phase liquid can be immediately wrapped by the continuous phase after it is sprayed out, avoiding the exposure of the dispersed phase and resulting in morphological changes. At the same time, it ensures that the shear force generated by the transverse vibration can be fully applied to the dispersed phase liquid to achieve uniform breakage of the droplets.

[0051] Preferably, the vibration frequency of the needle 3 driven by the vibration component is 10Hz to 50000Hz and the amplitude is 0.001cm to 0.1cm, so as to meet the crushing requirements of dispersed liquids with different viscosities, avoid excessive vibration leading to an increase in satellite microspheres, or insufficient vibration leading to droplet failure.

[0052] In one embodiment of this application, preferably, the lateral vibration of the needle 3 causes the droplet formation stage to satisfy the following basic formation conditions: Vibrational Weber number (We v Satisfy: We v >1; The capillary number (Ca) satisfies: 0.01 <Ca<1; The reciprocal Z of the Onezog number (oh) satisfies: 2 <Z<15。

[0053] Furthermore, when the viscosity of the dispersed phase liquid is greater than 500 cPa·s but less than 10000 cPa·s, the following condition must be met: The vibration frequency of needle 3 is not less than 50Hz, and the amplitude is not less than 0.2mm; The flow velocity v of the continuous liquid medium c The flow rate v of the dispersed phase liquid d Satisfy v c >0.1v d ; The interfacial tension γ between the continuous liquid phase medium and the dispersed liquid phase satisfies γ < 50 mN / m.

[0054] Regarding the vibration parameters of the needle 3, in this embodiment, preferably, the vibration frequency of the needle 3 is close to the natural vibration frequency of the droplet to achieve a resonance effect.

[0055] Preferably, the amplitude h of the needle 3 satisfies h < 0.5 a, where a is the inner diameter of the needle 3, in order to avoid excessive disturbance.

[0056] Preferably, the vibration waveform is an asymmetrical waveform, such as a composite waveform of a triangular wave and a cosine wave.

[0057] When preparing microdroplets or microspheres using the microsphere preparation equipment of this application, it is possible to ensure that the droplet volume variation coefficient (CV) is less than 10%, the number of satellite droplets is less than 5% of the number of main droplets, and that continuous operation for more than 30 minutes will not cause clogging or instability.

[0058] In one embodiment of this application, preferably, the microsphere size Vd formed by the droplet satisfies:

[0059] Where k is a dimensionless fitting constant ranging from 0.1 to 1.0; , These are the viscosities of the dispersed phase and the continuous phase, respectively. γ is the interfacial tension, g is the vibration frequency, h is the vibration amplitude, and v is the flow rate of the dispersed phase liquid. The value of α ranges from 0.2 to 0.5, the value of β ranges from -0.3 to 0.6, and the value of δ ranges from 0.7 to 1.0.

[0060] Among them, the first item Represents the three-dimensional volume scale of the needle; the second term This reflects the effect of viscosity ratio on droplet size; the third item This reflects the combined effects of interfacial tension and vibration parameters; the fourth item This reflects the relative importance of flow velocity and vibration parameters.

[0061] The specific steps for preparing microspheres using the microsphere preparation equipment described in this application are as follows: First, the dispersed phase liquid is loaded into the second container 1, and the continuous phase medium is loaded into the first container 6. According to the particle size of the microspheres to be prepared, a needle 3 with a corresponding inner diameter is selected, and the needle 3 is installed on the drive end of the vibration component. At the same time, the height is adjusted so that the needle 3 extends into the continuous phase by 0.1 cm to 5 cm. The needle 3 is a conical needle 3 to ensure that the contact angle between the needle 3 and the continuous phase is 0 to 140°.

[0062] Then, the vibration frequency and amplitude, the liquid supply flow rate of the liquid supply component to the dispersed phase, and the flow rate control of the circulating stirring of the collection component are set by the controller; if it is necessary to control the reaction temperature, the temperature of the first container 6 is controlled by the controller to control the temperature of the continuous phase.

[0063] Then, the system is started, so that after the dispersed phase is ejected from the needle tip, it is broken into uniform tiny droplets under the shearing action of lateral vibration.

[0064] To prepare microspheres of different sizes, the following methods can be used: replace needles 3 with needles of different inner diameters; the larger the inner diameter of needle 3, the larger the microsphere size. Adjust the flow rate of the dispersed phase; the faster the flow rate, the larger the microsphere size. Adjust the frequency and amplitude of the transverse vibration; the higher the vibration frequency and the larger the amplitude, the stronger the shearing effect, and the smaller the microsphere size. Through the synergistic control of the above parameters, the precise preparation of uniform microspheres of different sizes in the range of 1~1000μm can be achieved.

[0065] Take the preparation of uniform polymer microspheres with a particle size of 100 μm as an example.

