A device for manufacturing developing microspheres and a method for manufacturing developing microspheres

Abstract

The present invention discloses a device for manufacturing developing microspheres and a method for manufacturing developing microspheres, wherein the device for manufacturing developing microspheres is used to manufacture developing microspheres, aiming to solve the problems of inconsistent microsphere size, low production efficiency and complex operation in the prior art. The device comprises a rotatable inner cylinder and a stationary outer cylinder. A microsphere precursor solution is introduced into the space between the inner cylinder and the outer cylinder as a dispersed phase through a syringe. The space has a continuous phase and forms uniform microspheres under the shear force of the inner cylinder, which are finally collected in a collection tray. By precisely controlling the rotation speed of the motor, the aperture of the injection needle of the syringe and the flow rate of the precursor solution, the present invention can manufacture developing microspheres with uniform size and low polydispersity. In addition, the design of the developing microsphere manufacturing device also takes fluid stability into consideration. By adding a rod in the collection tray and arranging a bearing at the bottom of the inner cylinder, the bearing and the rod cooperate to reduce the swing and turbulence of the inner cylinder, thereby further improving the production quality of the developing microspheres.

Description

Technical Field

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

[0002] Currently, 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 causes 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, it is sensitive to fluid viscosity, and the yield is low.

[0003] Therefore, there is an urgent need for a device that can efficiently and stably produce 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:

[0006] The present invention provides a developer microsphere manufacturing device, comprising: a collection tray, a support rod is arranged at the center of the collection tray; an outer cylinder, the outer cylinder is sealed and arranged on the collection tray; 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; the syringe, the syringe is used to pass the developer microsphere precursor solution into the annular space; the controller is used to control the motor and the syringe; a disc is provided at the bottom of the inner cylinder, a bearing is provided 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 during rotation.

[0007] Furthermore, a top cover is provided on the top of the outer cylinder, a groove for accommodating a gear is provided 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 provided at the center of the bottom of the groove.

[0008] Furthermore, an upper shaft is fixedly connected to the top of the inner cylinder, and the upper shaft passes through the through hole from the bottom of the top cover and is fixedly connected to gear one.

[0009] 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 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, driving the inner cylinder to rotate at a certain speed.

[0010] Furthermore, an O-ring is fixedly connected to the bottom of the outer cylinder, an external thread is provided at the bottom of the O-ring, an internal thread is provided inside the collecting tray, and the external thread is threadedly connected with the internal thread to seal the outer cylinder and the collecting tray.

[0011] 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.

[0012] Furthermore, the syringe includes 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.

[0013] 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.

[0014] Furthermore, the collecting tray is provided with a discharge device for discharging the continuous phase solution.

[0015] The present invention also provides a method for manufacturing developing microspheres, comprising:

[0016] Step 1: dissolving 4-arm polyethylene glycol acrylate in 0.3M triethanolamine buffer at pH 7.4 to prepare a 20% w / v solution 1; then adding bovine serum albumin to the solution 1 to a final concentration of 5% w / v to obtain a solution 2; then adding 1 μm barium sulfate particles to the solution 2 to a concentration of 10% w / v to obtain a solution 3;

[0017] Dissolving polyethylene glycol dithiol in a 0.3 M triethanolamine buffer solution at pH 7.4 to obtain a 20% w / v solution 4, shaking the solution 3 for 30 seconds, ultrasonicating the solution 3 for 10 minutes, and then immediately mixing the solution 4 with the solution 4 to obtain a developing microsphere precursor solution;

[0018] Step 2: After vortexing the developed microsphere precursor solution obtained in step 1 for 30 seconds, the solution was loaded into a syringe and the continuous phase solution was loaded into the annular space;

[0019] Step 3: Start the motor to drive the inner drum to rotate at a certain speed;

[0020] Step 4: The syringe injects the developer microsphere precursor solution into the continuous phase solution at a certain flow rate;

[0021] Step 5: After all the microspheres have settled into the collection tray, the continuous phase solution is discharged through the discharge device on the collection tray, and the microspheres are collected and dried.

