Developing microsphere manufacturing device and developing microsphere manufacturing method

Abstract

The invention discloses a developing microsphere manufacturing device and a developing microsphere manufacturing method, the developing microsphere manufacturing device is used for manufacturing developing microspheres, and the problems that in the prior art, microspheres are inconsistent in size, low in production efficiency and complex in operation are solved. The device comprises a rotatable inner cylinder and a stationary outer cylinder. A microsphere precursor solution serving as a dispersion phase is introduced into a space between the inner cylinder and the outer cylinder through an injector, a continuous phase exists in the space, uniform microspheres are formed under the action of shearing force of the inner cylinder, and finally the microspheres are collected in a collecting disc. By accurately controlling the rotating speed of the motor, the aperture of the injection needle of the injector and the flow velocity of the precursor solution, the developing microspheres with uniform size and low polydispersity can be manufactured. In addition, the fluid stability is also considered in the design of the developing microsphere manufacturing device, a rod is additionally arranged in a collecting disc, a bearing is arranged at the bottom of an inner cylinder, the bearing is matched with the rod to reduce swing and turbulence of the inner cylinder, and the production quality of developing microspheres is further improved.

Description

Technical Field

[0001] The invention relates to the field of microsphere manufacturing, and in particular to a developing microsphere manufacturing device and a method for manufacturing developing microspheres. Background Art

[0002] At present, there are many methods for manufacturing microspheres, including batch emulsification, electro-hydroxyl dynamic injection, phase separation, solvent evaporation and microfluidic methods. However, these methods have some limitations. For example, although the batch emulsification method is simple to operate, it is difficult to control the size and shape of the microspheres, resulting in high polydispersity of the microspheres and low yield, which is not conducive to large-scale production. Although the electro-hydroxyl dynamic injection method can produce smaller droplets, the control requirements for parameters such as voltage and the distance between the needle and the collection pool are complex, and there are safety hazards. The phase separation method easily leads to microsphere aggregation and the process is difficult to control. Although the solvent evaporation method is suitable for drug encapsulation, it is difficult to accurately control the particle size of the microspheres. Although the microfluidic method can achieve high-precision and low-polydispersity microsphere manufacturing, the equipment is complex, sensitive to fluid viscosity, and the yield is low.

[0003] Therefore, there is an urgent need for a device that can efficiently and stably manufacture microspheres with uniform and adjustable sizes to meet the demand for high-quality microspheres in the biomedical field. Summary of the invention

[0004] The present invention provides a developing microsphere manufacturing device and a method for manufacturing developing microspheres, which are suitable for manufacturing microspheres of various hydrogel materials. The device can solve the problems existing in the prior art, realize efficient and stable manufacturing of microspheres, and can accurately control the size and polydispersity of the microspheres.

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions: The present invention provides a developer microsphere manufacturing device, comprising: a collecting plate, a support rod is arranged at the center of the collecting plate; an outer cylinder, the outer cylinder is sealed and arranged on the collecting plate; an inner cylinder, the inner cylinder is rotatably arranged in the outer cylinder and is arranged concentrically, and an annular space is formed between the outer wall of the inner cylinder and the inner wall of the outer cylinder; a motor, the motor is used to drive the inner cylinder to rotate; a syringe, the syringe is used to pass a developer microsphere precursor solution into the annular space; a controller, the controller is used to control the motor and the syringe; a disc is arranged at the bottom of the inner cylinder, a bearing is arranged at the center of the disc, the bearing corresponds to the position of the support rod, the support rod is inserted into the bearing, and is used to support the rotation of the inner cylinder to reduce the shaking of the inner cylinder when it rotates.

[0006] Furthermore, a top cover is arranged on the top of the outer cylinder, a groove for accommodating a gear is arranged at the center of the upper surface of the top cover, and a through hole leading to the bottom surface of the top cover is arranged at the center of the bottom of the groove.

[0007] Furthermore, a rotating shaft is fixedly connected to the top of the inner cylinder, and the rotating shaft passes through the through hole from the bottom of the top cover and is fixedly connected to the gear one.

[0008] Furthermore, a motor plate is provided on the top cover, a motor is fixed on the motor plate, the output shaft of the motor is connected to a gear 2, a belt is used for transmission between gear 1 and gear 2, and the rotation of the motor is transmitted to the inner cylinder through gear 1, the belt and gear 2, thereby driving the inner cylinder to rotate at a certain speed.