[0066] A conical injection needle 3 with an inner diameter of 100 μm was selected, and the contact angle between the needle 3 and the continuous phase was 70° to 90°, for example, 80°. The dispersed phase was a 3% dichloromethane PLGA solution with a viscosity of 2000 cps, and the continuous phase was an aqueous solution containing 2% polyvinyl alcohol. The transverse vibration frequency was set to 100 Hz, and the amplitude was set to 0.1 cm; the dispersed phase supply flow rate was set to 0.1 mL / min, and the continuous phase temperature was controlled at 20℃; the depth of the needle tip into the continuous phase was adjusted to 1 cm.

[0067] When the preparation is started, the dispersed phase is ejected from the needle tip and broken into tiny droplets under the action of transverse vibration and shearing. The droplets then enter the mineral oil solution and solidify to form microspheres.

[0068] The polymer microspheres prepared in this way have an average particle size of 100 μm, a particle size distribution CV% of 3.2%, no obvious agglomeration or satellite microspheres, and a preparation efficiency of 5 mL / h. Compared with traditional microfluidic equipment, the efficiency is improved by 8 times, which meets the needs of drug-loaded microspheres in the biopharmaceutical field.

[0069] Take the preparation of uniform drug-loaded microspheres with a particle size of 50 μm as an example.

[0070] A conical injection needle (3) with an inner diameter of 50 μm was selected, and the contact angle between the needle tip (3) and the continuous phase was 75°. The dispersed phase was a collagen phosphate solution containing dexamethasone and a small amount of sodium alginate (viscosity 2500 cps, density 1.03 g / mL), and the continuous phase was a phosphate buffer solution containing a small amount of calcium chloride (viscosity 5 cps, density 1.01 g / mL, interfacial tension 40 mN / m). The transverse vibration frequency was set to 150 Hz, and the amplitude was set to 0.08 cm; the dispersed phase supply flow rate was set to 0.05 mL / min, and the continuous phase temperature was controlled at 35 °C; the depth of the needle tip into the continuous phase was adjusted to 0.8 cm.

[0071] When the preparation is started, the dispersed phase is supplied at a constant speed, and the needle 3 vibrates laterally to shear the liquid to form tiny droplets. The droplets enter the crosslinking solution (continuous phase) and undergo a crosslinking reaction, solidifying to form drug-loaded microspheres.

[0072] The polymer microspheres prepared in this way have an average particle size of 50 μm, a particle size distribution CV% of 2.8%, a drug encapsulation efficiency of 92%, regular microsphere morphology, no drug leakage, and a preparation efficiency of 3 mL / h, which meets the drug loading requirements of the biopharmaceutical field.

[0073] Take the preparation of uniform inorganic microspheres with a particle size of 500 μm as an example.

[0074] A conical injection needle 3 with an inner diameter of 200 μm was selected, and the contact angle between the needle tip 3 and the continuous phase was 90°. The dispersed phase was silica sol (viscosity 70 cps, density 1.10 g / mL), and the continuous phase was a mixed solution of ethanol and ammonia (viscosity 2 cps, density 0.85 g / mL, interfacial tension 28 mN / m). The transverse vibration frequency was set to 50 Hz, and the amplitude was set to 0.2 cm; the dispersed phase supply flow rate was set to 0.5 mL / min, and the continuous phase temperature was controlled at 40 °C; the depth of the needle tip into the continuous phase was adjusted to 2 cm.

[0075] When the preparation is started, the dispersed phase is supplied at a constant speed, and the needle 3 vibrates laterally to shear the liquid to form tiny droplets. The droplets enter the continuous phase and undergo hydrolysis and condensation reaction, solidifying to form silica microspheres.

[0076] The polymer microspheres prepared in this way have an average particle size of 500 μm, a particle size distribution CV% of 4.5%, no obvious agglomeration or satellite microspheres, and a preparation efficiency of 30 mL / h. They can be used in catalysis, adsorption and other fields.

[0077] In summary, this application employs lateral vibration in the preparation of microspheres, combined with a conical needle 3, which effectively improves the transmission efficiency of vibration energy and effectively avoids phenomena such as jetting and droplet aggregation. Furthermore, the prepared microspheres have a uniform particle size distribution and a volume variation coefficient CV% ≤ 5%, meeting the requirements of high-precision applications.

[0078] Simultaneously, the supply of the dispersed phase and vibration are carried out in sync, resulting in rapid droplet breakup and effectively improving the preparation efficiency. Compared with the microfluidic method, the preparation efficiency can be increased by 5 to 10 times, enabling rapid batch preparation of microspheres while balancing accuracy and throughput.

[0079] Meanwhile, by replacing needles with different inner diameters, adjusting the dispersed phase supply speed, vibration frequency, and amplitude, precise preparation of microspheres with different particle sizes in the range of 1~1000μm can be achieved without changing the main structure of the equipment, making it highly versatile.

[0080] Meanwhile, the equipment has a simple structure and is easy to operate, inspect, and maintain.

[0081] Meanwhile, it can adapt to liquids of different viscosities (including high-viscosity liquids of 100~10000cps) and can prepare various types of microspheres such as polymer microspheres, drug-loaded microspheres, and inorganic microspheres. The preparation process is gentle and can avoid the damage of high temperature and high pressure to the active ingredients of the liquid (such as drugs and bioactive substances), making it especially suitable for the biomedical field.