[0022] 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.

[0023] The device for manufacturing developing microspheres provided by the present invention can produce the following beneficial effects:

[0024] The developer microsphere manufacturing device of the present invention can flexibly adjust the inner drum rotation speed, dispersed phase flow rate, and injection needle specifications according to the microsphere size requirements to produce developer microspheres with uniform size and low polydispersity. Furthermore, by precisely controlling the motor rotation speed and dispersed phase solution flow rate, a large number of uniform microspheres can be formed in a short period of time, thereby reducing the production cycle and significantly improving production efficiency.

[0025] The developing microsphere manufacturing device has a disc at the bottom of the inner cylinder. The bearings set in the disc and the support rods set in the collection plate reduce the swing and turbulence of the inner cylinder. The rotation of the inner cylinder brings uniform shear force, which helps to form microspheres of uniform size, reduces the size variation of microspheres caused by fluid instability, and further improves the quality of microspheres.

[0026] The design of the developed microsphere manufacturing apparatus allows for increasing the number of syringes to further improve microsphere yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] 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. Those skilled in the art can also derive other drawings based on these drawings without inventive work, among which:

[0028] Figure 1 Schematic diagram of the structure of an embodiment of the developing microsphere manufacturing device of the present invention;

[0029] Figure 2 It is a structural schematic diagram of an embodiment of the upper shaft of the present invention;

[0030] Figure 3 It is a structural schematic diagram of an embodiment of the top cover of the present invention;

[0031] Figure 4 It is a structural schematic diagram of an embodiment of a collecting tray of the present invention;

[0032] Figure 5 The diagram is a comparison of the developing microspheres prepared by the methods of Comparative Example 1, Comparative Example 2, Comparative Example 3 and the present invention observed under a microscope. DETAILED DESCRIPTION

[0033] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. 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 making creative efforts are within the scope of protection of the present invention.

[0034] 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 tray 3, a base plate 4, a top cover 5, a motor plate 6, a motor 6-2, a syringe, and a controller; the collecting tray 3 is fixedly arranged on the base plate 4, the outer cylinder 2 is sealed on the collecting tray 3, the inner cylinder 1 is concentrically arranged inside the outer cylinder 2, and is rotatably connected to the collecting tray 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.

[0035] 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 and the lower boss 1-12 are relatively fixedly connected. The upper boss 1-11 passes through the top cover 5 and is engaged with the gear. Figure 1 and Figure 2 As shown, upper boss 1-11 has a notch. After assembly with the gear, it is relatively fixed in the circumferential direction and can rotate synchronously with the gear, thereby driving the rotation of inner cylinder 1. Lower boss 1-12 is relatively fixedly connected to the upper end of inner cylinder 1. This relatively fixed connection can be achieved by any feasible method such as clamping, bonding, etc., which is not limited here.

[0036] Specifically, the bottom of the inner cylinder 1 is fixedly connected to a circular disc 1-2. The bottoms of the inner cylinder 1 and disc 1-2 are relatively fixed and tightly connected to each other, ensuring that the internal space enclosed by the inner cylinder 1 and disc 1-2 is relatively isolated from the external annular space. A bearing is positioned at the center of disc 1-2, which rotates around the collection tray 3. Because the outer cylinder 2 is sealed against the collection tray 3, the space reserved between the bottoms of the inner cylinder 1 and disc 1-2 and the collection tray 3 communicates with the annular space to accommodate the generated microspheres.