[0009] Furthermore, an O-ring is fixedly connected to the bottom of the outer cylinder, an external thread is arranged at the bottom of the O-ring, an internal thread is arranged inside the collecting tray, and the external thread is threadedly connected with the internal thread to seal the outer cylinder and the collecting tray.

[0010] Furthermore, the top cover is provided with one or more through holes, which extend longitudinally from the top surface of the top cover to the bottom surface, and the positions of the through holes correspond to the positions of the annular spaces.

[0011] Furthermore, the syringe comprises an injection needle, which passes through the through hole and enters the continuous phase solution in the annular space to pass the developer microsphere precursor solution into the continuous phase solution.

[0012] Furthermore, the injection needle does not have a pointed end surface, and the end surface of the injection needle is perpendicular to the length direction of the injection needle.

[0013] Furthermore, a discharge device is provided on the collecting plate, and the discharge device is used to discharge the continuous phase solution.

[0014] The present invention also provides a method for manufacturing developing microspheres, comprising: Step 1: Dissolve 4-arm polyethylene glycol acrylate in a triethanolamine buffer solution with a concentration of 0.3M and a pH of 7.4 to prepare a 20% w / v solution 1; then add bovine serum albumin to the solution 1 to make its final concentration reach 5% w / v to obtain a solution 2; then add barium sulfate particles with a particle size of 1 um to the solution 2 to make its concentration reach 10% w / v to obtain a solution 3; Dissolving polyethylene glycol dithiol in a triethanolamine buffer having a concentration of 0.3 M and a pH of 7.4 to obtain a 20% w / v solution 4, oscillating the solution 3 for 30 seconds, and then ultrasonically treating the solution 3 for 10 minutes and then immediately mixing the solution 4 with the solution 4 to obtain a developing microsphere precursor solution; Step 2: After vortexing the developed microsphere precursor solution obtained in step 1 for 30 seconds, the solution is loaded into a syringe, and the continuous phase solution is loaded into the annular space; Step 3: Start the motor to drive the inner drum to rotate at a certain speed; Step 4: injecting the developer microsphere precursor solution into the continuous phase solution at a certain flow rate by a syringe; Step 5: After all the microspheres have settled in the collection tray, the continuous phase solution is discharged through the discharge device on the collection tray, and the microspheres are collected and dried.

[0015] Furthermore, the specification of the injection needle of the syringe is 22G, the rotation speed of the inner cylinder is 12.5 rpm, and the flow rate of the developed microsphere precursor solution is 10 µL / min.

[0016] The developing microsphere manufacturing device provided by the present invention can produce the following beneficial effects: The developer microsphere manufacturing device of the present invention can flexibly adjust the inner cylinder rotation speed, dispersed phase flow rate, and injection needle specifications according to the microsphere size requirements to manufacture developer microspheres with uniform size and low polydispersity; and can form a large number of uniform microspheres in a short time by accurately controlling the rotation speed of the motor and the flow rate of the dispersed phase solution, thereby reducing the production cycle and significantly improving the production efficiency; The developing microsphere manufacturing device is provided with a disc at the bottom of the inner cylinder, and the swing and turbulence of the inner cylinder are reduced by the bearings provided in the disc and the support rods provided in the collecting plate. The rotation of the inner cylinder brings uniform shear force, which helps to form microspheres of uniform size, reduces the size change of microspheres caused by fluid instability, and further improves the quality of microspheres. The design of the developed microsphere manufacturing apparatus allows for increasing the number of syringes to further improve microsphere production. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative work, among which: Figure 1 It is a schematic structural diagram of an embodiment of a developing microsphere manufacturing device of the present invention; Figure 2 It is a structural schematic diagram of an embodiment of an upper rotating shaft of the present invention; Figure 3 It is a structural schematic diagram of an embodiment of a top cover of the present invention; Figure 4 It is a structural schematic diagram of an embodiment of a collecting plate of the present invention; Figure 5 It is a comparison diagram of the developing microspheres prepared by using the method of Comparative Example 1, Comparative Example 2, Comparative Example 3 and the method of the present invention observed under a microscope. DETAILED DESCRIPTION

[0018] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0019] The present invention provides a device for manufacturing developing microspheres, such as Figures 1 to 4 As shown, it includes an inner cylinder 1, an outer cylinder 2, a collecting plate 3, a base plate 4, a top cover 5, a motor plate 6, a motor 6-2, a syringe, and a controller; the collecting plate 3 is fixedly arranged on the base plate 4, the outer cylinder 2 is sealed on the collecting plate 3, the inner cylinder 1 is concentrically arranged inside the outer cylinder 2, and is rotatably connected to the collecting plate 3, an annular space is formed between the inner cylinder 1 and the outer cylinder 2, and a continuous phase solution is filled in the annular space; the top cover 5 is arranged on the top of the outer cylinder 2, the motor is used to drive the inner cylinder 1 to rotate, the syringe is used to inject the developing microsphere precursor solution, and the controller controls the operation of the motor and the syringe.