[0082] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A microsphere preparation device, characterized in that, Includes needle, liquid supply assembly, collection assembly and vibration assembly; The collection component includes a first container for containing a continuous phase medium of liquid or gas, and when the continuous phase medium is gas, the first container also contains a receiving liquid. The needle is suspended above the first container, and the tip of the needle at its lower end extends into the continuous phase medium; The upper end of the needle is connected to the liquid supply assembly, which is used to deliver the dispersed phase liquid to the needle. The needle is mounted on the drive end of the vibration assembly, which drives the needle to reciprocate. The vibration direction of the needle is perpendicular to the flow direction of the dispersed liquid in the needle, so that the dispersed liquid forms continuous microdroplets with a predetermined particle size at the needle tip and drips into the first container.

2. The microsphere preparation equipment according to claim 1, characterized in that, The vibration assembly includes a reciprocating vibrator and a vibration transmission rod, and the needle is connected to the drive end of the reciprocating vibrator through the vibration transmission rod; The microsphere preparation equipment also includes a support frame with a column, and the reciprocating vibrator is mounted on the column in an adjustable manner via a slider.

3. The microsphere preparation equipment according to claim 1, characterized in that, The liquid supply assembly includes a second container, a first delivery pump, and a connecting pipe; The second container is used to hold the dispersed phase liquid. The inlet of the first delivery pump is connected to the first container, and the outlet of the first delivery pump is connected to the needle through the connecting pipe.

4. The microsphere preparation apparatus according to claim 1, characterized in that, The needle is a single-channel needle or a multi-channel coaxial needle; The number of needles is at least one; when the number of needles is multiple, the microsphere preparation device further includes a dispenser. The distributor is connected to the drive end of the vibration assembly. The distributor has a cavity, and the upper end of the distributor has a liquid inlet that communicates with the cavity. The liquid inlet is connected to the liquid supply assembly. The dispenser has a base plate, and a plurality of needles are inserted into the base plate, with the upper ends of the plurality of needles extending into the cavity by a predetermined length to communicate with the cavity.

5. The microsphere preparation apparatus according to claim 3, characterized in that, The first container and / or the second container are provided with a temperature control element for temperature regulation; The collection assembly also includes a third container and a second delivery pump, the inlet of the second delivery pump being connected to the third container and the outlet of the second delivery pump being connected to the first container; The collection assembly further includes a fourth container, and the first container is provided with a drain outlet, which is connected to the fourth container; The microsphere preparation equipment also includes a controller; The liquid supply component, the collection component, and the vibration component are all communicatively connected to the controller.

6. The microsphere preparation apparatus according to claim 1, characterized in that, The needle is a flat-tipped needle or a tapered needle; The contact angle between the needle tip and the continuous phase medium is 0 to 140°; the inner diameter of the needle is 82 μm to 3800 μm. When the continuous phase medium is a liquid phase, the depth to which the needle penetrates the continuous phase medium is 0.1 cm to 5 cm; The needle vibrates at a frequency of 10 Hz to 50,000 Hz and an amplitude of 0.001 cm to 0.1 cm under the drive of the vibration component.

7. The microsphere preparation apparatus according to claim 1, characterized in that, The vibrational Weber number We during the microdroplet formation stage v Satisfy: We v >1; The number of capillaries Ca during the microdroplet formation stage satisfies: 0.01 <Ca<1; The reciprocal Z of the Onezog number during the microdroplet formation stage satisfies: 2 <Z<15。 8. The microsphere preparation apparatus according to claim 1, characterized in that, The viscosity of the dispersed phase liquid is greater than 500 cPa·s but less than 10000 cPa·s. The vibration frequency of the needle is not less than 50Hz and the amplitude is not less than 0.02mm; The flow velocity v of the continuous phase medium in the liquid phase c The flow rate v of the dispersed phase liquid d Satisfy v c >0.1v d ; The interfacial tension γ between the continuous liquid phase medium and the dispersed liquid phase satisfies γ < 50 mN / m.

9. The microsphere preparation apparatus according to claim 1, characterized in that, The needle and the microdroplet form a resonance effect; The amplitude h of the needle meets the condition that h < 0.5 a, where a is the inner diameter of the needle; The vibration waveform of the needle is an asymmetric waveform.

10. The microsphere preparation apparatus according to claim 1, characterized in that, The microsphere particle size Vd formed by the microdroplets satisfies: Where k is a dimensionless fitting constant ranging from 0.1 to 1.0; The value of α ranges from 0.2 to 0.5, the value of β ranges from -0.3 to 0.6, and the value of δ ranges from 0.7 to 1.

0. , These are the viscosities of the dispersed liquid and the continuous phase medium, respectively. γ is the interfacial tension, g is the vibration frequency, h is the vibration amplitude, and v is the flow rate of the dispersed phase liquid in the needle.

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