[0037] A top cover 5 is provided on the top of the outer cylinder 2. After being mounted on the top of the outer cylinder 2, the top cover 5 remains fixed relative to the outer cylinder 2. A recess 5-1 is provided at the center of the top surface of the top cover 5 for accommodating gear 1 6-1. A through hole 5-2 is provided at the center of the bottom of the recess 5-1, leading to the bottom surface of the top cover 5. An upper boss 1-11 passes through the through hole 5-2 from the bottom of the top cover 5 and is fixedly connected to gear 1 6-1. A motor plate 6 is provided on the top cover 5. A motor 6-2 is fixed to the motor plate 6. The output shaft of motor 6-2 is connected to gear 2 6-3. A belt drives gear 1 6-1 and gear 2. The rotation of motor 6-2 is ultimately transmitted to the inner cylinder 1 via gear 1, the belt, and gear 2, driving the inner cylinder 1 to rotate at a constant speed.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] It is understood that there are dispersed phases and continuous phases in a dispersed system. The dispersed phase refers to the substance dispersed in the dispersed system, and the continuous phase refers to the substance that disperses other substances in the dispersed system. In the embodiment of the present application, the continuous phase solution in the annular space 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 may surround the dispersed phase. The continuous phase may also solidify the dispersed phase to make the dispersed phase state more stable.

[0042] When the developing microsphere manufacturing device in the present application prepares the developing microspheres, the top cover 5 is stably placed 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); and 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 collection tray 3.

[0043] Since the inner cylinder 1 and the outer cylinder 2 are concentrically arranged and stably rotate relative to the outer cylinder 2, the inner cylinder 1, as part of the annular space, extends in the same direction as 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 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 swirl state of the continuous phase solution can exert a shear force with a regular direction and stable magnitude on the precursor solution, thereby continuously and stably shearing off the precursor solution injected into the annular space. Moreover, 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 without other fluctuation interference. The shear force of the continuous phase solution on the precursor solution is uniform and regular in direction, and the size of the microspheres is uniform, thereby achieving efficient and stable production of microspheres.

[0044] Since the present application relies on the stable vortex formed by the rotation of the continuous phase solution to uniformly and continuously shear 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 the continuous phase solution to generate turbulence, 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 to avoid shaking and causing turbulence in the continuous phase solution in the annular space. The stably rotating continuous phase solution will shear the continuously injected precursor solution to form size-stable developing microspheres.

[0045] 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 in distance, which is convenient for liquid transportation and cleaning.

[0046] Therefore, the output of the precursor solution in this 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 can reduce or avoid residue.

[0047] 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.

[0048] 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 pointed end, 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 yield of microspheres to be increased by increasing the number of through holes.

[0049] In one embodiment, optionally, the specification of the injection needle tip can be 22G, 23G, or 25G, and the flow rate of the precursor solution can be 10 µL / min-30 µL / min, specifically 10 µL / min, 20 µL / min, or 30 µL / min.

[0050] Table 1

[0051]

[0052] Table 2

[0053]

[0054] Table 3

[0055]

[0056] Tables 1-3 show the average particle size and average sedimentation time of microspheres produced under different manufacturing conditions tested. 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 size increases; when the needle size 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 size 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 size according to the microsphere size requirements to produce developing microspheres with uniform size and low polydispersity.

[0057] In one embodiment, an O-ring 2-1 is fixedly connected to the bottom of the outer tube 2. The bottom of the O-ring 2-1 is provided with an external thread. The inner side of the collection tray 3 is provided with an internal thread. The outer tube 2 is sealed to the external thread of the collection tray 3 through the internal thread of the O-ring 2-1. The outer tube 2 and the O-ring are fixed by bonding.

[0058] In order to maintain the stability of the device, the collecting tray 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 tray 3. The support rod 3-1 penetrates into the bearing of the disc 1-2 to support the rotation of the inner cylinder 1, making the rotation of the inner cylinder 1 more stable.

[0059] 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.

[0060] 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 are not limited here. 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 disposed on the discharge pipe. The discharge of the continuous phase is controlled by opening and closing the valve.

[0061] In addition, the present application also discloses a method for manufacturing developing microspheres, comprising: step 1, manufacturing a developing microsphere precursor solution.

[0062] In the prior art, microspheres typically lack sufficient radiopacity, making accurate tracking difficult during treatment. In addition, certain non-absorbable or poorly absorbed materials may remain in the body for a long time, increasing complications. The present invention provides a method for manufacturing a developer microsphere precursor solution, which can produce degradable microspheres with good developer dispersibility.

[0063] A method for preparing a precursor solution for developing microspheres comprises:

[0064] 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.