[0020] Specifically, the top of the inner cylinder 1 is fixedly connected to an upper shaft 1-1; the upper shaft 1-1 includes an upper boss 1-11 and a lower boss 1-12, wherein the inner cylinder 1 is relatively fixedly connected to the lower boss 1-12. The upper boss 1-11 passes through the top cover 5 and is engaged with the gear. Figure 1 and Figure 2 As shown, the upper boss 1-11 has a notch, and after being assembled with the gear, it is relatively fixed in the circumferential direction and can rotate synchronously with the gear, thereby driving the inner tube 1 to rotate. The lower boss 1-12 is relatively fixedly connected to the upper end of the inner tube 1, and it can be relatively fixedly connected by any feasible method such as clamping, bonding, etc., which is not limited here.

[0021] Specifically, the bottom of the inner cylinder 1 is fixedly connected to a disc 1-2, the bottom of the inner cylinder 1 is relatively fixed to the disc 1-2, and the bottom of the inner cylinder 1 is closely connected to the disc 1-2, so that the inner space formed by the inner cylinder 1 and the disc 1-2 is relatively isolated from the external annular space. A bearing is arranged at the center of the disc 1-2, and the disc 1-2 is rotatably arranged on the collection disc 3 through the bearing. Since the outer cylinder 2 is sealed and arranged on the collection disc 3, the space reserved between the bottom of the inner cylinder 1 and the disc 1-2 and the collection disc 3 is connected to the annular space to accommodate the generated microspheres.

[0022] A top cover 5 is provided on the top of the outer cylinder 2. After the top cover 5 is installed on the top of the outer cylinder 2, it remains relatively fixed with the outer cylinder 2. A groove 5-1 for accommodating the gear 1 6-1 is provided at the center position of the upper surface of the top cover 5. A through hole 5-2 leading to the bottom surface of the top cover 5 is provided at the center position of the bottom of the groove 5-1. The upper boss 1-11 passes through the through hole 5-2 from the bottom of the top cover 5 and is fixedly connected with the gear 1 6-1. A motor plate 6 is provided on the top cover 5. A motor 6-2 is fixed on the motor plate 6. The output shaft of the motor 6-2 is connected to the gear 2 6-3. The gear 1 6-1 and the gear 2 are driven by a belt. The rotation of the motor 6-2 is finally transmitted to the inner cylinder 1 through the gear 1, the belt, and the gear 2, and the inner cylinder 1 is driven to rotate at a certain speed.

[0023] In one embodiment, optionally, the rotation speed of the inner drum 1 is 7.5 rpm-18 rpm, specifically 7.5 rpm, 12.5 rpm, and 18 rpm.

[0024] In one embodiment, the motor plate 6 is fixed to the top surface of the top cover 5 by screws; the motor 6-2 is preferably a stepper motor.

[0025] In an embodiment of the present application, the inner cylinder 1 is sleeved inside the outer cylinder 2 and is concentrically arranged to form an annular space between the two, and the annular space is filled with a continuous phase solution; the top cover 5 is also provided with one or more through holes extending from the top surface to the bottom surface, and the position of the through hole corresponds to the position of the annular space, so that the precursor solution can be injected into the continuous phase solution through a syringe.

[0026] It is understandable that there are dispersed phase and continuous phase in the dispersed system. Dispersed phase refers to the substance dispersed in the dispersed system, and continuous phase refers to the substance that disperses other substances in the dispersed system. The continuous phase solution in the annular space in the embodiment of the present application is the continuous phase, and the developer microsphere precursor solution in the present application is the dispersed phase. When the developer microsphere precursor solution is injected into the continuous phase solution, the continuous phase can present a state of surrounding the dispersed phase. The continuous phase can also solidify the dispersed phase to make the dispersed phase state more stable.