[0065] Step 1.2: Add bovine serum albumin to the solution obtained in step 1 to a final concentration of 5% w / v.

[0066] Step 1.3: Add barium sulfate particles to the solution obtained in step 2 to a concentration of 10% w / v. The barium sulfate particles have a particle size of 1 μm.

[0067] In the above steps, bovine serum albumin (BSA) was added to Solution 1 to improve the dispersion of barium sulfate in the microspheres. The addition of BSA as a surfactant effectively enhances the dispersibility of barium sulfate in the dispersed phase solution. The 5% w / v BSA precursor solution can maintain the barium sulfate in suspension for 10 minutes, ensuring that the barium sulfate does not settle during flow through the microsphere development apparatus, thereby maintaining uniformity and consistency in the microspheres.

[0068] Step 1.4: Dissolve polyethylene glycol dithiol in 0.3 M triethanolamine buffer (pH 7-7.6) to obtain a 20% w / v stock solution. The pH is preferably 7.4.

[0069] Step 1.5: The solution obtained in step 3 was shaken for 30 seconds, ultrasonicated 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.

[0070] During ultrasonic treatment, bovine serum albumin denatures and adsorbs onto the surface of the barium sulfate particles, reducing the interfacial tension between the particles and the aqueous solvent and preventing the barium sulfate particles from settling, thereby achieving a more uniform dispersion. The mechanical vibration and cavitation effect generated by ultrasonic treatment can break up the agglomeration of the barium sulfate particles, allowing them to be more evenly dispersed in the polyethylene glycol solution. This synergistic effect results in a more uniform distribution of the barium sulfate within the microspheres, improving the radioactive imaging effect of the microspheres.

[0071] During the preparation of radioactive PEG (polyethylene glycol) microspheres, bovine serum albumin (BSA) is added to improve the dispersion of barium sulfate (BaSO4) in the PEG solution. The reaction mechanism of BSA is primarily characterized by its surface activity, electrostatic stabilization, and physical adsorption. These effects synergistically enable the uniform dispersion of barium sulfate in the PEG solution, resulting in the formation of uniform and stable microspheres in the imaging microsphere manufacturing apparatus. This dispersion mechanism not only improves the quality and performance of the microspheres but also provides an important foundation for subsequent radioactive imaging and embolization therapy.

[0072] 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.

[0073] 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.

[0074] The method for manufacturing developing microspheres of the present invention further comprises the following steps:

[0075] Step 2: After vortexing the developed microsphere precursor solution for 30 seconds, the solution was loaded into a syringe and the continuous phase solution was loaded into the annular space;

[0076] Step 3: Start the motor to drive the inner drum 1 to rotate at a certain speed;

[0077] Step 4: injecting the developer microsphere precursor solution into the continuous phase solution at a certain flow rate using a syringe;

[0078] In step five, after all microspheres have settled into the collection tray, the continuous phase solution is discharged through a discharge device, and the microspheres are collected and dried. When the developing 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 positioned within the continuous phase solution, the shear force on the continuous phase solution is more uniform, thereby forming more uniform microspheres from the developing microsphere precursor solution. The microspheres complete the gelation process as they drip onto the collection tray, and the microspheres that drip into the collection tray will not stick together.

[0079] During the preparation of radioactive PEG microspheres, bovine serum albumin (BSA) is added to improve the dispersibility of barium sulfate (BaSO4) in the PEG solution. The reaction mechanism is reflected in at least the following aspects:

[0080] (1) Surface activity

[0081] Reduce surface tension: BSA is a natural surfactant that reduces the surface tension between the aqueous and oil phases. In the microsphere manufacturing device, BSA can adsorb at the interface between the PEG solution and olive oil, forming a stable interfacial film, thereby reducing the interfacial energy between the two phases and preventing microsphere aggregation during collection.

[0082] Stabilizing the dispersed phase: BSA molecules unfold in the solution, forming a protective film that wraps around the barium sulfate particles and prevents aggregation. This protective effect allows the barium sulfate to be evenly dispersed in the PEG solution, rather than forming large aggregates.