[0027] When the developing microsphere manufacturing device in the present application prepares the developing microspheres, the top cover 5 is stably covered on the top of the outer cylinder 2 and is in a relatively static state. The syringe injects the precursor solution into the continuous phase solution in the annular space through the through hole of the top cover 5 (the precursor solution does not pass through the inner cylinder 1); the inner cylinder 1 rotates relative to the outer cylinder 2, and the continuous phase solution in the annular space between the inner cylinder 1 and the outer cylinder 2 rotates stably to form a vortex. The rotating continuous phase solution has a shear force on the continuously injected precursor solution, so as to uniformly and continuously shear, cut off and surround the precursor solution to form developing microspheres. The developing microspheres gradually settle and solidify in the continuous phase solution, and finally fall into the collecting plate 3.

[0028] Since the inner cylinder 1 is concentrically arranged with the outer cylinder 2 and rotates stably relative to the outer cylinder 2, the inner cylinder 1, as a part of the annular space, has an extension direction consistent with the extension direction of the annular space, that is, the inner cylinder 1 is not arranged in a partial area of ​​the continuous phase solution, but is evenly distributed on the inner side of the continuous phase solution, which can drive the continuous phase solution to be in a regular and stable swirl state. When the inner cylinder 1 rotates, the continuous phase solution submerges the output port of the precursor solution. When the precursor solution enters the annular space through the output port, the continuous phase solution in a swirl state can exert a shear force with a regular direction and a stable size on the precursor solution, thereby continuously and stably shearing off the precursor solution injected into the annular space; and since the top cover 5 is stably covered on the top of the outer cylinder 2 and is in a stationary state, the precursor solution can be stably input into the annular space, the relative motion between the precursor solution and the continuous phase solution is controllable, there is no other fluctuation interference, the precursor solution is subjected to a uniform and regular shear force of the continuous phase solution, the size of the microspheres is uniform, and efficient and stable manufacturing of the microspheres is achieved.

[0029] Since the present application relies on the stable vortex formed by the rotation of the continuous phase solution to uniformly and continuously shear off the precursor solution, the power source of the continuous phase solution needs to be stable, that is, the rotation of the inner cylinder 1 needs to be stable. If the inner cylinder 1 shakes during rotation, it will cause turbulence in the continuous phase solution, which will lead to rapid changes in the flow rate of the solution and irregularities in direction, thereby affecting the stable production of microspheres. The present application further provides a support rod 3-1 at the center of the collection tray 3, a disc 1-2 at the bottom of the inner cylinder 1, and a bearing at the center of the disc 1-2. The bearing corresponds to the position of the support rod 3-1, and the support rod 3-1 is inserted into the bearing to support the rotation of the inner cylinder 1 to reduce the shaking of the inner cylinder 1 during rotation. Therefore, the inner cylinder 1 in the present application can further maintain stable rotation, avoid shaking and cause turbulence in the continuous phase solution in the annular space, and the stably rotating continuous phase solution will shear the continuously injected precursor solution to form size-stable developing microspheres.

[0030] In addition, the syringe can inject the precursor solution into the continuous phase solution in the annular space through the through hole of the top cover 5. The through hole extends from the top surface to the bottom surface of the top cover 5. The through hole is linear and short, which is convenient for liquid transportation and cleaning.

[0031] Therefore, the output of the precursor solution in the present application does not pass through the inner tube 1. In addition to being able to directly output the precursor solution through the top cover 5 in conjunction with the syringe, it also has the advantages of a simple output structure, high output efficiency, and the ability to reduce or avoid residues.

[0032] It should be noted that when the injection needle 7 of the syringe passes through the through hole and enters the interior of the annular space, the output port of the precursor solution is the outlet of the injection needle 7 of the syringe.

[0033] In some embodiments, the injection needle 7 of the syringe passes through the through hole and enters the annular space to inject the developed microsphere precursor solution into the continuous phase of the annular space at a certain speed; the needle head of the injection needle 7 is a needle head without a tip, that is, the end face of the needle head is a surface perpendicular to the length direction of the injection needle 7; the number of injection needles 7 corresponds to the number of through holes, and the number of through holes can be adjusted according to actual production needs, allowing the output of microspheres to be increased by increasing the number of through holes.

[0034] In one embodiment, optionally, the specification of the injection needle tip can be selected as 22G, 23G, 25G, and the flow rate of the precursor solution can be 10 µL / min-30 µL / min, specifically 10 µL / min, 20 µL / min, 30 µL / min.

[0035] Table 1

[0036] Table 2

[0037] Table 3

[0038] Tables 1 to 3 show the average particle size and average sedimentation time of microspheres produced under different manufacturing conditions. The results show that when the rotation speed of the inner cylinder 1 and the flow rate of the precursor solution remain unchanged, the diameter of the microspheres decreases as the needle specifications increase; when the needle specifications and the flow rate of the precursor solution remain unchanged, the diameter of the microspheres decreases as the rotation speed of the inner cylinder 1 increases; when the needle specifications and the rotation speed of the inner cylinder 1 remain unchanged, the diameter of the microspheres increases as the flow rate of the precursor solution increases. The developing microsphere manufacturing device provided by the present invention can flexibly adjust the rotation speed of the inner cylinder 1, the dispersed phase flow rate, and the injection needle specifications according to the requirements of the size of the microspheres, so as to produce developing microspheres with uniform size and low polydispersity.

[0039] In one embodiment, an O-ring 2-1 is fixedly connected to the bottom of the outer tube 2, an outer thread is provided at the bottom of the O-ring 2-1, an inner thread is provided on the inner side of the collecting tray 3, and the outer tube 2 is sealed and connected to the outer thread of the collecting tray 3 through the inner thread of the O-ring 2-1. The outer tube 2 is fixed to the O-ring by bonding.

[0040] In order to maintain the stability of the device, the collecting plate 3 is fixed on the base plate 4; in order to improve the stability of the rotation of the inner cylinder 1, a support rod 3-1 is also provided at the center of the collecting plate 3. The support rod 3-1 penetrates into the bearing of the disc 1-2 to support the rotation of the inner cylinder 1, so that the rotation of the inner cylinder 1 is more stable.

[0041] A base 3-2 is also provided at the center of the collecting tray 3, and the support rod 3-1 is fixed on the base 3-2, so that sufficient space is reserved between the bottom of the inner cylinder 1 and the bottom of the collecting tray 3 to accommodate the generated microspheres.

[0042] The continuous phase solution in the annular space can be pre-injected between the outer tube 2 and the inner tube 1 before the top cover is installed on the top of the outer tube 2, or can be injected through other conventional means such as pipe access, which is not limited here. In order to facilitate the discharge of the continuous phase solution, a discharge device 8 is also provided on the side of the collection tray 3; the discharge device 8 includes a discharge pipe and a valve provided on the discharge pipe, and the discharge of the continuous phase is controlled by switching the valve.

[0043] In addition, the present application also discloses a method for manufacturing developer microspheres, comprising: step 1, manufacturing a developer microsphere precursor solution.

[0044] In the prior art, microspheres usually lack sufficient radio-opaqueness, making it difficult to accurately track during treatment. In addition, certain non-absorbable or poorly absorbable materials may remain in the body for a long time, increasing complications. The present invention provides a method for preparing a developer microsphere precursor solution, which can produce degradable microspheres with good developer dispersibility.

[0045] A method for preparing a precursor solution of developer microspheres, comprising: Step 1.1: Dissolve 4-arm polyethylene glycol acrylate in 0.3 M triethanolamine buffer at pH 7-7.6 to a concentration of 20% weight / volume (w / v) to obtain solution 1; the pH is preferably 7.4.

[0046] Step 1.2: Add BSA to the solution obtained in step 1 to a final concentration of 5% w / v.

[0047] Step 1.3: Add barium sulfate particles to the solution obtained in step 2 to a concentration of 10% w / v, wherein the barium sulfate particles have a particle size of 1 um.

[0048] In the above steps, bovine serum albumin is added to Solution 1 to improve the dispersibility of barium sulfate in the microspheres. Adding bovine serum albumin as a surfactant can effectively improve the dispersibility of barium sulfate in the dispersed phase solution. The 5% w / v bovine serum albumin precursor solution can keep the barium sulfate in a suspended state within 10 minutes, which ensures that the barium sulfate will not settle when flowing in the developing microsphere manufacturing device, thereby ensuring the uniformity and consistency of the microspheres.

[0049] Step 1.4: Dissolve polyethylene glycol dithiol in 0.3 M triethanolamine buffer at pH 7-7.6 to obtain a 20% w / v stock solution. The pH is preferably 7.4.

[0050] Step 1.5: The solution obtained in step 3 was oscillated for 30 seconds, and then ultrasonically treated for 10 minutes, and then immediately mixed with the solution obtained in step 4 at a molar ratio of 1:1 to obtain a developing microsphere precursor solution.

[0051] During the ultrasonic treatment, bovine serum albumin denatures and adsorbs on the surface of barium sulfate particles, reducing the interfacial tension between the particles and the aqueous solvent, preventing the barium sulfate particles from settling, and thus achieving a more uniform dispersion; the mechanical vibration and cavitation effect generated by the ultrasonic treatment can break up the agglomeration of barium sulfate particles, making them more evenly dispersed in the polyethylene glycol solution. This synergistic effect makes the distribution of barium sulfate in the microspheres more uniform, improving the radioactive imaging effect of the microspheres.