[0083] (2) Electrostatic stabilization

[0084] Charge shielding: BSA molecules have negative surface charges (under neutral or weakly alkaline conditions). These negative charges repel other negatively charged barium sulfate particles, thus preventing aggregation. This electrostatic repulsion helps maintain solution stability and allows the barium sulfate particles to be evenly dispersed in the PEG solution.

[0085] Increase solution stability: Through electrostatic repulsion, BSA can significantly prolong the suspension time of barium sulfate in PEG solution, thereby forming uniform microspheres in the developing microsphere manufacturing device.

[0086] (3) Physical adsorption

[0087] Adsorption on particle surfaces: BSA molecules can adhere to the surface of barium sulfate particles through physical adsorption. This adsorption not only prevents direct contact between particles but also forms a protective layer on the particle surface, further improving dispersibility.

[0088] Improve the compatibility between particles and PEG: Since BSA is a water-soluble protein, after being adsorbed on the surface of barium sulfate particles, it can improve the compatibility between the particles and PEG solution, making the particles easier to be wrapped by the PEG solution, thereby forming uniform microspheres.

[0089] (4) Synergistic effect of ultrasonic treatment

[0090] Mechanical disruption: During the preparation process, ultrasonic treatment generates strong mechanical vibrations that 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.

[0091] Thermal effect: Ultrasonic treatment also generates local high temperature, which helps the adsorption and expansion of BSA molecules on the surface of barium sulfate particles, further improving the stability of the solution.

[0092] The role of BSA in the preparation of radioactive PEG microspheres is primarily reflected in its surface activity, electrostatic stabilization, and physical adsorption. These interactions synergistically enable the uniform dispersion of barium sulfate in the PEG solution, resulting in the formation of uniform and stable microspheres in the imaging microsphere manufacturing apparatus. This dispersion mechanism not only improves the quality and performance of the microspheres but also provides an important foundation for subsequent radioactive imaging and embolization therapy.

[0093] 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 varied by changing the flow rate of the developed microsphere precursor solution, the rotation speed of the inner cylinder 1, and the gauge of the injection needle. A lower coefficient of variation indicates a more uniform particle size distribution. To minimize the coefficient of variation in microsphere size, a 22G injection needle, a rotation speed of 12.5 rpm for the inner cylinder 1, and a dispersed phase flow rate of 10 µL / min are preferred.

[0094] Comparative Example 1

[0095] Comparative Example 1 provides a method for preparing developer microspheres as a blank experiment. The difference between the method for preparing developer microspheres of the present invention is only that the step 2 of the preparation method does not contain a precursor solution.

[0096] Comparative Example 2

[0097] 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.

[0098] Comparative Example 3

[0099] Comparative Example 3 provides a method for preparing developing microspheres, which differs from the method for manufacturing 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.

[0100] Figure 5 A series of microscope observation images of developed microspheres are shown, which are four sub-images A, B, C and D. Figure 5 Figure A in FIG shows the developed microspheres manufactured by the method of Comparative Example 1; Figure 5 Figure B shows the developed microspheres manufactured using the method of Comparative Example 2; Figure 5 Figure C shows the developing microspheres prepared by the method of Comparative Example 3; Figure 5 Figure D in FIG shows the developed microspheres produced by the method of the present invention.

[0101] The barium sulfate in the developing microspheres is used to block the passage of light for development. The circles observed under a microscope represent individual 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 barium sulfate is concentrated and distributed is darker, has low transparency, and has a good development effect. The area where 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 produced in Comparative Example 1 show a certain degree of barium sulfate aggregation inside. The dispersion between the barium sulfate particles is not uniform enough. The developing microspheres are difficult to distinguish the outline under a microscope. The internal local transparency is high, and the developing effect of the developing microspheres is poor. The dispersibility of the barium sulfate particles inside the single developing microspheres produced in Comparative Examples 2 and 3 is improved, but the barium sulfate particles still have a small amount of aggregation, resulting in a certain degree of transparency in the area where barium sulfate is not distributed or is less distributed. Under a 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 light from passing through. The developing microspheres have clear contours and low and uniform internal transparency, which makes the developing microspheres have good developing effect. The developing microspheres prepared by the present invention have good dispersibility and developing effect.