[0052] In the process of preparing radioactive PEG (polyethylene glycol) microspheres, bovine serum albumin (BSA) is added to improve the dispersibility of barium sulfate (BaSO4) in PEG solution. The reaction mechanism of BSA is mainly reflected in its surface activity, electrostatic stabilization and physical adsorption. These effects work synergistically to enable the barium sulfate to be evenly dispersed in the PEG solution, thereby forming uniform and stable microspheres in the developing microsphere manufacturing device. This dispersion mechanism not only improves the quality and performance of the microspheres, but also provides an important basis for subsequent radioactive imaging and embolization therapy.

[0053] Among them, 4-arm polyethylene glycol acrylate (CAS No.: 9051-31-4) and polyethylene glycol dithiol (CAS No.: 89141-22-0) were purchased from Xi'an Qiyue Biotechnology Co., Ltd., triethanolamine (CAS No.: 102-71-6) was purchased from Shandong Xuchen Chemical Technology Co., Ltd., bovine serum albumin (CAS No.: 9048-46-8) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., and barium sulfate particles (CAS No.: 7727-43-7) were purchased from Shanghai Yuanjiang Chemical Co., Ltd.

[0054] It should be noted that hydrogel microsphere materials include but are not limited to polyethylene glycol, and other hydrogel materials such as polyvinyl alcohol can also be used. Different hydrogel materials can optimize the manufacturing conditions of microspheres by adjusting the parameters of the device to meet different biomedical application requirements.

[0055] The method for manufacturing developing microspheres of the present invention further comprises the following steps: Step 2, vortex the developed microsphere precursor solution for 30 seconds, load it into a syringe, and load the continuous phase solution into the annular space; Step 3, starting the motor to drive the inner drum 1 to rotate at a certain speed; Step 4, injecting the developer microsphere precursor solution into the continuous phase solution at a certain flow rate by a syringe; Step 5: After all the microspheres have settled in the collection tray, the continuous phase solution is discharged through the discharge device, and the microspheres are collected and dried. When the developer microsphere precursor solution is injected into the annular space, the inner cylinder 1 drives the continuous phase solution in the annular space to rotate. Since the inner cylinder 1 is arranged in the continuous phase solution, the shear force of the continuous phase solution is more uniform, so that the developer microsphere precursor solution forms more uniform microspheres. The microspheres complete the gelation process in the process of dripping to the collection tray, and the microspheres dripping into the collection tray will not stick together.

[0056] In the process of preparing radioactive PEG microspheres, bovine serum albumin (BSA) is added to improve the dispersibility of barium sulfate (BaSO4) in PEG solution. Its reaction mechanism is reflected in at least the following aspects: (1) Surface activity Reduce surface tension: BSA is a natural surfactant that can reduce the surface tension between the water phase and the oil phase. In the developing microsphere manufacturing device, BSA can be adsorbed on the interface of the PEG solution and olive oil to form a stable interfacial film, thereby reducing the interfacial energy between the two phases and preventing the microspheres from aggregating during the collection process.

[0057] Stabilize the dispersed phase: BSA molecules unfold in the solution to form a protective film that wraps around the barium sulfate particles and prevents aggregation between particles. This protective effect allows the barium sulfate to be evenly dispersed in the PEG solution instead of forming large aggregates.

[0058] (2) Electrostatic stabilization Charge shielding: BSA molecules have negative charges on their surface (under neutral or weakly alkaline conditions), which can repel other negatively charged barium sulfate particles, thereby preventing aggregation between particles. This electrostatic repulsion helps maintain the stability of the solution and allows the barium sulfate particles to be evenly dispersed in the PEG solution.

[0059] Increase the stability of the solution: Through electrostatic repulsion, BSA can significantly prolong the suspension time of barium sulfate in the PEG solution, thereby forming uniform microspheres in the developing microsphere manufacturing device.

[0060] (3) Physical adsorption Adsorption on the particle surface: BSA molecules can be attached to the surface of barium sulfate particles by physical adsorption. This adsorption not only prevents direct contact between particles, but also forms a protective layer on the particle surface, further improving dispersibility.

[0061] Improve the compatibility of particles with PEG: Since BSA is a water-soluble protein, after being adsorbed on the surface of barium sulfate particles, it can improve the compatibility of particles with PEG solution, making the particles easier to be wrapped by the PEG solution, thereby forming uniform microspheres.

[0062] (4) Synergistic effect of ultrasonic treatment Mechanical disruption: During the preparation process, ultrasonic treatment can generate strong mechanical vibrations to break up the barium sulfate particles and prevent them from forming large aggregates. The presence of BSA further enhances this dispersion effect, allowing the particles to be evenly distributed in the PEG solution.

[0063] Thermal effect: Ultrasonic treatment also generates local high temperature, which helps the adsorption and unfolding of BSA molecules on the surface of barium sulfate particles, further improving the stability of the solution.

[0064] The role of BSA in the preparation of radioactive PEG microspheres is mainly reflected in its surface activity, electrostatic stabilization and physical adsorption. These effects work synergistically to enable barium sulfate to be evenly dispersed in the PEG solution, thereby forming uniform and stable microspheres in the developing microsphere manufacturing device. This dispersion mechanism not only improves the quality and performance of the microspheres, but also provides an important basis for subsequent radioactive imaging and embolization therapy.

[0065] The size of the microspheres depends on the flow rate of the precursor solution, the rotation speed of the inner cylinder 1 and the inner diameter of the injection needle 7. Therefore, the diameter of the microspheres can be changed by changing the flow rate of the developed microsphere precursor solution, the rotation speed of the inner cylinder 1 and the specifications of the injection needle. A lower coefficient of variation means a more uniform particle size distribution. In order to minimize the coefficient of variation of the microsphere size, it is preferred that the injection needle specification is 22G, the rotation speed of the inner cylinder 1 is 12.5 rpm, and the flow rate of the dispersed phase is 10 µL / min.

[0066] Comparative Example 1 Comparative Example 1 provides a method for preparing developer microspheres as a blank experiment, which differs from the method for preparing developer microspheres of the present invention only in step 2 of the preparation method without a precursor solution.

[0067] Comparative Example 2 Comparative Example 2 provides a method for preparing developing microspheres, which differs from the method for preparing developing microspheres of the present invention only in that the bovine serum albumin in step 2 of the preparation method of the precursor solution is replaced by DMSO with a volume concentration of 15% v / v.

[0068] Comparative Example 3 Comparative Example 3 provides a method for preparing developing microspheres, which differs from the method for preparing developing microspheres of the present invention only in that the bovine serum albumin in step 2 of the preparation method of the precursor solution is replaced by anhydrous ethanol with a volume concentration of 20% v / v.

[0069] Figure 5A series of microscope observation images of developed microspheres are shown, which are four sub-images A, B, C and D. Among them, Figure 5 Figure A in the figure shows the developing microspheres made by the method of Comparative Example 1; Figure 5 Figure B shows the developed microspheres manufactured by the method of Comparative Example 2; Figure 5 Figure C in the figure shows the developing microspheres prepared by the method of Comparative Example 3; Figure 5 Figure D in FIG. 1 shows the developed microspheres produced by the method of the present invention.

[0070] The barium sulfate in the developing microspheres is used to block the light from passing through for development, and the circles observed under the microscope represent the developing microspheres. When the barium sulfate in the developing microspheres is unevenly dispersed, the developing microspheres have a certain degree of transparency, which will cause local light transmission inside them. A single developing microsphere shows different brightness under a microscope. The area where the barium sulfate is concentrated and distributed is darker, has low transparency, and has a good development effect. The area where the barium sulfate is not distributed or is less distributed is brighter, has high transparency, and has a poor development effect. By analyzing these images, it can be found that the developing microspheres manufactured in Comparative Example 1 show a certain barium sulfate aggregation phenomenon inside, the dispersion between the barium sulfate particles is not uniform, the developing microspheres are difficult to distinguish the outline under a microscope, the internal local transparency is high, and the developing microspheres have a poor development effect; the dispersibility of the barium sulfate particles inside the single developing microspheres manufactured in Comparative Examples 2 and Comparative Examples 3 is improved, but the barium sulfate particles are still a small amount of aggregation, resulting in a certain degree of transparency in the area where the barium sulfate is not distributed or is less distributed. Under the microscope, the brightness inside the single developing microsphere is different, the imaging is mottled, and the development effect is poor. In contrast, it can be seen from Figure D that the barium sulfate of the developing microspheres prepared by the method of the present invention is evenly distributed in the microspheres to block the transmission of light. The developing microspheres have clear contours and low and uniform internal transparency, so that the developing microspheres have good developing effects. The developing microspheres prepared by the present invention have good dispersibility and developing effects.