[0102] The above description is only an embodiment 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 description and drawings of the present invention, 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 support rod is provided 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 being rotatably disposed within the outer cylinder and being concentrically disposed, an annular space being formed between the outer wall of the inner cylinder and the inner wall of the outer cylinder, the annular space being used to accommodate a continuous phase solution; A top cover is provided on the top of the outer cylinder, and one or more through holes extending from the top surface to the bottom surface are provided on the top cover, and the positions of the through holes correspond to the positions of the annular space; A disc is provided at the bottom of the inner cylinder, and a bearing is provided at the center of the disc. The bearing corresponds to the position of the support rod. The support rod is inserted into the bearing to support the rotation of the inner cylinder to reduce the shaking of the inner cylinder during rotation. The top of the inner cylinder is fixedly connected to an upper shaft, the upper shaft includes an upper boss and a lower boss, the inner cylinder is relatively fixedly connected to the lower boss, and the upper boss passes through the top cover and is engaged with the gear; A syringe, comprising an injection needle, the injection needle extending through the through hole into the continuous phase solution in the annular space, the syringe being used to pass the developer microsphere precursor solution into the continuous phase solution pre-stored in the annular space; a motor configured to drive the inner cylinder to rotate and drive the continuous phase solution to rotate to form a stable vortex, wherein the continuous phase solution submerges the output port of the injection needle. The rotating continuous phase solution exerts a shear force on the continuously injected precursor solution, thereby shearing the continuously injected precursor solution to form dimensionally stable developing microspheres. The developing microspheres gradually settle and solidify in the continuous phase solution, ultimately falling into the collection tray. The inner cylinder has a rotation speed of 7.5 rpm to 18 rpm, and a flow rate of the precursor solution of 10 µL / min to 30 µL / min. a controller, the controller being used to control the motor and the syringe; The discharge device is arranged on the collection tray. The inner cylinder and the space reserved between the bottom of the disc and the collection tray are connected with the annular space to accommodate the generated microspheres. The discharge device is used to discharge the continuous phase solution.

2. The developing microsphere manufacturing device according to claim 1, characterized in that: A groove for accommodating gear 1 is provided 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 provided at the center of the bottom of the groove.

3. The developing microsphere manufacturing device according to claim 2, characterized in that: The upper 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 provided on the top cover, the motor is fixed on the motor plate, the output shaft of the motor is connected to a gear 2, a belt is used between the gear 1 and the gear 2, and the rotation of the motor is transmitted to the inner cylinder through the gear 1, the belt and the gear 2, thereby driving the inner cylinder 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 provided at the bottom of the O-ring. An internal thread is provided inside the collecting tray. 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 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.

7. A method for manufacturing developing microspheres using the developing microsphere manufacturing device according to any one of claims 1 to 6, characterized in that: include: Step 1: Dissolve 4-arm polyethylene glycol acrylate in 0.3 M triethanolamine buffer at pH 7.4 to prepare a 20% w / v solution 1; Then, bovine serum albumin was added to the solution 1 to a final concentration of 5% w / v to obtain a solution 2; and barium sulfate particles with a particle size of 1 μm were added to the solution 2 to a final concentration of 10% w / v to obtain a solution 3; Dissolve polyethylene glycol dithiol in 0.3 M triethanolamine buffer at pH 7.4 to obtain a 20% w / v solution; The solution 3 was vibrated for 30 seconds, and then ultrasonicated for 10 minutes, and then immediately mixed with the solution 4 to obtain the developed 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 developed microsphere precursor solution into the continuous phase solution at a certain flow rate using a syringe; Step 5: After all the microspheres have settled into the collection tray, the continuous phase solution is discharged through the discharge device on the collection tray, and the microspheres are collected and dried.

8. The method for manufacturing developing microspheres according to claim 7, wherein: 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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