[0071] The above description is only an implementation mode of the present invention, and does not limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made by using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A developing microsphere manufacturing device, characterized in that: include: A collecting tray, wherein a supporting rod is disposed at the center of the collecting tray; an outer cylinder, the outer cylinder being sealingly disposed on the collecting tray; an inner cylinder, the inner cylinder is rotatably disposed in the outer cylinder and is concentrically disposed, an annular space is formed between the outer wall of the inner cylinder and the inner wall of the outer cylinder, and the annular space is used to contain a continuous phase solution; A motor, the motor is used to drive the inner drum to rotate; A syringe, the syringe being used to pass a developing microsphere precursor solution into the annular space; A controller, the controller is used to control the motor and the syringe; A disc is arranged at the bottom of the inner cylinder, a bearing is arranged at the center of the disc, the bearing corresponds to the position of the support rod, the support rod is inserted into the bearing, and is used to support the rotation of the inner cylinder to reduce the shaking of the inner cylinder when rotating; A top cover is arranged on the top of the outer cylinder, and one or more through holes extending from the top surface to the bottom surface are also arranged on the top cover, and the positions of the through holes correspond to the positions of the annular space, so that the precursor solution can be injected into the continuous phase solution through the syringe.

2. The developing microsphere manufacturing device according to claim 1, characterized in that: A groove for accommodating gear one is arranged at the center of the upper surface of the top cover, and a through hole leading to the bottom surface of the top cover is arranged at the center of the bottom of the groove.

3. The developing microsphere manufacturing device according to claim 2, characterized in that: The top of the inner cylinder is fixedly connected to a rotating shaft, and the rotating shaft passes through the through hole from below the top cover and is fixedly connected to the gear one.

4. The developing microsphere manufacturing device according to claim 2, characterized in that: A motor plate is arranged on the top cover, the motor is fixed on the motor plate, the output shaft of the motor is connected to a gear 2, the gear 1 and the gear 2 are driven by a belt, the rotation of the motor is transmitted to the inner cylinder through the gear 1, the belt and the gear 2, and the inner cylinder is driven to rotate at a certain speed.

5. The developing microsphere manufacturing device according to claim 1, characterized in that: An O-ring is fixedly connected to the bottom of the outer cylinder, an external thread is arranged at the bottom of the O-ring, an internal thread is arranged inside the collecting tray, and the external thread is threadedly connected with the internal thread to seal the outer cylinder and the collecting tray.

6. The developing microsphere manufacturing device according to claim 1, characterized in that: The syringe comprises an injection needle, which passes through the through hole and enters the continuous phase solution in the annular space to pass the developer microsphere precursor solution into the continuous phase solution.

7. The developing microsphere manufacturing device according to claim 6, characterized in that: The injection needle does not have a pointed end surface, and the end surface of the injection needle is perpendicular to the length direction of the injection needle.

8. The developing microsphere manufacturing device according to claim 6, characterized in that: The collecting plate is also provided with a discharge device, which is used to discharge the continuous phase solution.

9. A method for manufacturing developing microspheres using the developing microsphere manufacturing device according to any one of claims 1 to 8, characterized in that: include: Step 1: dissolving 4-arm polyethylene glycol acrylate in a 0.3 M, pH 7.4 triethanolamine buffer to prepare a 20% w / v solution 1; Then, bovine serum albumin was added to the solution one to make the final concentration reach 5% w / v, to obtain solution two; and barium sulfate particles with a particle size of 1 um were added to the solution two to make the concentration reach 10% w / v, to obtain solution three; Dissolve polyethylene glycol dithiol in 0.3 M triethanolamine buffer at pH 7.4 to obtain a 20% w / v solution; The solution three was vibrated for 30 seconds, and then ultrasonically treated for 10 minutes, and then immediately mixed with the solution four to obtain the developing microsphere precursor solution; Step 2: vortex the developed microsphere precursor solution obtained in step 1 for 30 seconds, load it into a syringe, and load the continuous phase solution into the annular space; Step 3: Start the motor to drive the inner drum to rotate at a certain speed; Step 4: injecting the developer microsphere precursor solution into the continuous phase solution at a certain flow rate by a syringe; Step 5: After all the microspheres have settled in the collection tray, the continuous phase solution is discharged through the discharge device on the collection tray, and the microspheres are collected and dried.

10. The method for manufacturing developer microspheres according to claim 9, characterized in that: The needle gauge of the injection needle of the syringe is 22G, the rotation speed of the inner cylinder is 12.5 rpm, and the flow rate of the developed microsphere precursor solution is 10 µL / min.

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